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 .
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.
Status of claim
Examined:
1-20
Independent:
1, 13, 17
Priority
As detailed on the 09/19/2023 filing receipt, this application does not claim domestic or foreign priority. The effective filing date of this application is 09/08/2023.
Drawings
The drawings filed 9/08/2023 are accepted.
Information Disclosure Statement
No Information Disclosure Statements are provided.
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.
Analysis of claims in Step 1.
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Independent claim 1 is directed to a 101 process, here a "computer-implemented method ," with process steps such as "computing…, obtaining…"
Independent claim 13 is directed to a 101 machine or manufacture, here a "system," with non-transitory elements such as "one or more processors, and a memory storing instructions."
Independent claim 17 is directed to a 101 machine or manufacture, here a non-transitory "computer-readable storage medium."
[Step 1: claims 1-20: YES]
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 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Mental processes recited include:
Claims 1, 13 and 17 recites: "computing electrostatic potentials of atoms in a protein molecule …modifying the drug molecule based on the electrostatic potentials of the atoms in the protein molecule, wherein the modifying comprises: introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule; and introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule." The limitation is an act of evaluating, analyzing, observing and judging data that could be practically performed in the human mind and/or with pen and paper (See MPEP 2106.04(a)(2) subsection III).
Claims 2 and 18 recite: “wherein the computing electrostatic potentials of atoms in the protein molecule comprises: computing an electrostatic potential for each atom based on a position of the atom within the protein molecule.”
Claims 3 and 19 recite: “wherein the computing electrostatic potentials of atoms in the protein molecule comprises: determining a Gaussian distribution surrounding each atom in the protein molecule; computing an electrostatic potential for the Gaussian distribution surrounding each atom in the protein molecule; and using the electrostatic potential for the Gaussian distribution surrounding the atom as the electrostatic potential for the atom.”
Claim 4 recites: “wherein the introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule comprises: if the absolute value of the electrostatic potential of an atom is negative, identifying a binding site in the drug molecule corresponding to the atom, and adding a functional group having an electric charge of +1 or a higher positive integer charges to the binding site of the drug molecule.”
Claim 5 recites: “wherein the introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule comprises: if the absolute value of the electrostatic potential of an atom is positive, identifying a binding site in the drug molecule corresponding to the atom, and adding a functional group having an electric charge of -1 or a higher negative integer charges to the binding site of the drug molecule.”
Claim 6 recites: “wherein the introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule comprises: identifying a region in the protein molecule that is more negatively charged based on the relative values of the electrostatic potentials of atoms in the region; and introducing one or more heteroatoms to a binding site in the drug molecule that corresponds to the region in the protein molecule.”
Claim 7 recites: “wherein a total number of charges in the drug protein stays the same after the introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule.”
Claim 10 recites: “wherein the modifying the drug molecule comprises: identifying a molecule fragment in the drug molecule that is to be modified; searching for a first node in the graph data structure that corresponds to the molecule fragment; iteratively searching for an edge associated with the first node that represents a desired modification operator; and in response to the edge being found, obtaining a second node associated with the edge as a modified version of the molecule fragment.”
Claims 14 and 20 recite: “wherein to introduce the charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule, the instructions cause the system to: if the absolute value of the electrostatic potential of an atom is negative, identify a binding site in the drug molecule corresponding to the atom, and add a functional group having an electric charge of +1 or a higher positive integer charges to the binding site of the drug molecule; and if the absolute value of the electrostatic potential of an atom is positive, identify a binding site in the drug molecule corresponding to the atom, and add a functional group having an electric charge of -1 or a higher negative integer charges to the binding site of the drug molecule.”
Claim 15 recites: “identify a region in the protein molecule that is more negatively charged based on the relative values of the electrostatic potentials of atoms in the region; and introduce one or more heteroatoms to a binding site in the drug molecule that corresponds to the region in the protein molecule.”
Mathematical concepts recited include:
Claims 1, 13 and 17 recites: "computing electrostatic potentials of atoms in a protein molecule…modifying the drug molecule based on the electrostatic potentials of the atoms in the protein molecule, wherein the modifying comprises: introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule; and introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule."
Claims 2 and 18 recite: “wherein the computing electrostatic potentials of atoms in the protein molecule comprises: computing an electrostatic potential for each atom based on a position of the atom within the protein molecule.”
Claims 3 and 19 recite: “wherein the computing electrostatic potentials of atoms in the protein molecule comprises: determining a Gaussian distribution surrounding each atom in the protein molecule; computing an electrostatic potential for the Gaussian distribution surrounding each atom in the protein molecule; and using the electrostatic potential for the Gaussian distribution surrounding the atom as the electrostatic potential for the atom.”
Claim 4 recites: “wherein the introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule comprises: if the absolute value of the electrostatic potential of an atom is negative, identifying a binding site in the drug molecule corresponding to the atom, and adding a functional group having an electric charge of +1 or a higher positive integer charges to the binding site of the drug molecule.”
Claim 5 recites: “wherein the introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule comprises: if the absolute value of the electrostatic potential of an atom is positive, identifying a binding site in the drug molecule corresponding to the atom, and adding a functional group having an electric charge of -1 or a higher negative integer charges to the binding site of the drug molecule.”
Claim 6 recites: “wherein the introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule comprises: identifying a region in the protein molecule that is more negatively charged based on the relative values of the electrostatic potentials of atoms in the region; and introducing one or more heteroatoms to a binding site in the drug molecule that corresponds to the region in the protein molecule.”
Claim 7 recites: “wherein a total number of charges in the drug protein stays the same after the introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule.”
Claims 14 and 20 recite: “wherein to introduce the charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule, the instructions cause the system to: if the absolute value of the electrostatic potential of an atom is negative, identify a binding site in the drug molecule corresponding to the atom, and add a functional group having an electric charge of +1 or a higher positive integer charges to the binding site of the drug molecule; and if the absolute value of the electrostatic potential of an atom is positive, identify a binding site in the drug molecule corresponding to the atom, and add a functional group having an electric charge of -1 or a higher negative integer charges to the binding site of the drug molecule.”
The claims as indicated above recite mental processes, because the claim elements are involved with acts of evaluating, analyzing, observing and judging data. Acts of evaluating and analyzing data could be practically performed in the human mind and/or with pen and paper because they merely require making observations, evaluations, judgments, and opinions (See MPEP 2106.04(a)(2) subsection III). Overall, under the broadest reasonable interpretation, the indicated claims above can be practically carried out in the human mind or with pen and paper as claimed, which falls under the "mental processes" grouping of abstract ideas.
The claims as indicated above are mathematical concepts and/or mathematical formulas that requires performing a series of calculations/operations. Therefore, under the broadest reasonable interpretation, the indicated claims above falls under the “mathematical concepts” grouping of abstract ideas.
As such, claims 1-20 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The above indicated judicial exceptions are not integrated into a practical application because the claims do not recite an additional elements that apply, rely on or use the judicial exception in such a manner to amount to integration into a practical application. For example, there are no limitations that reflect an improvement to technology or applies or uses the recited judicial exception in some other meaningful way. Rather, the instant claims recite additional elements that equate to mere instructions to implement an abstract idea or insignificant extra solution activity. Specifically, the instant claims recite the following additional elements:
Claim 1 recites "A computer-implemented method... obtaining a drug molecule for binding to the protein molecule…"
Claim 13 recites "A system comprising one or more processors, and a memory storing instructions that, when executed by the one or more processors… obtaining a drug molecule for binding to the protein molecule…"
Claim 17 recites "A non-transitory computer-readable medium storing a set of instructions, the set of instructions comprising one or more instructions that, when executed by one or more processors of a device… obtaining a drug molecule for binding to the protein molecule…"
Claims 8 and 16 recite “constructing a molecule fragment library from a compound database, wherein the molecule fragment library comprises structure patterns exist in the compound database; and restraining the modifying of the drug molecule based on the molecule fragment such that a modified molecule fragment is required to exist in the molecule fragment library.”
Claim 9 recites "wherein the constructing the molecule fragment library comprises: constructing the molecule fragment library as a graph data structure, wherein each node in the graph data structure represents a functional group of atoms, neighboring nodes of a given node represent permissible modified variants of the given node according to the compound library, and edges between nodes represent modification operators."
Claim 12 recites “visualizing the electrostatic potentials of atoms in the protein molecule by using point clouds surrounding the atoms, wherein: (1) radiuses of the point clouds are greater than radiuses of the atoms; and (2) point clouds corresponding to atoms with positive electrostatic potentials are visualized in a first color, and point clouds corresponding to atoms with negative electrostatic potentials are visualized in a second color.”
As indicated above, claims 1, 13 and 17 recite a computer-implemented method, a system comprising one or more processors, and a memory storing instructions, and a non-transitory computer-readable medium storing a set of instructions, which equate to generic computer components that are tools used to execute the abstract idea. The use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application or provide significantly more. (see MPEP 2106.05(f)). Claims 1, 8-9, 12-13 and 16-17, as indicated above, equate to insignificant extra solutional activities of data gathering and outputting. Claims 1, 13 and 17 recite obtaining a drug molecule, claim 8-9 and 16 recites constructing a molecule fragment library and claim 12 is outputting data for visualization. The elements of Extra-solution activity includes both pre-solution and post-solution activity. An example of pre-solution activity is a step of gathering data for use in a claimed process, e.g., a step of obtaining information about credit card transactions, which is recited as part of a claimed process of analyzing and manipulating the gathered information by a series of steps in order to detect whether the transactions were fraudulent. An example of post-solution activity is an element that is not integrated into the claim as a whole, e.g., a printer that is used to output a report of fraudulent transactions, which is recited in a claim to a computer programmed to analyze and manipulate information about credit card transactions in order to detect whether the transactions were fraudulent (See MPEP 2106.05(g)). Limitations that add insignificant extra-solution activity to the judicial exception, as discussed in MPEP § 2106.05(g) have been identified by the courts to not integrate a judicial exception into a practical application (MPEP 2106.04(d)(I)). Additionally, the listed additional elements are mere instructions to apply an exception because they recite no more than an idea of a solution or outcome and does not recite a technological solution to a technological problem. (See MPEP 2106.05(f)(1)). As such, as currently recited, the claims do not appear to recite an improvement to technology or apply or use the recited judicial exception in some other meaningful way. Therefore, claims 1-20 are directed to an abstract idea (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that equate to well-understood, routine and conventional activities, insignificant extra-solution activity or mere instructions to implement the abstract idea on a generic computer. The instant claims recite the following additional elements:
Claim 1 recites "A computer-implemented method... obtaining a drug molecule for binding to the protein molecule…"
Claim 13 recites "A system comprising one or more processors, and a memory storing instructions that, when executed by the one or more processors… obtaining a drug molecule for binding to the protein molecule…"
Claim 17 recites "A non-transitory computer-readable medium storing a set of instructions, the set of instructions comprising one or more instructions that, when executed by one or more processors of a device… obtaining a drug molecule for binding to the protein molecule…"
Claims 8 and 16 recite “constructing a molecule fragment library from a compound database, wherein the molecule fragment library comprises structure patterns exist in the compound database; and restraining the modifying of the drug molecule based on the molecule fragment such that a modified molecule fragment is required to exist in the molecule fragment library.”
Claim 9 recites "wherein the constructing the molecule fragment library comprises: constructing the molecule fragment library as a graph data structure, wherein each node in the graph data structure represents a functional group of atoms, neighboring nodes of a given node represent permissible modified variants of the given node according to the compound library, and edges between nodes represent modification operators."
Claim 12 recites “visualizing the electrostatic potentials of atoms in the protein molecule by using point clouds surrounding the atoms, wherein: (1) radiuses of the point clouds are greater than radiuses of the atoms; and (2) point clouds corresponding to atoms with positive electrostatic potentials are visualized in a first color, and point clouds corresponding to atoms with negative electrostatic potentials are visualized in a second color.”
The additional elements in the claims indicated above do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. The limitations equate to insignificant extra solutional activities. As explained by the Supreme Court, the addition of insignificant extra-solution activity does not amount to an inventive concept, particularly when the activity is well-understood or conventional. (see MPEP 2106.05(g)). Limitations that add insignificant extra-solution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea such as a step of obtaining information about credit card transactions so that the information can be analyzed by an abstract mental process, as discussed in CyberSource v. Retail Decisions, Inc., 654 F.3d 1366, 1375, 99 USPQ2d 1690, 1694 (Fed. Cir. 2011) (see MPEP § 2106.05(g)) have been identified by the courts to not to be enough to qualify as "significantly more" when recited in a claim with a judicial exception.
Furthermore, limitations that equate to mere data gathering and outputting via generic computer components, such as receiving data at a computer or outputting data via a graphic display, amount to insignificant extra-solution activity as set forth by the courts in Mayo, 566 U.S. at 79, 101 USPQ2d at 1968 and OIP Techs., Inc, v, Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015). Storing and retrieving information in memory were identified by the courts as well-understood, routine and conventional in Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93. Also, the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application or provide significantly more as identified by the courts in Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Therefore, the 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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-2, 4-8, 12-18 and 20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cons ("Electrostatic complementarity in structure-based drug design: miniperspective." Journal of Medicinal Chemistry 65.11 (2022): 7476-7488.; cited on the attached 892 form).
Regarding independent claim 1, Cons teaches computing electrostatic potentials of atoms in a protein molecule with “To improve the computation speed, atom-centered charges can be parametrized to reproduce ESP surfaces obtained from QM methods” (page 7476, col. 2, para. 2); “This use of atomic charges enables fast ESP calculation for macromolecules including proteins and DNA because the same atomic charges can be used for different species based on the predefined atom types. To model the continuum solvent with atom-centered charges, methods have been developed to rapidly solve the Poisson− Boltzmann equation and its application has been demonstrated for complex macromolecules such as microtubules and ribosomes.” (page 7477, col. 1, para. 1); Section titled Calculation of Electrostatic Potentials (page 7476) and “The calculation of the electrostatic potential is performed for each fragment separately with the program ‘cubegen’ distributed with the Gaussian 98 program package.” (page 11793, col. 2, para. 2)
Cons teaches obtaining a drug molecule for binding to the protein molecule with “Overall, this model enables the computation of highly accurate ligand and protein ESP surfaces on a time scale suitable for interactive SBDD (the calculation of a GC-DNN ESP for a typical drug-like molecule…” (page 7477, col. 2, para. 3) and “A series of selective CatS compounds had been previously reported by Roche which formed the starting point for the dual CatS/CatL inhibitors.” (page 7478, col. 2, para. 1).
Cons teaches modifying the drug molecule based on the electrostatic potentials of the atoms in the protein molecule, wherein the modifying comprises: introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule with “Hydrogen atoms in protein and ligands were added and optimized using an internally developed code base.” (Fig. 2 caption, page 7478); “To test this hypothesis, analogues of 18 with arrange of electronegativities were synthesized, installing a selection of electron-donating or electron-withdrawing substituents in the C-6 position of the indoline…” (page 7480, col. 1, para. 4).
Cons teaches introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule with “This approach also allowed the installation of a polar heterocycle into a pocket which historically required a more lipophilic group resulting in an increase in lipophilic ligand efficiency (LLE or LipE) from 2.9 to 4.4.” (page 7483, col. 2, para. 1); “To improve the electrostatic complementarity with CatL, one of the cyclopropyl linkers in 1 was exchanged for a basic azetidine group (Figure 2). This resulted in an 11-fold improvement in CatL binding affinity while only reducing the affinity for CatS by 2-fold. 2 also maintained a good selectivity window over cathepsin K (CatK). The X-ray crystal structure of 2 bound to CatL (Figure 2c) shows that the azetidine makes no direct interactions with the acidic residues, but due to the long-range nature of electrostatic interactions, the benefit is seen in the improvement in potency. Further optimization of the 5-chloropyridine based on a previously reported exploration of halogen bonding in the S3 pocket of CatL gave 3 which is a single digit nanomolar inhibitor of both CatL and CatS which maintains selectivity over CatK (Figure 3).” (page 7479, col. 1, para. 1) and “While looking to optimize the S4 pocket interactions, there was also a desire to reduce the lipophilicity of the compounds, and so the ortho-fluorophenyl in 4 was replaced with a pyridine and a range of substituents were installed in the ortho position of the terminal aromatic ring to give 5−15 (Table 1).” (page 7479, col. 2, para. 2).
Cons teaches a computer-implemented method with “The recent development of a GC-DNN model for generation of near-DFT quality ESP surfaces many orders of magnitude faster than conventional QM methods (for example, a typical drug-like molecule of molecular weight 400 could take around 30 min to calculate a DFT ESP; this calculation time can be cut to ∼0.3s using the recently developed GC-DNN model), and using routinely available computer hardware, could open ESP generation to laboratories that had historically been unable to access conventionally generated QM ESP surfaces. We hope that lowering the activation barrier to accessing ESP data will act as a catalyst for an increased uptake of the use of ESP surfaces in medicinal chemistry.” (page 7485, col. 2, para. 1).
Regarding claim 2, Cons teaches wherein the computing electrostatic potentials of atoms in the protein molecule comprises: computing an electrostatic potential for each atom based on a position of the atom within the protein molecule with “To improve the computation speed, atom-centered charges can be parametrized to reproduce ESP surfaces obtained from QM methods.” (page 7476, col. 2, para. 2) and “This use of atomic charges enables fast ESP calculation for macromolecules including proteins and DNA because the same atomic charges can be used for different species based on the predefined atom types. To model the continuum solvent with atom-centered charges, methods have been developed to rapidly solve the Poisson− Boltzmann equation and its application has been demonstrated for complex macromolecules such as microtubules and ribosomes.” (page 7477, col. 1, para. 1)
Regarding claim 4, Cons teaches wherein the introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule comprises: if the absolute value of the electrostatic potential of an atom is negative, identifying a binding site in the drug molecule corresponding to the atom, and adding a functional group having an electric charge of +1 or a higher positive integer charges to the binding site of the drug molecule with Figure 8. Figure 8’s caption states “ESP surface of XIAP superimposed on the X-ray crystal structure of XIAP-BIR3 with 18. Green dashed oval indicates the negative electrostatic surface patch. The Connolly surface of the protein is colored by electrostatic potential with a color gradient of −50 (red) to 0 (white) to 50 (blue) kcal/mol. Hydrogen atoms in protein and ligands were added and optimized as described in Figure2.”
Regarding claim 5, Cons teaches wherein the introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule comprises: if the absolute value of the electrostatic potential of an atom is positive, identifying a binding site in the drug molecule corresponding to the atom, and adding a functional group having an electric charge of -1 or a higher negative integer charges to the binding site of the drug molecule with “To test this hypothesis, analogues of 18 with arrange of electronegativities were synthesized, installing a selection of electron-donating or electron-withdrawing substituents in the C-6 position of the indoline…” (page 7480, col. 1, para. 4); In the related protein cIAP1, tyrosine 324 is replaced with a phenylalanine. This results in a reduction of the electronegative patch seen in XIAP, and when the affinities of 18−27 were measured against cIAP1(Table2), the affinities showed no correlation with the Hammett σp values (Figure9B)…” (page 7480, col. 2, para. 2) and “To further dissipate the electropositivity of the indoline ring, the ESP surface of putative azaindoline target 28 was calculated using ab initio methods and compared to the ESP surface of indoline 19 (Figure 10).” (page 7481, col.1 para. 2).
Regarding claim 6, Cons teaches wherein the introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule comprises: identifying a region in the protein molecule that is more negatively charged based on the relative values of the electrostatic potentials of atoms in the region; and introducing one or more heteroatoms to a binding site in the drug molecule that corresponds to the region in the protein molecule with “While looking to optimize the S4 pocket interactions, there was also a desire to reduce the lipophilicity of the compounds, and so the ortho-fluorophenyl in 4 was replaced with a pyridine and a range of substituents were installed in the ortho position of the terminal aromatic ring to give 5–15 (Table 1).” (page 7479, col. 2, para. 2); Table 1 (page 7480) where R includes heteroatoms and Table 2 (page 7480) where X includes heteroatoms.
Regarding claim 7, Cons teaches wherein a total number of charges in the drug protein stays the same after the introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule with Table 2 (page 7480). Table 2 depicts that compound 24 has X as CL and compound 25 has X as Br. The charges for Cl and Br are the same.
Regarding claim 8, Cons teaches constructing a molecule fragment library from a compound database, wherein the molecule fragment library comprises structure patterns exist in the compound database; and restraining the modifying of the drug molecule based on the molecule fragment such that a modified molecule fragment is required to exist in the molecule fragment library with “By use of SBDD and a small, focused library of compounds, pyrrolidine 17 was optimized to indoline 18 (Figure7).” (page 7480, col. 1, para. 2).
Regarding claim 12, Cons teaches visualizing the electrostatic potentials of atoms in the protein molecule by using point clouds surrounding the atoms, wherein: (1) radiuses of the point clouds are greater than radiuses of the atoms; and (2) point clouds corresponding to atoms with positive electrostatic potentials are visualized in a first color, and point clouds corresponding to atoms with negative electrostatic potentials are visualized in a second color with Figure 2 (page 7478) and Figure 15 (page 7484) (B) ESP surfaces of two representative examples from (A). Negative areas are colored red, and positive areas are colored blue (Figure 15 caption).
Regarding independent claim 13, Cons teaches compute electrostatic potentials of atoms in a protein molecule with “To improve the computation speed, atom-centered charges can be parametrized to reproduce ESP surfaces obtained from QM methods” (page 7476, col. 2, para. 2); “This use of atomic charges enables fast ESP calculation for macromolecules including proteins and DNA because the same atomic charges can be used for different species based on the predefined atom types. To model the continuum solvent with atom-centered charges, methods have been developed to rapidly solve the Poisson− Boltzmann equation and its application has been demonstrated for complex macromolecules such as microtubules and ribosomes.” (page 7477, col. 1, para. 1); Section titled Calculation of Electrostatic Potentials (page 7476) and “The calculation of the electrostatic potential is performed for each fragment separately with the program ‘cubegen’ distributed with the Gaussian 98 program package.” (page 11793, col. 2, para. 2)
Cons teaches obtain a drug molecule for binding to the protein molecule with “Overall, this model enables the computation of highly accurate ligand and protein ESP surfaces on a time scale suitable for interactive SBDD (the calculation of a GC-DNN ESP for a typical drug-like molecule…” (page 7477, col. 2, para. 3) and “A series of selective CatS compounds had been previously reported by Roche which formed the starting point for the dual CatS/CatL inhibitors.” (page 7478, col. 2, para. 1).
Cons teaches modify the drug molecule based on the electrostatic potentials of the atoms in the protein molecule, wherein the modifying comprises: introduce charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule with “Hydrogen atoms in protein and ligands were added and optimized using an internally developed code base.” (Fig. 2 caption, page 7478); “To test this hypothesis, analogues of 18 with arrange of electronegativities were synthesized, installing a selection of electron-donating or electron-withdrawing substituents in the C-6 position of the indoline…” (page 7480, col. 1, para. 4).
Cons teaches introduce polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule with “This approach also allowed the installation of a polar heterocycle into a pocket which historically required a more lipophilic group resulting in an increase in lipophilic ligand efficiency (LLE or LipE) from 2.9 to 4.4.” (page 7483, col. 2, para. 1); “To improve the electrostatic complementarity with CatL, one of the cyclopropyl linkers in 1 was exchanged for a basic azetidine group (Figure 2). This resulted in an 11-fold improvement in CatL binding affinity while only reducing the affinity for CatS by 2-fold. 2 also maintained a good selectivity window over cathepsin K (CatK). The X-ray crystal structure of 2 bound to CatL (Figure 2c) shows that the azetidine makes no direct interactions with the acidic residues, but due to the long-range nature of electrostatic interactions, the benefit is seen in the improvement in potency. Further optimization of the 5-chloropyridine based on a previously reported exploration of halogen bonding in the S3 pocket of CatL gave 3 which is a single digit nanomolar inhibitor of both CatL and CatS which maintains selectivity over CatK (Figure 3).” (page 7479, col. 1, para. 1) and “While looking to optimize the S4 pocket interactions, there was also a desire to reduce the lipophilicity of the compounds, and so the ortho-fluorophenyl in 4 was replaced with a pyridine and a range of substituents were installed in the ortho position of the terminal aromatic ring to give 5−15 (Table 1).” (page 7479, col. 2, para. 2).
Cons teaches a system comprising one or more processors, and a memory storing instructions that, when executed by the one or more processors with “The recent development of a GC-DNN model for generation of near-DFT quality ESP surfaces many orders of magnitude faster than conventional QM methods (for example, a typical drug-like molecule of molecular weight 400 could take around 30 min to calculate a DFT ESP; this calculation time can be cut to ∼0.3 s using the recently developed GC-DNN model), and using routinely available computer hardware, could open ESP generation to laboratories that had historically been unable to access conventionally generated QM ESP surfaces. We hope that lowering the activation barrier to accessing ESP data will act as a catalyst for an increased uptake of the use of ESP surfaces in medicinal chemistry.” (page 7485, col. 2, para. 1).
Regarding claim 14, Cons teaches wherein the introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule comprises: if the absolute value of the electrostatic potential of an atom is negative, identifying a binding site in the drug molecule corresponding to the atom, and adding a functional group having an electric charge of +1 or a higher positive integer charges to the binding site of the drug molecule with Figure 8. Figure 8’s caption states “ESP surface of XIAP superimposed on the X-ray crystal structure of XIAP-BIR3 with 18. Green dashed oval indicates the negative electrostatic surface patch. The Connolly surface of the protein is colored by electrostatic potential with a color gradient of −50 (red) to 0 (white) to 50 (blue) kcal/mol. Hydrogen atoms in protein and ligands were added and optimized as described in Figure2.”
Cons teaches wherein the introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule comprises: if the absolute value of the electrostatic potential of an atom is positive, identifying a binding site in the drug molecule corresponding to the atom, and adding a functional group having an electric charge of -1 or a higher negative integer charges to the binding site of the drug molecule with “To test this hypothesis, analogues of 18 with arrange of electronegativities were synthesized, installing a selection of electron-donating or electron-withdrawing substituents in the C-6 position of the indoline…” (page 7480, col. 1, para. 4); In the related protein cIAP1, tyrosine 324 is replaced with a phenylalanine. This results in a reduction of the electronegative patch seen in XIAP, and when the affinities of 18−27 were measured against cIAP1(Table2), the affinities showed no correlation with the Hammett σp values (Figure9B)…” (page 7480, col. 2, para. 2) and “To further dissipate the electropositivity of the indoline ring, the ESP surface of putative azaindoline target 28 was calculated using ab initio methods and compared to the ESP surface of indoline 19 (Figure 10).” (page 7481, col.1 para. 2).
Regarding claim 15, Cons teaches wherein the introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule comprises: identifying a region in the protein molecule that is more negatively charged based on the relative values of the electrostatic potentials of atoms in the region; and introducing one or more heteroatoms to a binding site in the drug molecule that corresponds to the region in the protein molecule with “While looking to optimize the S4 pocket interactions, there was also a desire to reduce the lipophilicity of the compounds, and so the ortho-fluorophenyl in 4 was replaced with a pyridine and a range of substituents were installed in the ortho position of the terminal aromatic
Regarding claim 16, Cons teaches constructing a molecule fragment library from a compound database, wherein the molecule fragment library comprises structure patterns exist in the compound database; and restraining the modifying of the drug molecule based on the molecule fragment such that a modified molecule fragment is required to exist in the molecule fragment library with “By use of SBDD and a small, focused library of compounds, pyrrolidine 17 was optimized to indoline 18 (Figure7).” (page 7480, col. 1, para. 2).
Regarding independent claim 17, Cons teaches computing electrostatic potentials of atoms in a protein molecule with “To improve the computation speed, atom-centered charges can be parametrized to reproduce ESP surfaces obtained from QM methods” (page 7476, col. 2, para. 2); “This use of atomic charges enables fast ESP calculation for macromolecules including proteins and DNA because the same atomic charges can be used for different species based on the predefined atom types. To model the continuum solvent with atom-centered charges, methods have been developed to rapidly solve the Poisson− Boltzmann equation and its application has been demonstrated for complex macromolecules such as microtubules and ribosomes.” (page 7477, col. 1, para. 1); Section titled Calculation of Electrostatic Potentials (page 7476) and “The calculation of the electrostatic potential is performed for each fragment separately with the program ‘cubegen’ distributed with the Gaussian 98 program package.” (page 11793, col. 2, para. 2)
Cons teaches obtaining a drug molecule for binding to the protein molecule with “Overall, this model enables the computation of highly accurate ligand and protein ESP surfaces on a time scale suitable for interactive SBDD (the calculation of a GC-DNN ESP for a typical drug-like molecule…” (page 7477, col. 2, para. 3) and “A series of selective CatS compounds had been previously reported by Roche which formed the starting point for the dual CatS/CatL inhibitors.” (page 7478, col. 2, para. 1).
Cons teaches modifying the drug molecule based on the electrostatic potentials of the atoms in the protein molecule, wherein the modifying comprises: introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule with “Hydrogen atoms in protein and ligands were added and optimized using an internally developed code base.” (Fig. 2 caption, page 7478); “To test this hypothesis, analogues of 18 with arrange of electronegativities were synthesized, installing a selection of electron-donating or electron-withdrawing substituents in the C-6 position of the indoline…” (page 7480, col. 1, para. 4).
Cons teaches introducing polar functional groups or heteroatoms into the drug molecule based on relative values of the electrostatic potentials of the atoms in the protein molecule with “This approach also allowed the installation of a polar heterocycle into a pocket which historically required a more lipophilic group resulting in an increase in lipophilic ligand efficiency (LLE or LipE) from 2.9 to 4.4.” (page 7483, col. 2, para. 1); “To improve the electrostatic complementarity with CatL, one of the cyclopropyl linkers in 1 was exchanged for a basic azetidine group (Figure 2). This resulted in an 11-fold improvement in CatL binding affinity while only reducing the affinity for CatS by 2-fold. 2 also maintained a good selectivity window over cathepsin K (CatK). The X-ray crystal structure of 2 bound to CatL (Figure 2c) shows that the azetidine makes no direct interactions with the acidic residues, but due to the long-range nature of electrostatic interactions, the benefit is seen in the improvement in potency. Further optimization of the 5-chloropyridine based on a previously reported exploration of halogen bonding in the S3 pocket of CatL gave 3 which is a single digit nanomolar inhibitor of both CatL and CatS which maintains selectivity over CatK (Figure 3).” (page 7479, col. 1, para. 1) and “While looking to optimize the S4 pocket interactions, there was also a desire to reduce the lipophilicity of the compounds, and so the ortho-fluorophenyl in 4 was replaced with a pyridine and a range of substituents were installed in the ortho position of the terminal aromatic ring to give 5−15 (Table 1).” (page 7479, col. 2, para. 2).
Cons teaches a non-transitory computer-readable medium storing a set of instructions, the set of instructions comprising one or more instructions that, when executed by one or more processors of a device with “The recent development of a GC-DNN model for generation of near-DFT quality ESP surfaces many orders of magnitude faster than conventional QM methods (for example, a typical drug-like molecule of molecular weight 400 could take around 30 min to calculate a DFT ESP; this calculation time can be cut to ∼0.3 s using the recently developed GC-DNN model), and using routinely available computer hardware, could open ESP generation to laboratories that had historically been unable to access conventionally generated QM ESP surfaces. We hope that lowering the activation barrier to accessing ESP data will act as a catalyst for an increased uptake of the use of ESP surfaces in medicinal chemistry.” (page 7485, col. 2, para. 1).
Regarding claim 18, Cons teaches wherein the computing electrostatic potentials of atoms in the protein molecule comprises: computing an electrostatic potential for each atom based on a position of the atom within the protein molecule with “To improve the computation speed, atom-centered charges can be parametrized to reproduce ESP surfaces obtained from QM methods.” (page 7476, col. 2, para. 2) and “This use of atomic charges enables fast ESP calculation for macromolecules including proteins and DNA because the same atomic charges can be used for different species based on the predefined atom types. To model the continuum solvent with atom-centered charges, methods have been developed to rapidly solve the Poisson− Boltzmann equation and its application has been demonstrated for complex macromolecules such as microtubules and ribosomes.” (page 7477, col. 1, para. 1).
Regarding claim 20, Cons teaches wherein the introducing charged functional groups on the drug molecule based on absolute values of the electrostatic potentials of the atoms in the protein molecule comprises: if the absolute value of the electrostatic potential of an atom is negative, identifying a binding site in the drug molecule corresponding to the atom, and adding a functional group having an electric charge of +1 or a higher positive integer charges to the binding site of the drug molecule with Figure 8. Figure 8’s caption states “ESP surface of XIAP superimposed on the X-ray crystal structure of XIAP-BIR3 with 18. Green dashed oval indicates the negative electrostatic surface patch. The Connolly surface of the protein is colored by electrostatic potential with a color gradient of −50 (red) to 0 (white) to 50 (blue) kcal/mol. Hydrogen atoms in protein and ligands were added and optimized as described in Figure2.”
Cons teaches if the absolute value of the electrostatic potential of an atom is positive, identifying a binding site in the drug molecule corresponding to the atom, and adding a functional group having an electric charge of -1 or a higher negative integer charges to the binding site of the drug molecule with “To test this hypothesis, analogues of 18 with arrange of electronegativities were synthesized, installing a selection of electron-donating or electron-withdrawing substituents in the C-6 position of the indoline…” (page 7480, col. 1, para. 4); In the related protein cIAP1, tyrosine 324 is replaced with a phenylalanine. This results in a reduction of the electronegative patch seen in XIAP, and when the affinities of 18−27 were measured against cIAP1(Table2), the affinities showed no correlation with the Hammett σp values (Figure9B)…” (page 7480, col. 2, para. 2) and “To further dissipate the electropositivity of the indoline ring, the ESP surface of putative azaindoline target 28 was calculated using ab initio methods and compared to the ESP surface of indoline 19 (Figure 10).” (page 7481, col.1 para. 2).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 3 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cons ("Electrostatic complementarity in structure-based drug design: miniperspective." Journal of Medicinal Chemistry 65.11 (2022): 7476-7488.; cited on the attached 892 form) as applied to claims 1-2, 4-8, 12-18 and 20 above, and further in view of Hazra (A super-Gaussian Poisson–Boltzmann model for electrostatic free energy calculation: smooth dielectric distribution for protein cavities and in both water and vacuum states. J. Math. Biol. 79, 631–672 (2019).; cited on the attached 892 form).
Cons is applied to claims 1-2, 4-8, 12-18 and 20 as discussed in the USC 102 claims rejections section above.
Cons does not teach determining a Gaussian distribution surrounding each atom in the protein molecule; computing an electrostatic potential for the Gaussian distribution surrounding each atom in the protein molecule; and using the electrostatic potential for the Gaussian distribution surrounding the atom as the electrostatic potential for the atom in claims 3 and 19. However, this limitation is taught by Hazra.
Regarding claims 3 and 19, Hazra teaches wherein the computing electrostatic potentials of atoms in the protein molecule comprises: determining a Gaussian distribution surrounding each atom in the protein molecule; computing an electrostatic potential for the Gaussian distribution surrounding each atom in the protein molecule; and using the electrostatic potential for the Gaussian distribution surrounding the atom as the electrostatic potential for the atom with “The density function of the super-Gaussian model defined in (11) and (12) depends on the centers and radii of all atoms.” (page 661, para. 3); “To avoid geometric singularities associated with “hard sphere” definitions of the molecular surface, ‘soft sphere’ models have been developed, where each atom is outlined by a Gaussian density distribution function. While dealing with multiple atoms, the summation of these Gaussian soft clouds forms a density map which generates Gaussian molecular surfaces at appropriate isosurfaces or level sets to approximate the VDW surface, SAS, or SES.” (page 632, para. 3); “In our opinion, physical considerations have to be taken into account, so that the super Gaussian PB model can capture as many atomic details as possible in the continuum electrostatics modeling.” (page 654, para.2) and
It would have been prima facia obvious to combine the teachings of Cons and Harza to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Cons to include determining a Gaussian distribution surrounding each atom in the protein molecule as taught by Harza to avoid geometric singularities. Furthermore, there would have been a reasonable expectation of success, since Cons and Harza teach methods that pertain to the electrostatic potential of molecules.
Claim(s) 9-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cons ("Electrostatic complementarity in structure-based drug design: miniperspective." Journal of Medicinal Chemistry 65.11 (2022): 7476-7488.; cited on the attached 892 form) ) as applied to claims 1-2, 4-8, 12-18 and 20 above, and further in view of Vangala ("pBRICS: a novel fragmentation method for explainable property prediction of drug-like small molecules." Journal of Chemical Information and Modeling 63.16 (2023): 5066-5076.; published August 16, 2023; cited on the attached 892 form).
Cons is applied to claims 1-2, 4-8, 12-18 and 20 as discussed in the USC 102 claims rejections section above.
Cons does not teach wherein the constructing the molecule fragment library comprises: constructing the molecule fragment library as a graph data structure, wherein each node in the graph data structure represents a functional group of atoms, neighboring nodes of a given node represent permissible modified variants of the given node according to the compound library, and edges between nodes represent modification operators in claim 9; wherein the modifying the drug molecule comprises: identifying a molecule fragment in the drug molecule that is to be modified; searching for a first node in the graph data structure that corresponds to the molecule fragment; iteratively searching for an edge associated with the first node that represents a desired modification operator; and in response to the edge being found, obtaining a second node associated with the edge as a modified version of the molecule fragment in claim 10 and wherein the modification operators comprise: introducing a charged functional group, a polar functional group, or a heteroatom in claim 11. However, these limitations are taught by Vangala.
Regarding claim 9, Vangala teaches wherein the constructing the molecule fragment library comprises: constructing the molecule fragment library as a graph data structure, wherein each node in the graph data structure represents a functional group of atoms, neighboring nodes of a given node represent permissible modified variants of the given node according to the compound library, and edges between nodes represent modification operators with Figure 1 (page 5066) and Figure 2 (page 5068). Figure 1 depicts a Flowchart of molecule fragmentation using the pBRICS method and Figure 2 depicts Graph construction process starting from the molecule of interest and subsequent BRICS, pBRICS fragmentation, and final fragment graph formation. The post-processing of BRICS fragments allowed the pBRICS method to further divide the molecules into smaller and chemically interesting fragments. (Figure 2 caption)
Regarding claim 10, Vangala teaches wherein the modifying the drug molecule comprises: identifying a molecule fragment in the drug molecule that is to be modified; searching for a first node in the graph data structure that corresponds to the molecule fragment; iteratively searching for an edge associated with the first node that represents a desired modification operator; and in response to the edge being found, obtaining a second node associated with the edge as a modified version of the molecule fragment with Figure 1 (page 5066). Figure 1 depicts a Flowchart of molecule fragmentation using the pBRICS method.
Regarding claim 11, Vangala teaches wherein the modification operators comprise: introducing a charged functional group, a polar functional group, or a heteroatom with “Concurrently, it is important to understand the contribution of functional groups toward these properties and modify them to obtain property optimized lead compounds.” (abstract)
It would have been prima facia obvious to combine the teachings of Cons and Vangala to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Cons to include a fragment library as taught by Vangala to better analyze functional groups and their properties. Furthermore, there would have been a reasonable expectation of success, since Cons and Vangala teach methods that pertain to analysis of molecules.
Conclusion
No claims are allowed.
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/K.K./Examiner, Art Unit 1686
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687
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