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 .
Claim Status
Claims 1-20 are pending and examined herein.
Claims 1-20 are rejected.
Priority
This application is a 371 of PCT/CN2021/082783 filed 24 March 2021. Thus, the effective filling date of claims 1-20 is 24 March 2021.
Information Disclosure Statement
The information disclosure statement (IDS) was received on 21 November 2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Drawings
The drawings received 21 September 2023 are accepted.
Claim Interpretation
112/f 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.
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 conversion module for respectively converting, into corresponding density maps, obtained Ramachandran plot of…” in claim 15.
“a calculation module for respectively dividing the density map of…” in claim 15.
“a marking module for comparing the density of the proteins to be identified in each of the regions with the corresponding average density of the region…” in claim 15.
“a determining module for according to the proportion or number of the density deviation regions of the proteins to be identified, determining the mutation of the proteins to be identified, and…” in claim 15.
“an obtaining module for obtaining the Ramachandran plot of…” in claim 16.
The instant disclosure does not provide a corresponding structure (i.e., associated computer hardware or algorithm) for “a conversion module”, “a calculation module”, “a marking module”, “a determining module”, or “an obtaining module” for performing the respective functions in the claims.
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.
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
112/a
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 15 recites “a conversion module for respectively converting, into corresponding density maps…”, “a calculation module for respectively dividing the density map of…”, “a marking module for comparing the density of the proteins to be identified…”, “a determining module for according to the proportion or number of the density deviation regions of the proteins to be identified, determining the mutation of the proteins to be identified …” and claim 16 recites “an obtaining module for obtaining the Ramachandran plot of…”. The MPEP states “When a claim containing a computer-implemented 35 U.S.C. 112(f) claim limitation is found to be indefinite under 35 U.S.C. 112(b) for failure to disclose sufficient corresponding structure (e.g., the computer and the algorithm) in the specification that performs the entire claimed function, it will also lack written description under section 112(a)” (see MPEP 2181(IV)). The instant disclosure describes these modules in [0008], [0042], and [0043] by providing the functional description of each of these modules (as set out in the claims). The instant disclosure fails to disclose a corresponding structure for these modules (e.g., computer hardware such as a processor). Dependent claims 17 and 18 are rejected by virtue of their dependency on a rejected claim without alleviating the rejection. It is noted that computer hardware is described in the instant disclosure in [0009] and [0046]-[0050], however the computer hardware is not linked to the disclosed modules and appears to be a separate embodiment (which is separately claimed see claim 19).
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 15 recite “if the deviation between the density of the proteins to be identified in the region and the average density of the region…” in lines 13-14 of claim 1 and lines 14-15 in claim 15 and claim 7 recites “if the deviation between the density of the pathogenic protein variants in the region and the average density of the region…” in lines 3-4 in claim 7. There is insufficient antecedent basis for these limitations in the claims. The indefiniteness arises because the claim does not make clear what “the deviation between the density of the proteins to be identified in the region and the average density of the region” or “the deviation between the density of the pathogenic protein variants in the region and the average density of the region” is referring to in the claims. This rejection may be overcome by amendment to claims 1 and 15 of “comparing… with the corresponding average density of the region to determine a deviation between the density of the proteins to be identified in the region and the average density of the region, if the deviation between…” and by amendment to claim 7 of “comparing… with the corresponding average density of the region to determine a deviation between the density of the pathogenic variants in the region and the average density of the region, if the deviation between…” with the Dependent claims 2-6, 8-14 and 16-20 are rejected by virtue of their dependency on a rejected claim without alleviating the indefiniteness. For the sake of furthering examination, these claims will be interpreted as the comparison determines a deviation between the recited densities.
Claims 1 and 15 recite “the density of the proteins to be identified in each of the regions…” in lines 12-13 of claim 1 and in line 13-14 in claim 15 and claim 7 recites “the density of the pathogenic protein variants in each of the regions…” in lines 2-3 of claim 7. There is insufficient antecedent basis for these limitations in the claims. The indefiniteness arises because the claim does not make clear what “the density of the proteins to be identified in each of the regions…” or “the density of the pathogenic protein variants in each of the regions…” is referring to in the claims (i.e., it is unclear if “the density” is meant to refer to “the density map” itself in each region or if “the density” is meant to be different than the density map itself in each region). Dependent claims 2-6, 8-14 and 16-20 are rejected by virtue of their dependency on a rejected claim without alleviating the indefiniteness. For the sake of furthering examination, the limitations of “the density… in each of the regions” will be interpreted as a measure of density corresponding to a region of each of the regions.
Claims 1 and 15 recites “by using N cases of the density map of the benign protein variants, the density map of the pathogenic protein variants and the density map of the wild-type proteins as a reference, calculating an average density and a standard deviation of each of the regions, wherein n ≥ 2 and N ≥ 2” which renders the metes and bounds of the claim indefinite. The indefiniteness arises because it is unclear if “by using N cases” means using N cases of the density map of the benign protein variants, using N cases of the density map of the pathogenic protein variants and using N cases of the density map of the wild-type protein as a reference (i.e., using N cases from each of these groups) or if this means using N cases selected from a collection of data that includes the density map of benign protein variants, the density map of the pathogenic protein variants and the density map of the wild-type proteins as a reference (i.e., the N cases are not required to be from each group and encompasses using cases from certain groups but not others). Dependent claims 2-14 and 16-20 are rejected by virtue of their dependency on a rejected claim without alleviating the indefiniteness. For the sake of furthering examination, this limitation will be interpreted as using N cases selected from a collection of data that includes the density map of benign protein variants, the density map of the pathogenic protein variants and the density map of the wild-type proteins as a reference.
Claims 1 and 15 recite “the mutation of the proteins to be identified” in line 18 of claim 1 and line 19 of claim 15. There is insufficient antecedent basis for this limitation in the claim. The indefiniteness arises because the claim does not make clear what “the mutation of the proteins to be identified” is referring to. This rejection could be overcome by amendment of this limitation to “a mutation of the proteins to be identified”. Dependent claims 2-14 and 16-20 are rejected by virtue of their dependency on a rejected claim without alleviating the indefiniteness. For the sake of furthering examination, this limitation will be interpreted as a mutation of the proteins to be identified.
Claims 3 and 17 recite “the Ramachandran plots corresponding to the trajectories of the protein at any 2 or more time points” and claims 4 and 18 recite “the Ramachandran plots corresponding to the trajectories of the protein obtained every 5-100 ps during the last 1-20 ns of the protein trajectory”. There is insufficient antecedent basis for these limitations in the claims. The indefiniteness arises because it is unclear what “the trajectories of the protein at any 2 or more time points” (in claims 3 and 17) and “the trajectories of the protein obtained every 5-100 ps during the last 1-20 ns of the protein trajectory” (in claims 4 and 18) are referring to in the claims. Due to the lack of antecedent basis for these limitations, it is further unclear which Ramachandran plots are the Ramachandran plots which correspond to these trajectories. For the sake of furthering examination, claims 3 and 17 will be interpreted as generating a Ramachandran plot with data generated at timepoints of a molecular dynamic simulation and claims 4 and 18 are interpreted as generating a Ramachandran plot with data generated from timepoints during the last 1-20 ns of a molecular dynamic simulation.
Claims 3, 4, 17, and 18 recite “using same as the Ramachandran plot of the protein obtained on the basis of molecular dynamics simulation method” which renders the metes and bounds of the claim indefinite. The indefiniteness arises because it is unclear if “using same as the Ramachandran plot of the protein obtained on the basis…” means that this Ramachandran plot is the obtained Ramachandran plot or does this limitation mean that this Ramachandran plot is used in the same manner as the obtained Ramachandran plot on the basis molecular dynamics simulation method. For the sake of furthering examination, this limitation will be interpreted as this Ramachandran plot is the same as the obtained Ramachandran plot.
Claim 5 recites “wherein d > 0 and n1 ≥ 2; preferably, n1 ≥ 10; preferably, n1 ≥ 30, and preferably n1 ≥ 32”, claim 6 recites “wherein N ≥ 30; preferably, N ≥ 100; and preferably, N ≥ 300”, claim 11 recites “wherein M ≥ 30; preferably, M ≥ 100; and preferably, M ≥ 300 ”, and claim 13 recites “… and preferably, the type of the gene mutation is base substation mutation” which renders the metes and bounds of the claim indefinite. The indefiniteness arises because it is unclear if the limitations following the term “preferably” are required by the claims. The specification does not provide a clear and precise definition of the limitation, nor would one skilled in the art recognize the metes and bounds of said limitation. For the sake of furthering examination, claim 5 will be interpreted as “wherein d > 0 and n1 ≥ 2”, claim 6 will be interpreted as “wherein N ≥ 30”, claim 11 will be interpreted as “wherein M ≥ 30”, and claim 13 will be interpreted as “wherein the type of the gene mutation is selected from: at least one of base substitution mutation, deletion mutation, and insertion mutation”.
Claim 5 recites “wherein the dividing manner of the density map comprises: dividing the abscissa and ordinate of the density map at intervals of d, to obtain n1 x n1 the regions, wherein d > 0 and n1 ≥ 2” which renders the metes and bounds of the claim indefinite. The indefiniteness arises because it is unclear if each of the regions (which refers to the n or more regions where n ≥ 2 in claim 1) themselves have a dimension of n1 x n1 or if this is meant to mean the number of produced regions by the dividing process is the product of n1 and n1 (e.g., 2 x 2 would produce 4 regions). For the sake of furthering examination, this limitation will be interpreted as the number of produced regions by dividing process is the product of n1 and n1.
Claim 7 recites “wherein comparing the density of the pathogenic protein variants in each of the regions with the corresponding average density of the region… marking the region as a density deviation region of the pathogenic protein variants; and constructing a probability distribution on the basis of M cases of…” which renders the metes and bounds of the claim indefinite. The indefiniteness arises because it is unclear if this claim is meant to provide an additional active step of the method or if this claim is meant to further limit an active step of the method (if so it is unclear which active step of the method this limitation is meant to further limit) or if this claim is meant to recite an intended use of the density map of the pathogenic protein variants. Dependent claims 8-11 are rejected by virtue of their dependency on a rejected claim without alleviating the indefiniteness. For the sake of furthering examination, claim 7 will be interpreted as “The method for identifying deleterious genetic mutations of claim 1, furthering comprising comparing…” which provides that this claim is adding an additional active step of the method.
Claim 14 recites “wherein the target protein is P53 protein” in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim. The indefiniteness arises because the claim does not make clear what “the target protein” is referring to in the claims. For the sake of furthering examination, this limitation will be interpreted as wherein the wild-type proteins, the benign protein variants, the pathogenic protein variants and the proteins to be identified include a P53 protein.
Claims 17 and 18 recite “wherein the method for obtaining the Ramachandran plots on the basis of molecular dynamics simulation method comprises: overlapping…” in lines 2-3 of the claims. The indefiniteness arises because the claim does not make clear what “the method for obtaining…” is referring to in the claims. This rejection could be overcome by amendment of this limitation to “wherein the obtaining module for obtaining the Ramachandran plots on the basis of molecular dynamics method is further configured to overlap…”. For the sake of furthering examination this limitation will be interpreted as wherein the obtaining module for obtaining the Ramachandran plots on the basis of molecular dynamics method is further configured to…”.
112/b Indefiniteness based on 112/f claim interpretation:
Claim limitations “a conversion module for respectively converting, into corresponding density maps…” in claim 15, “a calculation module for respectively dividing the density map of…” in claim 15, “a marking module for comparing the density of the proteins to be identified…” in claim 15, “a determining module for according to the proportion or number of the density deviation regions of the proteins to be identified, determining the mutation of the proteins to be identified …” in claim 15, and “an obtaining module for obtaining the Ramachandran plot of…” in claim 16. There is an inadequate written description invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function.
There is an inadequate written description for the corresponding structure of a conversion module, a calculation module, a marking module, a determining module, and an obtaining module. The instant disclosure describes these modules in [0008], [0042], and [0043] by providing the functional description of each of these modules (as set out in the claims). The instant disclosure fails to disclose a corresponding structure for these modules (e.g., computer hardware such as a processor). Although computer hardware is described in the instant disclosure in [0009] and [0046]-[0050], the computer hardware is not linked to the disclosed modules and appears to be a separate embodiment (which is separately claimed see claim 19). Thus, the instant disclosure fails to provide the corresponding structure (e.g., computer hardware such as a processor) associated with these modules. Dependent claims 17 and 18 are rejected by virtue of their dependency on a rejected claim without alleviating the indefiniteness. For the sake of furthering examination, these modules will be interpreted as having the structure of a computer processor.
Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
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 a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
(Step 1)
Claims 1-14 fall under the statutory category of a process and claims 15-20 fall under the statutory category of a machine.
(Step 2A Prong 1)
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mental process”, such as procedures for evaluating, analyzing or organizing information, and forming judgement or an opinion. The instant claims further recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mathematical concept”, such as mathematical relationships and mathematical equations.
Claims 1, 15, 19, and 20 recite mental processes of “respectively dividing the density map of the wild-type proteins, the density map of… into n or more regions in the same dividing manner”, “comparing the density map of the proteins to be identified in each of the regions with the corresponding average density of the region to determine a deviation, if the deviation between… marking the region as a density deviation region of the proteins to be identified”, “on the basis of the proportion or number of the density deviation regions of the proteins to be identified, determining a mutation of the proteins to be identified, and if the proportion or number of…then the mutation of the proteins to be identified is deterred as a undefined variation”
Claims 1, 15, 19, and 20 recite mathematical concepts of “respectively converting, into corresponding density maps, obtained Ramachandran plot of wild-type proteins, obtained Ramachandran plot of…”, “by using N cases of the density map of the benign protein variants, the density map of the pathogenic protein variants and the density map of the wild-type proteins as a reference, calculating an average density and a standard deviation of each of the regions, wherein n ≥ 2 and N ≥ 2”.
Dependent claims 2 and 16 recite a mental process of “obtaining the Ramachandran plot of at least one protein of the wild-type proteins… on the basis of molecular dynamics simulation method before converting the Ramachandran plot into the density map”. Dependent claims 3 and 17 recite a mental process of generating a Ramachandran plot from data generated at timepoints of a molecular dynamic simulation. Dependent claims 4 and 18 recite a mental process of generating a Ramachandran plot from data generated at timepoints during the last 1-20 ns of a molecular dynamic simulation. Dependent claim 7 recites a mental process of “comparing the density map of the pathogenic protein variants in each of the regions with the corresponding average density of the region… marking the region as a density deviation region”. Dependent claim 7 recites mathematical concepts of “constructing a probability distribution on the basis of M cases of the proportions or numbers of the density deviation regions and determining the set threshold of the pathogenic variants by a goodness of fit test, wherein M ≥ 2”.
The instant claims recite mental processes of analyzing/evaluating data, organizing data, and making observations and judgments of respectively dividing the density maps into n or more regions in the same dividing manner (which encompasses organizing data by partitioning data into segments), comparing regions of the density maps with an average density to determine a deviation and marking a region as a density deviation region based on criteria (which encompasses analyzing density map data to make a judgment on a deviation and marking a region based on criteria using the deviation), determining a mutation of the proteins to be identified by comparing a proportion or number of the density deviation regions against a set threshold (which encompasses comparing a numerical value representing a number of regions identified as deviating from a standard deviation of a region with set threshold criteria to make a judgment on a mutation present in the protein to be identified), obtaining the Ramachandran plot of at least one protein on the basis of molecular dynamics simulation method before converting the Ramachandran plot into the density map (which encompasses evaluating data produced by a molecular dynamic simulation by generating a Ramachandran plot from data generated at certain timepoints from a molecular dynamic simulation). The human mind is capable of organizing data, analyzing/evaluating data, and making comparisons/judgments based on criteria. Thus, the claims recite mental processes.
The instant claims recite mathematical concepts as mathematical calculations of converting Ramachandran plots into density maps (which encompasses a mathematical calculation performing a Kernel Density Estimation on a Ramachandran plot to produce a density map see instant disclosure [0024]), calculating an average density and standard deviation from regions of the density map (which is a mathematical calculation of calculating an average and standard deviation), constructing a probability distribution (which encompasses a mathematical calculation of fitting a distribution utilizing the numerical data representing the proportion or number of deviation regions), and determining a set threshold by a goodness of fit test (which encompasses performing a mathematical calculation of a goodness of fit test such as a KS-test or Anderson-Darling test to generate a numerical value as a set threshold). There is no particular word or set of words that indicates a claim recites a mathematical calculation. The MPEP states “There is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word "calculating" in order to be considered a mathematical calculation. For example, a step of "determining" a variable or number using mathematical methods or "performing" a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation” (see MPEP 2106.04(a)(2)(I)(C)).
Dependent claims 5, 6, and 8-14 further limit the mental process/mathematical concept recited in the independent claim but do not change their nature as a mental process/mathematical concept. Thus, claims 1-20 recite abstract ideas.
(Step 2A Prong 2)
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). Integration into a practical application is evaluated by identifying whether there are any additional elements recited in the claim and evaluating those additional elements to determine whether they integrate the exception into a practical application.
The additional element in claims 15, 19, and 20 of using a generic computer/computer environment to perform the juridical exceptions does not integrate the judicial exceptions into a practical application because this is applying a generic computer to the judicial exceptions without an improvement to computer technology (see MPEP 2106.04(d)(I)). This additional element constitutes as applying a generic computer to the judicial exceptions because the generic computer/computer environment only interacts with the judicial exceptions in a manner of being invoked as a tool to perform the recited judicial exceptions.
Thus, the additional elements do not integrate the judicial exceptions into a practical application and claims 1-20 are directed to the abstract idea.
(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 because:
The additional element in claims 15, 19, and 20 of using a generic computer/computer environment to perform juridical exceptions is conventional as shown by MPEP 2106.05(b) and MPEP 2106.05(d)(II).
Thus, the additional elements are not sufficient to amount to significantly more than the judicial exception because they are conventional.
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 and 7-20 are rejected under 35 U.S.C. 102 as being anticipated by Tam et al. (Computational and Structural Biotechnology Journal, Research Network of Computational and Structural Biotechnology, Sweden, vol. 18, 1 January 2020, Sweden, pages 4033-4039; cited in IDS received 21 November 2023).
Claim 1 is directed to method for identifying deleterious genetic mutations, wherein the method comprises the following steps: respectively converting, into corresponding density maps, obtained Ramachandran plot of wild-type proteins, obtained Ramachandran plot of benign protein variants, obtained Ramachandran plot of pathogenic protein variants and obtained Ramachandran plot of proteins to be identified
Tam et al. shows transforming obtained Ramachandran plots of wild-type proteins (native protein structure), benign protein variants, pathogenic protein variants and proteins to be identified into density maps (Tam et al. page 4034 Fig. 1, page 4035 section 2.3, page 4038 section 3.4).
respectively dividing the density map of the wild-type proteins, the density map of the benign protein variants, the density map of the pathogenic protein variants and the density map of the proteins to be identified into n or more regions in the same dividing manner,
Tam et al. shows producing a number of regions by dividing the generated density maps as each plot was transformed into a density plot with a grid dimension of 32 x 32 which produces 1024 grid point regions (Tam et al. page 4035 section 2.3).
using N cases selected from a collection of data that includes the density map of benign protein variants, the density map of the pathogenic protein variants and the density map of the wild-type proteins as a reference, calculating an average density and a standard deviation of each of the regions, wherein n > 2 and N ≥ 2
Tam et al. shows calculating the average density using cases from Benign protein variants, Likely Benign protein variants and wild type proteins and a standard deviation for each grid point was calculated (Tam et al. page 4035 section 2.3). Tam et al. shows that 8 Benign/Likely Benign protein variants and a native (wild-type) protein were used as a reference (Tam et al. page 4034 section 2.1)
comparing the density of the proteins to be identified in each of the regions with the corresponding average density of the region, if the deviation between the density of the proteins to be identified in the region and the average density of the region exceeds the corresponding standard deviation of the region, marking the region as a density deviation region of the protein to be identified
Tam et al. shows comparing the protein with a variant of unknown significance (which is interpreted as the proteins to be identified) with the “trained data” which includes average density and standard deviation for each grid point determined from the reference data of Benign, Likely Benign variants and wild type P53 (Tam et al. page 4034 Fig. 1 and page 4035 section 2.3). Tam et al. shows if the know variant was beyond the standard deviation, the grid point was marked as a density deviation region and subsequently, the percentage of the density-deviated grid points was calculated for each variant (Tam et al. page 4035 section 2.3).
and on the basis of the proportion or number of the density deviation regions of the proteins to be identified, determining a mutation of the proteins to be identified, and if the proportion or number of the density deviation regions of the proteins to be identified > a set threshold, then the mutation of the proteins to be identified is determined as a deleterious variation, and if the proportion or number of the density deviation regions of the proteins to be identified the set threshold, then the mutation of the proteins to be identified is determined as a undefined variation.
Tam et al. shows determining a mutation of the protein to be identified by comparing the number of the density-deviated grid points to a set threshold and if the density-deviated grid points exceeded the set threshold then the mutation of the proteins to be identified are determined to be deleterious and if the density-deviated grid points for the proteins to be identified were below the set threshold then the variant was determined to be an undefined variant (Tam et al. page 4035 section 2.3).
Claim 15 is directed to a device including a processor which performs the operations of method claim 1. Claim 19 is directed to electronic equipment including a processor and a memory which performs the method of claim 1. Claim 20 is directed a computer readable storage medium, wherein the computer storage medium stores a computer program that when executed by a processor performs the method of claim 1.
Tam et al. shows the method steps of claim 1 as set out above. Tam et al. further shows the process was performed at a high-performance computing cluster (Tam et al. page 4039 left col.).
Claims 2 and 16 are directed to wherein the method further comprises obtaining the Ramachandran plot of at least one protein of the wild- type proteins, the benign protein variants, the pathogenic protein variants and the proteins to be identified on the basis of molecular dynamics simulation method before converting the Ramachandran plot into the density map.
Tam et al. shows obtaining the Ramachandran plot of at least one protein from wild-type proteins, the benign protein variants, the pathogenic protein variants and the proteins to be identified based on molecular dynamics simulation method before converting the Ramachandran plot into the density map (Tam et al. page 4034 Fig. 1, page 4034 section 2.2, page 4035 section 2.3 and page 4035 section 3.3).
Claims 3 and 17 are directed to generating a Ramachandran plot from data generated at timepoints of a molecular dynamic simulation. Claims 4 and 18 are directed to generating a Ramachandran plot from data generated at timepoints during the last 1-20 ns of a molecular dynamic simulation.
Tam et al. shows generating a Ramachandran plot from data generated during the last 10 ns of the molecular dynamic simulation (Tam et al. page 4035 section 2.3).
Claim 5 is directed to wherein the dividing manner of the density map comprises: dividing the abscissa and ordinate of the density map at intervals of d, to obtain a number of regions as a product of n1 x n1, wherein d > 0 and n1 ≥ 2.
Tam et al. shows producing a number of regions by dividing the generated density maps as each plot was transformed into a density plot with a grid dimension of 32 x 32 which produces 1024 grid point regions (Tam et al. page 4035 section 2.3).
Claim 7 is directed to wherein comparing the density map of the pathogenic protein variants in each of the regions with the corresponding average density of the region, if the deviation between the density of the pathogenic protein variants in the region and the average density of the region exceeds the corresponding standard deviation of the region, marking the region as a density deviation region of the pathogenic protein variants
Tam et al. shows comparing the density map of the pathogenic protein variants in each of the regions with the corresponding average density of the region (determined by the reference data) to determine if the density deviates and marking the region as a density deviation region of the pathogenic protein variants when it exceeds the standard deviation of the reference data (Tam et al. page 4035 section 2.3).
and constructing a probability distribution on the basis of M cases of the proportions or numbers of the density deviation regions of the pathogenic protein variants, and determining the set threshold of the pathogenic variants by a goodness of fit test, wherein M ≥ 2
constructing a lognormal distribution from the percentage of the density-deviated grid points and performing an Anderson-Darling and Kolmogorov-Smirnov (KS) goodness of fit tests to set the cutoff threshold for pathogenic variants for comparing variants of unknown significance (Tam et al. page 4035 section 2.3). Tam et al. shows the use of 38 Pathogenic cases in the data for deriving the set thresholds (Tam et al. page 4034 section 2.1 and page 4035 section 2.3).
Claim 8 is directed to wherein the probability distribution is a normal distribution or Weibull distribution. Claim 9 is directed to wherein the probability distribution is a logarithmic normal distribution. Claim 10 is directed to wherein the test method comprises at least one of Anderson-Darling and KS-test. Claim 11 is directed to wherein M ≥ 30.
Tam et al. shows constructing a lognormal distribution from the percentage of the density-deviated grid points and performing an Anderson-Darling and Kolmogorov-Smirnov (KS) goodness of fit tests to set the cutoff threshold for pathogenic variants for comparing variants of unknown significance (Tam et al. page 4035 section 2.3). Tam et al. shows the use of 38 Pathogenic cases in the data for deriving the set thresholds (Tam et al. page 4034 section 2.1 and page 4035 section 2.3).
Claim 12 is directed to wherein the gene mutation is selected from any one of germline mutation and somatic mutation. Claim 13 is directed to wherein the type of the gene mutation is selected from: at least one of base substitution mutation, deletion mutation and insertion mutation. Claim 14 is directed to wherein the wild-type proteins, the benign protein variants, the pathogenic protein variants and the proteins to be identified include a P53 protein.
Tam et al. shows using germline variants, base substitution mutations, and the proteins being analyzed are P53 proteins (Tam et al. page 4034 left col. and page 4037 Table 2).
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.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Tam et al. as applied to claim 1 under 35 U.S.C. 102 above, and further in view of Yadegari et al. (Molecular biology research communications 8.4 (2019): 141).
Dependent claim 6 is directed to wherein N ≥ 30.
Tam et al. does not show using N cases as a reference wherein N ≥ 30.
Like Tam et al., Yadegari et al. shows predicting variants of unknown significance as deleterious. Yadegari et al. shows analyzing variants of unknown significance of BRCA1 and BRCA 2 and that 413 BRCA 1 variants and 683 BRCA 2 variants fell under most likely neutral (e.g., not pathogenic) (Yadegari et al. page 145).
It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have substituted the protein data used (in which the wild-type proteins, the benign/likely benign protein variant, and pathogenic protein variant models are derived from) in the analysis of variants of unknown significance of Tam et al. with the BRCA 1 protein or BRCA 2 protein of Yadegari et al. because both Tam et al. and Yadegari et al. show proteins with variants which contain deleterious mutations and would provide predictable results of predicting deleterious mutations of the BRCA 1 or BRCA 2 protein using the analysis of structural changes using density maps and the use of the BRCA 1 or BRCA 2 protein would provide more than 30 cases of non-pathogenic protein variants which may be used as a reference/”trained data” in the analysis of variants of unknown significance.
Conclusion
No claims are allowed.
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/JONATHAN EDWARD HAYES/Examiner, Art Unit 1685
