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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on 3/16/2026 has been entered and considered. Rejections and/or objections not reiterated from the previous office action mailed 12/16/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of Claims
Claims 1, 5-7, 9-10, and 13-20 pending and examined on the merits.
Claims 2-4, 8, and 11-12 cancelled.
Priority
The instant application filed on 6/14/2021 claims the benefit of priority to U.S. Provisional Patent Application No. 63/039,872 filed on 6/16/2020. Thus, the effective filing date of the claims is 6/16/2020.
The applicant is reminded that amendments to the claims and specification must comply with 35 U.S.C. § 120 and 37 C.F.R. § 1.121 to maintain priority to an earlier-filed application. Claim amendments may impact the effective filing date if new subject matter is introduced that lacks support in the originally filed disclosure. If an amendment adds limitations that were not adequately described in the parent application, the claim may no longer be entitled to the priority date of the earlier filing.
Claim Objections
Claims 1, 19, and 20 objected to because of the following informalities:
Claim 1 page 1 last line, and claim 20 page5 line 7, "to produce at least one set of simulation data; and," should read "to produce at least one set of simulation data;".
Claim 1, 19, and 20 lines 14-17, the limitation "wherein the first and second spatial resolutions are selected to obtain equivalent statistics per voxel despite a concentration of the simulated nonionic solvent molecules being higher than a concentration of the simulated ionic solvent molecules in the 3D simulation structure" should be removed because it is a duplication of lines 12-14.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1, 5-7, 9-10, and 13-20 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 19, and 20 recite "the first and second spatial resolutions are selected to obtain equivalent statistics per voxel". It is not clear what is meant by "equivalent statistics" because this could be interpreted as the statistics per voxel have statistical values that are equivalent, or simply that the set of statistics calculated per voxel (the only definition for any statistics is given in para.0033 "Continuous Statistics: As used herein, "continuous statistics" refers to the collection, analysis, interpretation, and/or presentation of numerical data that involves variables that can take an infinite set of values") are equivalent (or not) due to the select spatial resolutions. However, the instant specification suggests in para.0074-75 that the "equivalent statistics" do not mean the values of the statistics are the same, but that the same set of statistics is obtainable from the selected resolutions. To further prosecution, the limitation is interpreted as "the first and second spatial resolutions are selected to obtain an equivalent set of continuous statistics per voxel".
The claims dependent from claim 1 do not mitigate the issue and therefore are also rejected under 35 U.S.C. §112b.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 14 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 14 rejected as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends. Claim 14 recites "the first spatial resolution and the second spatial resolution are sufficient to obtain substantially continuous statistics from the set of simulation data", which does not further limit claim 1 because the "substantially continuous statistics" has already been achieved in claim 1 due to the limitation of "the first and second spatial resolutions are selected to obtain an equivalent set of continuous statistics per voxel" (as interpreted above).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 5-7, 9-10, and 13-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of a mental process, a mathematical concept, organizing human activity, or a law of nature or natural phenomenon without significantly more. 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:
Claim 1, 19, and 20: “defining, by the computer, a plurality of three-dimensional (3D) grids of voxels on at least a portion of two or more simulated target molecules solvated with simulated solvent molecules to produce a 3D simulation structure” provides for organizing information (defining grids of voxels involves sorting or structuring data) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“the first and second spatial resolutions are selected to obtain an equivalent set of continuous statistics per voxel” (as interpreted above) provides a comparison (selecting spatial resolutions to obtain equivalent statistics involves comparing statistics at various spatial resolutions) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“the second spatial resolution is selected such that a volume of a given simulated ionic solvent molecule is less than a volume of a given voxel in the second 3D grid” provides a comparison (selecting a spatial resolution that results in a volume being less than another involves comparing volumes at various spatial resolutions) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“determining, by the computer, one or more thermodynamic, dynamic, and/or structural parameters using the 3D simulation structure as part of one or more atomistic simulations” provides an evaluation (determining a set of parameters) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
“averaging the parameters over time frames of the MD simulations” provides a mathematical calculation (determining parameters by averaging them over a time frame involves mathematical calculations) that is considered a mathematical concept, which is an abstract idea.
“determining spatially resolved enthalpy contributions using pair-wise additive interactions between the simulated nonionic and ionic solvent molecules that are sampled in both the first and second spatial resolutions and attributing said contributions equally to the nonionic and ionic solvent molecules” provides a mathematical calculation (determining spatially resolved enthalpy contributions using pair-wise additive interactions involves mathematical calculations) that is considered a mathematical concept, which is an abstract idea.
“determining spatially resolved entropy contributions using vibrational density of states (VDoS) obtained from Fourier transformed fluctuations of atomic velocities in the 3D simulation structure” provides a mathematical calculation (determining spatially resolved entropy contributions using vibrational density of states involves mathematical calculations) that is considered a mathematical concept, which is an abstract idea.
“determining a difference in solvation free energies” provides a mathematical calculation (determining a difference involves mathematical calculations) that is considered a mathematical concept, which is an abstract idea.
Claim 9: “identifying one or more at least potential binding sites on one or more of the simulated target molecules from the 3D solvation free energy map” provides an evaluation (identifying a potential binding site) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 10: “determining an impact of solvation on binding affinity between the simulated target molecules from the 3D solvation free energy map” provides an evaluation (determining solvation impact on binding affinity) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 16: “determining spatially resolved enthalpy and entropy contributions from the simulated nonionic solvent molecules and from the simulated ionic solvent molecules” provides an evaluation (determining enthalpy and entropy contributions) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 17: “distinguishing interactions between the simulated target molecules and the simulated nonionic solvent molecules, interactions between the simulated target molecules and the simulated ionic solvent molecules, interactions between the simulated nonionic solvent molecules, interactions between the simulated ionic solvent molecules, and interactions between the simulated nonionic solvent molecules and the simulated ionic solvent molecules from one another” provides an evaluation (distinguishing interactions between molecules) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
These recitations are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or are mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. Additionally, while claims 19 and 20 recite performing some aspects of the analysis on “A system, comprising at least one controller that comprises, or is capable of accessing, computer readable media comprising non-transitory computer-executable instructions” and “A computer readable media comprising non-transitory computer-executable instructions”, there are no additional limitations that indicate that this requires anything other than carrying out the recited mental processes or mathematical concepts in a generic computer environment. Merely reciting that a mental process is being performed in a generic computer environment does not preclude the steps from being performed practically in the human mind or with pen and paper as claimed. If a claim limitation, under its broadest reasonable interpretation, covers performance of the limitation in the mind but for the recitation of generic computer components, then it falls within the “Mental processes” grouping of abstract ideas. As such, claims 1, 5-7, 9-10, and 13-20 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 judicial exceptions listed above are not integrated into a practical application because the claims do not recite an additional element or elements that reflects an improvement to technology. Specifically, the claims recite the following additional elements:
Claim 1, 19, and 20: “producing the 3D solvation free energy map” provides insignificant extra-solution activities (outputting data visualization is a post-solution activity involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 18: “sampling interactions between the simulated nonionic solvent molecules and the simulated ionic solvent molecules in both the first and second spatial resolutions” provides insignificant extra-solution activities (sampling interaction data a is a post-solution activity involving data gathering steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 19: “A system, comprising at least one controller that comprises, or is capable of accessing, computer readable media comprising non-transitory computer-executable instructions” provides insignificant extra-solution activities (running instructions on generic computer components) that do not serve to integrate the judicial exceptions into a practical application.
Claim 20: “A computer readable media comprising non-transitory computer-executable instructions” provides insignificant extra-solution activities (running instructions on generic computer components) that do not serve to integrate the judicial exceptions into a practical application.
The steps for visualizing and sampling data are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application because they are post-solution activities involving data gathering and manipulation steps (see MPEP 2106.04(d)(2)). Furthermore, the limitations regarding implementing program instructions do not indicate that they require anything other than mere instructions to implement the abstract idea in a generic way or in a generic computing environment. As such, this limitation equates to mere instructions to implement the abstract idea on a generic computer that the courts have stated does not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. Therefore, claims 1, 5-7, 9-10, and 13-20 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 are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application, or equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment.
As discussed above, there are no additional elements to indicate that the claimed “A system, comprising at least one controller that comprises, or is capable of accessing, computer readable media comprising non-transitory computer-executable instructions” and “A computer readable media comprising non-transitory computer-executable instructions” requires anything other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. MPEP 2106.05(f) discloses that mere instructions to apply the judicial exception cannot provide an inventive concept to the claims. Additionally, the limitations for visualizing and sampling data are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application. Furthermore, no inventive concept is claimed by these limitations as they are well-understood, routine, and conventional.
The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1, 5-7, 9-10, and 13-20 are not patent eligible.
Response to Arguments under 35 USC § 101
Applicant’s arguments filed 3/16/2026 are fully considered but they are not persuasive.
Regarding independent claims 1 and 19-20, Applicant asserts that "the claims do not recite a mathematical or mental process in the abstract" because "the claims as a whole recite a specific technological implementation that cannot practically be performed in the human mind" (Remarks 3/16/2026 page 2). Additionally, Applicant argues that the "analogy to the 'electronic post office' example in MPEP 2106/04(a)(2)(III)(C) is out of place because "that example involved routine data routing without any recited technological improvement" and that the instant invention has steps that "process millions of MD frames on a 3D grid structure in a manner that is not practically performable mentally or with pen and paper (Remarks 3/16/2026 page 2). Examiner notes again that the example explicitly mentions volume ("100s of billions of emails") as not factoring into whether or not claims may be performed by a human, mentally or with pen and paper, therefore the mere fact that the instant invention is processing millions of frames in a particular way is not grounds for patent-eligibility.
Applicant also asserts that "the claims recite 'a specific, technological implementation' that improves the function of the computer itself and the technical field of computer-based molecular modeling/simulation", and goes on to explain that "the specification expressly identifies a technical problem" that the improvements in the claims solves (Remarks 3/16/2026 pages 2-3). Examiner notes that there is no part of the claimed method that explicitly improves "the function of the computer itself and the technological field", and rather, simply restricts use to a particular environment or application ("the technical field of computer-based molecular modeling/simulation") without adding significant innovation, that does not serve to integrate the judicial exceptions into a practical application because they are post-solution activities involving a mere field of use (see MPEP 2106.04(d)(2) - Integration of a Judicial Exception Into A Practical Application; MPEP 2106.05(g) - Insignificant Extra-Solution Activity; and MPEP 2106.05(h) - Field of Use and Technological Environment). Therefore, "limitations that amount to merely indicating a field of use or technological environment in which to apply a judicial exception do not amount to significantly more than the exception itself, and cannot integrate a judicial exception into a practical application."
Finally, Applicant asserts that "MD averaging, dual-resolution cross-term sampling with equal attribution to enthalpy, VDoS entropy, and delta solvation free energy for complex vs. separate state" are additional elements that amount to significantly more than any judicial exception because they are not well-understood, routine, or conventional. Therefore "when considered as an ordered combination, these elements transform any alleged abstract idea into a patent-eligible application" (Remarks 3/16/2026 page 3). Examiner notes that the listed elements have been identified above as judicial exceptions, and are not additional elements, therefore the argument is moot.
Therefore, the rejection of claims 1, 19, and 20 under 35 USC 101 is maintained. All other claims depend from these independent claims; therefore, their rejection is likewise maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 5-7, 9-10, and 13-20 rejected under 35 U.S.C. 103 as being unpatentable over Mackerell et al. (US-20150095007) in view of Nguyen et al. (Chem. Phys. 137, 044101 (2012). doi: https://doi.org/10.1063/1.4733951) and Meier et al. (Angewandte Chemie International Edition 52.10 (2013): 2820-2834).
Regarding claims 1, 19, and 20, Mackerell teaches at least two of the simulated target molecules form a complex with one another (Para.0142 "The SSFEP protocol was applied to the computer aided design of inhibitors of the S100B-p53 protein-protein interaction.", the protein-protein interaction implies at least two target molecules forming a complex with one another).
Mackerell also teaches a plurality of grids comprising a range of spatial resolutions (Para.0078 "In one embodiment, wherein a SILCS simulation is carried out, small molecule atoms [] may be binned into a 3D grid or "FragMap". [] The size of the volume elements is not particularly limited, and may suitably range from (1 Angstrom)^3 to (10 Angstrom)^3, or any value therebetween.").
Mackerell also provides determining one or more thermodynamic, dynamic, and/or structural parameters using the 3D simulation structure as part of one or more atomistic simulations to produce at least one set of simulation data (Para.0109 " Thermodynamic Integration (TI) calculations were performed using the PERT ("Perturbation") module in CHARMM to obtain the relative hydration free energies of benzene analogues in order to check for any dependence of the results on the force field. The system setup for the alchemical transformation in solution involved the same dynamics parameters as used for the benzene-water MD simulation described above.").
Mackerell also teaches generating at least one 3D solvation free energy map from the set of simulation data, thereby analyzing solvation free energies and predicting solvent-mediated interactions between solvated molecules (Para.0008 "in combination with control simulations in the absence of the target protein allows for generation of normalized three-dimensional ("3D") probability distributions, so-called, "FragMaps" that identify the favorable locations of different functional groups on the entire protein surface. Conversion of the FragMaps to free energies, based on a Boltzmann distribution, yields Grid Free Energies (GFEs) that may be used to calculate free-energy contributions of fragments to ligand binding").
Mackerell also teaches the first and second spatial resolutions are selected to obtain an equivalent set of continuous statistics per voxel despite a concentration of the simulated nonionic solvent molecules being higher than a concentration of the simulated ionic solvent molecules in the 3D simulation structure (throughout the disclosure of Mackerell, all embodiments of the invention are concerned with solvation free energy, which would be the result for all grid sizes and sets of parameters used, including differing concentrations, and is also a continuous variable (para.0083 "In one embodiment, a binding environment is or includes a region where binding occurs between the small and large molecule, a vacuum, a solvent, water, a site on the large molecule (e.g., a protein pocket), a cluster, or any combination thereof", also see "FIG. 4. Presents data for various exemplary and comparative embodiments (a) Parent MAP kinase inhibitor ("MKI"), (b) 16 substitutions forming the congeneric series with their experimentally obtained concentration at which 50% inhibition occurs, or pIC50, converted experimental and computed .DELTA..DELTA.G values using protein restrained simulation", implies that a range of concentrations would be simulated).
Mackerell also teaches the second spatial resolution is selected such that a volume of a given simulated ionic solvent molecule is less than a volume of a given voxel in the second 3D grid, thereby permitting intra-voxel interactions among the simulated ionic solvent molecules (Mackerell discusses using an ionic solvents as well as a voxel grid size of up to 1000 cubic Angstroms (i.e. (10A)^3), which is significantly larger than most ionic solvents as evidenced by Shi et al. (Shi, R., Wang, Y. Dual Ionic and Organic Nature of Ionic Liquids. Sci Rep 6, 19644 (2016). https://doi.org/10.1038/srep19644), Page 4, Figure 3 description lists the sizes of several ionic solvents all around 5A in size), and para.0039 "The large molecule may be in a vacuum, water, single solvent, or ionic solvent").
Mackerell also teaches averaging the parameters over time frames of the MD simulations (Para.0064 "Though not required, one or more other modules may be added or used in conjunction with the MD simulation, as known in the art. Non-limiting examples include those relating to periodic boundary conditions, integrators, time steps, water and/or ligand geometries and/or bonds, electrostatic and other interactions, switching functions, energy, pressure, temperature, number of particles, n, positional restraints, weak restraints, isotropic correction, velocity reassignment, ligand rotation, descent algorithm, force constant, and the like. Any of these may be suitably applied to the system (for example, including the small molecule, large molecule, binding environment), or any of the small molecule, large molecule, binding environment, and/or modified small molecule alone or in any combination").
Mackerell does not explicitly teach: a method of analyzing solvation free energies and predicting solvent-mediated interactions between solvated molecules; defining a plurality of three-dimensional (3D) grids of voxels on at least a portion of two or more simulated target molecules solvated with simulated solvent molecules to produce a 3D simulation structure, wherein the simulated solvent molecules comprise one or more simulated nonionic solvent molecules and one or more simulated ionic solvent molecules; determining spatially resolved entropy contributions using vibrational density of states (VDoS) obtained from Fourier transformed fluctuations of atomic velocities in the 3D simulation structure; nor determining a difference in solvation free energies between a state when the two or more simulated target molecules form a complex with one another and a state when the simulated target molecules are separate from one another using the 3D solvation free energy map.
However, Nguyen teaches a method of analyzing solvation free energies and predicting solvent-mediated interactions between solvated molecules (Page 2 Abstract "GIST can also provide a well-defined estimate of the solvation free energy and therefore enables a rigorous end-states analysis of binding.").
Nguyen also teaches defining a plurality of three-dimensional (3D) grids of voxels on at least a portion of two or more simulated target molecules solvated with simulated solvent molecules to produce a 3D simulation structure, wherein the simulated solvent molecules comprise one or more simulated nonionic solvent molecules and one or more simulated ionic solvent molecules (Page 6 col 1 paragraph 3 "In GIST, the spatial integrals in the IST expressions are replaced by discrete sums over the boxes, or voxels, of a three-dimensional grid, where the quantities on the grid are computed from the stored frames of an MD simulation." and Page 7 col 1 paragraph 1 "The total solute-water interaction energy in region R is readily decomposed into a sum over voxels").
Nguyen also teaches determining a difference in solvation free energies between a state when the two or more simulated target molecules form a complex with one another and a state when the simulated target molecules are separate from one another using the 3D solvation free energy map (Page 17 col 1 paragraph D "A (initial ligand) would be used to compute a “before” estimate of the total solvation free energy via IST, Gsolv,A = Esolv,A − TSsolv,A. A second simulation of the system in state B (modified ligand) would then be used to compute an “after” estimate of the total solvation free energy Gsolv,B = Esolv,B − TSsolv,B. The change in solvation free energy for the two states is then estimated simply as GIST = Gsolv,B − Gsolv,A").
However, Meier teaches determining spatially resolved entropy contributions using vibrational density of states (VDoS) obtained from Fourier transformed fluctuations of atomic velocities in the 3D simulation structure (Page 4 col 2 section 3.1 reviews quantum effects including vibrational energy for 3D atomic models).
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Mackerell as taught by Nguyen in order to discretize IST (inhomogeneous solvation theory) onto a 3D grid around the region of interest of a target molecule (Page 2 Abstract "The displacement of perturbed water upon binding is believed to play a critical role in the thermodynamics of biomolecular recognition, but it is nontrivial to unambiguously define and answer questions about this process. We address this issue by introducing grid inhomogeneous solvation theory (GIST), which discretizes the equations of inhomogeneous solvation theory (IST) onto a three-dimensional grid situated in the region of interest around a solute molecule or complex."). One skilled in the art would have a reasonable expectation of success because the approaches of both Mackerell and Nguyen are in the field of molecular simulation.
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Mackerell as taught by Meier in order to enhance computation efficiency of an atomic model (Page 2 abstract "In multi-resolution simulation, various levels of resolution, for example, electronic, atomic, supra-atomic or supra-molecular, are combined in one model. This allows an enhancement of the computational efficiency, while maintaining sufficient detail with respect to particular degrees of freedom"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with modeling chemical interactions at an atomic scale at multiple resolutions.
Regarding claim 5, Mackerell in view of Nguyen teach the method of Claim 1, on which this claim depends. Mackerell also teaches at least two of the simulated target molecules are identical to one another and/or wherein at least two of the simulated target molecules differ from one another (Para.0142 "The SSFEP protocol was applied to the computer aided design of inhibitors of the S100B-p53 protein-protein interaction.", the protein-protein interaction implies two target molecules that may be identical or different from one another).
Regarding claim 6, Mackerell in view of Nguyen teach the method of Claim 1, on which this claim depends. Mackerell also teaches the simulated target molecules comprise a simulated biomolecule, a simulated pharmaceutical molecule, a simulated organic molecule, a simulated inorganic molecule, a portion thereof, or a combination thereof (Para.0038 "Some examples of the large molecule, which are not intended to be limiting, include nucleotide, oligonucleotide, DNA, single-stranded DNA, RNA, carbohydrate, glycolipid, protein, glycoprotein, receptor, phospholipid, ribosomal protein, antibody, F(ab) fragment, F(ab).sub.2 fragment, chimeric antibody, humanized antibody, human antibody, peptide, aptamer, complex thereof, ligand-bound complex thereof, fragment-bound complex thereof, ligand-binding domain thereof, binding site thereof, surface thereof, and combination thereof.").
Regarding claim 7, Mackerell in view of Nguyen teach the method of Claim 1, on which this claim depends. Mackerell also teaches the simulated nonionic solvent molecules comprise simulated water molecules and/or wherein the simulated ionic solvent molecules comprise simulated monoatomic ionic molecules (Para.0039 "The large molecule may be any of hydrated, dehydrated, solvated, unsolvated, denatured, or in aqueous or ionic solution. The large molecule may be in a vacuum, water, single solvent, or ionic solvent. In one embodiment the large molecule is in water or physiological solution.").
Regarding claims 9 and 10, Mackerell in view of Nguyen teach the method of Claim 1, on which these claims depend. Mackerell also teaches identifying potential binding sites on the simulated target molecules from the 3D solvation free energy map as well as determining an impact of solvation on binding affinity between the simulated target molecules from the 3D solvation free energy map (Para.0008 "in combination with control simulations in the absence of the target protein allows for generation of normalized three-dimensional ("3D") probability distributions, so-called, "FragMaps" that identify the favorable locations of different functional groups on the entire protein surface. Conversion of the FragMaps to free energies, based on a Boltzmann distribution, yields Grid Free Energies (GFEs) that may be used to calculate free-energy contributions of fragments to ligand binding.").
Regarding claims 13 and 15, Mackerell in view of Nguyen teach the method of Claim 1, on which these claims depend. Mackerell also teaches the first spatial resolution is higher than the second spatial resolution and the first spatial resolution is about 1 cubic Angstroms and/or wherein the second spatial resolution is about 125 cubic Angstroms (Para.0078 "The size of the volume elements is not particularly limited, and may suitably range from (1 Angstrom)^3 to (10 Angstrom)^3, or any value therebetween.", therefore simulations of various sizes can be run).
Regarding claim 16, Mackerell in view of Nguyen teach the method of Claim 1, on which this claim depends. Nguyen also teaches determining spatially resolved enthalpy and entropy contributions from the simulated nonionic solvent molecules and from the simulated ionic solvent molecules (Page 2 Abstract "Snapshots from explicit solvent simulations are used to estimate localized solvation entropies, energies, and free energies associated with the grid boxes, or voxels, and properly summing these thermodynamic quantities over voxels yields information about hydration thermodynamics.").
Regarding claim 17, Mackerell in view of Nguyen teach the method of Claim 1, on which this claim depends. Mackerell also teaches distinguishing interactions between the simulated target molecules and the simulated nonionic solvent molecules, interactions between the simulated target molecules and the simulated ionic solvent molecules, interactions between the simulated nonionic solvent molecules, interactions between the simulated ionic solvent molecules, and interactions between the simulated nonionic solvent molecules and the simulated ionic solvent molecules from one another (Para.0008 "An earlier approach developed in our laboratory involves MD (molecular dynamics) simulations of the target protein in an aqueous solution of organic molecules representative of fragments of more complex drug-like molecules. In that approach, so-called Site Identification by Ligand Competitive Saturation ("SILCS"), flexibility of the protein and fragments is included explicitly as is the aqueous environment allowing exhaustive MD simulations to yield an ensemble of the distribution of the fragments and of water on the protein surface." and para.0083 "In one embodiment, a binding environment is or includes a region where binding occurs between the small and large molecule, a vacuum, a solvent, water, a site on the large molecule (e.g., a protein pocket), a cluster, or any combination thereof").
Regarding claim 18, Mackerell in view of Nguyen teach the method of Claim 1, on which this claim depends. Mackerell also teaches sampling interactions between the simulated nonionic solvent molecules and the simulated ionic solvent molecules in both the first and second spatial resolutions (Para.0036 "an efficient computational protocol is presented that uses sampling of the protein-fragment conformational space obtained from molecular dynamics simulations" coupled with a range of grid sizes from para.0078 (claim 15 of instant app), it would be obvious that sampling would occur at various resolutions).
Response to Arguments under 35 USC § 103
Applicant’s arguments filed 3/16/2026 are fully considered but they are not persuasive.
Applicant asserts that "even if the references were combined, the combination does not teach or suggest the amended independent claims, and there is no motivation or reasonable expectation of success for the specific combination required" (Remarks 3/16/2026 page 4). Examiner has indicated above the specific citations within Mackerell and Nguyen in which there is a perceived deficiency. Additionally, the citation of Meier is combined in order to complete the prior art rejection of the independent claims under 35 USC 103 (specifically incorporating VDoS computation for modeling).
Therefore, the rejection of claims 1, 19, and 20 under 35 USC 103 is maintained. All other claims depend from these independent claims; therefore, their rejection is likewise maintained.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Wickstrom et al., Parameterization of an effective potential for protein–ligand binding from host–guest affinity data. J. Mol. Recognit., 29: 10–21 (2015). doi: 10.1002/jmr.2489.
Ramsey et al., Solvation thermodynamic mapping of molecular surfaces in AmberTools: GIST, Volume 37, Issue 21, August 05, 2016, Pages 2029-2037, https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcc.24417
Ebel, C. (2007). Solvent Mediated Protein–Protein Interactions. In: Schuck, P. (eds) Protein Interactions. Protein Reviews, vol 5. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-35966-3_9
Conclusion
No claims are allowed.
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/R.A.P./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686