DETAILED ACTION
Applicant’s response, filed 28 January 2026, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-27 are pending and examined herein.
Claims 1-27 are rejected.
Priority
Claims 1-27 are granted the claim to the benefit of priority to foreign application GB1904340.5 filed 28 March 2019. Thus, the effective filling date of claims 1-27 is 28 March 2019.
Drawings
The drawings received 27 September 2021 are objected to for the reasons provided below.
The drawings are objected to because:
The labels read “Figure” but should be read “Fig.”. The MPEP states “View numbers must be preceded by the abbreviation "FIG."” (MPEP 608.02(V) 37 C.F.R. 1.84(u)(1)).
The partial views of Figure 3, Figure 5, Figure 9, and Figure 12 use lower case letters but should use capital letters (e.g., Figure 3a should be Fig. 3A, Figure 3b should be Fig. 3B…). The MPEP states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter” (MPEP 608.02(V) 37 C.F.R. 1.84(u)(1)).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: “400a” (in Fig. 8), “400b” (in Fig. 8), “400c” (in Fig. 8), “400d” (in Fig. 8), and “400e” (in Fig. 8). Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The rejection on the ground of 112/b in claims 6-27 in Office action mailed 28 July 2025 is withdrawn in view of the amendment of “dividing the configurational energy by the total number of simulation cells enclosed within the supercell to define a non-electrostatic potential energy per simulation cell” received 28 January 2026.
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.
The rejection below was previously recited.
Claims 1-27 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
(Step 1)
Claims 1-27 fall under the statutory category of a process.
(Step 2A Prong 1)
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mental process”, such as procedures for evaluating, analyzing or organizing information, and forming judgement or an opinion. The instant claims further recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mathematical concept”, such as mathematical relationships and mathematical equations.
Independent claim 1 recites mental processes of “defining a cut-off radius…”, “defining a set of cell vectors to generate a simulation cell” and “defining a set of supercell vectors to generate a supercell…”.
Independent claim 1 recites mathematical concepts of “calculating, for each particle located within the supercell, non-electrostatic pair potentials…” and “summing all distinct non-electrostatic pair potentials…”.
Independent claim 27 recites mental processes of “determine possible crystal structure polymorphs of the pharmaceutical product…”, “defining a cut-off radius…”, “defining a set of cell vectors to generate a simulation cell”, “defining a set of supercell vectors to generate a supercell…”, “selecting the lowest local minimum…”, and “select crystal structure polymorphs having lowest global minima…”.
Independent claim 27 recites mathematical concepts of “calculating, for each particle located within the supercell, non-electrostatic pair potentials…”, “summing all distinct non-electrostatic pair potentials…”, “dividing the configurational energy by the total number of simulation cells enclosed within the supercell…”, and “determining global minimum of the configurational energy per simulation cell by using a basin-hopping global optimization algorithm…”.
Dependent claim 4 recites mathematical concepts of “calculating, for each particle located within a selected simulation cell, non-electrostatic pair potentials…”, “summing the distinct non-electrostatic pair potentials…”, and “multiplying the summation by the number of simulation cells inside the supercell…”. Dependent claim 6 recites a mathematical concept of “dividing the configurational energy by the total number of simulation cells enclosed within the supercell…”. Dependent claim 7 recites mathematical concepts of “calculating the non-electrostatic potential per simulation cell…” and “determining one or more crystal structures of the particles that correspond to local minima of an enthalpy per simulation cell, using a basin-hopping optimization algorithm…”. Dependent claim 11 recites a mathematical concept of “converting the multipole interactions from a Cartesian coordinate system…”. Dependent claim 12 recites a mental process of “diagrammatically representing the multipole interactions as a series of nodes and spokes radiating from the nodes…”. Dependent claim 13 recites a mental process of “conjoining spokes of interacting multipoles of particles…”. Dependent claim 15 recites a mental process of “for each node, braiding the spokes to transform each spoke…”. Dependent claim 16 recites a mental process of “braiding the spoked connections between nodes on a piece by pieces basis…”. Dependent claim 19 recites mathematical processes of “obtaining a local minimum of H(X) with coordinate X by employing a local optimization algorithm”, “generating a random displacement vector ΔX…”, “calculating a transformed enthalpy Hmin (Xtrail) per simulation cell by employing the local optimization algorithm on H(Xtrail)” and repeating steps. Dependent claim 19 recites mental processes of “accepting Xtrail if Xtrail produces separation between any two particles inside the simulation cell greater than or equal to a set minimum distance rmin…”, “setting H = Hmin and X = Xtrail if the standard Metropolis Monte Carlo criterion is met…”, and repeating steps. Dependent claim 23 recites a mathematical concept of “calculating a transition probability…”.
The claims recite steps of analyzing/ evaluating data, making judgments, and organizing data of “defining a cut-off radius…”, “defining a set of cell vectors to generate a simulation cell”, “defining a set of supercell vectors to generate a supercell…”, “diagrammatically representing the multipole interactions as a series of nodes and spokes radiating from the nodes…”, “conjoining spokes of interacting multipoles of particles…”, “for each node, braiding the spokes to transform each spoke…”, “accepting Xtrail if Xtrail produces separation between any two particles inside the simulation cell greater than or equal to a set minimum distance rmin…”, “setting H = Hmin and X = Xtrail if the standard Metropolis Monte Carlo criterion is met…”, “determine possible crystal structure polymorphs of the pharmaceutical product…”, “selecting the lowest local minimum…”, and “select crystal structure polymorphs having lowest global minima…”. The human mind is capable of analyzing/ evaluating data, making judgments, and organizing data. The claims recite mathematical concepts of “calculating, for each particle located within the supercell, non-electrostatic pair potentials…” , “summing all distinct non-electrostatic pair potentials…”, “calculating, for each particle located within a selected simulation cell, non-electrostatic pair potentials…”, “summing the distinct non-electrostatic pair potentials…”, and “multiplying the summation by the number of simulation cells inside the supercell…”, “dividing the configurational energy by the total number of…”, “calculating the non-electrostatic potential per simulation cell…” and “determining local minima of an enthalpy per simulation cell, using a basin-hopping optimization algorithm…”, “converting the multipole interactions from a Cartesian coordinate system…”, “obtaining a local minimum of H(X) with coordinate X by employing a local optimization algorithm”, “generating a random displacement vector ΔX…”, “calculating a transformed enthalpy Hmin (Xtrail) per simulation cell by employing the local optimization algorithm on H(Xtrail)”, and “calculating a transition probability…” because these all fall under mathematical calculations. Dependent claims 2, 3, 5, 8-10, 14, 17, 18, 20-22, 24-26 further limit the mental process/mathematical concept recited in the independent claim but do not change their nature as a mental process/mathematical concept.
(Step 2A Prong 2)
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). Integration into a practical application is evaluated by identifying whether there are any additional elements recited in the claim and evaluating those additional elements to determine whether they integrate the exception into a practical application.
The additional element in claims 1 and 27 of a generic computer to perform judicial exceptions does not integrate the judicial exceptions into a practical application because this is simply applying the judicial exceptions to a generic computer without an improvement to computer technology. The additional element (i.e. the computer) interacts with the judicial exceptions in a manner in which the computer is used as a tool to perform the judicial exceptions.
Thus, the additional elements do not integrate the judicial exceptions into a practical application and claims 1-27 are directed to the abstract idea.
(Step 2B)
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because:
The additional element in claims 1 and 27 of a generic computer to perform judicial exceptions is conventional as shown in MPEP 2106.05(b) and MPEP2106.05(d)(II).
Thus, the additional elements are not sufficient to amount to significantly more than the judicial exception because they are conventional.
Response to Arguments
Applicant's arguments filed 28 January 2026 have been fully considered but they are not persuasive.
Argument 1:
Applicant argues that it would not be possible to implement in the human mind method set out in the claims of the current application. The sheer amount of data required to perform the method precludes even the most skilled person from performing the invention using “pen and paper” (Reply p. 10).
This argument has been fully considered but found to be not persuasive. It is noted the entire method was not identified as reciting a mental process, rather particular limitations are identified as being mental processes (see Step 2A Prong 1 analysis above). As described above the human mind is capable of defining a cut-off radius, defining a set of cell vectors, defining a set of supercell vectors, determine possible crystal structure polymorphs of the pharmaceutical product, accepting Xtrail, setting H = Hmin and X = Xtrail, selecting the lowest local minimum, and select crystal structure polymorphs having lowest global minima because these steps encompass making judgments in the abstract analysis by defining/setting parameters and accepting/selecting/determining based on criteria. Further, the human mind is capable of diagrammatically representing the multipole interactions, conjoining spokes of interacting multipoles of particles, and braiding the spokes to transform each spoke because these steps encompass analyzing abstract data by way of representing the data as a diagram. It is noted that the limitations identified as reciting mathematical concepts fall under a separate abstract grouping (mathematical concepts) and the determination of whether a claim recites a mathematical concept does not include the determination of whether the limitation can be practically performed in the human mind.
Argument 2:
Applicant argues the method set out in claims 1 and 27 certainly recites the use of some mathematical concepts, such as “calculating”, but these mathematical methods are used to determine the crystal structure of the system as recited in the claims. The claims therefore fail to recite a judicial exception but involve the use of a mathematical method (Reply p. 10).
This argument has been fully considered but found to be not persuasive. The MPEP states “A claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the "mathematical concepts" grouping. A mathematical calculation is a mathematical operation (such as multiplication) or an act of calculating using mathematical methods to determine a variable or number” (see MPEP 2106.04(a)(2)(I)(C)). The instant claims recite mathematical calculations of mathematical operations (e.g., summing, multiplying, and dividing numerical values) and mathematical methods for determining variables (e.g., calculating non-electrostatic pair potentials). Thus, the claims recite mathematical concepts. It is noted that the use of mathematical calculations to calculate certain variables (such as in a process to determine the crystal structures of the system) does not preclude the claim from reciting mathematical calculations. It is further noted that the memorandum focuses on distinguishing limitations of a claim which involve a broad array of techniques and/or activities which may involve or rely on mathematical concepts but the limitation itself does not recite a mathematical calculation/mathematical operation. In the instant case, the claims recite calculating variable and performing mathematical operations as steps of the claim which goes beyond involving or relying on mathematical concepts because the step itself is the performance of a mathematical calculation.
Argument 3:
Applicant argues that the claims provide a specific, technical improvement to computer aided molecular modeling (Reply p. 10). Applicant argues the method recited in the claims does not merely “calculate” or “evaluate” data in the abstract. Instead, the recited method solves a technical problem in the field of crystal structure prediction: the high computational cost of global optimization for crystalline states (Reply p. 11).
This argument has been fully considered but found to be not persuasive. The MPEP states at 2106.05(a) “It is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements… In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception”. The determination of an improvement to technology has two steps, the identification of additional elements (which define the technology) and the evaluation of the additional elements to determine if the improvement is provided by the additional elements either by the additional elements themselves or the additional element in combination with the judicial exception (i.e. the interaction between the judicial exceptions and the additional elements). In the instant case, the argued improvement in the field of crystal structure prediction is interpreted as being provided by the judicial exceptions alone (i.e., the steps which fall under abstract ideas identified above). Although the claimed method addresses high computation costs in crystal structure prediction, this improvement is provided by the abstract idea itself (i.e., the particular abstract ideas performed).
Argument 4:
Applicant argues the method uses a specific supercell- modified basin-hopping approach to define energy “per simulation cell” and enables a more efficient exploration of the potential energy surface than generic optimization techniques and goes beyond the assertion that the additional element is merely a conventional computer (Reply p. 11).
This argument has been fully considered but found to be not persuasive. Further, the MPEP states “In computer-related technologies, the examiner should determine whether the claim purports to improve computer capabilities or, instead, invokes computers merely as a tool. Enfish, LLC v. Microsoft Corp., 822 F.3d 1327, 1336, 118 USPQ2d 1684, 1689 (Fed. Cir. 2016)” (see MPEP 2106.05(a)(I)). The steps of the method fall under judicial exceptions of mental processes and mathematical concepts as set out above and the only limitation besides the judicial exception is a computer recited generically. Thus, the method of a specific supercell- modified basin-hopping approach to define energy “per simulation cell” which enables efficient exploration is a series of abstract ideas for analyzing a chemical system. Although the abstract ideas themselves may be more efficient in the exploration of the potential energy surface than generic optimization techniques, the computer itself is not functioning in an improved or different manner. The computer is being invoked as a tool to perform these particular efficient abstract ideas. Due to the improvement being provided by the abstract ideas which invoke a generically recited computer as a tool (rather than an improvement in computer capabilities), the computer is interpreted as being a conventional computer that implements an improved abstract idea.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The rejection below was previously recited.
Claims 1 and 2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lima et al. (Physica A: Statistical Mechanics and its Applications 391.18 (2012): 4281-4289; previously cited).
Claim 1 is directed to a computer implemented method of calculating a non-electrostatic configurational energy of a system with periodic boundary conditions for determining one or more crystal structures of the system, where the system having a plurality of particles, wherein the particles comprise atoms and molecules
Lima et al. shows calculating a configurational energy which corresponds to the total Lennard Jones potential (i.e. a non-electrostatic potential) of a system that employs periodic boundary conditions (Lima et al. page 4283 para. 1-2 i.e. first and second full paragraph and page 4284 para. 1 and equation 10). Lima et al. shows that the atoms are initially disposed randomly at the sites of a face centered cubic lattice of parameter a (Lima et al. page 4283 para. 1-2 i.e. first and second full paragraph).
defining a cut-off radius, said radius defining a non-electrostatic interaction potential cut-off distance between particles in the system;
Lima et al. shows defining a cut-off radius defining a Lennard Jones potential between particles (i.e. non-electrostatic interaction) (Lima et al. page 4284 para. 1).
defining a set of cell vectors to generate a simulation cell, defining a set of supercell vectors to generate a supercell, wherein said supercell comprises a plurality of replicas of the simulation cell
Lima et al. shows the simulation’s supercell was built by repeating the unit cell NX, Ny, NZ times which shows the unit cell is defined and then replicated to build a supercell (Lima et al. page 4283 para. 1 i.e. the first full paragraph).
calculating, for each particle located within the supercell, non-electrostatic pair potentials between the particle and any and all additional particles surrounding the particle within the cut-off radius, said non-electrostatic pair potentials resulting from the interaction of the particle with any and all other particles located within the cut-off radius
Lima et al. shows calculating the Lennard-Jones potential for the atom-atom interactions within the cut-off radius (Lima et al. page 4283 para. 2, 3, and equations 7-9 and page 4284 para. 1).
and summing all distinct non-electrostatic pair potentials to provide a non-electrostatic configurational energy of the system
Lima et al. shows the configurational energy U corresponds to the total potential energy, given by a sum over all atomic pairs of the system (Lima et al. page 4284 para. 1 and equation 10).
Dependent claim 2 is directed to wherein the non-electrostatic pair potentials of a particle includes contributions from particles lying outside the supercell, but within the cut-off radius.
Lima et al. shows using periodic boundary conditions (which mimic an infinite system by repeating simulations cells) in the simulation of the supercell due to complications that arise from atoms behavior near system walls and that a cut-off radius is used to ensure that each atom only interacts with atoms in the cutoff radius (Lima et al. page 4283 para. 2 i.e. second full paragraph and page 4284 para. 1). This shows that non-electrostatic pair potentials include contributions from particles lying outside the supercell but within the cut-off radius.
Response to Arguments
Applicant's arguments filed 28 January 2026 have been fully considered but they are not persuasive.
Argument 1:
Applicant argues that Lima et al is not relevant art (or analogous art). The properties of fluids are inherently different from the crystal structure prediction recited in the present application. Fluids have a disordered structure whereas crystal structures are highly ordered.
The primary goal of Lima et al is to analyze the coalescence and segregation of atoms in a fluid system (see, for example, page 4283) (Reply p. 12).
This argument has been fully considered but found to be not persuasive. The MPEP states that “there is no analogous art requirement for a reference being applied in an anticipation rejection under 35 U.S.C. 102 In re Schreiber, 128 F.3d 1473, 1478, 44 USPQ2d 1429, 1432 (Fed. Cir. 1997)”. Thus, whether Lima et al. is analogous art is not a requirement for the anticipation rejection.
Argument 2:
Applicant argues that Lima does not teach the use in a crystal structure. The present invention, however, is directed to identifying global minima for crystal structure prediction (see paras. [0005], [0045], [0206], [0208] and elsewhere in the publication). Applicant acknowledges that Lima et al uses supercells in fluids (see page 4283, second paragraph, and 4284, first paragraph) and periodic boundary conditions solely to avoid wall effects in a liquid simulation (Reply p. 12).
This argument has been fully considered but found to be not persuasive. The MPEP states “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)” (see MPEP 2111.02(II)). The recitation of “for determining one or more crystal structures of the system, the system having a plurality of particles, wherein the particles comprise atoms and molecules, said method comprising the steps of…” in the preamble is interpreted as being an intended use of the invention because the body of the claim fully and intrinsically sets forth all of the limitations of the claimed invention (i.e., all manipulative steps applied to a system where the system is defined as having a plurality of particles, wherein the particles comprise atoms and molecules). Further, the recitation of “for determining one or more crystal structures of the system” does not provide any distinct definition of any of the claimed inventions limitations because all manipulative steps are performed on the system which encompasses plurality of particles which may be any atom and molecule.
The MPEP states “During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art” (see MPEP 2111.02(II)). In the instant case, the intended use of “for determining one or more crystal structures of the system” is interpreted as not resulting in a manipulative difference between the claimed invention and the prior art because the manipulative steps of the invention act on a system comprising atoms and molecules to determine a configurational energy and Lima et al. shows all manipulative steps on a system comprising atoms and molecules to determine a configurational energy.
Argument 3:
Applicant argues that Lima does not teach or suggest the step of dividing total configurational energy by the number of simulation cells to establish a "per cell" energy as a prerequisite for a basin-hopping global optimization of a crystal (Reply p. 12).
This argument has been fully considered but found to be not persuasive. Claims 1 and 2 which are rejected under 35 U.S.C. 102 as being anticipated by Lima do not recite dividing total configurational energy by the number of simulation cells. It is noted, this argument is addressed below in the context of the 35 U.S.C. 103 rejection of claims 4-6 and claim 27 which recite this step of dividing the total configurational energy.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The rejection below was previously recited.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Lima et al. as applied to claims 1-2 under 35 U.S.C. 102 above, and further in view of Viscardy (Physical Review E 68.4 (2003): 041204; previously cited).
Dependent claim 3 is directed to wherein the step iv) considers additional image particles surrounding a particle using the standard minimum image convention to select said non-electrostatic pair potentials resulting from the interaction of the particle with closest particles or image particles located inside and/or outside the supercell.
Lima et al. does not explicitly show considering additional image particles surrounding a particle using the standard minimum image convention to select pair potentials resulting from the interaction of the particle with closest particles or image particles located inside and/or outside the supercell
Viscardy et al. shows the periodic boundary conditions (PBC) usually considered in molecular dynamics are based on the so-called minimum image convention according to which interaction should occur between pairs of particles separated by the minimum distance among the infinitely many images of the particles allowed by the PBC (Viscardy et al. page 68 left col.).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to modify reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the periodic boundary conditions of Lima et al. with the use of minimum image convention of Viscardy et al. because this allows for interactions to occur between pairs of particles separated by the minimum image distance amount the infinitely many images allowed by periodic boundary conditions (Viscardy et al. page 68 left col.) which would lead to a more representative energy of a supercell in a periodic system by allowing interactions to occur with the images surrounding the supercell. One would have a reasonable expectation of success because the minimum image convention of Viscardy et al. is employed with periodic boundary conditions and can be employed in Lima et al. which shows the use of periodic boundary conditions.
The rejection below was previously recited.
Claims 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Lima et al. as applied to claims 1 and 2 under 35 U.S.C. 102 above, and further in view of Lima et al. (Physica A: Statistical Mechanics and its Applications 391.18 (2012): 4281-4289; previously cited).
Dependent claim 4 is directed to calculating, for each particle located within a selected simulation cell, non-electrostatic pair potentials between the particle and any and all additional particles surrounding the particle within the cut-off radius; and summing the distinct non-electrostatic pair potentials for each particle inside the selected simulation cell; and multiplying the summation by the number of simulation cells inside the supercell, to obtain configurational energy, and wherein the configurational energy is a non-electrostatic potential energy per supercell of the system.
Lima et al. shows calculating the Lennard-Jones potential for the atom-atom interactions within the cut-off radius (Lima et al. page 4283 para. 2, 3, and equations 7-9 and page 4284 para. 1).
Lima et al. shows the unit cell is defined (Lima et al. page 4283 para. 1 i.e. the first full paragraph). Lima et al. shows the configurational energy U corresponds to the total potential energy, given by a sum over all atomic pairs of the system (Lima et al. page 4284 para. 1 and equation 10).
Lima et al. does not explicitly show multiplying the summation by the number of simulation cells inside the supercell, to obtain configurational energy, and wherein the configurational energy is a non-electrostatic potential energy per supercell of the system.
Lima et al. shows the simulation’s supercell was built by repeating the unit cell NX, Ny, NZ times which shows the unit cell is defined and then replicated to build a supercell (Lima et al. page 4283 para. 1 i.e. the first full paragraph). Lima et al. shows a cubic supercell corresponds to a cube of sides NX = Ny = NZ = L and the total number of atoms is N = 4NXNyNZ = 4L3 (Lima et al. page 4283 para. 1 i.e. the first full paragraph).
Dependent claim 5 is directed to wherein the non-electrostatic pair potentials of a particle inside the selected simulation cell includes contributions from particles lying outside the selected simulation cell, but within the cut-off radius.
Lima et al. shows calculating the Lennard-Jones potential for the atom-atom interactions within the cut-off radius (Lima et al. page 4283 para. 2, 3, and equations 7-9 and page 4284 para. 1).
It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the calculation and representation of configurational energy of a system as a supercell Lima et al. to multiply the non-electrostatic energy of a single simulation cell by the total number of simulation cells in a supercell to get the total energy of the supercell because the supercell is composed of repeating unit cells (i.e. the smallest repeating unit which contain the same atoms in the same positions) and contribute to the configurational energy (Lima et al. page 4283 para. 1 i.e. first full paragraph). Therefore, the non-electrostatic potential energy of the supercell is a multiple of the repeating simulation cells (i.e. the unit cells) which can be derived by dividing the total configurational energy by the number of repeating unit cells. One would have a reasonable expectation of success because the supercell is composed of repeating unit cells that contribute to the overall energy of the supercell and can be multiplied by the number of contribution unit cells to achieve the overall energy in the supercell.
Dependent claim 6 is directed to dividing the configurational energy by the total number of simulation cells to define a non- electrostatic potential energy per simulation cell.
Lima et al. shows the configurational energy U corresponds to the total potential energy, given by a sum over all atomic pairs of the system (Lima et al. page 4284 para. 1).
Lima et al. does not explicitly show dividing the configurational energy by the total number of simulation cells to define a non-electrostatic potential energy per simulation cell.
Lima et al. shows that the simulation’s supercell was built by repeating the unit cell NX, Ny, NZ times, respectively, along the x, y, and z axis (Lima et al. page 4283 para. 1 i.e. first full paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the calculation and representation of configurational energy of a system as a supercell Lima et al. to define non-electrostatic potential energy per simulation cell by dividing the configurational energy by the total number of simulation cells because the supercell is composed of repeating unit cells (i.e. the smallest repeating unit which contain the same atoms in the same positions) and contribute to the configurational energy (Lima et al. page 4283 para. 1 i.e. first full paragraph). Therefore, the non-electrostatic potential energy of the supercell is a multiple of the repeating simulation cells (i.e. the unit cells) which can be derived by dividing the total configurational energy by the number of repeating unit cells. One would have a reasonable expectation of success because the supercell is composed of repeating unit cells that contribute to the overall energy of the supercell and the total energy can be divided by the contributing unit cells to achieve the energy of the a single unit cell.
The rejection below was previously recited.
Claims 7-10, 18-20, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Lima et al. as applied to claims 6 above, and further in view of Buch et al. (Journal of chemical physics, vol. 123, no.5, 1 August 2005, page 051108; previously cited) in view of Rondina et al. (Journal of chemical information and modeling 53.9 (2013): 2282-2298; previously cited).
Dependent claims 7 is directed to a) calculating the non-electrostatic potential energy per simulation cell of the system, according to claim 6 for one arrangement of the particles and b) determining local minima of an enthalpy per simulation cell, using a basin-hopping global optimization algorithm, wherein the enthalpy per simulation cell comprises the non-electrostatic potential energy per simulation cell.
Lima et al. as applied to claim 6 does not show determining an enthalpy per simulation cell, using a basin-hopping global optimization algorithm, wherein the enthalpy per simulation cell comprises the non-electrostatic potential energy per simulation cell.
Like Lima et al., Buch et al. shows a calculates non-electrostatic potentials (through a molecular dynamics simulation) in a system with periodic boundary conditions. Buch et al. shows that at zero-temperature that the identification of the free energy minima for crystal structure prediction is simplified to the minimization of enthalpy (Buch et al. page 051108-1). Buch et al. shows minimizing the enthalpy with respect to coordinates and the cell dimensions to obtain the final crystal structure (Buch et al. page 051108-3 right col.).
Lima et al. in view of Buch et al. does not show using a basin hopping optimization algorithm.
Like Lima et al. in view of Buch et al., Rondina et al. shows minimizing the potential energy surface to discover crystal structures with low-lying minima. Rondina et al. shows using a basin hopping global optimization algorithm to minimize the energy of a system (Rondina et al. page 2284 left and right col.).
Dependent claim 8 is directed to wherein the enthalpy per simulation cell, H(X), where X is a vector defining the real space coordinates of particles within the simulation cell, further comprises an external pressure acting on the system such that the enthalpy is given by multiplying the external pressure with a volume of the simulation cell volume and adding this to the non- electrostatic energy per simulation cell.
Buch et al. shows that at zero-temperature that the identification of the free energy minima for crystal structure prediction is simplified to the minimization of enthalpy (Butch et al. page 051108-1). Buch et al. further shows the equation for enthalpy is H = U + PV which shows the pressure is multiplied to the volume and added to the energy of the system under investigation (Butch et al. page 051108-1).
Dependent claim 9 is directed to wherein the enthalpy per simulation cell further comprises contributions from electrostatic interactions between particles.
Buch et al. shows performing a molecular dynamic simulation on water molecules (which gives the energy of the system which is used to minimize the enthalpy) to predict crystal structures of ice polymorphs (Buch et al. page 051108-1 right col.). Performing molecular dynamic simulations implicitly shows calculating interatomic potentials such as electrostatic interactions based on positions of atoms.
Dependent claim 10 is directed to wherein each particle comprises one or more multipoles, and wherein the electrostatic interactions between the particles comprise contractions between particle multipoles that are combined using an Ewald sum.
Buch et al. shows water molecules which comprise multipoles and the electrostatic interactions between particles comprise contractions between multipoles (Buch et al. page 051108-1 right col.). Further, the limitation of combined using an Ewald sum is not an active step of the method and is merely descriptive and does not limit the further limitation of what the electrostatic interactions comprise.
Dependent claim 18 is directed to wherein the enthalpy per simulation cell comprises contributions from interactions outside the cut-off radius.
Lima et al. shows adding long range corrections to the internal energy, which take into account, through an average, the effect of the remaining atoms outside the sphere (which is defined by the cutoff radius) (Lima et al. page 4284 para. 1). This changes the potential energy of the system which is used in Lima et al. in view of Buch et al. in view of Rondina et al. to determine the enthalpy.
Dependent claim 19 is directed to obtaining a local minimum of H(X) with coordinate X by employing a local optimization, generating a random displacement vector to obtain new trial coordinates, accepting the trail displacement between any two particles inside the simulation cell greater than or equal to a set minimum distance, or rejecting if the separation is smaller than the minimum distance, repeating steps until an acceptable value for the trail displacement is found, calculating the transformed enthalpy per simulation cell through optimization, setting the enthalpy to the enthalpy produced by the trail operator if the Metropolis Monte Carlo criterion is met, repeating steps b) and f) to calculate a plurality of local minima of H(X).
Rondia et al. shows obtaining a local minimization with respect to atomic coordinates (Rondia et al. page 2284 right col.). Rondia et al. shows generating random displacements to obtain new trial coordinates using trial operators (Rondia et al. page 2284 left col.- page 2286). Rondia et al. shows using an auxiliary filter (i.e. (1 − η) Rcαβ < dij < (1 + η) Rcαβ wherein η is the parameter controlling the tightness of the filter) which can either accept or reject the trial operator displacement to avoid configurations with atoms becoming very close to each other and if rejected the a new configuration is generated using the trial operator that caused the rejection (Rondia et al. page 2286 right col.). Rondia et al. shows the trial operators are used to explore the potential energy surface which implicitly shows that the energy is calculated for the new displacements generated (Rondia et al. page 2287 left col.). Rondia et al. shows using the Metropolis criterion for allowing reasonable sampling of the potential energy surface which shows a plurality of local minima are calculated (Rondia et al. page 2287 left col.).
Dependent claim 20 is directed to wherein the minimum distance constrained by a set maximum.
Rondia et al. shows using an auxiliary filter which can either accept or reject the trial operator displacement to avoid configurations with atoms becoming very close to each other (Rondia et al. page 2286 right col.). The auxiliary filter of (1 − η) Rcαβ < dij < (1 + η) Rcαβ (wherein η is the parameter controlling the tightness of the filter) is constrained by a set maximum (Rondia et al. page 2286 right col.).
Dependent claim 24 is directed to wherein the size of the supercell is varied during the basin-hopping global optimization algorithm such that the supercell is always large enough to hold the cut-off radius.
Buch et al. shows the unit cells shape was altered during the optimization through a process of elongations (Buch et al. page 051108-3 right col.). When combined with Lima et al. this variable cell shape will distort the overall supercell because these cells make up the overall super cell. Lima et al. shows the cut off radius is the length of the supercell divided by a parameter (Lima et al. page 4284 para. 1). It would have been obvious to one of ordinary skill that since the cut-off radius is less than the length of the supercell it will fit inside the supercell even when varied because the radius will always be dependent on the length of the supercell.
Dependent claim 25 is directed to wherein the cut- off radius is equal to or greater than a unit cell of the crystal structure.
Lima et al. shows the cut off radius is the length of the supercell divided by 2 times sigma (in the context of Lennard Jones potentials sigma represents the distance at which the potential between two particles is zero) (Lima et al. page 4284 para. 1). It would have been obvious to one of ordinary in the art that the distance at which the potential between two particles is zero is relatively small compared to the overall size of a supercell length the cut-off radius (which is dependent on the length of the supercell) will exceed the individual unit cells that make up the supercell.
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to combine reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have combined the calculation of non-electrostatic potentials in a system of Lima et al. with the minimization of enthalpy to obtain a crystal structure because at zero-temperature the identification of the free energy minima for crystal structure prediction is simplified to the minimization of enthalpy (Buch et al. page 051108-1). It would have been further obvious to one of ordinary skill in the art before the effective filling date to have modified the optimization algorithm of Lima et al. in view of Buch et al. with the basin hopping optimization algorithm of Rondia et al. because this basin hopping optimization algorithm with several trail operators that allow for a greater variety of structural changes and consequently a more thorough exploration of the potential energy surface (Rondia et al. page 2287 left col.) and by using this more thorough exploration more structures can be identified at energy minima. One would have a reasonable expectation of success because Lima et al. shows calculating non-electrostatic energy of a system while Buch et al. shows utilizing the process of minimizing enthalpy to obtain crystal structures while Rondia et al. shows an optimization algorithm that can be applied to the minimization of enthalpy for a more thorough exploration of the potential energy to identify low lying minima.
The rejection below was previously recited.
Claims 11-17 are rejected under 35 U.S.C. 103 as being unpatentable over Lima et al. in view of Buch et al. in view of Rondia et al. as applied to claims 10 above, and further in view of Simmonet et al. (J. Chem. Phys. 14 May 2014; 140 (18): 184101; previously cited) as evidence by Stone (J. Phys. A: Math. Gen. 9 485, 1976; previously cited).
Dependent claim 11 is directed to converting the multipole interactions from a Cartesian coordinate system into a spherical harmonic form suitable for implementation into the Ewald sum.
Lima et al. in view of Buch et al. in view of Rondia et al. as applied to 7-10, 18-20, 24, and 25 does not show converting the multipole interactions from a Cartesian coordinate system into a spherical harmonic form suitable for implementation into the Ewald sum.
Simmonett et al. show converting the multipole interactions from a Cartesian coordinate system into a spherical harmonic form using the method in Stone et al. for Cartersian-spherical (CS) transformation (Simmonett et al. page 184101-4 left col.).
Dependent claim 12 is directed to diagrammatically representing the multipole interactions as a series of nodes and spokes radiating from the nodes, wherein each node represents a symmetric multipole tensor defining a multipole of a particle and wherein the number of spokes radiating from each node is equal to the rank of the symmetric multipole tensor of that node.
Simmonett et al. show converting the multipole interactions from a Cartesian coordinate system into a spherical harmonic form using the method in Stone et al. for Cartersian-sphereical (CS) transformation (Simmonett et al. page 184101-4 left col.). In the method of Stone et al. contains a graphical technique which diagrammatically represents multipole interactions as a series of nodes and spokes (as evidence by Stone et al. pages 490-497).
Dependent claim 13 is directed to conjoining spokes of interacting multipoles of particles to form spoked connections between the respective nodes, each spoked connection representing an interaction between the nodes. Dependent claim 14 is directed to wherein a degree of contraction acting between any two nodes is equal to the number of spoked connections shared between two nodes.
Simmonett et al. show converting the multipole interactions from a Cartesian coordinate system into a spherical harmonic form using the method in Stone et al. for Cartersian-sphereical (CS) transformation (Simmonett et al. page 184101-4 left col.). In the method of Stone et al. contains a graphical technique which conjoins nodes of interacting multipoles of particles to form spoked connections (as evidence by Stone et al. pages 490-491).
Dependent claim 15 is directed to wherein the step of diagrammatic representing further comprises the step of: for each node, braiding the spokes to transform each spoke of the node from Cartesian components into a spherical harmonic form. Dependent claim 16 is directed to braiding the spoked connections between nodes on a piece-by-piece basis, wherein each piece constitutes a subset of spoked connections between the nodes.
Simmonett et al. show converting the multipole interactions from a Cartesian coordinate system into a spherical harmonic form using the method in Stone et al. for Cartersian-sphereical (CS) transformation (Simmonett et al. page 184101-4 left col.). In the method of Stone et al. contains a graphical technique which braids spokes piece by piece basis (as evidence by Stone et al. pages 490-497).
Dependent claim 17 is directed wherein the symmetric multipole tensors are traceless.
Simmonett et al. shows symmetric multipole tensors are traceless (Simmonett et al. page 184101-4 left col.).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to combine reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have combined the method of predicting crystal structures of ice crystal polymorphs that contain multipoles of Lima et al. in view of Buch et al. in view of Rondia et al. with the conversion of from Cartesian coordinates to spherical harmonic coordinates for multipole moments in calculating electrostatic potentials of Simmonett et al. because the computational cost of evaluating the electrostatic potential in spherical harmonic coordinates scales as O(I3), as opposed to the best cartesian based approach which scales as O(I4) (Simmonett et al. page 184101-7 left col.) which shows the use of spherical harmonic components are more computationally efficient for larger systems. One would have a reasonable expectation of success because Lima et al. in view of Buch et al. in view of Rondia et al. calculate electrostatic potential energy in terms of cartesian coordinates which can be converted to spherical harmonic coordinates using the method of Simmonett et al. which makes the calculations more efficient.
The rejection below was previously recited.
Claims 21-23 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Lima et al. in view of Buch et al. in view of Rondia et al. as applied to claim 7 and 20 above, and further in view of Iuzzolino et al. (Journal of Chemical Theory and Computation 13.10 (2017): 5163-5171; previously cited).
Lima et al. in view of Buch et al. in view of Rondia et al. does not explicitly show wherein H(X) comprises contributions from intramolecular potential energy corresponding to a conformer of the molecule inside the simulation cell, taking into account different conformers of the molecule from a conformer database, calculating a transition probability, wherein the system comprises a pharmaceutical candidate.
Dependent claim 21 is directed to wherein the particle is a molecule, and wherein H(X) comprises contributions from intramolecular potential energy corresponding to a conformer of the molecule inside the simulation cell.
Like Lima et al. in view of Buch et al. in view of Rondia et al., Iuzzolino et al. shows a crystal structure prediction method which calculates the energy of molecules to identify polymorphs in structures. Iuzzolino et al. shows calculating a lattice energy of molecules in a lattice by taking into account intramolecular energy corresponding to a conformer (Iuzzolino et al. page 5163 right col.)
Dependent claim 22 is directed to calculating the plurality of local minima of H(X) comprises taking into account different conformers of the molecule from a conformer database, each conformer corresponding to a local minimum of an intramolecular potential energy surface of the molecule.
Iuzzolino et al. shows the use of conformational information from the crystal structures in the Cambridge Structural Database (Iuzzolino et al. page 5163 abstract).
Dependent claim 23 is directed to calculating the plurality of local minima of H(X) further comprises calculating a transition probability, said transition probability indicating the probability of the molecule transitioning from one conformer to another conformer at a given temperature.
Iuzzolino et al. shows eliminating conformational regions that are energetically implausible by only keeping conformational regions whose optimized energies relative to the most stable fully optimized molecular structure that were plausible for crystalline conformers where kept (Iuzzolino et al. page 5166 right col.). Iuzzolino et al. shows this gives a low-energy conformational space of the molecule, as a set of conformational region and torsion angles that can adopt a specified range of possible values (Iuzzolino et al. page 5166 right col.). This shows that the probability of the molecule transitioning from one conformer to another conformer in a given environment are calculated to only keep the most probable conformers that will be seen.
Dependent claim 26 is directed to wherein the system comprises a pharmaceutical candidate, and wherein each crystal structure comprises a polymorph of the pharmaceutical candidate
Iuzzolino et al. shows the system comprises a pharmaceutical candidate (i.e. pharmaceutical-like molecules) to identify potential conformational polymorphs (Iuzzolino et al. page 5164 right col.).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to modify reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the method of predicting crystal structures through the minimization of enthalpy to identify polymorphs in a structure of Lima et al. in view of Buch et al. in view of Rondia et al. with the use of calculating the intramolecular energy corresponding to a conformer to determine a plausible conformational region of Iuzzolino et al. because this method of calculating intramolecular energy of a conformer to restrict the conformational region lowers the computational cost by restricting the search space to a set of sufficiently low-energy conformational regions (Iuzzolino et al. page 5170 left col.). One would have a reasonable expectation of succuss because the method of Lima et al. in view of Buch et al. in view of Rondia et al. shows identifying polymorph crystal structures of ice by minimizing energy while the method of Iuzzolino et al. shows identifying pharmaceutical polymorphs by minimizing energy in a reduced conformational region with sufficiently low-energy.
The rejection below was previously recited.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Lima et al. (Physica A: Statistical Mechanics and its Applications 391.18 (2012): 4281-4289; previously cited) in view of Rondina et al. (Journal of chemical information and modeling 53.9 (2013): 2282-2298; previously cited) in view of Iuzzolino et al. (Journal of Chemical Theory and Computation 13.10 (2017): 5163-5171; previously cited).
Claim 27 is directed to determine possible crystal structure polymorphs of the pharmaceutical product, each crystal structure comprising a repeated unit cell, calculate a global minimum of configurational energy for each of the crystal structure polymorphs by: defining a cut-off radius, said radius defining a non-electrostatic interaction potential cut-off distance between particles in the system;
Lima et al. shows defining a cut-off radius defining a Lennard Jones potential between particles (i.e. non-electrostatic interaction) (Lima et al. page 4284 para. 1). Lima et al. a system that employs periodic boundary conditions (Lima et al. page 4283 para. 1-2 i.e. first and second full paragraph).
defining a set of cell vectors to generate a simulation cell, defining a set of supercell vectors to generate a supercell, wherein said supercell comprises a plurality of replicas of the simulation cell
Lima et al. shows the simulation’s supercell was built by repeating the unit cell NX, Ny, NZ times which shows the unit cell is defined and then replicated to build a supercell (Lima et al. page 4283 para. 1 i.e. the first full paragraph).
calculating, for each particle located within the supercell, non-electrostatic pair potentials between the particle and any and all additional particles surrounding the particle within the cut-off radius, said non-electrostatic pair potentials resulting from the interaction of the particle with any and all other particles located within the cut-off radius
Lima et al. shows calculating the Lennard-Jones potential for the atom-atom interactions within the cut-off radius (Lima et al. page 4283 para. 2, 3, and equations 7-9 and page 4284 para. 1).
and summing all distinct non-electrostatic pair potentials to provide a non-electrostatic configurational energy of the system
Lima et al. shows the configurational energy U corresponds to the total potential energy, given by a sum over all atomic pairs of the system (Lima et al. page 4284 para. 1 and equation 10).
vi) dividing the configurational energy by the total number of simulation cells enclosed within the supercell to define a non-electrostatic potential energy per simulation cell;
Lima et al. shows that the simulation’s supercell was built by repeating the unit cell NX, Ny, NZ times, respectively, along the x, y, and z axis (Lima et al. page 4283 para. 1 i.e. first full paragraph). It would be obvious to one of ordinary skill in the art to derive the configurational energy of a simulation cell from the supercell because the non-electrostatic potential energy of the supercell is a multiple of the repeating simulation cells (i.e. the unit cells) and dividing the total configurational energy by the number of repeating unit cells will give the configurational energy of the individual simulation cells.
Lima et al. does not show determining global minimum of the configurational energy per simulation cell by using a basin-hopping global optimization algorithm to obtain a plurality of local minima of the configurational energy, and by selecting the lowest local minimum to be the global minimum, and wherein the unit cell is equivalent to the simulation cell
When combined with Lima et al., Rondina et al. shows using a basin hopping global optimization algorithm to minimize the energy of a system to identify crystal structures with low-lying minima. Rondina et al. shows minimizing the potential energy surface to discover crystal structures with low-lying minima. Rondina et al. shows using a basin hopping global optimization algorithm to minimize the energy of a system (Rondina et al. page 2284 left and right col.).
Lima et al. in view of Rondina et al., does not show determine possible crystal structure polymorphs of the pharmaceutical product, each crystal structure comprising a repeated unit cell and select crystal structure polymorphs having lowest global minima to be candidates for the pharmaceutical product.
When combined with Lima et al. in view of Rondina et al., Iuzzolino et al. shows determining possible crystal structure polymorphs of a pharmaceutical product and selecting crystal structure polymorphs having lowest global minima to be candidates for the pharmaceutical product. Iuzzolino et al. shows generating polymorphic crystal structures of flexible pharmaceutical molecule using conformational information (Iuzzolino et al. page 5169 right col. and page 5170 left col.).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to combine reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art to have combined the structure prediction method that calculates non-electrostatic configurational energy of Lima et al. with the basin hopping energy minimization algorithm of Rondina et al. because basin hopping optimization algorithm with several trail operators that allow for a greater variety of structural changes and consequently a more thorough exploration of the potential energy surface (Rondia et al. page 2287 left col.) and by using this more thorough exploration more structures can be identified at energy minima. It would have been further obvious to one of ordinary skill in the art before the effective filling date to have modified the method of identifying structures at low lying minima of Lima et al. in view of Rondina et al. with the predicting crystal structure polymorphs for pharmaceuticals of Iuzzolino et al. because the physical properties of the crystalline form are dependent on the crystal structure (Iuzzolino et al. page 5163 left col.) and the identification of crystal structure polymorphs in pharmaceuticals will give insight into the physical properties of these pharmaceuticals. One would have a reasonable expectation of success because Lima et al. shows calculating non-electrostatic energy of a molecular system which can be used in the method of Rondia et al. for optimization by ways of a more thorough exploration of the potential energy to identify structures at a low-lying minimum which can be modified to predict pharmaceutical polymorph structures shown in Iuzzolino et al. that utilize intermolecular energy and intramolecular energy of the compounds.
Response to Arguments
Applicant's arguments filed 28 January 2026 have been fully considered but they are not persuasive.
Argument 1:
Applicant argues that the teachings of Viscardy et al are also directed towards fluids as the publication focuses on viscosity in fluids. As noted above, the current invention is directed towards crystal structure prediction. Applicant submits that the skilled person would not be in a position to combine the teachings of Viscardy et al and Lima et al to arrive at the subject matter of claim 3 (or any of the above claims) (Reply p. 13).
This argument has been fully considered but found to be not persuasive. As described above, the recitation of “for determining one or more crystal structures of the system, the system having a plurality of particles, wherein the particles comprise atoms and molecules, said method comprising the steps of…” in the preamble is interpreted as being an intended use of the invention. The invention is directed to a method of performing molecular dynamic calculations on a system comprising atoms and molecules and determining the configurational energy of a system comprising atoms and molecules. Further, Lima et al shows methods for performing molecular dynamic calculations on a system comprising atoms and molecules and determining the configurational energy of the system and Viscardy et al. shows methods for performing molecular dynamic calculations on a system. Thus, Lima et al. and Viscardy et al. are analogous to the claimed method of molecular dynamics.
Argument 2:
Applicant argues that the with respect to claims 4-6 and the rejection by Examiner as being unpatentable, Applicant refers to the arguments set out above why the person skilled in the art would not have considered the teachings of Lima (Reply p. 13). Applicant argues that Lima does not teach or suggest the step of dividing total configurational energy by the number of simulation cells to establish a "per cell" energy as a prerequisite for a basin-hopping global optimization of a crystal (Reply p. 12).
These arguments have been fully considered but found to be not persuasive. As described above, the recitation of “for determining one or more crystal structures of the system, the system having a plurality of particles, wherein the particles comprise atoms and molecules, said method comprising the steps of…” in the preamble is interpreted being an intended use of the invention. The invention is directed to a method of performing molecular dynamics simulation on a system comprising atoms and molecules. Further, Lima et al. show a method for performing molecular dynamic calculations on a system comprising atoms and molecules to calculate the configurational energy of a system. Also as stated in the 103 rejection above, it is acknowledged that Lima et al. does not explicitly show dividing total configurational energy by the number of simulation cells to get a “per-cell” energy but it would have been obvious to one of ordinary skill in the art that the “per-cell” energy of a supercell composed of repeating unit cells (i.e., the smallest repeating unit which contain the same atoms in the same positions) which all contribute to the total supercell energy is derived by dividing the total supercell energy by the number of repeating unit cells which contribute to the total supercell energy.
Argument 3:
Applicant states the teachings of Buch et al are directed towards molecular crystalline structures and the teachings of Rondina are directed to optimization of clusters and nanoparticles, which are finite systems (Reply 13). Applicant argues as set out above, there is no technical motivation to combine a fluid-dynamics study (Lima) with a study of molecular crystalline structures (Buch et al) as well as with a cluster- optimization tool (Rondina et al) to arrive at the specific "supercell-modified" crystal prediction method claimed here (Reply p. 13).
This argument has been fully considered but found to be not persuasive. As described above, the recitation of “for determining one or more crystal structures of the system, the system having a plurality of particles, wherein the particles comprise atoms and molecules, said method comprising the steps of…” in the preamble is interpreted being an intended use of the invention. The invention is directed to a method of performing molecular dynamics simulation on a system comprising atoms and molecules. Further, Lima et al., Buch et al., and Rodina et al. all show methods for of molecular dynamic calculations on a system comprising atoms and molecules.
Argument 4:
Applicant argues that Lima et al. is not relevant to the current patent application (Reply p. 13). Applicant further argues that the need to combine the teachings of FIVE documents to allegedly arrive at the teaching of claims 11-17 is an indication that there would be no motivation for the person skilled in the art to combine the teachings (Reply p. 13).
In response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991). Further, as addressed above Lima et al. is relevant to the claimed method of calculating a configurational energy of a system comprising atoms and molecules by utilizing molecular dynamic calculations.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JONATHAN EDWARD HAYES whose telephone number is (571)272-6165. The examiner can normally be reached M-F 9am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia Wise can be reached at 571-272-2249. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.E.H./Examiner, Art Unit 1685
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
Prosecution Insights