DETAILED ACTION
Notice of Pre-AIA or AIA Status
Applicant's response, filed 08/11/2025, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. Herein, "the previous Office action" refers to the Non-Final Rejection of 04/11/2025.
Status of the Claims
Claims 1-22, 25 and 27 are examined; claim 26 is canceled; claims 23-24 are withdrawn.
Priority
This application is a 371 of PCT/EP2019/084195 (12/09/2019) which claims priority from Foreign Application No. EP18211231.8 (12/10/2018) as reflected in the filing receipt mailed on 01/25/2022. The claims to the benefit of priority are acknowledged and the effective filing date of claims 1-22, 25 and 27 is 12/10/2018.
Withdrawal / Revision of Objections and/or Rejections
In view of the amendment and remarks from 08/11/2025:
The rejection of claim 20 under 35 USC § 112b is withdrawn.
The rejection of claim 26 under 35 USC § 101 is withdrawn.
The rejection of claims 1-13, 15-17, 21-22 and 25-26 under 35 U.S.C. 103(a) over Niu Dees Berman Pagadala and Osterberg is withdrawn.
The following rejections and/or objections are either maintained or newly applied for claims 1-22, 25 and 27. They constitute the complete set applied to the instant application.
Claim objections
Claim 2 recites “identifying at least one mutation by at least one step selected from the group consisting of:” which should read “(c) identifying at least one mutation by at least one step selected from the group consisting of” to follow the proper sequence of steps.
Claim 12 recites a duplicated term “the surface of the protein”.
Claim interpretation
Claims 1, 6, 9-12 and 27 recite “docking spaces” which is interpreted by one of ordinary skill in the art to comprise areas in the target structure in which the compound is more probable to bind which constitutes the drug-binding pocket.
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.
Claim 12 is 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.
Claim 12 as currently written is indefinite by reciting “wherein a docking space embraces the whole protein, the surface of the protein the surface of the protein, the surface of the protein and one or more potential binding pockets or only the surrounding area of the pharmacophore binding site”. The recitation causes the limitation to be unclear since it is not clear if the limitation applies to the surface of the protein only or the entire protein including the inner core or the surrounding area of the pharmacophore binding site. In the interest of compact prosecution, the examiner interprets the limitation applicable to the protein surface, as it refers to the region involved in binding events. However, appropriate correction is required.
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 1-22, 25 and 27 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements both individually and in combination, do not amount to significantly more than the abstract idea of “identifying one or more compounds specifically binding to a target structure of a given diseased tissue”.
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The instant claims are directed to a method (claims 1-22 and 27), and a CRM (claim 25); which falls within one of the categories of statutory subject matter. [Step 1: Yes]
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
Mathematical concepts recited in instant claims 6, 9-11 and 27, include the terms “calculating binding affinity for each compound”; “calculated hypothetical three-dimensional structure”; and “determining the binding affinity”, which involve mathematical concepts. The limitations that recite calculating/determining binding affinity or fitting a compound require algorithms in order to be performed, and thus involve math. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one having ordinary skill in the art. Thus, the recited terms corresponds to verbal equivalents of mathematical concepts (MPEP 2106.04(a)(2)). A mathematical concept need not be expressed in mathematical symbols, because "words used in a claim operating on data to solve a problem can serve the same purpose as a formula." In re Grams, 888 F.2d 835, 837 and n.1, 12 USPQ2d 1824, 1826 and n.1 (Fed. Cir. 1989).
Mental processes, defined as concepts or steps practically performed in the human mind such as steps of observations, evaluations, judgments, and opinions, include “identifying at least one mutation” (claim 2); “fitting each 3D structure of each compound with the one or more docking spaces” (claims 1 and 9), “fitting the compounds with these one or more docking spaces” (claim 10), “identifying a mutated gene” (claims 1 and 2), “identifying a compound/one or more compounds” (claims 10, 19 and 27), and “determining toxicological and pharmacologic properties of the compounds … from one or more databases” (claim 19). Under the BRI, the recited limitations are mental processes because the human mind is sufficiently capable of identifying and evaluating information using a list of set values from a transcriptome readout/database; or fitting a 3D structure using a visual representation.
Hence, the claims explicitly recite numerous elements that, individually and in combination, constitute abstract ideas. Dependent claims 3-5, 8-12, 14-18, and 20-22 recite further details about “identifying one or more compounds specifically binding to a target structure of a given diseased tissue”; not reciting any additional non-abstract elements; all reciting further aspects of the information being analyzed, the manner in which that analysis is performed. The instant claims must therefore be examined further to determine whether they integrate that abstract idea into a practical application (MPEP 2106.04(d)). [Step 2A Prong One: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Instant claims 1-2, 6-7 and 25 recite additional elements that are not abstract ideas: performing some claim steps: “providing a sample … generating cDNA from the mRNA by a polymerase chain reaction … sequencing the mRNA and/or the cDNA … hybridizing the mRNA and/or the cDNA .. and conducting a polymerase chain reaction” (claim 2); “hypothetical three-dimensional structure obtained from a database” (claim 6); and “computer-assisted manner” (claim 7), and “computer program” (claims 25). The recited limitations in these claims are interpreted to require the use of a computer. The use of a computer is broadly interpreted and not actually described in the claims or specification. Under BRI, the 3D structure generated in the instant application amounts to applying computer methods. Hence, the claims explicitly recite steps executed by computers and therefore can be described as computer functions.
Claims reciting “providing a 3D structure” (claim 1), “creating a 3D model of a protein” (claim 1); “obtaining a 3D structure” (claim 6), and “providing a sample from the diseased tissue containing mRNA” (claim 2) read on gathering data necessary to guide the “computer-assisted” method in “identifying one or more compounds specifically binding to a target structure of a given diseased tissue”. Thus, the recited additional elements, alone or in combination with the judicial exceptions, do not appear to provide an inventive concept. These additional elements appear to be insignificant extra-solution activity (MPEP 2106.05(g) because they merely serve as necessary data gathering/outputting and do not amount to a practical application.
Claims reciting “providing a sample … generating cDNA from the mRNA by a polymerase chain reaction … sequencing the mRNA and/or the cDNA … hybridizing the mRNA and/or the cDNA .. and conducting a polymerase chain reaction” (claim 2) read on detecting genetic material in a patient sample, being an insignificant extra-solution activity since this limitation merely serve to gather data that is utilized as input for the judicial exception. See MPEP 2106.05(g) and MPEP 2106.04(d).
Dependent claim 13 recites details about using the sample to gather/compare data; not amounting to a practical application.
Therefore, claims 1-2, 7, 13, and 25 relate to computers, and do not describe any specific computational steps by which the computer performs or carries out the abstract idea, nor do they provide any details of how specific structures of the computer are used to implement these functions. Dependent claim 6 recites receiving the 3D structure from a database and claim 8 recites limitations on the type compounds represented by the 3D structures. However, these limitations merely further limitation the type of data received and do not change the steps as mere data gathering activity using a generic computer, reading on receiving or transmitting data over a network, e.g., using the Internet to gather data, Symantec, 838 F.3d at 1321. Therefore, all embodiments of the invention do not include a practical application. Hence, these are mere instructions to apply the abstract idea using a computer and insignificant extra-solution activity, and therefore the claim does not integrate that abstract idea into a practical application (see MPEP 2106.04(d) § I; 2106.05(f); and 2106.05(g)). [Step 2A Prong Two: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
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 of the 35 USC § 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05).
Claims 1-2, 7, 13, 19, and 25 recite a computer or computer assisted functions, interpreted as instructions to apply the abstract idea using a computer, where the computer does not impose meaningful limitations on the judicial exceptions; which can be performed without the use of a computer (MPEP 2106.04(d) § I; and MPEP 2106.05(f)). Additionally, the instant specification recites that “model evaluation was done with the help several tools (Anolea, GROMOS, QMEAN, DFIRE etc.)” (pg. 35 lines 14-15), which reveals the use of known commercially available software that assist with docking exercise; demonstrating the well-understood, routine, conventional nature of additional elements. See MPEP 2106.07(a).III(A). Additionally, it is known in the art that the use of molecular docking to explores the behavior of compounds in the binding site of a target is well-understood, routine and conventional (Pagadala N. et. al. “Software for molecular docking: a review” Biophys. Rev. 9:91–102 (2017)). Thus, the recited additional elements, alone or in combination with the judicial exceptions, do not appear to provide an inventive concept. [Step 2B: No]
Response to applicant's remarks in regards of Claim Rejection 35 U.S.C. ~ 101
The Remarks of 08/11/2025 have been fully considered but are not persuasive for the reasons below:
Applicant asserts “The Office rejected claims 1-22 and 25-26 26 under 35 U.S.C. § 101 as being directed to an abstract idea without significantly more. Id. at 5-9. Specifically, the Office alleged that claims 1, 6, and 9- 11 include mathematical processes according to the terms "calculating binding affinity for each compound", and "determining the binding affinity". Without acquiescing the reasons for the rejection and solely to facilitate prosecution, Applicant amendments claim 1 to remove "determining" and "identifying" steps (iii), (v), and (vi), thereby removing the judicial exception from claim 1. Therefore, Applicant respectfully request that the Office reconsider and withdraw the judicial exception rejection of claim 1 and claims dependent thereon” – pg. 8 para. 3-4. The amendment for the described step does remove “determining” steps and “identifying” steps from claim 1, however claim 1 still recites other judicial exceptions such as “fitting each 3D structure of each compound with the one or more docking spaces”; and “identifying a mutated gene”. Under the BRI, the recited limitations are mental processes because the human mind is sufficiently capable of identifying and evaluating information using a list of set values from a transcriptome readout/database; or fitting a 3D structure using a visual representation. Hence, the claims explicitly recite numerous elements that, individually and in combination, constitute abstract ideas.
Furthermore, in this instant application, the amendments support existing claim rejections, in which the recited limitations are all addressed, see Claim Rejections above.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 3-13, 15-17, 21-22 25 and 27 are rejected under 35 U.S.C. 103(a) as being unpatentable over Niu B. et. al., “Protein-structure-guided discovery of functional mutations across 19 cancer types” Nature Genetics 48:827–837 (2016) – referred to in the action as Niu – as evidenced by Dees N. D. et. al. “MuSiC: identifying mutational significance in cancer genomes” Genome Res. 22:1589–1598 (2012) – referred to in the action as Dees; as evidenced by Berman H. M. et. al. “The Protein Data Bank” Nucleic Acids Res. 28:235–242 (2000) – referred to in the action as Berman – and as evidenced by Tomczak et. al. "Review The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge." Contemporary Oncology/Współczesna Onkologia 2015(1):68-77 (2015) – referred to in the action as Tomczak – in view of Pagadala N. et. al. “Software for molecular docking: a review” Biophys. Rev. 9:91–102 (2017) – referred to in the action as Pagadala – as evidenced by Osterberg F. et. al. “Automated Docking to Multiple Target Structures: Incorporation of Protein Mobility and Structural Water Heterogeneity in AutoDock” PROTEINS: Structure, Function, and Genetics 46:34-40 (2002) – referred to in the action as Osterberg.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Independent claim 1 recites “(i) identifying a mutated gene in the transcriptome of said diseased tissue and identifying at least one mutation comprised in said mutated gene; (ii) providing a three-dimensional (3D) structure of a wild-type or homolog protein expressed by a wild-type or homolog gene corresponding to the mutated gene identified in step (i); (iii) (a) adapting the amino acid sequence of the 3D structure of the wild-type or homolog protein of step (ii) to the expression product of the mutated gene identified in step (i) and defining one or more docking spaces of the obtained 3D structure of mutated protein, or (b) defining one or more docking spaces of the 3D structure of the wild-type or homolog protein of step (ii) and adapting the amino acid sequence of said one or more docking spaces to the expression product of the mutated gene identified in step (i)”. Dependent claim 3 recites “wherein the diseased tissue is a neoplasm”. Dependent claim 25 recites “computer program stored on anon-transitory computer readable medium, the computer program comprising instructions which, when the program is executed by a computer, cause the computer to carry out at least steps (iv) and (v) of the method of claim1”.
Niu teaches a computational tool that identifies mutation–mutation and mutation–drug clusters and correlates these clusters with known or potentially interacting functional variants, domains, and proteins (pg. 827 col. 2 para. 3); wherein each gene analyzed has an ID, transcript, protein ID, sequence and region of interest (col. 1 para. 3 Online Methods) to identify potential intramolecular, intermolecular, and variant–drug interactions near a drug-binding pocket in samples from 19 major cancer types (pg. 828 col. 1 para. 2); wherein annotated gene variants are aligned and mapped onto appropriate wild type Protein Database three-dimensional protein structures (pg.82 Fig 1a) (i.e.; reading on “adapting the amino acid sequence of the 3D structure of the wild-type or homolog protein of step (ii) to the expression product of the mutated gene”) with the 3D structure of the gene variant clusters (i.e.; reading on “expression product of the mutated gene”) being visualized after structural analysis of variants interactions (pg. 828 Fig. 1a); reading on the recited limitations in claims 1 and 3. Niu teaches the use of a server runs on a Dell PowerEdge M620 blade server with one 8-core Intel Xeon E-2603 1.8-GHz CPU and 128 GB of RAM; reading on the recited limitations in claim 25.
Independent claim 1 recites “a method for identifying one or more compounds specifically binding to a target structure of a given diseased tissue; (iv) providing 3D structures of a selection of compounds from a database and fitting each 3D structure of each compound with the one or more docking spaces of step (iii); and (vi) identifying one or more compounds specifically binding to the mutated protein”. Dependent claim 7 recites “wherein at least steps (ii)-(v) are conducted in a computer-assisted manner”. Dependent claim 27 recites “(vi) identifying one or more compounds specifically binding to the mutated protein”. Niu teaches a HotSpot3D computational tool using resources from several databases to contextualize input data sets including user-defined DNA variants (pg. 828 Fig. 1) to provide a three-dimensional analysis of genes and their transcripts and proteins procured from public sources (pg. 838 col. 1 para. 2 Methods); wherein hormone receptor ESR1 variants formed significant pairs with all five compounds and could potentially affect responses (pg. 836 col. 1para. 2 and Fig. 7e); reading on the recited limitation in claims 1, 7 and 27.
Independent claim 1 recites “creating a 3D model of a protein encoded by an RNA transcript in a sample obtained from a diseased tissue or fluid of a subject, wherein the sample comprises a transcriptome of at least one diseased cell”. Niu teaches a computational tool that analyzes somatic mutations from TCGA tumor samples from 19 cancer types (Cancer mutation data set and cancer types section in Online Methods - supplemental information); wherein all constructs were confirmed by sequencing (Cluster validation section in Online Methods - supplemental information); wherein the Cancer Genome Atlas (TCGA) applied high-throughput technologies based on microarrays and next-generation sequencing methods such as RNA sequencing which is defined as a high-throughput technology for transcriptome (total RNA) profiling, deriving strand information with very high precision to rapidly identify and quantify rare and common transcripts, isoforms, novel transcripts, gene fusions, and non-coding RNA (as evidenced by Tomczak pg. A69 col. 1 para. 4); wherein multi-dimensional data visualization as a component of cancer genomic data analysis (as evidenced by Tomczak pg. A71 col. 1 para. 2); reading on the recited limitations in claim 1.
Dependent claim 4 recites “wherein the mutated gene, the mutated protein, or a combination thereof is associated with the onset or progression of a neoplasm”. Dependent claim 13 recites “wherein the diseased tissue is compared with comparable healthy tissue”. Dependent claim 15 recites “wherein the comparable healthy tissue is obtained from another subject of the same species”. Dependent claim 16 recites “wherein the diseased tissue bears one or more genetic variations selected from the group consisting of one or more mutations, one or more different alleles, one or more polymorphisms, or combinations of two or more thereof, in comparison to corresponding healthy tissue”. Dependent claim 17 recites “wherein the diseased tissue bears one or more mutations associated with the disease state of the diseased tissue in comparison to corresponding healthy tissue”. Niu teaches a computational tool that analyzes somatic mutations from TCGA tumor samples from 19 cancer types (Cancer mutation data set and cancer types section in Online Methods - supplemental information); wherein all constructs were confirmed by sequencing (Cluster validation section in Online Methods - supplemental information); wherein the Cancer Genome Atlas (TCGA) is a program that provided statistically supported lists of significantly mutated genes, therapeutically targetable copy number amplifications in several genes, evidence of overlaps between DNA methylation clusters and gene expression subtypes (i.e. reading on identified mutations in comparison to corresponding healthy tissue) (as evidenced by Dees pg. 1589 col. 2 para. 2). The described teachings by Niu read on the recited limitations in claims 4,13 and 15-17.
Dependent claim 5 recites “wherein the selection of compounds used in step (iv) comprises at least five compounds. Niu teaches three-dimensional structures displaying gene variant–drug clusters interactions near the drug-binding pocket suggesting the binding of a list of cancer related compounds to gene variant regions; wherein a list of roughly 20 compounds are displayed in Fig. 7b; reading on the recited limitations in claim 5. Dependent claim 6 recites “wherein: the 3D structure of the wild-type or homolog protein of step (ii) is a crystal structure, a 3D NMR structure or a calculated hypothetical three-dimensional structure; and/or the mutation is a point mutation and the mutated protein differs from the non-mutated protein by a single amino acid moiety only and each docking space embraces the different single amino acid moiety”. Niu teaches annotated gene variants are aligned and mapped onto appropriate wild type PDB (Protein Database) three-dimensional protein structures (pg.827 and Fig 1a); wherein PDB structures are primarily obtained through techniques like X-ray crystallography and NMR spectroscopy (as evidenced by Berman pg. 235 col. 1 para. 4); reading on the recited limitations in claim 6.
Dependent claim 8 recites “wherein at least one of the compounds of which 3D structures are provided in step (iv) is characterized by one or more of the properties selected from the group consisting of: the compound has a molecular weight of not more than 1000 Da, the compound is not approved as an antineoplastic agent, the compound is has known pharmacokinetic properties, and the compound is approved for one or more pharmaceutical purposes other than antineoplastic activity.” Dependent claim 21 recites “wherein the compounds of the selection of compounds are approved for one or more pharmaceutical purposes.” Dependent claim 22 recites “wherein the compounds of the selection of compounds are approved for one or more pharmaceutical purposes other than antineoplastic activity and are not approved as antineoplastic agents”. Niu teaches three-dimensional structures displaying gene variant–drug clusters interactions near the drug-binding pocket suggesting the binding of a list of cancer related compounds to gene variant regions – such as BRAF gene and sorafenib drug (465 Da) ( pg. 834 Fig. 7c), EGFR gene and lapatinib drug (581 Da) (pg. 834 Fig. 7d), and ESR1 gene and raloxifene drug (510 Da) (Fig. 7e), wherein the mutated genes are identified as variants; reading on the recited limitations in claim 1. All compounds described have molecular weight of not more than 1000 Da and all approved for pharmaceutical purposes (pg. 834 Fig. 7a) – including purposes other than antineoplastic activity and are not approved as antineoplastic agents (i.e., antiasthmatics and antiallergics) ; reading on the recited limitations in claims 8 and 21-22.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
Regarding claim 1; Niu does not explicitly teach “the protein comprises at least one docking space for a compound”. Regarding claim 27, Niu does not explicitly teach “(v) determining the binding affinity of each compound to the one or more docking spaces”., Pagadala teaches computational tools for molecular docking methods wherein docking algorithms predict the binding mode and binding affinity of a molecule to a binding pocket and also relative to other compounds (pg. 92 col. 1 para. 2); reading on the recited limitations in claims 1 and 27.
Regarding claim 9, Niu does not explicitly teach “wherein step (v) of determining the binding affinity of each compound to the one or more docking spaces comprises:(a) generating a 3D grid box of each docking space of the mutated protein and of each compound, wherein each grid box comprises grid points defined in all three dimensions that provide pieces of information selected from the group consisting of charges, partial charges, the ability to form hydrogen bonds, the ability to form pi-pi-electron interactions, and the ability to form van-der-Waals forces; (b) fitting each 3D structure of a compound with the one or more docking spaces in a manner that the 3D structure of the compound can rotate and scans over each docking space; (c) determining the binding energy between each compound and each docking space at each grid point and calculating binding affinity for each compound at each 3D orientation with each docking space; and (d) determining the lowest binding affinity for each compound-protein interaction”. However, Pagadala teaches computational tools for molecular docking methods wherein docking algorithms: generate docking conformations in a grid-based 3D space using an fast Fourier Transform (pg. 93 col. 1 para. 2); performs a systematic rigid-body search of one molecule, carrying out both translational and rotational orientation on a second molecule (pg. 93 col. 1 para. 2); scan using the translational and rotational space of two molecules based on surface complementarity and electrostatics (pg. 93 col. 1 para. 3); and search for candidate low-energy conformations (pg. 92 col. 2 para. 3); wherein one method successfully predicted the electron transfer complex of the positively charged cytochrome c to the negative region on the cytochrome c oxidase surface (pg. 94 col. 1 para. 3); reading on the recited limitations in claim 9.
Regarding claim 10, Niu does not explicitly teach “wherein the method further comprises the following steps: defining one or more docking spaces of the structure of the wild-type or homolog protein of step (ii) each corresponding to the respective docking spaces of the structure of the mutated protein of step (iii); fitting the compounds with these one or more docking spaces; determining the lowest binding energy of each compound to these one or more docking spaces and thereby determining the binding affinity; comparing the binding affinity of each compound to the docking spaces of the mutated and of the wild-type or homolog compound; and identifying one or more compounds having a higher binding affinity to the docking space of the wild-type or homolog protein than to the corresponding docking space of the mutated protein”. However, Pagadala teaches computational tools for molecular docking methods wherein docking algorithms search for candidate low-energy conformations and predict the binding mode binding affinity of a molecule to a binding pocket and also relative to other compounds for the same target and other targets; producing a large number of docked conformations with favorable surface complementarity, followed by the reranking of the conformations using the free energy of approximation. (pg. 92 col. 2 para. 3); reading on the recited limitations in claim 10.
Regarding claim 11, Niu does not explicitly teach “wherein determining the binding affinity of each compound to the one or more docking spaces includes using Lamarckian Genetic Algorithm”. However, Pagadala teaches computational tools for molecular docking methods wherein AutoDock is taught as an open-source docking program to predict binding affinity and the orientation of the ligand when it is bound to a protein receptor or enzyme using shape and electrostatic interactions to quantify it (pg. 91 col. 2 para. 1); wherein Lamarckian Genetic Algorithm is an algorithm incorporated in the AutoDock software as evidenced by Osterberg (pg. 37 col. 1 para. 1) reading on the recited limitations in claim 11.
Regarding claim 12, Niu does not explicitly teach “wherein a docking space embraces the whole protein, the surface of the protein the surface of the protein, the surface of the protein and one or more potential binding pockets or only the surrounding area of the pharmacophore binding site”. However, Pagadala teaches computational tools for molecular docking methods wherein docking algorithms produce a large number of docked conformations with favorable surface complementarity, followed by the reranking of the conformations using the free energy of approximation. (pg. 92 col. 2 para. 3) and predict binding poses most likely to occur on the broad surface regions and then define the sites into high-affinity complex structures (pg. 99 col. 1 para. 2); reading on the recited limitations in claim 12.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 1, 3-13, 15-17, 21-22, 25 and 27; it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings by Pagadala to the computational tool that identifies mutation–mutation and mutation–drug clusters and correlates these clusters with known or potentially interacting functional variants, domains, and proteins as taught by Niu to determine the binding affinity of each compound to the one or more docking spaces and compare the binding affinity to the docking space of the wild-type or homolog protein to the corresponding docking space of the mutated protein. One of ordinary skill in the art would be motivated to apply the teachings by Pagadala to the method by Niu to use a computational tool to obtain rapid identification of small molecules against the 3D structure of the macromolecular targets available by either X-ray, NMR, or homology models (pg. 98). One of ordinary skill in the art would be able to motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for investigation of interactions between a compound and a target structure.
Claim 2 is rejected under 35 U.S.C. 103(a) as being unpatentable over Niu and Pagadala as applied to claim 1 above further in view of Jordan et. al. “Large-scale expression measurement by hybridization methods: from high-density membranes to “DNA chips”." The journal of biochemistry 124(2):251-258 (1998) – referred to in the action as Jordan.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Dependent claim 2 recites “wherein the step (i) of identifying a mutated gene and the at least one mutation comprises: (a) providing a sample from the diseased tissue containing mRNA; and (b) generating cDNA from the mRNA by a polymerase chain reaction; and identifying at least one mutation by at least one step selected from the group consisting of: sequencing the mRNA and/or the cDNA generated from the mRNA by a polymerase chain reaction; hybridizing the mRNA and/or the cDNA generated from the mRNA by a polymerase chain reaction with a chip containing a variety of single- stranded nucleotides embracing mutated and non-mutated sequences; and conducting a polymerase chain reaction with a number of primers including those specific for a particular mutation”.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
Regarding claim 2; Niu and Pagadala are silent with respect to the above limitations. However, Jordan teaches methods for large scale measurements of gene expression (pg. 251 col. 2 para. 2); wherein for expression profiling, microarrays are hybridized with probes in which cDNA copy of the mRNA mixture has been labeled by inclusion of a nucleotide derivative containing fluorochrome (pg. 255 col. 2 para. 2); wherein DNA chips are used for hybridization of a fluorescent labeled probe prepared from a normal p53 gene that yield a characteristic intensity pattern; and if one or several mutations are present, the pattern will change in a characteristic way that allows to specify the nature of the mutations and the positions in which they occur (pg. 256 col. 2 col. 2); reading on claim 2.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claim 2; it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings by Jordan to the computational tool that identifies mutation–mutation and mutation–drug clusters and correlates these clusters with known or potentially interacting functional variants, domains, and proteins as taught by Niu and Pagadala to incorporate a step for identifying a mutated gene and the at least one mutation comprises: (a) providing a sample from the diseased tissue containing mRNA; and (b) generating cDNA from the mRNA by a polymerase chain reaction; and identifying at least one mutation by at least one step selected from the group consisting of: sequencing the mRNA and/or the cDNA generated from the mRNA by a polymerase chain reaction; hybridizing the mRNA and/or the cDNA generated from the mRNA by a polymerase chain reaction with a chip containing a variety of single- stranded nucleotides embracing mutated and non-mutated sequences; and conducting a polymerase chain reaction with a number of primers including those specific for a particular mutation. One of ordinary skill in the art would be motivated to apply the teachings by Jordan to the method by Niu and Pagadala to interpret massive amount of data, correlate it with available information and extract as much biological significance as possible (pg. 258 col. 1 para. 2 Jordan). One of ordinary skill in the art would be able to motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for investigation of biological systems.
Claims 14 and 18 are rejected under 35 U.S.C. 103(a) as being unpatentable over Niu and Pagadala as applied to claims 1 and 13 above further in view of Sahin U. et al. "Human neoplasms elicit multiple specific immune responses in the autologous host." Proc. Natl. Acad. Sci. USA 92: 11810-11813 (1995) – referred to in the action as Sahin.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Dependent claim 14 recites “wherein the comparable healthy tissue is obtained from the same subject as the diseased tissue” Dependent claim 18 recites “wherein the comparison between the diseased tissue with comparable healthy tissue is comparing the specific binding of the one or more compounds to one or more target structures of a given diseased tissue with the binding of said one or more compounds to target structures which are the counterparts in healthy tissue of the one or more target structures of the given diseased tissue”.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
Regarding claims 14 and 18, Niu and Pagadala are silent with respect to the above limitations. However, Sahin teaches sequence analysis and detection of antigen specific antibodies wherein serum antibodies binding to recombinant proteins was detected to investigate specific immune response in autologous host (pg. 11810 col. 1 para. 1) , involving tumor tissue and their normal counterpart of the diseased tissue (11811 col. 1 para. 4 and Table 2); reading on the recited limitations in claims 14 and 18.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 14 and 18; it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings by Sahin to the computational tools that identifies mutation–mutation and mutation–drug clusters and correlates these clusters with known or potentially interacting functional variants and its binding affinity as taught by Niu and Pagadala to compare binding between diseased and healthy tissue from the same individual. One of ordinary skill in the art would be motivated to apply the teachings by Sahin to the method by Niu and Pagadala to arrive at additional approaches to gene therapy of human neoplasms (pg. 11813 col. 2para. 1). One of ordinary skill in the art would be able to motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for investigation of interactions between a compound and a target structure.
Claims 19-20 are rejected under 35 U.S.C. 103(a) as being unpatentable over Niu and Pagadala as applied to claim 1 above further in view of Shim J. et. al. "Recent advances in drug repositioning for the discovery of new anticancer drugs." Int. J. Biol. Sci. 10(7):654–663 (2014) – referred to in the action as Shim.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Dependent claim 19 recites “wherein said method further comprises the step (vii) of determining toxicological and pharmacologic properties of the compounds identified in step (vi) from one or more databases and identifying a compound of comparably low toxicity and high pharmacologic activity in antineoplastic treatment”. Dependent claim 20 recites “wherein said method is a method for identifying an antineoplastic agent which has antineoplastic activity against a neoplasm, wherein said antineoplastic agent is or comprises one or more compounds identified in any of steps (vi) or (vii)”.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
Regarding claims 19-20, Niu and Pagadala are silent with respect to the above limitations. However, Shim teaches a method for the discovery of new anticancer drugs (pg. 654 para. 1); with focus on toxicity analysis (pg. 656 col. 2 para. 1) and pharmacology analysis (pg. 661 Table 2); reading on the recited limitations in claims 19-20.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Regarding claims 19-20; it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings by Shim to the computational tools that identifies mutation–mutation and mutation–drug clusters and correlates these clusters with known or potentially interacting functional variants and its binding affinity as taught by Niu and Pagadala to identify an antineoplastic agent which has antineoplastic activity against the neoplasm, determining toxicological and pharmacologic properties of the compounds identified. One of ordinary skill in the art would be motivated to apply the teachings by Shim to the method by Niu and Pagadala to quickly identify clinically advanced anticancer drugs against targets of interest (pg. 661 col. para. 1). One of ordinary skill in the art would be able to motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for investigation of interactions between a compound and a target structure.
Response to applicant's remarks in regards of Claim Rejection 35 U.S.C. ~ 103
The Remarks of 08/11/2025 have been fully considered but are not persuasive for the reasons below:
Applicant asserts “The inventive contribution of the present invention resides in the specific combination of method steps and, in particular, in the ultimate identification and application of a suitable compound for the targeted treatment of a specific diseased tissue. A key distinction between the present invention and the disclosure of Niu lies in the focus of the respective approaches. As indicated, for example, in the Abstract, Niu investigates tissues from 19 cancer types broadly, rather than targeting a specifically identified diseased tissue. Moreover, Niu emphasizes the analysis of local concentrations of mutations, rather than focusing on one or more specific mutations within the transcriptome. The objective of Niu appears to be the identification of general mutation patterns and the development of broadly applicable cancer treatment compounds. In contrast, the present invention is directed toward identifying individualized treatment strategies tailored to a specific diseased tissue, which is an approach aligned with the principles of personalized medicine. Accordingly, it is not reasonable that a person skilled in the art would have considered Niu when attempting to solve the problem addressed by the present invention. Furthermore, Niu is silent with respect to the identification of actual docking sites, the fitting of compound 3D structures, and the determination of binding affinities within the transcriptome of the analyzed tissues. While the concept of binding pockets in the context of cancer is mentioned in passing, there is no suggestion or indication that such binding sites or docking spaces should be further evaluated, nor is there any disclosure of assessing the interaction between mutated proteins and candidate compounds for the purpose of identifying the most suitable compounds for a specific therapeutic application”. – pg. 8 para. 5 to pg. 9 para. 5. "One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references" (MPEP 2145 § IV). Despite the fact that Niu is silent regarding identification of docking spaces; Pagadala teachings recite the identification of binding pockets using docking software which reads on the identification of docking spaces. Thus, the argument is unpersuasive, because it analyzes the teachings of the references separately and independently, whereas the rejection is based on the combined teachings of the references. While none of the references teach all claim limitations, and the examiner does not dispute Appellant's identification of material missing from each one, all the claim limitations are taught by the combination of references, as explained previously. Furthermore, regarding the disclosure of assessing the interaction between mutated proteins and candidate compounds for the purpose of identifying the most suitable compounds for a specific therapeutic application; Niu specifically teaches a computational tool that identifies mutation–mutation and mutation–drug clusters and correlates these clusters with known or potentially interacting functional variants, domains, and proteins which reads on the argued aspect of the claimed invention. It is correct to affirm that a person skilled in the art would have considered the combined teachings by Niu and Pagadala when attempting to solve the problem addressed by the present invention because obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Applicant asserts “However, for the reasons discussed above with respect to Niu focuses on 19 cancer types and failure to disclose docking sites, fitting 3D structures of compounds, or determine binding affinities in the transcriptome, it is the Applicant's position that the claimed matter is non-obvious but inventive in the view of the prior art” – pg. 10 para. 2 and 4. There is sufficient teaching, suggestion, or motivation in the combination of arts recited in this examination to establish a rationale for obviousness; "to support the conclusion that the claimed invention is directed to obvious subject matter, either the references must expressly or impliedly suggest the claimed invention or the examiner must present a convincing line of reasoning as to why the artisan would have found the claimed invention to have been obvious in light of the teachings of the references" (Ex parte Clapp, 227 USPQ 972 at 973 (BPAI 1985)); "Office personnel may also take into account 'the inferences and creative steps that a person of ordinary skill in the art would employ' (KSR v. Teleflex Inc., 82 USPQ2d 1385 at 1396 (SC 2007))" (MPEP 2141 § 11.C); "the rationale to support a rejection under 35 U.S.C. 103 may rely on logic and sound scientific principle" (MPEP 2144.02). The prima facie case of obviousness has been established. MPEP 2141.III for “RATIONALES TO SUPPORT REJECTIONS UNDER 35 U.S.C. 103”; wherein “(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention”.
Furthermore, in this instant application, the amendments support existing claim rejections, in which the recited limitations are all addressed, see Claim Rejections above.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/F.F.L./Examiner, Art Unit 1685
/G. STEVEN VANNI/Primary patents examiner, Art Unit 1686
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