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
The instant application is a 371 of PCT/CN2021/132568, filed 11/23/2021. The instant application does not claim domestic or foreign benefit, as reflected in the filing receipt mailed 2/27/2024. The filing date of the 371 application is the effective filing date of claims 1-20. As such, the effective filing date of claims 1-20 is 11/23/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 1/3/2024, 6/21/2024, and 12/3/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS’s have been considered by the examiner.
Specification
Examiner notes that the section of the specification for “Cross-reference to related applications” as described in MPEP § 608.01(a) is missing. Although it is not required, it is suggested to include a reference to the priority of the instant application, as a 371 of PCT/CN2021/132568 (See 37 CFR 1.78 and MPEP § 211).
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “from a Hi-C matrix”, which should be corrected to “from a High-throughput chromosome conformation capture (Hi-C) matrix”, for clarity, as this is the first recitation of the abbreviation in the claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 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.
1. Claims 15-20 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 enablement requirement. The claims contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable?. See also In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation (MPEP § 2164.06).
The specification fails to enable the if a person of ordinary skill in the art would be faced with an undue burden of experimentation when trying to implement the invention based on the disclosure. In re Wands (858 F.2d 731 at 737, 8 USPQ2d 1400 at 1404 (Fed. Cir. 1988)) sets forth a non-exclusive list of factors by which this burden of experimentation may be judged to be due or undue; factors that are germane to the instant case include the breadth of the claims, the state of the prior art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to use the invention based on the content of the disclosure.
Claim 15 recites the limitation “relating the chromatin structural characteristic to a medical condition or disease”. Claim 17 recites an analogous limitation in “wherein the chromatin structural characteristic is indicative of a medical condition or disease”. The specification (Para. [0056]) discloses that the visualized cell type atlas is used to identify the chromatin structural characteristic by distinguishing between normal and cancer cells, describing the development of cancer, or distinguishing between different types of cancer. The specification further discloses that the identification may be of a locus with a structural chromatin aberration, and that locus may be SPAG9, TOBI, and UTP18. However, the specification does not provide any indication of how, for example, the chromatin structural aberration is determined for a particular loci or how that particular loci is tied to a specific medical condition.
Claims 17 and 18 recites the limitations “administering a gene therapy vector to a subject in need thereof” and “wherein the gene therapy includes usage of transcription or translation production of at least one locus associated with the chromatin structural characteristic in target cells as a medical condition or disease target”. The specification (Para. [0057]) recites that if the chromatin structural characteristic is indicative of a disease, a gene vector therapy can be administered, which may include the usage of transcription or translation production at a particular locus. The specification broadly recites both limitations but does not provide any indication of how the gene therapy vector was determined based on the identified chromatin structural characteristic for any disease.
Claims 16 and 19 recite the limitation “wherein the medical condition or disease is selected from the group consisting of cancer, cardiovascular disease, kidney disease, kidney disease, pulmonary disease, liver disease, lymphoid disease, bone marrow disease, bone disease, and blood disorder”. Claim 20 recites an analogous limitation for cancer. The specification (Para. [0060]) discloses that the methodology is applicable to any medical condition or disease with a genetic basis, and lists the conditions indicated in the claim. The specification (Para. [0071]-[0083]) also indicates a few examples wherein the samples are from normal cells, or cancer cells (specifically, oral, colon, bladder, lung, and blood/leukemia). However, the specification does not provide support for how the methodology is applicable to the other medical conditions listed in claims 16 and 19 (e.g., at least cardiovascular disease, kidney disease, kidney disease, liver disease, lymphoid disease, bone marrow disease, or bone disease).
Regarding the relationship between the chromatin structural characteristic and a medical condition, Baxter et al. discloses a method to identify target genes at 33 breast cancer risk loci using Hi-C technology (Capture Hi-C identifies putative target genes at 33 breast cancer risk loci. Nat Commun. 9: 1028 (2018)). They were able to assign 110 putative target genes to 33 loci; 94 were protein-coding and 16 were non-coding RNAs (Pg. 8, Col. 1, Para. 1). However, they also disclose that it is difficult to evaluate their list of putative target genes, as fully understanding the mechanisms by which a given gene influences cancer risk are often complex and require many years’ work. The list of genes determined by Baxter et al, however, can be used as a first stage of the process for follow up studies, including high-throughput Hi-C analysis to functionally annotate risk loci (Pg. 9, Col. 2, Para. 3).
As described above, the instant specification (Para. [0056]) broadly recites that the claimed method can distinguish between normal and cancer cells, describe the development of cancer, or distinguish between different types of cancer. As highlighted by Baxter et al., identification of genes and loci requires significant experimentation. However, the specification does not provide an indication of how the particular loci are tied to a specific medical condition or any additional guidance on how to performed claimed function for any disease or medical condition.
Regarding the administration of a gene therapy, a review on gene therapies for cancer by Das et al. (Gene Therapies for Cancer: Strategies, Challenges and Successes. J Cell Physiol. 230(2): 259-71 (2015)), highlights that gene therapy success in the clinic requires overcoming numerous hurdles. These include non-specific expression, low-efficiency delivery, and biosafety (Abstract). Das et al. further discloses that the major reasons for failure or limited success of cancer gene therapy are not only technical, but also related to ethical, policy and financial issues. Unlike chemotherapies, gene therapies are only effective in a subset of patients with any given cancer, making each gene therapy agent an orphan drug. Moreover, failure to target metastatic cells, the major driver of cancer-associated mortality has limited the general utility of cancer gene therapy (Pg. 268, Col, 2, Para. 3). Gene therapies, therefore, require significant experimentation to make them effective and safe for a given disease.
As described above, the instant specification (Para. [0057]) broadly recites that a gene vector therapy can be administered. However, the specification provides no working examples or additional guidance on how the gene vector therapy is determined for any disease or medical condition, in order to perform the claimed invention.
Because the disclosure does not provide a description of how to correlate the chromatin structural characteristic with a particular loci and disease, because the disclosure does not provide a description of how the gene therapy vector is determined, and because gene therapy vectors for any disease or medical condition are not readily available within the teachings of the prior art, a person of ordinary skill in the art who wished to practice the invention would have to perform additional experimentation to make and use the claimed invention. Specifically, that person would have to experiment to determine the appropriate relationship between the identified chromatin structural characteristic and any medical condition as well as experiment to determine an appropriate gene vector therapy to treat any medical condition. Whether or not a gene vector therapy will be effective for any of the claimed medical conditions cannot be predicted ahead of time, only by actually creating the therapy and testing it. The vast number of correlations between an identified characteristic and any medical condition, the vast number of gene therapies that could be designed for any of the claimed medical conditions, the total absence of direction from the inventor regarding how to determine the correlation between the chromatin structural characteristic and any disease, and the total absence of direction from the inventor regarding how to determine the gene vector therapy results in that burden of experimentation being undue. The claims therefore fail to comply with the enablement requirement of 35 U.S.C. § 112(a).
2. Claims 15-20 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 the limitation “relating the chromatin structural characteristic to a medical condition or disease”. Claim 17 recites an analogous limitation in “wherein the chromatin structural characteristic is indicative of a medical condition or disease”. The specification (Para. [0056]) discloses that the visualized cell type atlas is used to identify the chromatin structural characteristic by distinguishing between normal and cancer cells, describing the development of cancer, or distinguishing between different types of cancer. Examples distinguishing between normal and cancer cells or between different types of cancer cells are shown in examples 1-5 of the specification (Para. [0072]-[0083]). However, claims 15 and 17 are directed to methods for diagnosing a medical condition and treating a medical condition, respectively. The specification does not provide any support for distinguishing between normal vs. cancer cells, or between different types of cancer cells or description that Applicant had possession of said methods to diagnose or treat the any medical condition, as claimed. Accordingly, the disclosure in not commensurate with the written description scope of the claim. Claims 16 and 18-20 are also rejected due to their dependency from claims 15 and 17.
Claim 17 recites the limitation “administering a gene therapy vector to a subject in need thereof”. The specification (Para. [0057]) recites that if the chromatin structural characteristic is indicative of a disease, a gene vector therapy can be administered. The specification broadly recites this limitation but does not provide any examples or indication that the inventor had possession of an invention to administer any and all gene therapy vectors w based on the identified chromatin structural characteristic for any disease. The specification also does not provide any examples of a gene therapy vector that was determined using the claimed method to treat a particular disease. Accordingly, the disclosure in not commensurate with the scope of the claim. Claims 18-20 are also rejected due to their dependency on claim 17.
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 15-20 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 15 and 17 recite the limitations “relating the chromatin structural characteristic to a medical condition or disease” and “wherein the chromatin structural characteristic is indicative of a medical condition or disease”, respectively. The metes and bounds of the claims are rendered indefinite due to the lack of clarity. The claims are directed to diagnosing or treating a medical condition or disease. However, it is unclear what steps or parameters would be required in order to relate the chromatin structural characteristic to the medical condition or disease. The specification discloses that the chromatin structural characteristic can be used to distinguish between normal and cancer cells, specifically with regards to identifying a locus with the chromatin aberration (see Para. [0055]-[0060]). However, it is unclear if these or other steps are required to relate the structural characteristic to the diagnosis or treatment of any disease. This rejection can be overcome by amendment of claims 15 and 17 to clarify the steps required to relate the chromatin structural characteristic to the medical condition or disease. Claims 16 and 18-20 are also rejected due to their dependency from claims 15 and 17.
Claims 16 and 19 recite the limitation “wherein the medical condition or disease is selected from the group consisting of cancer, cardiovascular disease, kidney disease, autoimmune disease, pulmonary disease, liver disease, lymphoid disease, bone marrow disease, bone disease, and blood disorder”. The metes and bounds of the claims are rendered indefinite due to the lack of clarity. It is unclear what steps would be required to diagnose (claim 16) or treat (claim 19) each condition recited in the claims. The specification (Para. [0056]) broadly recites that the chromatin structural characteristic can distinguish between normal cells or cancer cells. The specification (Para. [0060]) also broadly recites that the chromatin structural characteristic is applicable to any medical condition or disease with a genetic basis, but does not provide the steps required for diagnose or treat each of the listed conditions. This rejection can be overcome by amendment of claims 16 and 19 to clarify the steps required to relate the chromatin structural characteristic to each of the listed medical conditions. Claim 20 is also rejected due to its dependency from claim 19.
Claim 17 recites the limitation “administering a gene therapy vector to a subject in need thereof” in line 4 of the claim. The metes and bounds of the claims are rendered indefinite due to the lack of clarity. It is unclear what steps would be required after the identification of the chromatin structural characteristic to determine the appropriate gene vector therapy for administration. The specification (Para. [0057]) reiterates the claim language to administer a gene vector but is silent on the steps required to determine the appropriate gene vector therapy for any medical condition or disease. This rejection can be overcome by amendment of claim 17 to recite the steps required to relate the identified chromatin structural characteristic to the appropriate gene vector therapy. Claims 18-20 are also rejected due to their dependency from claim 17.
Claim 18 recites the limitation “wherein the gene therapy includes usage of transcription or translation production of at least one locus associated with the chromatin structural characteristic in target cells as a medical condition or disease target” in lines 1-4 of the claim. The claim recites a use without any active positive steps delimiting how this use is actually practiced. The specification (Para. [0056]) reiterates the claim language but does not provide any indication of the steps required to use the transcription or translation product. Therefore, the scope of the claim is indefinite (MPEP § 2173.05(q)).
Applicant in kindly reminded that any amendment must find adequate support in the Specification as originally filed.
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)).
Step 1:
In the instant application, claims 1-13 and 15-20 are directed towards a method and claim 14 is directed towards a manufacture, which falls into one of the categories of statutory subject matter (Step 1: YES).
Step 2A, Prong One:
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong One). The following instant claims recite limitations that equate to one or more categories of judicial exceptions:
Claims 1 and 14 recites a mathematical concept (i.e., calculation of a correlation matrix) in “performing a correlation process on the Hi-C matrix to calculate a correlation matrix”; a mathematical concept (i.e., vector calculation) in “calculating a structural characteristic vector based on the correlation matrix”; a mathematical concept (i.e., matrix calculation) in “calculating a principal component fraction matrix from the structural characteristic vector”; and a mental process (i.e., an evaluation of the matrix to determine a chromatin structural characteristic) in “identifying at least one chromatin structural characteristic in the principal component fraction matrix”.
Claim 2 recites a mental process (i.e., an observation of the type of matrix) in “wherein the Hi-C matrix is a raw-data Hi-C matrix”.
Claim 3 recites a mental process (i.e., an observation of the type of matrix) in “wherein the Hi-C matrix is a normalized Hi-C matrix”.
Claim 4 recites a mathematical concept (i.e., correlation calculation) in “wherein the correlation process is at least one process selected from the group consisting of Pearson correlation, Spearman correlation, and cosine similarity”.
Claim 5 recites a mathematical concept (i.e., quantile calculation and similarity calculation) in “wherein calculating the structural characteristic vector based on the correlation matrix includes at least one of calculating a quantile of the correlation matrix and characterizing similarity between a locus and at least one neighbor of the locus”.
Claim 6 recites a mathematical concept (i.e., quantile calculation) in “wherein calculating the structural characteristic vector based on the correlation matrix includes calculating the quantile of the correlation matrix”.
Claim 7 recites a mathematical concept (i.e., binary matrix calculation) in “wherein the correlation matrix is converted into a binary matrix”; and a mathematical concept (i.e., matrix element conversion) in “matrix elements greater than the quantile are converted to 1 or 0 and matrix elements less than the quantile are converted to the other of 1 or 0”.
Claim 8 recites a mathematical concept (i.e., similarity calculation) in “wherein calculating the structural characteristic vector based on the correlation matrix includes characterizing similarity between at least one locus and at least one neighbor of the locus”.
Claim 9 recites a mathematical concept (i.e., average similarity calculation) in “wherein, for each locus, an average similarity between neighbor loci in a window is calculated”; a mathematical concept (i.e., sub-matrix generation) in “a sub-matrix is generated from the correlation matrix based on a size of the window”; and a mathematical calculation (i.e., sub-matrix averaging) in “the sub-matrix is averaged into the structural characteristic vector having a length equal to a number of chromatin bins”.
Claim 10 recites a mathematical concept (i.e., matrix generation) in “splicing the structural characteristic vector into an input matrix with a defined shape so that each row of the input matrix is a structural eigenvector”; a mathematical concept (i.e., matrix normalization) in “normalizing the input matrix”; and a mathematical concept (i.e., dimensionality reduction) in “performing matrix decomposition and dimensionality reduction to obtain a coefficient matrix and the principal component fraction matrix”.
Claim 11 recites a mathematical concept (i.e., dimensionality reduction) in “wherein performing matrix decomposition and dimensionality reduction includes at least one selected from the group consisting of principal component analysis, non-negative matrix decomposition eigenvalue decomposition, and singular value decomposition algorithm”.
Claim 15 recites a mental process (i.e., an identification of a chromatin structural characteristic as described for claim 1 above) in “identifying the chromatin structural characteristic according to the method of claim 1”; and a mental process (i.e., evaluating a correlation with a medical condition/disease) in “relating the chromatin structural characteristic to a medical condition or disease”.
Claim 16 recites a mental process (i.e., an evaluation of the type of disease) in “wherein the medical condition or disease is selected from the group consisting of cancer, cardiovascular disease, kidney disease, autoimmune disease, pulmonary disease, liver disease, lymphoid disease, bone marrow disease, bone disease, and blood disorder”.
Claim 17 recites a mental process (i.e., an identification of a chromatin structural characteristic as described for claim 1 above) in “identifying the chromatin structural characteristic according to the method of claim 1”; and a mental process (i.e., evaluating a correlation with a medical condition/disease) in “wherein the chromatin structural characteristic is indicative of a medical condition or disease”.
Claim 19 recites a mental process (i.e., an evaluation of the type of disease) in “wherein the medical condition or disease is selected from the group consisting of cancer, cardiovascular disease, kidney disease, autoimmune disease, pulmonary disease, liver disease, lymphoid disease, bone marrow disease, bone disease, and blood disorder”.
Claim 20 recites a mental process (i.e., an evaluation of the type of disease) in “wherein the medical condition or disease is cancer”.
These recitations are similar to the concepts of collecting information, and displaying certain results of the collection and analysis is Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)), and organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships.
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification, and are determined to be directed to mental processes that in the simplest embodiments are not too complex to practically perform in the human mind. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind. 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:
Claim 14 recites “a non-transitory computer readable medium storing a program the program causing a processor to execute a method”.
Regarding the above cited limitations in claim 14 of (i) a non-transitory computer readable medium storing a program the program causing a processor to execute a method. This limitation requires only a generic computer component, which does not improve computer technology. Therefore, this limitations equates to mere instructions to implement an abstract idea on a generic computer, which the courts have established does not render an abstract idea eligible in Alice Corp. 573 U.S. at 223, 110 USPQ2d at 1983.
Additionally, none of the recited dependent claims recite additional elements which would integrate the judicial exception into a practical application. Specifically, claims 12-13 recite an extra solution activity of data visualization and claims 17-18 recite an extra solution activity of generically administering a gene therapy (equating to instructions to “apply” the recited judicial exceptions in a generic way; see MPEP § 2106.04(d)(2)). 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). Independent claim 1 does not contain any additional elements. Independent claim 14 recites the computer implementation, “a non-transitory computer readable medium storing a program the program causing a processor to execute a method’. This limitation equates to instructions to implement an abstract idea on a generic computing environment, which the courts have established does not provide an inventive concept (see MPEP § 2106.05(d) and MPEP § 2106.05(f)).
This additional element does 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1. Claims 1-5, 8, and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Dekker et al. (U.S. Patent Publication US 2013/0096009 A1; published 4/18/2013) in view of Zhang et al. (Multiscale and integrative single-cell Hi-C analysis with Higashi. Nat. Biotechnol. 40: 254-261 (2022); published 10/11/2021; cited in the IDS dated 1/3/2024).
Regarding claim 1, Dekker et al. teaches a Hi-C protocol to identify genomic loci that are spatially co-located in vivo. The interactions were defined using a correlation matrix (i.e., a method for identifying a chromatic structural characteristic from a Hi-C matrix) (Abstract and Para. [0019]). Dekker et al. further teaches that a genome-wide contact matrix (M) was constructed by dividing the genome into 1 Mb regions ('loci') and defining the matrix entry
m
i
j
to be the number of ligation products between locus i and locus j. This matrix reflects an ensemble average of the interactions present in the original sample of cells (Para. [0226]). If two loci (i.e., for example, 1 Mb regions) are nearby in space, they might share neighbors and have correlated interaction profiles. In the study of this interaction, a correlation matrix (C) was defined in which
c
i
j
is the Pearson correlation between the ith row and jth column of the normalized contact matrix (M*) (i.e., performing a correlation process on the Hi-C matrix to calculate a correlation matrix) (Para. [0230]-[0231]).
Regarding claim 2, Dekker et al. teaches an example wherein a genome-wide contact matrix (M) was constructed by dividing the genome into 1 Mb regions ('loci') and defining the matrix entry
m
i
j
to be the number of ligation products between locus i and locus j (i.e., wherein the Hi-C matrix is a raw-data Hi-C matrix) (Para. [0226]).
Regarding claim 3, Dekker et al. teaches that because sequence proximity strongly influences contact probability, a normalized contact matrix (M*) was defined by dividing each entry in the contact matrix by the genome-wide average contact probability for loci at that genomic distance. For example, a normalized matrix was generated showing many large blocks of enriched and depleted interactions generating a 'plaid' pattern (i.e., wherein the Hi-C matrix is a normalized Hi-C matrix) (Para. [0230]).
Regarding claim 4, Dekker et al. teaches that if two loci are nearby in space, they might share neighbors and have correlated interaction profiles. In the study of this interaction, a correlation matrix (C) was defined in which
c
i
j
is the Pearson correlation between the ith row and jth column of M* (i.e., wherein the correlation process is at least one process selected from the group consisting of Pearson correlation) (Para. [0231]).
Regarding claim 12, Dekker et al. teaches that the matrix can be visually represented as a heatmap, with intensity indicating contact frequency (i.e., wherein identifying the at least one chromatin structural characteristic in the principal component fraction matrix includes performing geometric visualization) (Para. [0226]).
Regarding claim 14, Dekker et al. teaches the limitation of performing a correlation processes on the Hi-C matrix to calculate a correlation matrix as described for claim 1 above.
Dekker et al. does not teach calculating a structural characteristic vector based on the correlation matrix; calculating a principal component fraction matrix from the structural characteristic vector; identifying at least one chromatin structural characteristic in the principal component fraction matrix; wherein calculating the structural characteristic vector based on the correlation matrix includes at least one of calculating a quantile of the correlation matrix and characterizing similarity between a locus and at least one neighbor of the locus; wherein calculating the structural characteristic vector based on the correlation matrix includes characterizing similarity between at least one locus and at least one neighbor of the locus; wherein the geometric visualization is a visualized cell type atlas; and a non-transitory computer readable medium storing a program for identifying a chromatin structural characteristic from a Hi-C matrix, the program causing a processor to execute the method.
Regarding claim 1, Zhang et al. teaches a method for generating node attributes from merged Hi-C contact maps. The method includes normalizing each contact map based on the total read count. The contact maps are then flattened into one-dimensional vectors and concatenated across the cell population (i.e., calculating a structural characteristic vector based on the correlation matrix). Singular value decomposition is then used to reduce the dimensions of the matrix (i.e., calculating a principal component fraction matrix from the structural characteristic vector). Subsequently, the corresponding row in the feature matrix is used as the attributes for the corresponding cell (i.e., identifying at least one chromatin structural characteristic in the principal component fraction matrix) (Methods, Pg. 1, Col. 2, "Node attribute generation in Higashi").
Regarding claims 5 and 8, Zhang et al. teaches that each non-zero entry in the single-cell contact map is modeled as a hyperedge connecting the corresponding cell and the two genomic loci of that particular chromatin interaction (i.e., wherein calculating the structural characteristic vector based on the correlation matrix includes characterizing similarity between a locus and at least one neighbor of the locus) (Pg. 254, Col. 2, Para. 3).
Regarding claim 13, Zhang et al. teaches the visualization of the Higashi embeddings of the joint modeling of both chromatin conformation and methylation of the sn-m3C-seq data. The visualization highlights several cell types (i.e., wherein the geometric visualization is a visualized cell type atlas) (Pg. 255, Fig. 1d).
Regarding claim 14, in In re Venner, 262 F.2d 91, 95, 120 USPQ 193, 194 (CCPA 1958), the court held that broadly providing an automatic or mechanical means to replace a manual activity which accomplish the same result is not sufficient to distinguish over the prior art (see also MPEP § 2144.04(III)). In the instant case, the claimed invention merely makes the process of Dekker et al. in view of Zhang et al. as computer-implemented or automatic and indeed accomplishes the same result. It is thus not sufficient to distinguish over Dekker et al. in view of Zhang et al. Therefore, the claimed invention, i.e. “A non-transitory computer readable medium storing a program for identifying a chromatin structural characteristic from a Hi-C matrix, the program causing a processor to execute the method” would have been obvious to a person of ordinary skill in the art at the time the invention was made over the process disclosed by Dekker et al.in view of Zhang et al. There would have been a reasonable expectation of success because the court held regarding software that “writing code for such software is within the skill of the art, not requiring undue experimentation, once its functions have been disclosed.” Fonar Corp., 107 F.3d at 1549, 41 USPQ2d at 1805."
Therefore, regarding claims 1-5, 8, and 12-14, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of analyzing Hi-C data of Dekker et al. with the vector and matrix analysis of Zhang et al. because the improved data enhancement in the contact maps of Zhang et al. enabled the systematic analysis of variable multiscale 3D genome features (A/B compartment scores and TAD-like domain boundaries) and their implications in gene transcription (Zhang et al., Pg. 260,Col. 2, Para. 3). One of ordinary skill in the art would be able to combine the teachings of Dekker et al. with Zhang 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 of analyzing Hi-C matrices. Therefore, regarding claims 1-5, 8, 12-14, the instant invention is prima facie obvious (MPEP § 2142).
2. Claims 6-7 and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Dekker et al. in view of Zhang et al. as applied to claims 1-5, 8, 12-14 above, and further in view of Zhou et al. (Robust single-cell Hi-C clustering by convolution- and random-walk–based imputation, Proc. Natl. Acad. Sci. U.S.A. 116(28): 14011-14018 (2019); published 6/24/2019; cited in the IDS dated 12/3/2024).
Regarding claim 9, Zhang et al. teaches the calculation of pairwise distances of cell embeddings that indicate the similarities among cells (i.e., wherein, for each locus, an average similarity between neighbor loci in a window is calculated) (Methods, Pg. 2, Col. 1, Para. 2).
Dekker et al. in view of Zhang et al., as applied to claims 1-5, 8, and 12-14 above, does not teach wherein calculating the structural characteristic vector based on the correlation matrix includes calculating the quantile of the correlation matrix; wherein the correlation matrix is converted into a binary matrix; matrix elements greater than the quantile are converted to 1 or 0 and matrix elements less than the quantile are converted to the other of 1 or 0; a sub-matrix is generated from the correlation matrix based on a size of the window; the sub-matrix is averaged into the structural characteristic vector having a length equal to a number of chromatin bins; splicing the structural characteristic vector into an input matrix with a defined shape so that each row of the input matrix is a structural eigenvector; normalizing the input matrix; performing matrix decomposition and dimensionality reduction to obtain a coefficient matrix and the principal component fraction matrix; and wherein performing matrix decomposition and dimensionality reduction includes at least one selected from the group consisting of principal component analysis, non-negative matrix decomposition eigenvalue decomposition, and singular value decomposition algorithm.
Regarding claim 6, Zhou et al. teaches a single-cell clustering algorithm for Hi-C contact matrices to identify topologically associating domain (TAD)-like structures (TLSs) (Abstract). Zhou et al. further teaches a threshold t was chosen to convert the real matrix Q into binary matrix Qb. The threshold t was set to be the 80th percentile of Q for all of the analysis (i.e., wherein calculating the structural characteristic vector based on the correlation matrix includes calculating the quantile of the correlation matrix) (Pg. 14017, Col. 1, "Embedding and Clustering").
Regarding claim 7, Zhou et al. teaches that a threshold t was chosen to convert the real matrix Q into binary matrix Qb (i.e., wherein the correlation matrix is converted into a binary matrix) (Pg. 14017, Col. 1, "Embedding and Clustering"). Though not explicitly disclosed by Zhou et al., it is well known to a person of ordinary skill in the art that the conversion of a matrix to a binary matrix is the transformation of matrix elements into 1 (greater than the threshold/quantile) or 0 (below the threshold/quantile) (i.e., matrix elements greater than the quantile are converted to 1 or 0 and matrix elements less than the quantile are converted to the other of 1 or 0).
Regarding claim 9, Zhou et al. teaches the down sampling of bulk Hi-C data. They down sampled each dataset to 500 k, 250 k, 100 k, 50 k, 25 k, 10 k, and 5 k contacts (i.e., a sub-matrix), respectively, with 1-Mbp and 200-kbp resolution contact maps (i.e., the size of the window) (i.e., a sub-matrix is generated from the correlation matrix based on a size of the window) (Pg. 14012, Col. 2, Para. 2). Zhou et al. further teaches that since the genome is linearly connected, their hypothesis is that the interaction partners of one bin may also be close to its neighboring bins. Specifically, given a window size of w, they applied a filter F of size m×m, where m=2w+1, to scan the contact matrix A of size n×n. All of the filters are set to be all-one matrices, which is equivalent to taking the average of the genomic neighbors. However, the filters could be tuned to incorporate different weights for elements during imputation. For instance, the elements located further from the imputed elements could be assigned smaller weights. The window size w was set to 1 for 1-Mbp resolution maps (i.e., the sub-matrix is averaged into the structural characteristic vector having a length equal to a number of chromatin bins) (Methods, Pg. 14016, Col. 2, "Convolution-based imputation").
Regarding claim 10, Zhou et al. teaches that the raw contact matrices of each cell were log2 transformed and reshaped to 1×n2. The matrices from m different cells were concatenated into a m×n2 matrix (i.e., splicing the structural characteristic vector into an input matrix with a defined shape so that each row of the input matrix is a structural eigenvector) (Pg. 14017, Col. 2, "PCA"). Zhou et al. further teaches that the distance-normalized matrix B of each cell was computed (i.e., normalizing the input matrix) (Pg. 14017, Col. 2, "Eigenvector"). Zhou et al. further teaches that PCA was performed on the correlation matrix of B and the PC1 was kept as features of the cell. They computed the mean CpG content of the bins with positive and negative features, respectively, and reversed the features if the negative features corresponded to higher CpG content. The features from m different cells were concatenated into a m×n matrix and PCA transformed (i.e., performing matrix decomposition and dimensionality reduction to obtain a coefficient matrix and the principal component fraction matrix) (Pg. 14017, Col. 2, "Eigenvector").
Regarding claim 11, Zhou et al. teaches that the matrix was transformed using PCA (i.e., wherein performing matrix decomposition and dimensionality reduction includes at least one selected from the group consisting of principal component analysis) (Pg. 14017, Col. 2, "Eigenvector").
Therefore, regarding claims 6-7 and 9-11, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of analyzing Hi-C data of Dekker et al. in view of Zhang et al. with the analysis of Zhou et al. because the method of Zhou et al. improves the clustering of single-cell data into constituent cell types, thereby facilitating the identification of local chromosome interaction domains. The method also aids in the visualization of chromosome contact maps for single cells (Zhou et al., Pg. 14015, Col. 2, Para. 2 and Pg. 14016, Col. 1, Para. 3). One of ordinary skill in the art would be able to combine the teachings of Dekker et al. in view of Zhang et al. with Zhou et al. with reasonable expectation of success due to the same nature of the problem to be solved, since both incorporate a method for analyzing Hi-C data. Therefore, regarding claims 6-7 and 9-11, the instant invention is prima facie obvious (MPEP § 2142).
Conclusion
No claims allowed.
It is noted that claims 15-20 as currently recited are not enabled nor do they have adequate written in the instant Specification, rendering a meaningful search of the art not possible at this moment. Insofar as prior art is not applied to claims 15-20 in the instant rejection, prior art will be re-assessed upon any amendment.
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/D.P.S./Examiner, Art Unit 1687
/Lori A. Clow/Primary Examiner, Art Unit 1687