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 1-20 are pending and under consideration in this action.
Priority
This application claim is a CON of PCT/JP2021/042153, filed 11/17/2021, which claims foreign priority from Japanese Application 2020-195943, filed 11/26/2020, as reflected in the filing receipt mailed 06/08/2023. 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 1-20 is 11/26/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/21/2023 and 05/15/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS’s have been considered by the examiner.
Specification
The use of the terms National Center for Biotechnology Information (NCBI) (see Specification Para. [0093]-[0094]) and European Molecular Biology Laboratory (EMBL) (see Specification Para. [0093]), which are trade names or a marks used in commerce, has been noted in this application. The terms 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, 5-6, 10, and 14-15 are objected to because of the following informalities:
Claims 1 and 10 recite the phrase “the predetermined selection conditions include (1) a Tm is within a predetermined range”, which should be corrected to “the predetermined selection conditions include (1) a melting temperature (Tm) is within a predetermined range”, to include the appropriate definition before the abbreviation.
Claims 5-6 and 14-15 recite the phrase “a range of position” and “the specified range of position”, which should be corrected to “a range of positions” and “the specified range of positions”, for clarity.
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitations are: “a base sequence data acquisition unit that acquires…”, “a target site information acquisition unit that acquires…”, “a base conversion unit that converts…”, “a complementary strand generation unit that generates…”, “a partial sequence cutting unit that selects…”, “a primer candidate selection unit that selects…”, “a primer sequence determination unit that adopts…”., and “a control unit that controls…” in claim 10.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof. The Specification discloses the following structure for the recited limitations:
The base sequence acquisition unit (Specification Para. [0044]): The base sequence data acquisition unit 20 shown in Fig. 1 is a unit that performs the base sequence data acquisition step S10 shown in Fig. 2, and acquires the data of the double-stranded DNA sequence (reference sequence) of the genome of biological species, for which a primer is to be designed, via the input unit 12. In a case where the data of the reference sequence is stored in the storage unit 14 in advance, the data may be acquired from the storage unit 14.
The target site information acquisition unit (Specification Para. [0045]): The target site information acquisition unit 22 shown in Fig. 1 is a unit that performs the target site information acquisition step S12 shown in Fig. 2, and can acquire one or more target sites included in the double-stranded genomic DNA acquired by the base sequence data acquisition unit 20 and the position information of the target sites via the input unit 12. In a case where the target sites and the position information thereof are stored in the storage unit 14 in advance, the target sites and the position information thereof may be acquired from the storage unit 14.
The base conversion unit (Specification Para. [0046]): The base conversion unit 24 is a unit that performs the base conversion step S14 shown in Fig. 2. As shown in Figs. 3A and 3B, the base conversion unit 24 converts cytosine (C) of a CG sequence on the template DNA acquired from the base sequence data acquisition unit 20 into "Y" (see the bases indicated by the arrows in Figs. 3A and 3B) and converts cytosine (C) of other sequences into thymine (T). Note that this conversion processing is computer simulation that reproduces the generation of DNA amplified by PCR after a bisulfite treatment.
The complementary strand generation unit (Specification Para. [0048]): The complementary strand generation unit 26 is a unit that performs the complementary strand generation step S16 shown in Fig. 2, and generates a complementary strand for each of two DNA strands after the base conversion processing. The complementary strand generation unit 26 is configured with a computer and functions to generate the aforementioned complementary strand for each of the two strands of DNA after base conversion processing.
The partial sequence cutting unit (Specification Para. [0050]): The partial sequence cutting unit 28 is a unit that performs the partial sequence cutting step S18 shown in Fig. 2. The partial sequence cutting unit 28 is configured with a computer and functions to cut partial sequences as much as possible from partial sequences having a predetermined length from "Y" of the selected target site or "R" complementary to "Y" from the DNA sequence of each strand based on the position information of the selected target site described above to obtain one or more partial sequences.
The primer candidate sequence selection unit (Specification Para. [0054]): The primer candidate sequence selection unit 30 is a unit that performs the primer candidate sequence selection step S20 shown in Fig. 2, and selects partial sequences satisfying all the predetermined selection conditions (1) to (3) as primer candidate sequences from one or more partial sequences of each strand cut out by the partial sequence cutting unit 28. The primer candidate sequence selection unit 30 is configured with a computer and functions to select partial sequences that satisfy all the predetermined selection conditions (1) to (3) as primer candidate sequences.
The control unit (Specification Para. [0066]): The control unit 34 is a unit that is connected not only to the portions in the primer design processing unit 18 but also to the input unit 12, the storage unit 14, and the output unit 16 directly or indirectly, controls each unit of the primer design device 10 based on the user's instruction from the input unit 12 or based on a predetermined operation program stored in the storage unit 14, and designs a primer. The control unit 34 is configured with, for example, a central processing unit (CPU) of a computer or the like.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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 1-20 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 10 recite the limitation “a primer sequence determination step of adopting and determining a forward primer sequence and a reverse primer sequence …”. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. It is unclear what parameters differentiate the “adopting” vs. “determining” for the sequence determination of both primers. It appears that if the sequences of the forward primer and reverse primer are “determined”, then it is unclear what parameters or steps are performed in the “adopting” portion of the limitation. Examiner suggests amendment of claims 1 and 10 to recite “a primer sequence determination step of ”, or clarify the steps required to differentiate “adopting” and “determining”. Claims 2-9 and 11-20 are also rejected due to their dependency from claims 1 and 10.
Claims 1 and 10 also recite the limitation “wherein the predetermined selection conditions include … (3) an upper limit on the number of binding sites with a sequence outside a related region on the double-stranded genomic DNA after base conversion is equal to or less than a predetermined number that is equal to or more than 1”. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. First, it is unclear what parameters define the “related region”, and its correlation to the selection of partial sequences that satisfy the predetermined selection conditions. Additionally, it appears that the “upper limit on the number of binding sites … is equal to or less than a predetermined number that is equal to or more than 1” introduces ambiguity from the combined equal to or less than/equal to or more than clauses. Examiner suggests amendment of claims 1 and 10 to recite “upper limit on the number of binding sites … is equal to or less than a non-zero, positive, predetermined integer”, or similar. Clarification through clearer claim language for condition (3) is respectfully requested. Claims 2-9 and 11-20 are also rejected due to their dependency from claims 1 and 10.
Claims 4 and 13 recite the limitation “wherein the predetermined selection conditions further include (6) three bases from the 3’ end of the partial sequence are not complementary to three bases from the 3’ end of the other partial sequence”. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. It is unclear if the “other partial sequence” is referring to one of the “one or more partial sequences” from the partial sequence cutting/primer candidate sequence selection steps, as there is no “other partial sequence” referenced in claim 1. The instant Specification (see Pg. 32-33, Para. [0079] and Fig. 7) reiterates the claim language, but does not appear to define what sequence the “other partial sequence” is referring to. Clarification through clearer claim language is respectfully requested.
Claims 5/14 and 6/15 recite the limitations “wherein the predetermined selection conditions further include (9) in a case where the predetermined number of YHG sequences or CDR sequences included in the partial sequence is set to 1 or more in the condition (4)…” and “wherein the predetermined selection conditions further include (10) in a case where the predetermined number of YHH sequences or DDR sequences included in the partial sequence is set to 1 or more in the condition (5)…”, respectively. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. It appears the selection conditions include the list of (1)-(6) and (9)-(10), as described in claims 1-6. However, the claims appear to be missing selection conditions (7) and (8). For consistency, Examiner suggests amendment of claims 5/14 and 6/15 to recite wherein the predetermined selection conditions further include (7) in a case where the predetermined number of YHG sequences or CDR sequences included in the partial sequence is set to 1 or more in the condition (4)…” and “wherein the predetermined selection conditions further include (8) in a case where the predetermined number of YHH sequences or DDR sequences included in the partial sequence is set to 1 or more in the condition (5)…”, for consistent numbering throughout the claims.
Claims 5/14 and 6/15 also recite the limitations “a range of position of the YHG sequences or CDR sequences in the partial sequence is also specified, and the number of YHG sequences or CDR sequences included in the specified range of position is equal to or less than a predetermined number” and “a range of position of the YHH sequences or DDR sequences in the partial sequence is also specified and the number of the YHH sequences or DDR sequences included in the specified range of position is equal to or less than a predetermined number”, respectively. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. It is unclear what “the range of positions” is referring to, for example, a specific number of residues on each side of the target site, or on either the 3’ side/5’ side of the target site. The Specification (see Para. [0081], “Modification Example 5”) discloses that it is preferable to specify a range of position on the 5' end side of the partial sequence, because then the influence of methylation of cytosine (C) can be further reduced, compared to a case where a range of position on the 3' end side of the partial sequence is specified. Therefore, it appears the range of positions refers to a specific number of residues on either the 3’ side or the 5’ side of the target site, such that the count of the YHG/CDR/YHH/DDR sequences within that range is determined. Clarification through clearer claim language is respectfully requested.
Claims 9 and 18 recite the limitation “…and adopts and determines a combination for which the local alignment scores are calculated to be lower than a predetermined threshold value as a primer sequence”. The metes and bounds of the claim are rendered indefinite due to the lack of clarity. Analogous to claims 1 and 10 above, it is unclear what parameters differentiate the “adopting” vs. “determining” for the combination. It appears that if the combination is “determined”, then it is unclear what parameters or steps are performed in the “adopts” portion of the limitation. Examiner suggests amendment of claims 9 and 18 to recite “…and ”, or similar.
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 1-20 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)).
Framework with which to evaluate Subject Matter Eligibility as outlined in MPEP § 2106:
Step 1: Are the claims directed to a process, machine, manufacture or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework as it pertains to the instant claims:
Step 1:
In the instant application, claims 1-9 are directed towards a method and claims 10-18 are directed towards a machine, which falls into one of the categories of statutory subject matter (Step 1: YES).
Claim 19 is are directed towards a primer design program, which does not fall within one of the categories of statutory subject matter (Step 1: NO). Regarding claim 19, the recitation of “the primer design program” does not provide any structural components and therefore equates to “software per se”. Claims that equate to “software per se” are not a statutory category of invention (see MPEP § 2106.03(I)). However, claim 19 could be amended to be statutory subject matter by adding in structural components such as by replacing “a computer program” with the phrase “a non-transitory computer-readable 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 19 has also been analyzed below under 35 U.S.C. 101 using the Alice/Mayo two-part test below.
Claim 20 is directed towards a computer-readable recording medium, which does not fall within one of the categories of statutory subject matter (Step 1: NO). Regarding claim 20, the BRI of computer-readable recording 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 20 could be amended to be statutory subject matter by replacing the phrase “computer-readable recording medium” with the phrase “non-transitory computer-readable recording 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 20 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:
Claim 1 and 10 recite a mental process (i.e., an evaluation of sequences to convert “C” into “Y”) in “a base conversion step/unit of converting methylatable “C” into “Y” and converting other “C” into “T” in the base sequence data of the double-stranded genomic DNA, wherein the methylatable “C” is “C” in a CG sequence”; a mental process (i.e., an evaluation of sequences to generate a complementary strand) in “a complementary strand generation step/unit of generating a complementary strand for each template strand of the double-stranded genomic DNA after base conversion”; a mental process (i.e., an evaluation of sequences relative to target site to determine locations for cutting) in “a partial sequence cutting step/unit of selecting one target site from the one or more target sites and cutting one or more partial sequences from each strand based on the position information of the selected target site, the one or more partial sequences having a predetermined length from a base sequence positioned on the 5' end side of “Y” formed as a result of conversion of the selected target site or “R” complementary to “Y””; a mental process (i.e., an evaluation of sequences based on selection conditions) in “a primer candidate sequence selection step/unit of selecting partial sequences that satisfy predetermined selection conditions as primer candidate sequences from the one or more partial sequences cut out from each strand, wherein the predetermined selection conditions include (1) a Tm value within a predetermined range, (2) the number of YG sequences or CR sequences included in a partial sequence is equal to or less than a predetermined number, and (3) an upper limit of the number of binding sites with a sequence outside a related region on the double-stranded genomic DNA after base conversion is equal to or less than a predetermined number that is equal to or more than 1”; a mental process (i.e., an evaluation of sequences as forward/reverse primers) in “a primer sequence determination step/unit of adopting and determining a forward primer sequence and a reverse primer sequence to amplify a region including the selected target site cut out from each template strand, from the one or more selected primer candidate sequences”; and a mental process (i.e., an evaluation of the target sites to determine repetition of the method) in “a repetition step [or a control unit that controls] of repeating the partial sequence cutting step, the primer candidate sequence selection step, and the primer sequence determination step until all of the one or more target sites are selected in the partial sequence cutting step”.
Claims 2 and 11 recite a mental process (i.e., an evaluation of the sequence) in “wherein the methylatable “C” further includes “C” in a CHG sequence”; and a mental process (i.e., an evaluation of the selection conditions) in “wherein the predetermined selection conditions further include (4) the number of YHG sequences or CDR sequences included in the partial sequence is equal to or less than a predetermined number”.
Claims 3 and 12 recite a mental process (i.e., an evaluation of the sequence) in “wherein the methylatable “C” further includes “C” in a CHH sequence” and a mental process (i.e., an evaluation of the selection conditions) in “wherein the predetermined selection conditions further include (5) the number of YHH sequences or DDR sequences included in the partial sequence is equal to or less than a predetermined number”.
Claims 4 and 13 recite a mental process (i.e., an evaluation of the selection conditions for sequence complementarity) in “wherein the predetermined selection conditions further include (6) three bases from the 3’ end of the partial sequence are not complementary to three bases from the 3’ end of the other partial sequence”.
Claims 5 and 14 recite a mental process (i.e., an evaluation of the selection conditions for sequences) in “wherein the predetermined selection conditions further include (9) in a case where the predetermined number of YHG sequences or CDR sequences included in the partial sequence is set to 1 or more in the condition (4), a range of position of the YHG sequences or CDR sequences in the partial sequence is also specified, and the number of the YHG sequences or CDR sequences included in the specified range of position is equal to or less than a predetermined number”.
Claims 6 and 15 recite a mental process (i.e., an evaluation of the selection conditions for sequences) in “wherein the predetermined selection conditions further include (10) in a case where the predetermined number of YHH sequences or DDR sequences included in the partial sequence is set to 1 or more in the condition (5), a range of position of the YHH sequences or DDR sequences in the partial sequence is also specified, and the number of the YHH sequences or DDR sequences included in the specified range of position is equal to or less than a predetermined number”.
Claims 7 and 16 recite a mental process (i.e., an evaluation of sequences by dividing and selecting strands) in “wherein the primer candidate sequence selection step is a step of dividing the double-stranded genomic DNA after the base conversion into a first template strand and a second template strand, adopting a complementary strand of the first template strand as a first complementary strand, adopting a complementary strand of the second template strand as a second complementary strand”; a mental process (i.e., an evaluation of predetermined selection conditions to select strands) in “selecting a partial sequence satisfying predetermined selection conditions as a forward primer candidate sequence of the first template strand among one or more partial sequences cut out from the first template strand, selecting a partial sequence satisfying the predetermined selection conditions as a reverse primer candidate sequence of the first template strand among one or more partial sequences cut out from the first complementary strand, selecting a partial sequence satisfying the predetermined selection conditions as a forward primer candidate sequence of the second template strand among one or more partial sequences cut out from the second template strand, and selecting a partial sequence satisfying the predetermined selection conditions as a reverse primer candidate sequence of the second template strand among one or more partial sequences cut out from the second complementary strand”.
Claims 8 and 17 recite a mental process (i.e., evaluation the sequences to determine a length) in “wherein the primer sequence determination step is a step of calculating a length of a PCR amplification product predicted to be amplified by PCR for all combinations of the one or more forward primer candidate sequences of the first template strand and the one or more reverse primer candidate sequences of the first template strand selected in the primer candidate sequence selections step”; a mental process (i.e., selecting a primer pair based on length within a predetermined range) in “adopting a combination of primer candidate sequences for which the length of the PCR amplification product is calculated to be within a predetermined range as a forward primer sequence and a reverse primer sequence of the first template strand to amplify a region including the target site selected in the partial sequence cutting step”; a mental process (i.e., an evaluation of sequences to determine a length) in “calculating a length of a PCR amplification product predicted to be amplified by PCR for all combinations of the one or more forward primer candidate sequences of the second template strand and the one or more reverse primer candidate sequences of the second template strand selected in the primer candidate sequence selection step”; and a mental process (i.e., selecting a primer pair based on length within a predetermined range) in “adopting a combination of primer candidate sequences for which the length of the PCR amplification product is calculated to be within a predetermined range as a forward primer sequence and a reverse primer sequence of the second template strand to amplify a region including the target site selected in the partial sequence cutting step”.
Claims 9 and 18 recite a mathematical calculation (i.e., determining local alignment scores) in “wherein after the forward primer sequence and the reverse primer sequence are adopted for all target sites, the primer sequence determination step further calculates local alignment scores for all combinations of the adopted primer sequences”; and a mental process (i.e., an evaluation of scores below a threshold) in “adopts and determines a combination for which the local alignment scores are calculated to be lower than a predetermined threshold value as a primer sequence”.
Claims 19 and 20 recite mental processes as disclosed above for claim 1.
These recitations are similar to the concepts of collecting information, and displaying certain results of the collection and analysis in 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 10 involves nothing more than converting methylatable “C”s, generating a complementary strand, cutting sequences to a predetermined length, selecting sequences that satisfy selection conditions, determining forward and reverse primer sequences, and repeating until sequences are determined for all target sites. Since there are no specifics in the methodology, the steps reciting converting methylatable “C”s, generating a complementary strand, cutting sequences to a predetermined length, selecting sequences that satisfy selection conditions, determining forward and reverse primer sequences, and repeating until sequences are determined for all target sites, are something that, under the 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. 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 10 recite “a base sequence acquisition step/unit of acquiring base sequence data of the double-stranded genomic DNA” and “a target site information acquisition step/unit of acquiring one or more target sites and position information thereof”.
Regarding the above cited limitations in claims 1 and 10 of (i) a base sequence data acquisition step/unit that acquires base sequence data of the double-stranded genomic DNA; and (ii) a target site information acquisition step/unit that acquires the one or more target sites and position information thereof. These limitations equate to insignificant, extra-solution activity of mere data gathering because these limitations gather data before the recited judicial exceptions of converting methylatable “C”s, generating a complementary strand, cutting sequences to a predetermined length, selecting sequences that satisfy selection conditions, determining forward and reverse primer sequences, and repeating until sequences are determined for all target sites (see MPEP § 2106.04(d)).
Additionally, none of the recited dependent claims recite additional elements which would integrate the judicial exception into a practical application. Specifically, claims 19 and 20 recite generic computer components that equate to mere instructions to implement an abstract idea on a generic computer. As such, claims 1-20 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 limitations in claims 1 and 10 of (i) a base sequence data acquisition step/unit that acquires base sequence data of the double-stranded genomic DNA; and (ii) a target site information acquisition step/unit that acquires the one or more target sites and position information thereof. These limitations do not include any specific steps for acquiring base sequence data of DNA, or for acquiring information about target sites/position information. Under the BRI, these limitations are merely receiving data for the subsequent steps of converting methylatable “C”s, generating a complementary strand, cutting sequences to a predetermined length, selecting sequences that satisfy selection conditions, determining forward and reverse primer sequences, and repeating until sequences are determined for all target sites. Therefore, these limitations equate to receiving/transmitting data over a network, which the courts have established as a WURC limitation of a generic computer in buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014).
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 1-20 are not patent eligible.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
1. Claims 1, 7, 10, 16, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Pandey et al. (MSP-HTPrimer: a high-throughput primer design tool to improve assay design for DNA methylation analysis in epigenetics. Clinical Epigenetics. 8: 101 (10 pages) (2016); published 09/21/2016) in view of Srivastava et al. (PRIMEGENS-v2: genome-wide primer design for analyzing DNA methylation patterns of CpG islands. Bioinformatics. 24(17): 1837-1842 (2008); published 06/25/2008).
Regarding claims 1 and 10, Pandey et al. teaches a web-based pipeline called MSP-HTPrimer, to design primer pairs for methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), pyrosequencing, COBRA, and methylation-sensitive restriction enzyme-based PCR (MSRE) assays on both genomic strands. First, their pipeline converts all target sequences into bisulfite-treated templates for both forward and reverse strand and designs all possible primer pairs, followed by filtering for single nucleotide polymorphisms (SNPs) and known repeat regions. Next, each primer pairs are annotated with the upstream and downstream RefSeq genes, CpG island, and cut sites (for COBRA and MSRE). Finally, MSP-HTPrimer selects specific primers from both strands based on custom and user-defined hierarchical selection criteria. MSP-HTPrimer produces a primer pair summary output table in TXT and HTML format for display and UCSC custom tracks for resulting primer pairs in GTF format (i.e., a primer design method/device for amplicon methylation sequence analysis that is a method for designing a primer used to simultaneous amplify a plurality of regions each including one or more target sites for measuring a methylation degree by using a bisulfite reaction or an enzyme reaction and multiplex PCR to measure a methylation degree of double-stranded genomic DNA in a predetermined site related to a predetermined biological phenomenon) (Abstract). Pandey et al. further teaches the workflow of the MSP-HTPrimer pipeline in Fig. 1. The first step is to download and prepare reference sequence and annotation from UCSC genome browser. During the first primer design process, MSP-HTPrimer downloads and prepares the reference FASTA sequence, common SNPs, RefSeq gene, CpG islands, and annotations of known repeat elements for the entire genome (human and mouse) based on the selected genome, genome assembly, and dbSNP (database) build number from the UCSC genome browser (i.e., a base sequence data acquisition step/unit of acquiring base sequence data of double-stranded genomic DNA) (Pg. 3, Col. 1, Para. 3 ("Step 1"); and Pg. 4, Fig. 1). Pandey et al. further teaches that the second step of the pipeline is to define primer design range for each target region. In this step, the genomic primer design range is prepared by adding the number of flanking upstream and downstream base pairs (optional) to the actual target region given as input in the target bed file. Subsequently, the FASTA sequence for each target region is prepared. Target sequences are extracted from the genome reference FASTA file based on the target chromosomal positions. For BS-based methods (BSP, MSP, COBRA), the in silico deduced sequences for methylated and unmethylated alleles from the plus and the minus strand are used for assay design to increase the success rate (i.e., a target site information acquisition step/unit of acquiring one or more target sites and position information thereof) (Pg. 3, Col. 1, Para. 4-5 ("Steps 2-3"); and Pg. 4, Fig. 1). Pandey et al. further teaches that the pipeline takes into account the deamination of double-stranded native DNA to result in four different template sequences for primer design. From the plus and minus strand, different methylation-dependent primer pairs can be designed. For example, in Fig. 2, C's in blue are not in a CpG context, and are usually unmethylated. On the plus strand, these unmethylated C's are converted to T's. Additionally, C's for methylation in CG are tagged as methylated C's (i.e., a base conversion step/unit of converting methylatable "C" into "Y", where "Y" represents thymine or cytosine, and converting other "C" into "T" in the base sequence data of the double-stranded genomic DNA and wherein the methylatable "C" is "C" in a CG sequence) (Pg. 5, Fig. 2). Pandey et al. further teaches that the double stranded template is used to generate both methylated and unmethylated versions for both the plus and minus strands. This yields four different template sequences, with two sets of complementary strands (i.e., a complementary strand generation step/unit of generating a complementary strand for each template strand of the double-stranded genomic DNA after base conversion) (Pg. 5, Fig. 2). Pandey et al. further teaches that the pipeline includes a step of restriction enzyme cut step prediction. In this step, the enzyme’s cut sites in amplicons are predicted. This step is only applicable for MSRE-PCR primer design and COBRA-PCR. COBRA primer design is similar to BSP, where amplicons should contain at least one cut site but no CpGs, and should contain several “Cs” which will amplify the bisulfite deaminated sequence and not the native DNA (i.e., a partial sequence cutting step/unit of selecting one target site from the one or more target sites and cutting one or more partial sequences from each strand based on the position information of the selected target site, the one or more partial sequences having a predetermined length from a base sequence positioned on the 5' end side of "Y" formed as a result of conversion of the selected target site or "R" complementary to "Y") (Pg. 3, Col. 2, Para. 4 ("Step 6"); and Pg. 4, Fig. 1). Pandey et al. further teaches that the pipeline includes a step for primer selection. Based on the user-defined selection criteria, the final primer pairs for each target region are selected. These selection criteria input file is optional. This step facilitates selection of primer candidates according to the filtering criteria and provides the specific primer pairs for hundreds of target regions in a time-effective manner. This customized hierarchical filtering process is a unique and very useful feature of the MSP-HTPrimer tool, which is lacking in all other freely available tools (i.e., a primer candidate sequence selection step/unit of selecting partial sequences that satisfy predetermined selection conditions as a primer candidate sequences from the one or more partial sequences cut out from each strand) (Pg. 4, Col. 1, Para. 1 – Col. 2, Para. 1 ("Step 8"); and Pg. 4, Fig. 1). Pandey et al. further teaches that the MSP-HTPrimer produces a summary output file in two formats: (1) a tab-delimited text file and (2) a HTML output file (Fig. 3b), which contain one line for each primer pair along with all annotations including target sequence ID, amplicon ID, hybridization probe and genome amplicon coordinates, number of cut sites, number of SNPs, number of CpG islands, repeat regions, upstream and downstream RefSeq genes (including their distance with respect to forward and reverse primer), and a direct link to UCSC genome browser. For all five primer design methods (BSP-PCR, PyroSeq primer, MSP-PCR, COBRA-PCR, and MSRE-PCR), the MSP-HTPrimer tool produces a uniform HTML summary output table, which facilitates an easy output handling and post-processing. An example forward/reverse primer sequence output is also show in Fig. 3b/c (i.e., a primer sequence determination step/unit of adopting and determining a forward primer sequence and a reverse primer sequence to amplify a region including the selected target site cut out from each template strand, from the one or more selected primer candidate sequences) (Pg. 5, Col. 2, Para. 2; and Pg. 6, Fig. 3). Pandey et al. further teaches that the steps of the method help to pick suitable primer pairs for each target region, thereby providing the specific primer pairs for hundreds of target regions in a time-effective manner (i.e., a repetition step/control unit of repeating the partial sequence cutting step, the primer candidate sequence selection step, and the primer sequence determination step until all of the one or more target sites are selected in the partial sequence cutting step) (Pg. 3, Col. 2, Para. 5 and Pg. 4, Col. 1, Para. 1 – Col. 2, Para. 1). Pandey et al. further teaches the use of a custom primer quality matrix. MSP-HTPrimer supports selection of primer pairs based on user-defined selection criteria. A custom quality-filtering matrix can be provided as input file. As shown in Additional file 4, user can define a set of selection criteria and rank them using a scale of 1–10. MSP-HTPrimer assigns these ranks to the primer pairs for all target sequences. If this input is not provided, then primer pairs are returned based on the Primer3 ranking (Pg. 5, Col. 2, Para. 1). The predefined design and filtering parameters of the MSP-HTPrimer tool, include the amount of number of CpG sites per assay, SNP filtering and avoiding position with repeats, as well as standard parameters of Primer3 (e.g., sequence length, melting temperature, GC content, and primer length) (i.e., wherein the predetermined selection conditions include (1) a Tm value is within a predetermined range, (2) the number of YG sequences or CR sequences included in a partial sequence is equal to or less than a predetermined number, where "R" represents adenine or guanine) (Pg. 7, Col. 1, Para. 3 – Col. 2, Para. 1).
Regarding claims 7 and 16, Pandey et al. teaches that the MSP-HTPrimer pipeline takes into account that deamination of double-stranded native DNA results in four different template sequences for primer design. Thus, from the plus and minus strand, different methylation-dependent primer pairs can be designed (M - methylated; U - unmethylated; Cs in blue - not in a CpG context are usually unmethylated) (i.e., wherein the primer candidate sequence selection step is a step of dividing the double-stranded genomic DNA after the base conversion into a first template strand and a second template strand, adopting a complementary strand of the first template strand as a first complementary strand, adopting a complementary strand of the second template strand as a second complementary strand) (Pg. 5, Fig. 2). Pandey et al. further teaches that MSP-HTPrimer considers both strands for primer design (Pg. 3, Col. 2, Para. 3, "Step 5"), as well as the selection of a partial sequence satisfying predetermined selection conditions as described for claim 1 above (i.e., selecting a partial sequence satisfying predetermined selection conditions as a forward primer candidate sequence of the first template strand among one or more partial sequences cut out from the first template strand, selecting a partial sequence satisfying the predetermined selection conditions as a reverse primer candidate sequence of the first template strand among one or more partial sequences cut out from the first complementary strand, selecting a partial sequence satisfying the predetermined selection conditions as a forward primer candidate sequence of the second template strand among one or more partial sequences cut out from the second template strand, and selecting a partial sequence satisfying the predetermined selection conditions as a reverse primer candidate sequence of the second template strand among one or more partial sequences cut out from the second complementary strand).
Regarding claims 19 and 20, Pandey et al. teaches that MSP-HTPrimer is a powerful, portable, and web-based tool, freely accessible to all researchers. It is available along with its intuitive web interface as a fully configured virtual machine (VM) at http://sourceforge.net/p/msp-htprimer/wiki/Virtual_Machine/. The virtual machine is configured to run without any installation and can be executed using Oracle’s VirtualBox system (https://www.virtualbox.org/). In addition to virtual machine, source codes for Linux (https://sourceforge.net/projects/msp-htprimer/files/Linux) and MacOS (https://sourceforge.net/projects/msp-htprimer/files/MacOS) are available, which can be easily installed on any Unix computer (i.e., a primer design program, wherein the primer design program performs the primer design method according to claim 1 on a computer and a computer-readable recording medium, wherein the primer design program according to claim 19 is recorded) (Pg. 6, Col. 2, Para. 2 – Pg. 7 Col. 1, Para. 1).
Pandey et al. does not teach wherein the predetermined selection conditions include (3) an upper limit of the number of binding sites with a sequence outside a related region on the double-stranded genomic DNA after base conversion is equal to or less than a predetermined number that is equal to or more than 1 (claims 1 and 10).
Regarding claims 1 and 10, Srivastava et al. teaches a primer design software capable of performing genome-wide scan for optimal primers from in silico bisulfite-treated genome sequences (Abstract). Srivastava et al. further teaches that in order to design primer for any sequence, they first convert the target sequence and the complete human genome into bisulfite-treated sequences, where all the cytosine (C) sites in original sequence are converted into thymine (T) except places where cytosine is preceding guanine (G) known as methylation of the CG. In order to run Mega BLAST for the designed primers, they consider the bisulfite-treated human genome as a database (Pg. 1838, Col. 1, Para. 3). Srivastava et al. further teaches that the potential non-specific PCR amplification with the designed primer pair is explored using MegaBLAST. MegaBLAST performs gapless alignments for the oligos designed in the preceding step against the four variant in silico bisulfite converted human genome sequences to determine the binding capacity of the oligos to the genome. If an oligo sequence has a significant similarity (either identical or with few mismatches, depending on the threshold used) to any part of the genome, then it would be a potential binding site for that oligo. In order to amplify non-specific PCR product, two conditions need to be satisfied: (1) both the left primer and right primer should behind at appropriate places and (2) the amplified PCR product length should not be too long, as long PCR products would not be amplified effectively. Based on these two restrictions, and the user-defined threshold for the non-specific PCR product size, the algorithm will select the most query sequence-specific primer pairs for further consideration (i.e., an upper limit of the number of binding sites with a sequence outside a related region on the double-stranded genomic DNA after base conversion is equal to or less than a predetermined number that is equal to or more than 1) (Pg. 1839, Col. 2, Para. 3).
Therefore, regarding claims 1, 7, 10, 16, and 19-20, 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 primer design pipeline for bisulfite sequencing of Pandey et al. with the selection conditions of Srivastava et al. because Pandey et a. discloses that the user can customize several primer design and selection parameters to obtain specific and optimized assays (Pandey et al., Pg. 5, Col. 1, Para. 1). Additionally, the addition of criteria for determining binding sites outside the target region provides an additional check for non-specific PCR amplification (Srivastava et al., Pg. 1839, Col. 2, Para. 3; and Pg 1841, Col. 1, Para. 1). One of ordinary skill in the art would be able to combine the teachings of Pandey et al. with Srivastava 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 by analyzing methylation patterns with specific selection criteria. Therefore, regarding claims 1, 7, 10, 16, and 19-20, the instant invention is prima facie obvious (MPEP § 2142).
2. Claims 2-6 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Pandey et al. in view of Srivastava et al. as applied to claims 1, 7, 10, 16, and 19-20 above, and further in view of Gruntman et al. (Kismeth: Analyzer of plant methylation states through bisulfite sequencing. BMC Bioinformatics. 9: 271 (14 pages) (2008); published 09/11/2008).
Regarding claims 2-3 and 11-12, Pandey et al. teaches the use of user-defined selection criteria (Pg. 4, Col. 1, Para. 1), as well as predefined design and filtering parameters, such as the number of CpG sites per assay, number of C's, and GC content (Pg. 7, Col. 1, Para. 2 – Col. 2, Para. 1). Though not explicitly disclosed by Pandey et al., it would have been obvious to one of ordinary skill in the art to provide another user defined selection parameter analogous to the count metrics of C/CG representing the number of YHG sequences or CDR sequences (claims 2 and 11) or the number of YHH sequences or DDR sequences (claims 3 and 12) for the purpose of developing optimized assays and significantly increasing speed and success rate of assay design (Pg. 8, Col. 1, Para. 1) (i.e., the predetermined selection conditions further include (4) the number of YHG sequences or CDR sequences included in the partial sequence is equal to or less than a predetermined number and the predetermined selection conditions further include (5) the number of YHH sequences or DDR sequences included in the partial sequence is equal to or less than a predetermined number).
Regarding claims 5-6 and 14-15, Pandey et al. teaches the use of user-defined selection criteria (Pg. 4, Col. 1, Para. 1), as well as predefined design and filtering parameters, including the CG position in primers (Pg. 7, Col. 1, Para. 2 – Col. 2, Para. 1). Though not explicitly disclosed by Pandey et al., it would have been obvious to one of ordinary skill in the art to provide another user defined selection parameter analogous to the CG position metric representing a range of position of the YHG sequences or CDR sequences (claims 5 and 14) or a range of position of the YHH sequences or DDR sequences (claims 6 and 15) for the purpose of developing optimized assays and significantly increasing speed and success rate of assay design (Pg. 8, Col. 1, Para. 1) (i.e., wherein the predetermined selection conditions further include (9) in a case where the predetermined number of YHG sequences or CDR sequences included in the partial sequence is set to 1 or more in the condition (4), a range of position of the YHG sequences or CDR sequences in the partial sequence is also specified, and the number of the YHG sequences or CDR sequences included in the specified range of position is equal to or less than a predetermined number and wherein the predetermined selection conditions further include (10) in a case where the predetermined number of YHH sequences or DDR sequences included in the partial sequence is set to 1 or more in the condition (5), a range of position of the YHH sequences or DDR sequences in the partial sequence is also specified, and the number of the YHH sequences or DDR sequences included in the specified range of position is equal to or less than a predetermined number).
Pandey et al. in view of Srivastava et al., as applied to claims 1, 7, 10, 16, and 19-20 above, does not teach wherein the methylatable "C" further includes "C" in a CHG sequence (claims 2 and 11); wherein the methylatable "C" further includes "C" in a CHH sequence (claims 3 and 12); and wherein the predetermined selection conditions further include (6) three bases from the 3' end of the partial sequence are not complementary to three bases from the 3' end of the other partial sequence (claims 4 and 13).
Regarding claims 2-3 and 11-12, Gruntman et al. teaches a web-based tool for bisulfite sequencing analysis called Kismeth. Kismeth was designed to be used with plants, since it considers potential cytosine methylation in any sequence context (CG, CHG, and CHH). It provides a tool for the design of bisulfite primers as well as several tools for the analysis of the bisulfite sequencing results. Kismeth is not limited to data from plants, as it can be used with data from any species (Abstract). Gruntman et al. further teaches that in plants, DNA methylation is critical for parental imprinting, the regulation of embryogenesis, transposon silencing and for seed viability. It has been shown that different pathways are involved in the methylation of cytosines in three different contexts; CG, CHG (C followed by a non-G followed by a G) and CHH (C followed by two non-Gs) (Pg. 2, Col. 1, Para. 2). An example is shown in Fig. 3, where the number of times each cytosine is sampled in the sequenced reads (as colored bars below the x-axis) and the fraction of times the cytosine at each location is methylated, as colored bars above the x-axis. The colors represent the three types of C's in the sequence, red for CG, blue for CHG and green for CHH (i.e., wherein the methylatable "C" further includes "C" in a CHG sequence, and wherein the methylatable "C" further includes "C" in a CHH sequence) (Pg. 5, Fig. 3).
Regarding claims 4 and 13, Gruntman et al. teaches that the sequenced read, as well as its reverse complement, is aligned against the reference sequence, only one of them will align properly, unless the read is of poor quality. Poor alignments, either in terms of the length of match (lengths less than 50 percent of the reference sequence length), or quality of match (less than 80% positive match in the alignment) are not considered for the analysis. These parameters (called min fraction of length and min fraction of positive matches) can be modified on the Kismeth website. Additionally, the portion of reference sequence used for analysis can be modified using the start of match and end of match variables. Sequence ends might have poorer sampling, since the quality of the reads at the ends is usually lower than in the middle, thus care must be taken in inferring position-dependent methylation. The program first identifies the various kinds of C's on the reference sequence (CG, CHG, and CHH). The output of cross_match is parsed by the program and a report is generated, that holds a synopsis for each alignment that is accepted, the alignments, as well as the identities of the various C's in the alignment. This is the central report file that is used to generate various reports and graphs (i.e., the start of match and end of match can be set to three bases from the 3' to determine alignment and complementarity; wherein the predetermined selection conditions further include (6) three bases from the 3' end of the partial sequence are not complementary to three bases from the 3' end of the other partial sequence) (Pg. 11, Col. 1, Para. 2-3).
Therefore, regarding claims 2-6 and 11-15, 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 primer design pipeline for bisulfite sequencing of Pandey et al. in view of Srivastava et al. with the additional methylatable cytosines of Gruntman et al. because the method of Gruntman et al. enables the design of bisulfite primers for plants, thereby facilitating the analysis of additional genetic pathways involved in DNA methylation (Gruntman et al., Abstract). One of ordinary skill in the art would be able to combine the teachings of Pandey et al. in view of Srivastava et al. with Gruntman 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 in bisulfite sequencing. Therefore, regarding claim 2-6 and 11-15, the instant invention is prima facie obvious (MPEP § 2142).
3. Claims 8 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Pandey et al. in view of Srivastava et al. as applied to claims 1, 7, 10, 16, and 19-20 above, and further in view of Kovacova et al. (Bisprimer—A Program for the Design of Primers for Bisulfite-Based Genomic Sequencing of Both Plant and Mammalian DNA Samples. Journal of Heredity. 103(2): 308-312 (2012); published 01/13/2012).
Regarding claims 8 and 17, Pandey et al. teaches that MSP-HTPrimer considers both strands for primer design (Pg. 3, Col. 2, Para. 3 ("Step 5")), and the use of first and second template strands as described for claim 7 above.
Pandey et al. in view of Srivastava et al., as applied to claims 1, 7, 10, 16, and 19-20 above, does not teach wherein the primer sequence determination step is a step of calculating a length of a PCR amplification product predicted to be amplified by PCR for all combinations of the one or more forward primer candidate sequences of the first template strand and the one or more reverse primer candidate sequences of the first template strand selected in the primer candidate sequence selection step, adopting a combination of primer candidate sequences for which the length of the PCR amplification product is calculated to be within a predetermined range as a forward primer sequence and a reverse primer sequence of the first template strand to amplify a region including the target site selected in the partial sequence cutting step, calculating a length of a PCR amplification product predicted to be amplified by PCR for all combinations of the one or more forward primer candidate sequences of the second template strand and the one or more reverse primer candidate sequences of the second template strand selected in the primer candidate sequence selection step, and adopting a combination of primer candidate sequences for which the length of the PCR amplification product is calculated to be within a predetermined range as a forward primer sequence and a reverse primer sequence of the second template strand to amplify a region including the target site selected in the partial sequence cutting step.
Regarding claims 8 and 17, Kovacova et al. teaches a method called BisPrimer, which designs primers that preferentially bind to the bisulfite-modified primer-binding sites (C to U conversion) to amplify the bisulfite-converted DNA strands (Abstract). Kovacova et al. further teaches that first, an initial population of primers with length between 25 and 40 nucleotides is created. This length is generally recommended for bisulfite-based genomic sequencing. These primers are then subjected to further selection. Each primer from the forward group is paired with each primer from the reverse group to create a large set of primer pair candidates to which a predicted product length condition (150–500 bp) is simultaneously applied (Pg. 310, Col. 1, Para. 2). The program displays a minimum of 1 and a maximum of 5 pairs of primers, if it is practicable and set conditions are met (i.e., a step of calculating a length of a PCR amplification product predicted to be amplified by PCR for all combinations of the one or more forward primer candidate sequences of the first template strand and the one or more reverse primer candidate sequences of the first template strand selected in the primer candidate sequence selection step, adopting a combination of primer candidate sequences for which the length of the PCR amplification product is calculated to be within a predetermined range as a forward primer sequence and a reverse primer sequence of the first template strand to amplify a region including the target site selected in the partial sequence cutting step, calculating a length of a PCR amplification product predicted to be amplified by PCR for all combinations of the one or more forward primer candidate sequences of the second template strand and the one or more reverse primer candidate sequences of the second template strand selected in the primer candidate sequence selection step, and adopting a combination of primer candidate sequences for which the length of the PCR amplification product is calculated to be within a predetermined range as a forward primer sequence and a reverse primer sequence of the second template strand to amplify a region including the target site selected in the partial sequence cutting step) (Pg. 311, Col. 1, Para. 2).
Therefore, regarding claims 8 and 17, 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 primer design pipeline for bisulfite sequencing of Pandey et al. in view of Srivastava et al. with length prediction of a PCR amplification product of Kovacova et al. because the method of Kovacova et al. enables the design of primers that preferentially amplify bisulfite-converted DNA as well as avoid problems with incomplete bisulfate modification (Kovacova et al., Abstract). One of ordinary skill in the art would be able to combine the teachings of Pandey et al. in view of Srivastava et al. with Kovacova 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 in bisulfite sequencing. Therefore, regarding claim 2-6 and 11-15, the instant invention is prima facie obvious (MPEP § 2142).
4. Claims 9 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Pandey et al. in view of Srivastava et al. as applied to claims 1, 7, 10, 16, and 19-20 above, and further in view of Tsujimoto et al. (U.S. Patent Application Publication US 2018/0032669 A1; published 02/01/2018, cited in the IDS dated 08/21/2023).
Pandey et al. in view of Srivastava et al., as applied to claims 1, 7, 10, 16, and 19-20 above, does not teach further calculates local alignment scores for all combinations of the adopted primer sequences and adopts and determines a combination for which the local alignment scores are calculated to be lower than a predetermined threshold value as a primer sequence (claims 9 and 18).
Regarding claims 9 and 18, Tsujimoto et al. teaches a method for designing a primer including a local alignment step of obtaining a local alignment score by performing pairwise local alignment on a base sequence of a primer candidate under a condition that a partial sequence to be subjected to comparison includes the 3' terminal of the base sequence of the primer candidate (Abstract). Tsujimoto et al. further teaches an example where forward and reverse primers were generated (Para. [0232]). Tsujimoto et al. further teaches the a local alignment may be calculated on a combination of pairs of base sequences (Para. [0101]). Tsujimoto et al. further teaches that the threshold value of the local alignment score is predetermined. In a case where the local alignment score of a pair of two base sequences is less than the first threshold value, the pair is selected and subsequent analysis can be performed (i.e., further calculates local alignment scores for all combinations of the adopted primer sequences and adopts and determines a combination for which the local alignment scores are calculated to be lower than a predetermined threshold value as a primer sequence) (Para. [0117-[0118]).
Therefore, regarding claims 9 and 18, 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 primer design pipeline for bisulfite sequencing of Pandey et al. in view of Srivastava et al. with the local alignment of Tsujimoto et al. because the method of Tsujimoto et al. improves the selectivity of the primer to efficiently amplify a selected gene region (Tsujimoto et al., Para. [0008]). One of ordinary skill in the art would be able to combine the teachings of Pandey et al. in view of Srivastava et al. with Tsujimoto 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 forward and reverse primer sets. Therefore, regarding claims 9 and 18, the instant invention is prima facie obvious (MPEP § 2142).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 7-12, and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-7, 10, 12-16, and 19-20 of copending Application No. 19/004,078 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to a primer design method/device, including the following steps: a base sequence data acquisition step; a target site information acquisition step; a base conversion step; a complementary strand generation step; a partial sequence cutting step; a primer candidate selections step; a primer sequence determinations step; and a repeating step to evaluate all target sites. The types of methylatable cytosines and predetermined selection conditions (1)-(5) are also not patentably distinct (see, for example, claim 2/11 of the instant application and claims 4/13 of copending application 19/004,078).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DIANA P SANFORD whose telephone number is (571)272-6504. The examiner can normally be reached Mon-Fri 8am-5pm EST.
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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.
/D.P.S./Examiner, Art Unit 1687
/Lori A. Clow/Primary Examiner, Art Unit 1687
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