DETAILED ACTION
Applicant’s response filed 11/12/2025 has been fully considered. The following rejections and/or objections are either reiterated or newly applied.
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 1-20 are currently pending and are herein under examination.
Claims 1-20 are rejected.
Priority
The instant application claims domestic benefit as a continuation of International Application No. PCT/US2020/044259, filed July 30, 2020, which claims domestic benefit to US Provisional Application No. 62/882,092, filed on August 2, 2019, and to US Provisional Application No. 63/009,712, filed on April 14, 2020. The claims to domestic benefit are acknowledged for claims 1-20. As such, the effective filing date for claims 1-20 is August 2, 2019.
Drawings
The objection to the drawings is withdrawn in view of amendments to the specification.
The drawings filed 01/28/2022 are accepted.
Withdrawn Rejections
35 USC 103
The rejection of claims 1-6, 8-13 and 15-20 under 35 U.S.C. 103 as being unpatentable over Chaudhri et al. in view of Anandakrishnan et al. is withdrawn in view of claim amendments.
The rejection of claims 7 and 14 under 35 U.S.C. 103 as being unpatentable over Chaudhri et al. in view of Anandakrishnan et al. and in further view of Agrawal et al. is withdrawn in view of claim amendments.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more.
Any newly recited portions herein are necessitated by claim amendment.
Step 2A, Prong 1:
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 phenomena (Step 2A, Prong 1). In the instant application, claims 1-8 recite a method, claims 9-14 recite a system, and claims 15-20 recite a product. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claims 1, 8 and 15 recite “creating a model of the antibody molecule by selecting a plurality of sites within a representation of the antibody molecule, wherein: a total number of the plurality of sites is less than a total number of atoms in the antibody molecule; the plurality of sites comprises a first subset of the plurality of sites and a second subset of the plurality of sites; and a total number of sites within the first subset of the plurality of sites is equal to a total number of molecular multipole moments within the plurality of molecular multipole moments; calculating a charge for each of the plurality of sites, wherein: a combination of calculated charges for the plurality of sites approximates the plurality of molecular multipole moments of the antibody molecule; and for each site of the second subset of the plurality of sites, a charge calculated for each site is equal to a charge calculated for a corresponding site of the first subset of the plurality of sites; predicting a property of the solution using data from the molecular dynamics simulation;
Claims 2, 9 and 16 recite “wherein for each site of the second subset of the plurality of sites, a location of the site within the representation of the antibody molecule mirrors a location of the corresponding site of the first subset of the plurality of sites within the representation of the antibody molecule.”
Claims 3, 10 and 17 recite “wherein locations of sites of the first subset of the plurality of sites and the plurality of molecular multipole moments are used to calculate charge values for the first subset of the plurality of sites.”
Claims 5, 12 and 19 recite “wherein: a total number of the second subset of the plurality of sites is less than the number of the first subset of the plurality of sites; and the total number of the second subset of the plurality of sites plus the total number of the first subset of the plurality of sites is equal to the total number of the plurality of sites.”
Claims 6, 13 and 20 recite “wherein: the antibody molecule is a Y-shaped protein having a first arm, a second arm, and a third arm; the first arm and the second arm are part of a Fab (antigen-binding fragment) region; the third arm is part of an Fc (fragment crystallizable) region; the first subset of the plurality of sites includes sites on the first arm and the third arm; and the second subset of the plurality of sites includes sites on the second arm, so that the second arm is modeled as a mirror image of the first arm.”
Claims 7 and 14 recite “further comprising, based on the predicted property of the solution: (i) adding the antibody molecule to a list of potential polypeptides to be used as at least part of a therapeutic agent, (ii) removing the antibody molecule from the list of potential polypeptides to be used as at least part of the therapeutic agent, (iii) ranking the antibody molecule within the list of potential polypeptides to be used as at least part of the therapeutic agent, or (iv) a combination thereof.”
Limitations reciting a mental process.
The limitations cited above in claims 1-3, 5-10, 12-17 and 19-20 are recited at such a high level of generality that they equate to a mental process because they 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)), which the courts have identified as concepts that can be practically performed in the human mind.
The broadest reasonable interpretation (BRI) of creating a model of an antibody by selecting a plurality of sites, calculating a charge for each of the plurality of sites, and predicting a property of the solution using data from a simulation include performing mental processes such as observation evaluation, and judgement, which are enumerated concepts that can be performed by a human using their mind or pen and paper (MPEP 2106.04(a)). The BRI of claims 1, 8 and 15 include a human looking at a representation of an antibody and selecting sites to create a model of the antibody. A human could practically calculate a charge at a site by summing the partial charges underlying a respective residue at each site, wherein the partial charges are based on a CHARMM force field. A human could also practically make predictions of a property of a solution as it requires assessing data and making a determination. The BRI of claims 7 and 14 include a mental process because a human could practically add an antibody to a list of potential antibodies.
Limitations reciting a mathematical concept.
Claims 1, 3, 8, 10, 15 and 17 recite calculating a charge which equates to a mathematical concept because it is similar to the concepts of 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)), which the courts have identified as mathematical concepts. The BRI in claims 1, 3, 8, 10, 15 and 17 of calculating a charge for each of the plurality of sites includes performing calculations to derive a numerical value.
Limitations reciting a natural phenomenon.
The above cited limitations in claims 1-3, 5-10, 12-17 and 19-20 equate to a natural phenomenon because they are similar to the concept of the chemical principle underlying the union between fatty elements and water, Tilghman v. Proctor, 102 U.S. 707, 729 (1880), which the courts have established as a natural phenomenon. Specifically, claims 1-3, 5-10, 12-17 and 19-20 use naturally occurring interactions of molecules in a solution to predict properties of the solution, wherein properties of a solution are a natural principle.
Limitations included in the recited judicial exception.
The following limitations in claims 1, 8 and 15 are included in the recited judicial exception of “creating a model” and “calculating a charge”, respectively, because they limit the judicial exception but do not change the fact that they are a judicial exception: “a number of the plurality of sites is less than a number of atoms in the antibody molecule; the plurality of sites comprises a first subset of the plurality of sites and a second subset of the plurality of sites; and a number of sites within the first subset of the plurality of sites is equal to a number of molecular multipole moments within the plurality of molecular multipole moments” and “a combination of calculated charges for the plurality of sites approximates the plurality of molecular multipole moments of the antibody molecule; and for each site of the second subset of the plurality of sites, a charge calculated for each site is equal to a charge calculated for a corresponding site of the first subset of the plurality of sites.”
Regarding the above cited limitations in claims 2, 5-6, 9, 12-13, 16 and 19-20, these limitations are included in the recited judicial exception in claims 1, 8 and 15 of “creating a model of the antibody molecule” because they limit the second subset of the plurality of sites, the antibody molecule, and the first subset of the plurality of sites but do not change the fact that “creating a model of the antibody molecule” recites a judicial exception.
As such, claims 1-20 recite an abstract idea and a natural phenomenon (Step 2A, Prong 1: Yes).
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). The judicial exception is not integrated into a practical application because the claims do not recite additional elements that reflect an improvement to a computer, technology, or technical field (MPEP § 2106.04(d)(1) and 2106.5(a)), require a particular treatment or prophylaxis for a disease or medical condition (MPEP § 2106.04(d)(2)), implement the recited judicial exception with a particular machine that is integral to the claim (MPEP § 2106.05(b)), effect a transformation or reduction of a particular article to a different state or thing (MPEP § 2106.05(c)), nor provide some other meaningful limitation (MPEP § 2106.05(e)). Rather, the claims include limitations that equate to an equivalent of the words “apply it” and/or to instructions to implement an abstract idea on a computer (MPEP § 2106.05(f)) and to insignificant extra-solution activity (MPEP § 2106.05(g)). The instant claims recite the following additional elements:
Claim 1 recites “A computer-implemented method comprising:”
Claims 1, 8 and 15 recite “ascertaining a plurality of molecular multipole moments of an antibody molecule; executing a molecular dynamics simulation representing a plurality of molecules in a solution to generate a time-dependent trajectory data for the model of the antibody molecule, wherein at least one molecule of the plurality of molecules is an instance of the model of the antibody molecule and the molecular dynamics simulation simulates interactions based on the charges calculated for each of the plurality of sites within the representation of the antibody molecule; outputting the predicted property of the solution.”
Claims 4, 11 and 18 recite “wherein ascertaining the plurality of molecular multipole moments of the antibody molecule is performed by: (i) modeling a charge distribution of the antibody molecule using an atomic model of the antibody molecule, or (ii) receiving an electric field calculation of the antibody molecule.”
Claims 2-7 recite “The computer-implemented method of claim 1.”
Claim 8 recites “A system comprising: one or more data processors; and a non-transitory, computer-readable storage medium containing instructions which, when executed on the one or more data processors, cause the one or more data processors to perform actions including:”
Claims 9-14 recite “The system of claim 8.”
Claim 15 recites “A computer-program product tangibly embodied in a non-transitory machine-readable storage medium, including instructions configured to cause one or more data processors to perform actions including:”
Claim 16-20 recite “The computer-program product of claim 15.”
Regarding the above cited limitations of a computer-implemented method (claims 1-7), a system comprising one or more data processors, a non-transitory computer-readable storage medium containing instructions (claims 8-14), and a computer-program connected to a non-transitory machine-readable storage medium containing instruction (claims 15-20). There are no limitations that these claims require anything other than a generic computer or generic computing system. Therefore, these limitations equate to mere instructions to implement an abstract idea on a generic computer, which the courts have established does not render an abstract idea eligible in Alice Corp. 573 U.S. at 223, 110 USPQ2d at 1983.
Regarding the above cited limitations in claims 1, 4, 8, 11, 15 and 18 of ascertaining a plurality of molecular multipole moments, executing a molecular dynamics simulation, outputting the predicted property of the solution, and receiving an electric field calculation of the antibody molecule. These limitations equate to insignificant, extra-solution activity of mere data gathering and outputting because they are necessary data gathering steps to perform the recited judicial exception in claims 1, 8 and 15 of “creating a model”, “calculating a charge”, and “predicting a property” and because they output the results of the judicial exception. Limitations that equate to insignificant, extra-solution activity and do not integrate the recited judicial exception into a practical application (MPEP 2106.05(g)(3)).
As such, claims 1-20 are directed to an abstract idea and a natural phenomenon (Step 2A, Prong 2: No).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). These claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these claims recite additional elements that equate to instructions to apply the recited exception in a generic way and/or in a generic computing environment (MPEP § 2106.05(f)) and to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The instant claims recite the following additional elements:
Claim 1 recites “A computer-implemented method comprising:”
Claims 1, 8 and 15 recite “ascertaining a plurality of molecular multipole moments of an antibody molecule; executing a molecular dynamics simulation representing a plurality of molecules in a solution to generate a time-dependent trajectory data for the model of the antibody molecule, wherein at least one molecule of the plurality of molecules is an instance of the model of the antibody molecule and the molecular dynamics simulation simulates interactions based on the charges calculated for each of the plurality of sites within the representation of the antibody molecule; outputting the predicted property of the solution.”
Claims 4, 11 and 18 recite “wherein ascertaining the plurality of molecular multipole moments of the antibody molecule is performed by: (i) modeling a charge distribution of the antibody molecule using an atomic model of the antibody molecule, or (ii) receiving an electric field calculation of the antibody molecule.”
Claims 2-7 recite “The computer-implemented method of claim 1.”
Claim 8 recites “A system comprising: one or more data processors; and a non-transitory, computer-readable storage medium containing instructions which, when executed on the one or more data processors, cause the one or more data processors to perform actions including:”
Claims 9-14 recite “The system of claim 8.”
Claim 15 recites “A computer-program product tangibly embodied in a non-transitory machine-readable storage medium, including instructions configured to cause one or more data processors to perform actions including:”
Claim 16-20 recite “The computer-program product of claim 15.”
Regarding the above cited limitations of a computer-implemented method (claims 1-7), a system comprising one or more data processors, a non-transitory computer-readable storage medium containing instructions (claims 8-14), and a computer-program connected to a non-transitory machine-readable storage medium containing instruction (claims 15-20). There are no limitations that these claims require anything other than a generic computer or generic computing system. Therefore, these limitations equate to instructions to implement an abstract idea on a generic computing environment, which the courts have established does not provide an inventive concept in Intellectual Ventures I LLC v. Capital One Bank (USA), 792 F.3d 1363, 1367, 115 USPQ2d 1636, 1639 (Fed. Cir. 2015).
Additionally, storing code on a non-transitory computer readable medium as recited in claims 8 and 15 equates to storing information in memory, which the courts have established as a WURC function of a generic computer in Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015).
Regarding the above cited limitations in claims 1, 4, 8, 11, 15 and 18 of ascertaining a plurality of molecular multipole moments, outputting the predicted property of the solution, and receiving an electric field calculation of the antibody molecule. These limitations equate to receiving/transmitting data over a network, which the courts have established as WURC limitation of a generic computer in buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014).
Regarding the above cited limitations in claims 1, 4, 8, 11, 15, and 18 of generic computer components/functions in combination with executing a molecular dynamics simulation, these limitations are WURC as taught below by Li et al. (“Li”; Journal of chemical theory and computation 12, no. 12 (2016): 6147-6156; newly cited), Liwo et al. (“Liwo”; Journal of molecular modeling 20, no. 8 (2014): 2306; newly cited), and Shen et al. (“Shen”; Journal of chemical theory and computation 10, no. 2 (2014): 731-750; previously cited on PTO892 mailed 08/11/2025).
Li discloses a two-bead multipole force field (TMFF) for coarse-grained (CG) molecular dynamics (MD) simulations of large biomolecular systems (title), wherein a single bead (CG site) represents a group of atoms or residues (pg. 6147, col. 1, para. 1). Li states “we develop a two-bead multipole force field (TMFF) CG model by incorporating electric multipoles into the CG sites in order to represent the anisotropic interactions at the CG level. In the present TMFF model, the multipoles of the CG beads are described by a local-frame strategy” (pg. 6148, col. 1, last para.). CG MD simulations were carried out up to 87 ns using the TMFF for proteins (pg. 6152, sec. 3.2.). Figure 6 shows RMSD trajectories from CG simulations as a function of time.
Liwo discloses a unified CG model of biological macromolecules, including proteins, based on mean-field multipole-multipole interactions (title). MD simulations were performed up to 20 fs (pg. 8, col. 1, para. 4) (Scheme 1). In CG methods, a number of atoms are merged into single interaction sites (pg. 1, col. 2). Liwo discloses representing repeated peptide groups as point multipoles (abstract).
Shen discloses an anisotropic CG model for proteins based on electric multipole potentials (title). Shen teaches describing electrostatic interactions between CG sites by introducing electric multipole potentials (pg. 732, col. 1, last para. – col. 2, para. 1) (pg. 734, col. 1, para. 2). The CG MD trajectories were carried up 2 microseconds for dipeptides and up to 20 ns for two proteins (pg. 734, col. 2, last para.) (Figure 12).
When these additional elements are considered individually and in combination, they do not provide an inventive concept because they all equate to WURC functions/components of a generic computer in combination with a generic molecular dynamics simulation as taught above by Li, Liwo, and Shen. Therefore, these additional elements do not transform the claimed judicial exception into a patent-eligible application of the judicial exception and do not amount to significantly more than the judicial exception itself (Step 2B: No).
As such, claims 1-20 are not patent eligible.
Response to Arguments under 35 USC 101
Applicant's arguments filed 11/12/2025 have been fully considered but they are persuasive only in part.
Applicant lists limitations believed to be additional elements in claim 1 (top of pg. 12 of Applicant’s remarks). Applicant’s arguments are persuasive in part for the following reasons:
All limitations listed by applicant have been identified as reciting an additional element except the limitation of “creating a model of the antibody molecule”.
Applicant argues that the following limitation in claim 1 is not a mental process because it requires computational analysis and numerical solution of systems of equations that are infeasible to perform using pen and paper: “creating a model of an antibody body molecular by selecting a plurality of sites within a representation of the antibody molecule”. Applicant references specification paras. that outline these computational steps (pg. 12, last para. of Applicant’s remarks). Applicant’s argument is not persuasive for the following reasons:
Claim 1 does not require solving charge values using three-dimensional molecular structure nor does it require numerical solution of systems of equations. The BRI of “creating a model” includes making a mental determination (i.e., selecting sites that represent the antibody), and then drawing the model on pen and paper.
Applicant argues that the following limitation in claims 1 does not recite a mathematical concept or natural phenomenon: “executing a molecular dynamics simulation representing a plurality of molecules in a solution to generate a time-dependent trajectory for the model of the antibody molecule” (pg. 13, para. 2 – pg. 15, para. 2 of Applicant’s remarks). Examiner agrees that this limitation is based on math but does not recite a mathematical concept or a natural phenomenon.
Applicant argues that their method improves computer functionality by running molecular dynamics simulations that are an order of magnitude less computationally expensive than all-atom simulations (pg. 16, para. 1-3). Applicant’s argument is not persuasive for the following reasons:
It appears that the alleged improvement in computer functionality is a result of performing “creating a model of the antibody by selecting a plurality of sites” and “calculating a charge for each of the plurality of sites”. These limitations are used in the molecular dynamics simulation. Although Applicant argues that this reduces computational complexity, nothing about a general-purpose computer itself is improved. For example, neither the way a processor functions nor the way in which the computer stores or accesses memory is improved. Rather, the computer performs the molecular dynamics simulations with a simpler, less computationally expensive model. However, nothing about the physical components of the computer nor the way the computer operates is changed merely by providing the computer with a simpler abstract idea. Therefore, the instant claims merely invoke computers as a tool. Applicant has not provided any evidence or technical explanation for how the abstract idea improves the way in which the computer processes or stores data.
Applicant argues that claim 1 improves the technical field of molecular simulations (pg. 16, para. 1 – pg. 17, para. 1 of Applicant’s remarks). Applicant’s arguments are not persuasive for the following reasons:
Although Applicant identifies a technical problem and explains details for how their invention provides a technical solution, the solution is not an unconventional technical solution. MPEP 2106.05(a) recites “An indication that the claimed invention provides an improvement can include a discussion in the specification that identifies a technical problem and explains the details of an unconventional technical solution expressed in the claim, or identifies technical improvements realized by the claim over the prior art”. However, as discussed in the rejection above, Li, Liwo, and Shen use coarse-grained models of proteins that integrate multipole moments for molecular dynamic simulations, which reduce computational expense. Coarse-grained models require less computational resources because they are not all-atom models. Thus, the independent claims of the instant invention do not recite an unconventional technical solution.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 1-6, 8-13 and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Chaudhri et al. (“Chaudhri”; The Journal of Physical Chemistry B 116, no. 28 (2012): 8045-8057; NPL ref. 7 on the IDS filed 02/25/2025) in view of Anandakrishnan et al. (“Anandakrishnan”; PloS one 8, no. 7 (2013): e67715; NPL ref. 5 on the IDS filed 02/25/2022) and Gramada et al. (“Gramada”; Computer Physics Communications 182, no. 7 (2011): 1455-1462; previously cited on PTO892 mailed 08/11/2025).
This rejection is newly recited as necessitated by claim amendment.
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claims 1, 8 and 15:
A computer-implemented method comprising:
A system comprising: one or more data processors; and a non-transitory, computer-readable storage medium containing instructions which, when executed on the one or more data processors, cause the one or more data processors to perform actions including:
A computer-program product tangibly embodied in a non-transitory machine-readable storage medium, including instructions configured to cause one or more data processors to perform actions including:
Chaudhri discloses coarse-grained (CG) models of monoclonal antibodies (MAbs) to understand effect of domain-level charge-charge electrostatics on self-association at high protein concentrations (abstract). Chaudhri uses a supercomputing facility to run software such as the LAMMPS package (pg. 8049, col. 2, para. 2; pg. 8056, col. 2, sec. Acknowledgements), indicating computer use which inherently contains processors and memory.
ascertaining a plurality of molecular multipole moments of an antibody molecule;
Chaudhri discloses using charge distributions of MAbs, but does not teach using molecular multipole moments of MAbs (pg. 8048, col. 1, para. 1).
Anandakrishnan discloses Optimal Point Charge Approximation (OPCA), which is “an approach for approximating electrostatic charge distributions with a small number of point charges to optimally represent the original charge distribution” (abstract). Anandakrishnan recites “OPCAs retain many of the useful properties of point multipole expansions, in particular they retain the asymptotic behavior of the point multipole expansion” (pg. 12, col. 1, para. 2), and “OPCAs (and their practical approximations, PPCAs) inherit the physically appealing asymptotic properties of the point multipole approximation, i.e. the error in potential is guaranteed to fall off at least as fast as 1=Rkz1, where R is the distance from the origin and k is the highest order of the multipole terms retained in the expansion” (pg. 12, col. 2, para. 2).
creating a model of the antibody molecule by selecting a plurality of sites within a representation of the antibody molecule, wherein: a total number of the plurality of sites is less than a total number of atoms in the antibody molecule;
Chaudhri shows in Figure 1 the CG models of the MAbs, which contain a 12 CG site and a 26 CG site model for the MAbs. Each CG site represents the underlying residues at the CG site (pg. 8048, col. 1, para. 1). Thus, the number of CG sites is less than a number of atoms within each MAb.
the plurality of sites comprises a first subset of the plurality of sites and a second subset of the plurality of sites;
Chaudhri shows in Figure 2 CG representations of the antibodies. Table 1 shows the symmetric pairings of CG sites in each antibody, which are symmetric along the AB plane in Figure 2. For example, in the 12 CG site model of MAb1, the symmetric pair of 1,7 equates to a plurality of sites wherein 1 is a first subset and 7 is the second subset.
and a total number of sites within the first subset of the plurality of sites is equal to a total number of molecular multipole moments within the plurality of molecular multipole moments;
Chaudhri shows in Figure 2 and Table 1 CG sites. In Figure 2, the first subset is to the left of the black vertical line. However, Chaudhri does not teach that the CG sites are equal to a number of molecular multipole moments within a plurality of molecular multipole moments.
Gramada teaches coarse-graining the electrostatic potential via distributed multipole expansions (abstract). Coarse-graining determines structural CG beads, which consists of distributing atoms of a molecule into separate subsystems (pg. 3, sec. 2.1). Gramada teaches “for the electrostatic interaction, which forms our main interest, the multipole expansions provide an ideal candidate for the coarse-graining of the electrostatic potential of a three dimensional molecule” (pg. 3, sec. 2.1). Gramada also recites “the selection of control points defining the domain of convergence of the multipole expansions (which determines the number of interaction CG beads in the model – i.e., the granularity at which the distribution of charged is analyzed by the partitioning scheme)” (pg. 10, last para.).
It would have been prima facie obvious to one of ordinary skill in the art to have modified the CG method of Chaudhri by making each CG site represent a domain of convergence of the multipole expansion as taught by Gramada. This would result in the number of CG sites being equal to the number of multipole expansions defined by control points. The motivation for doing so is taught by Gramada who recites “The advantages of this technique are: 1) it provides a systematic description of the electrostatic field in terms of a hierarchical set of multipoles describing features at various spatial scales (i.e., it is intrinsically a multi-scale approach)”.
One of ordinary skill in the art would have had a reasonable expectation of success because Gramada demonstrates their method is compatible with proteins (Figure 3; sec. 4), wherein Chaudhri uses proteins (abstract). Gramada also states that their CG model is used in molecular simulations (1, para. 1) (pg. 8, para. 4), wherein Chaudhri also uses a CG model in molecular dynamics simulations (pg. 8049, col. 2, para. 2).
calculating a charge for each of the plurality of sites, wherein: a combination of calculated charges for the plurality of sites approximates the plurality of molecular multipole moments of the antibody molecule;
Chaudhri discloses calculating charges at the CG sites for the antibodies (Table 1; pg. 8048, col. 1, para. 1). However, Chaudhri does not teach that a combination of charges at the CG sites approximates a plurality of molecular multipole moments of the antibody.
Anandakrishnan teaches that OPCA approximates a charge distribution using a given number of point charges, which optimally reproduce the lowest order multipoles in the expansion of the original distribution (pg. 2, col. 1, para. 2). Anandakrishnan recites “1-charge and 2-charge OPCAs are at least as accurate as the equivalent order point multipole approximations, i.e. the point monopole and dipole approximations” recites “OPCAs retain many of the useful properties of point multipole expansions, in particular they retain the asymptotic behavior of the point multipole expansion” (pg. 12, col. 1, para. 2). Thus, Chaudhri and Anandakrishnan disclose together that the CG sites would have OPCA values, which approximate the multipole moments of the antibody.
It would have been prima facie obvious to one of ordinary skill in the art to have modified the method of Chaudhri for calculating charges of CG sites by using the OPCA method of Anandakrishnan. The motivation for doing so is taught by Anandakrishnan who teaches “a limitation a of coarse-graining includes fitting representative charges to minimize electrostatic error over some arbitrary volume or surface does not guarantee asymptotic behavior and can potentially lead to relatively large errors outside the volume or surface used for fitting. OPCA, on the other hand, inherits the physically appealing asymptotic properties of the point multipole approximation, i.e. the error in potential is guaranteed to fall off at least as fast as 1/Rk+1, where R is the distance from the origin and k is the highest order of the multipole terms retained in the expansion” (pg. 12, col. 2, para. 2). Anandakrishnan also states that their method has many desirable properties that may be useful in practical computations such as in existing molecular dynamics protocols (pg. 12, col. 2, para. 3). Chaudhri also recites motivation by stating that viscosity profiles for MAbs that can be based on intermolecular interactions such as short-range attractive potentials from charge-dipole and dipole-dipole interactions, which are multipole moments (pg. 8046, col. 2, para. 2).
One of ordinary skill in the art would have had a reasonable expectation of success because Anandakrishnan states that their method is expected to have utility in coarse-grained methods, especially in molecular dynamics (pg. 12, col. 2, para. 4). Anandakrishnan provides a framework for computing OPCAs for any given number of approximating charges (abstract), which can be implemented in applications that already utilizes point charges such as in molecular dynamics packages (pg. 2, col. 1, last para.).
and for each site of the second subset of the plurality of sites, a charge calculated for each site is equal to a charge calculated for a corresponding site of the first subset of the plurality of sites;
Chaudhri shows in Table 1 that corresponding site numbers 1 and 7 for MAb1 have the same charge +3.5. All pairs of CG sites in the same antibody have the same calculated charge as seen in Table 1.
executing a molecular dynamics simulation representing a plurality of molecules in a solution to generate a time-dependent trajectory data for the model of the antibody molecule, wherein at least one molecule of the plurality of molecules is an instance of the model of the antibody molecule and the molecular dynamics simulation simulates interactions based on the charges calculated for each of the plurality of sites within the representation of the antibody molecule;
Chaudhri performed Langevin dynamics simulations using the CG sites to capture effect of solvent friction, which includes model parameters of 1,000 MAb molecules arranged in a cubic lattice (pg. 8049, col. 2, para. 2). CG simulations for rigid antibodies used a time step of 1 ps while flexible antibodies used 20 ns (Table 2). Table 1 shows the charge used at each CG site in all CG simulations.
predicting a property of the solution using data from the molecular dynamics simulation; and
Chaudhri states that CG model simulations predicted differences in self-association characteristics between the two antibodies (pg. 8055, col. 1, last para.). The models predicted that effective domain-level electrostatic interactions play a dominant role in the self-association of antibodies (pg. 8055, col. 2, para. 2).
outputting the predicted property of the solution.
Chaudhri shows in Figure 9 a radial distribution function plot for the antibodies at the CG sites and demonstrates homogenous structures of the antibodies in solutions. Figure 4 shows cluster formation in the equilibrated structure of the compact Y-shaped 12 site rigid MAb1 model after simulations in solution.
Claims 2, 9 and 16:
Chaudhri shows in Figures 1 and 2 and in Table 1 that the antibodies contain corresponding subsets of CG sites such as CG sites 1 and 7.
Claims 3, 10 and 17:
Chaudhri discloses calculating charges of the CG sites in Table 1, which were calculated by summing the partial charges of the underlying resides that each site represents (pg. 8047, col. 1, para. 1). However, Chaudhri does not teach calculating charges of the CG sites using multipole moments of the antibodies. Anandakrishnan teaches calculating charges of CG sites using multipole moments with the OPCA technique (abstract; Figure 1; Table 1).
Claims 4, 11 and 18:
Chaudhri does not teach ascertaining a plurality of molecular multipole moments of an antibody molecule by modeling a charge distribution of the antibody using an atomic model of the antibody. Anandakrishnan teaches “Atomic partial charges were taken from the AMBER force field parameters [28]. The electrostatic potential was calculated in the mid-field (for two values:
PNG
media_image1.png
12
45
media_image1.png
Greyscale
Å
PNG
media_image2.png
15
40
media_image2.png
Greyscale
and
PNG
media_image3.png
12
44
media_image3.png
Greyscale
Å
PNG
media_image4.png
15
40
media_image4.png
Greyscale
) where the approximation is likely to be least accurate. The electrostatic potential was computed at discrete points on a sphere of radius
PNG
media_image5.png
11
11
media_image5.png
Greyscale
, centered at the center of geometry. The spherical surface was discretized into 7200 grid points at which the electrostatic potential was calculated. The RMS error was calculated over all grid points and all the amino acid groups in the sample as
PNG
media_image6.png
30
144
media_image6.png
Greyscale
where
PNG
media_image7.png
12
11
media_image7.png
Greyscale
and
PNG
media_image8.png
17
27
media_image8.png
Greyscale
are the electrostatic potential calculated using the approximations and the reference (original) charge distributions, respectively, and
PNG
media_image9.png
12
14
media_image9.png
Greyscale
is the number of grid points. The 2-charge PPCA was compared to the optimal point dipole and the point quadrupole approximations. The center of expansion for the point dipole approximation for uncharged and charged distributions are chosen to be the center of dipole and center of charge, respectively, which are known to be optimal for the corresponding point multipole expansions” (pg. 8, col. 1 – pg. 9, col. 1, para. 1).
Claims 5, 12 and 19:
Chaudhri shows in Table 1 that there is a set of CG sites for the 12 site model (second subset) and a set of CG sites for a 26 site model (first subset).
Claims 6, 13 and 20:
Chaudhri shows in Figure 1 that the monoclonal antibodies are Y-shaped four chain polypeptides, which contains three arms. The CH2 and CH3 domains form the Fc region of the mAb. The VH, VL and CH1 domains from the Fab region of the mAb. Figure 2 shows that CG sites on the left side of the AB plane includes sites from the Fab (first arm) and Fc (third arm) regions. Figure also shows that the right side of the AB plane includes sites from the Fab (second arm) and Fc (third arm) regions. The AB plane in Figure 2 divides the antibodies into a mirror image.
Claim 7 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Chaudhri et al. (“Chaudhri”; The Journal of Physical Chemistry B 116, no. 28 (2012): 8045-8057; NPL ref. 7 on the IDS filed 02/25/2025) in view of Anandakrishnan et al. (“Anandakrishnan”; PloS one 8, no. 7 (2013): e67715; NPL ref. 5 on the IDS filed 02/25/2022) and Gramada et al. (“Gramada”; Computer Physics Communications 182, no. 7 (2011): 1455-1462; previously cited on PTO892 mailed 08/11/2025), as applied above to claims 1 and 8, and in further view of Agrawal et al. (“Agrawal”; In MAbs, vol. 8, no. 1, pp. 43-48. Taylor & Francis, 2016; previously cited on PTO892 mailed 08/11/2025).
This rejection is newly recited as necessitated by claim amendment.
The limitations of claims 1 and 8 have been taught in the rejection above by Chaudhri in view of Anandakrishnan and Gramada.
Regarding claims 7 and 14, Chaudhri predicts self-association characteristics of therapeutic antibodies (abstract). However, Chaudhri, Anandakrishnan, and Gramada do not disclose removing the antibodies from a list of potential polypeptides based upon a predicted property of the solution.
Agrawal discloses a computational tool for early screening of monoclonal antibodies (mAbs) for their viscosity (abstract). Agrawal states that mAbs are administered intravenously or subcutaneously at highly concentrated solutions and that highly vicious antibodies are difficult to inject subcutaneously (pg. 43, col. 1, last para.). Agrawal suggests that in order to develop high-concentration liquid formulation to overcome highly vicious antibodies, early identification and screening of problematic drugs such as highly vicious antibodies is necessary (pg. 43, col. 2, para. 1), thereby eliminating or reducing candidate drugs.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the method of Chaudhri, Anandakrishnan, and Gramada with Agrawal by eliminating an antibody predicted to be highly viscous in a high concentration formulation. Agrawal teaches motivation for doing so by stating that a screening step to remove poor candidate drugs is a prerequisite for successful developability studies (pg. 43, col. 2, para. 2). One of ordinary skill in the art would have had a reasonable expectation of success for the combination because Chaudhri states that the formation of dense clusters of mAb1 at 120 mg/Ml suggests a correlation between ordering observed using CG models and the high viscosity observed experimentally (pg. 8055, col. 2, para. 1), wherein an antibody that produces dense clusters indicates high viscosity.
Response to Arguments under 35 USC 103
Applicant's arguments filed 11/12/2025 have been fully considered but they are not persuasive.
Applicant argues that Anandakrishnan does not teach the limitation “a total number of the plurality of sites is less than a total number of atoms in the antibody molecule” (pg. 18, sec. I of Applicant’s remarks). Applicant’s argument is not persuasive for the following reasons:
Chaudhri teaches this limitation. Both in the current Office action and in the previous office action. Anandakrishnan was never used to teach this limitation.
Applicant argues that Anandakrishnan does not teach the limitation “a combination of calculated charges for the plurality of sites approximates the plurality of molecular multipole moments of the antibody molecule” (pg. 18-20, sec. II of Applicant’s remarks). Applicant’s argument is not persuasive for the following reasons:
Applicant argues against the references individually. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The combination of Chaudhri and Anandakrishnan teach this limitation. Chaudhri calculates charges (a combination of calculated charges) at the CG sites (for the plurality of sites) of the antibodies (of the antibody molecule) (Table 1; pg. 8048, col. 1, para. 1). However, Chaudhri does not teach that charges at the CG sites approximate a plurality of molecular multipole moments of the antibody. Anandakrishnan teaches that OPCA approximates a charge distribution using a given number of point charges, which optimally reproduce the lowest order multipoles in the expansion of the original distribution (pg. 2, col. 1, para. 2). Anandakrishnan recites “1-charge and 2-charge OPCAs are at least as accurate as the equivalent order point multipole approximations, i.e. the point monopole and dipole approximations” and recites “OPCAs retain many of the useful properties of point multipole expansions, in particular they retain the asymptotic behavior of the point multipole expansion” (pg. 12, col. 1, para. 2). Thus, Chaudhri and Anandakrishnan disclose together that the CG sites would have OPCA values, which approximate the multipole moments of the antibody.
Applicant argues that none of the cited references teach the limitation “executing a molecular dynamics simulation representing a plurality of molecules in a solution to generate a time-dependent trajectory data for the model of the antibody molecule” (pg. 20, sec. III of Applicant’s remarks). Applicant’s argument is not persuasive for the following reasons:
Applicant argues against the references individually. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The combination of Chaudhri, Anandakrishnan, and Gramada disclose the model in instant claim 1, as discussed in the rejection above. Chaudhri discloses Langevin dynamics simulations using the CG sites of the antibodies. Chaudhir teaches that CG simulations for rigid antibodies use a timestep of 1 ps while flexible antibodies use 20 ns (Table 2), and Table 1 shows the charges used at each CG site in all CG simulations (pg. 8049, col. 2, para. 2). The modifications to the CG model of the antibodies in Chaudhri by Anandakrishnan and Gramada would cause the modified model to be used in the molecular dynamics simulation of Chaudhri.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Noah A. Auger whose telephone number is (703)756-4518. The examiner can normally be reached M-F 7:30-4:30 EST.
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, Karlheinz Skowronek can be reached on (571) 272-9047. 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.
/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685