DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-23 are pending and examined on the merits.
Priority
The instant application filed on 3/15/2023 claims the benefit of priority to U.S. Provisional Patent Application No. 63/269,392 filed on 3/15/2022. Thus, the effective filing date of the claims is 3/15/2022.
The applicant is reminded that amendments to the claims and specification must comply with 35 U.S.C. § 120 and 37 C.F.R. § 1.121 to maintain priority to an earlier-filed application. Claim amendments may impact the effective filing date if new subject matter is introduced that lacks support in the originally filed disclosure. If an amendment adds limitations that were not adequately described in the parent application, the claim may no longer be entitled to the priority date of the earlier filing.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 8/19/2024 has been entered and considered. A signed copy of the corresponding 1449 form has been included with this Office action.
Specification
The disclosure is objected to because of the following informalities:
Abstract, last line, "and can further select which atomic structure is to be added the selected location" should read "and can further select which atomic structure is to be added to the selected location".
Appropriate correction is required.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color (Figures 5A and 5B). Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The drawings do not comply with 37 CFR 1.84(u)(1) and (u)(2):
(u)(1) The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). 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. View numbers must be preceded by the abbreviation "FIG." Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation "FIG." must not appear.
(u)(2) Numbers and letters identifying the views must be simple and clear and must not be used in association with brackets, circles, or inverted commas. The view numbers must be larger than the numbers used for reference characters.
Specifically, drawings may not use the (1 of 4), (2 of 4), etc. numbering as part of the view numbers, and they can’t have multiple FIG. 5A figures. Corrections should appear as FIG. 5A, FIG. 5B, FIG. 5C, etc.
Claim Objections
Claims 8 and 16 objected to because of the following informalities:
Claim 8 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. In this case, the use of the trained computational model to predict a binary label of whether a hydrogen would be or would not be replaced by the atomic structure limits the claimed model. The closest prior art is considered to be Ingman, as discussed below relating to the rejection of claim 1 under 35 U.S.C. 103. As discussed below, Ingman teaches replacing hydrogen (and other atoms) with various atomic structures. However, the further inclusion of a computational model for predicting and labeling hydrogens for replacement (or not) is not present in Ingman or any of the prior art of record.
Claim 16; "the core ligand compound structure is a computationally generated structure that is putatively expected to associate with target macromolecule structure" should read "the core ligand compound structure is a computationally generated structure that is putatively expected to associate with the target macromolecule structure".
Appropriate correction is required.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation (BRI) using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
The terms "associating" and "associate" found in claims 1 and 16, respectively, are interpreted as described in para.0044 of the instant specification: "the macromolecule is a protein (e.g., enzyme) and the associated ligand is designed to modulate the protein’s function and/or activity". I.e. the terms are interpreted as modulating a protein's function and/or activity.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 23 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 23, the written description of the instant specification does not explicitly disclose a means for the chemically synthesized ligand to be "utilized in a medicinal formula for treatment of a medical disorder or disease; [. . .] utilized as modulator in biochemical experimentation; or [. . .] utilized in an agricultural product". The instant specification does not provide any written descriptions of any active, positive steps delimiting how this use is actually practiced.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-23 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 16 recite "wherein the core ligand compound is putatively capable of associating with the target macromolecule via a chemical interaction" and "the core ligand compound structure is a computationally generated structure that is putatively expected to associate with target macromolecule structure", respectively. The metes and bounds of "putatively" capable/expected are not clear because there is no definition for what constitutes "putative" in these contexts, as the instant specification does not further illuminate its meaning beyond a strict dictionary definition (commonly accepted, supposed, or reputed to be true, even though there is no absolute proof). To further prosecution, the term "putatively" is interpreted as "may be".
Claim 8 recites "the binary label computed is whether a hydrogen would be or would not be replaced by the atomic structure in the generated three-dimensional ligand compound structure". There is insufficient antecedent basis for “the binary label” because claim 7 recites multiple binary labels: "the training is performed with supervision and binary labels are computed for each attachment location". To further prosecution, the limitation in claim 7 is interpreted as “the training is performed with supervision and a binary label is computed for each attachment location".
Claim 12 recites "the particular atomic structure that has been selected to be added is a small molecular structure selected from: an alkene, an alkyne, a carboxyl group, an amino groups, or a ring structure". The term "small" here is a relative term, therefore the metes and bounds of the limitation are unclear (i.e. How many atoms can those molecular structures contain and still be considered "small"?). To further prosecution the limitation is interpreted as "the particular atomic structure that has been selected to be added is selected from: an alkene, an alkyne, a carboxyl group, an amino groups, or a ring structure".
Claim 14 recites "the training is performed with supervision and labels can be computed for an additive state in which one label represents the correct additive state and a plurality of labels represents decoy states". There is insufficient antecedent basis for “the correct additive state”. It is not clear what a “correct additive state” is versus an incorrect state. So which additive state is this being referred to? There may even be multiple correct additive states.
Regarding claims 22 and 23, the steps of "chemically synthesizing the final three-dimensional ligand structure to yield a chemically synthesized ligand" and "the chemically synthesized ligand is utilized in a medicinal formula for treatment of a medical disorder or disease; wherein the chemically synthesized ligand is utilized as modulator in biochemical experimentation; or wherein the chemically synthesized ligand is utilized in an agricultural product" are not enabled by the "computational method" of claim 1, or by the computer system disclosed. The computer system has no disclosed parts or features that are enabled for physical sample manipulation. To further prosecution, the "computational method" is interpreted simply as a "method".
Claim 23 recites "the chemically synthesized ligand is utilized in a medicinal formula for treatment of a medical disorder or disease; wherein the chemically synthesized ligand is utilized as modulator in biochemical experimentation; or wherein the chemically synthesized ligand is utilized in an agricultural product". The limitation is claiming what the ligand's function is, rather than what the ligand is (i.e. how is a ligand being determined for use as one product or another?). According to MPEP 2173.05(g), the use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. Further, without reciting the particular structure, materials or steps that accomplish the function or achieve the result, all means or methods of resolving the problem may be encompassed by the claim. Therefore, the metes and bounds of the claim are indefinite. To further prosecution, the limitation is interpreted as further limiting the chemically synthesized ligand in some way (with the function of being able to be used in a treatment, as an agricultural product, etc.).All other claims depend from claim 1 and therefore are also rejected under 35 USC 112(b).
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 1-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of a mental process, a mathematical concept, organizing human activity, or a law of nature or natural phenomenon without significantly more. In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 1: “(a) selecting a target macromolecule structure and a core ligand compound structure, wherein the core ligand compound is putatively capable of associating with the target macromolecule via a chemical interaction; (b) selecting an attachment location on the core ligand structure for addition of an atomic structure; (c) selecting a particular atomic structure to be added at the selected attachment location” provides an evaluation (selecting molecules, locations, and structures all involve evaluating options) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
Claim 8: “the binary label computed is whether a hydrogen would be or would not be replaced by the atomic structure in the generated three-dimensional ligand compound structure” provides a mathematical calculation (encompasses utilizing mathematical algorithms such as nearest neighbor and naïve bayes, that can process coordinates) that is considered a mathematical concept, which is an abstract idea.
Claim 9: “the selecting of the particular atomic structure is performed utilizing a computational model capable of interpreting three-dimensional data, wherein the model is trained by utilizing known ligand-macromolecule structures that are deconstructed by removing atomic structures” provides a mathematical calculation (encompasses utilizing mathematical algorithms such as nearest neighbor and naïve bayes, that can process coordinates) that is considered a mathematical concept, which is an abstract idea.
Claim 14: “the training is performed with supervision and labels can be computed for an additive state in which one label represents the correct additive state and a plurality of labels represents decoy states” provides a mathematical calculation (encompasses utilizing mathematical algorithms such as nearest neighbor and naïve bayes, that can process coordinates) that is considered a mathematical concept, which is an abstract idea.
Claim 17-21: “iteratively repeating step(b), step(c) [. . .] resulting in an addition of another selected atomic structure to the ligand structure at another selected location at each iteration, wherein step (b), step (c) [. . .] are iteratively repeated until a final three-dimensional ligand structure is yielded” provides an evaluation (repeating the abstract ideas of selecting molecular locations and structures, as well as determining when to stop repeating, involves evaluations) that may be performed in the human mind and is therefore considered a mental process, which is an abstract idea.
These recitations are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or are mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. As such, claims 1-23 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exceptions listed above are not integrated into a practical application because the claims do not recite an additional element or elements that reflects an improvement to technology. Specifically, the claims recite the following additional elements:
Claim 1: “(d) generating a three-dimensional ligand compound structure that is the core ligand compound structure with the selected atomic structure added at the selected attachment location” provides insignificant extra-solution activities (rendering a three-dimensional structure of user selections is a post-solution activity involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 3: “the computational model is a neural network that is equivariant to rotation and translation” is generally linking the abstract idea identified in claim 1 to the technological environment of neural networks.
Claim 17-21: “iteratively repeating [. . .] step (d)” provides insignificant extra-solution activities (iterating generation of a 3D molecular model is a pre-solution activity involving data manipulation steps) that do not serve to integrate the judicial exceptions into a practical application.
Claim 22: “chemically synthesizing the final three-dimensional ligand structure to yield a chemically synthesized ligand” provides insignificant extra-solution activities (mere instructions to apply the judicial exception) that do not serve to integrate the judicial exceptions into a practical application.
The steps for generating a 3D structure and chemically synthesizing the ligand are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application because they are pre- and post-solution activities involving data gathering. Additionally, the steps for using the chemically synthesized ligand as a treatment, experimental modulator, or agricultural product restricts use to a particular environment or application without adding significant innovation that does not serve to integrate the judicial exceptions into a practical application because they are post-solution activities involving a mere field of use (see MPEP 2106.04(d)(2) - Integration of a Judicial Exception Into A Practical Application; MPEP 2106.05(g) - Insignificant Extra-Solution Activity; and MPEP 2106.05(h) - Field of Use and Technological Environment). Finally, the neural network (NN) model of claims 3 and 10 is used to generally apply the abstract idea (i.e., perform the evaluations for selection in steps (a) - (c)) without placing any limitation on how the NN operates to "interpret three-dimensional data" or be "equivariant to rotation and translation". The claim omits any details as to how the NN solves a technical problem and instead recites only the idea of a solution or outcome. See MPEP 2106.05(f). Therefore, the limitation represents no more than mere instructions to implement the abstract idea recited in steps (a) - (c), which is equivalent to adding the words “apply it” to the recited judicial exception. In addition, the claim confines the use of the recited judicial exception recited in claim 1 to the technological environment of a NN by generally linking the use of the judicial exception to the recited NN. Therefore, this general NN recitation does not integrate the judicial exception into a practical application. See MPEP 2106.05(h). Therefore, it can also be viewed as nothing more than an attempt to generally link the use of the judicial exception to a particular field of use or a technological environment. Therefore, claims 1-23 are directed to an abstract idea (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application, or equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment.
The limitations for generating a 3D structure and chemically synthesizing the ligand are insignificant extra-solution activities that do not serve to integrate the recited judicial exceptions into a practical application. Furthermore, no inventive concept is claimed by these limitations as they are well-understood, routine, and conventional. Furthermore, no inventive concept is claimed by these limitations as they are demonstrated by Bain et al. (The AAPS journal 20.3 (2018): 59),Verma et al. (Current topics in medicinal chemistry 10.1 (2010): 95-115), the instant specification, as well as case law in MPEP 2106.05(f)(2) to be well-understood, routine, and conventional:
Bain recites on page 5 col 2 paragraph 2 "Haijun Chen et al. gave a comprehensive summary on improvements in the deconstruction-reconstruction approach for recent decades in 2014 (30). Instead of using established fragment libraries for the screening towards the given binding pocket and selecting preferable fragments, the deconstruction-reconstruction approach uses known ligands as the source for fragment generation. A relatively small and specific fragment library can be generated through the deconstruction of known ligands. The following reconstruction step is supposed to combine fragments in different regions and create novel compounds with new scaffolds."
Verma recites on page 3 table 1 Free and Wilson (1964) "Formulated an additive model, where the activity is discretized as a simple sum of contributions from different substituents [16]".
The instant specification calls out the common nature of computationally and experimentally assessing molecule binding: para.0003 “A common goal in drug discovery is to identify pharmaceutical compounds that have the potential to treat disease. A typical computational drug discovery platform utilizes a digital library of small molecules and computationally assesses the ability of each molecule to bind within a pocket of a protein macromolecule. Hits are then biochemically assessed for their ability to bind the protein and/or modulate the protein’s functions. Top hits identified via biochemical assessment are then optimized chemically by medicinal chemists and then optimized compounds are reassessed via biochemical experimentation.”. These references together demonstrate that these concepts have been in use in the field for decades and therefore are well-understood, routine, and conventional.
MPEP 2106.05(f)(2): Conventionality of neural networks see Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone) and TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-23 are not patent eligible.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1 and 15-16 rejected under 35 U.S.C. 103 as being unpatentable over Ingman et al. (Wiley Interdisciplinary Reviews: Computational Molecular Science 11.4 (2021): e1510).
Regarding claim 1, Ingman teaches a method of generating a three-dimensional ligand compound structure (Page 2 last paragraph "SEQCROW is a plug-in for UCSF ChimeraX[4] that adds tools to build and modify complex molecular structures, map new catalysts and ligands onto previously-computed structures, manage AaronTools libraries, construct input files for quantum chemistry packages, and run and manage jobs" and in the context of AaronTools, page 8 paragraph 3 "One could use mapLigand to take previously computed structures along a reaction pathway and replace the catalyst with another across each structure").
Ingman also teaches: (a) selecting a target macromolecule structure and a core ligand compound structure, wherein the core ligand compound is putatively capable of associating with the target macromolecule via a chemical interaction; (b) selecting an attachment location on the core ligand structure for addition of an atomic structure; and (c) selecting a particular atomic structure to be added at the selected attachment location (Page 7 last paragraph "The substitute command provides a flexible means of replacing any monovalent atom or substituent with a substituent from the built-in or user-defined libraries. To demonstrate this, Figure 2c shows the replacement of hydrogens 11 and 13 with methyl groups and the methyl group at atom 25 with a Ph ring in a TS structure for an Ir-catalyzed CH activation reaction").
Ingman also teaches (d) generating a three-dimensional ligand compound structure that is the core ligand compound structure with the selected atomic structure added at the selected attachment location (Page 18 paragraph 1 "SEQCROW also contains graphics presets for the generation of publication quality images of small to medium sized molecular structures and extends the capabilities of ChimeraX to be able to generate input files for popular quantum chemistry packages and run these jobs, plot simulated spectra, calculate thermal energy corrections, etc").
It is recognized that the citations and evidence provided above are derived from potentially different embodiments of a single reference. Nevertheless, it 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 to employ combinations and sub-combinations of these complementary embodiments, because Ingman et al. explicitly motivates doing so at least on page 20 ”While these tools were initially developed for applications in computational catalysis, they should be of general use by the quantum chemistry community, AaronTools being particularly broad in its applicability", and otherwise motivating experimentation and optimization. Additionally, doing so merely combines prior art elements according to known methods to yield predictable results.
Regarding claim 15, Ingman teaches the methods of Claim 1 on which this claim depends/these claims depend, respectively. Ingman also teaches the core ligand compound structure is a known ligand that has one or more atomic structures removed (QChASM contains the function "remove_fragment" which enables removal of atomic structures).
Regarding claim 16, Ingman teaches the methods of Claim 1 on which this claim depends/these claims depend, respectively. Ingman also teaches the core ligand compound structure is a computationally generated structure that is putatively expected to associate with target macromolecule structure (page 8 paragraph 3 "One could use mapLigand to take previously computed structures along a reaction pathway and replace the catalyst with another across each structure").
Claims 2, 4-9, and 17-23 rejected under 35 U.S.C. 103 as being unpatentable over Ingman et al. (Wiley Interdisciplinary Reviews: Computational Molecular Science 11.4 (2021): e1510) as applied to claims 1 and 15-16 above, and further in view of Basith et al. (Current medicinal chemistry 24.42 (2017): 4753-4778).
Ingman et al. is applied to claims 1 and 15-16.
Regarding claims 2 and 9, Ingman teaches the method of Claim 1 on which this claim depends/these claims depend.
Ingman does not explicitly teach the selecting of the attachment location is performed utilizing a computational model capable of interpreting three-dimensional data, wherein the model is trained by utilizing known ligand-macromolecule structures that are deconstructed by removing atomic structures.
However, Basith teaches fragment-based drug design (FBDD) utilizing a deconstruction-reconstruction approach and several methods utilizing trained models (Page 11 col 2 paragraph 2 "Nowadays, an attractive strategy in the field of FBDD involves the ‘deconstruction’ of known active compounds into several fragments, elucidation of binding positions of these fragments, and ‘reconstruction’ of these fragments into a new molecule, known as the deconstruction-reconstruction approach").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Ingman as taught by Basith in order to identify novel scaffolds and with strong predictive value (page 11 col 2 paragraph 2 "This information may be useful for SAR studies and identification of novel scaffolds" and page 14 col 2 last paragraph "A main advantage of machine learning methods is the strong prediction ability". One skilled in the art would have a reasonable expectation of success because both methods are concerned with in silico drug discovery.
Regarding claims 4-6, Ingman and Basith teach the methods of Claim 2 on which this claim depends/these claims depend, respectively. Ingman also teaches: the attachment location is at a position of a hydrogen atom; the attachment location is at a position of a double bond or triple bond; and the attachment location is at a position of an atom capable of gaining a charge (Page 7 last paragraph "The substitute command provides a flexible means of replacing any monovalent atom or substituent with a substituent from the built-in or user-defined libraries. To demonstrate this, Figure 2c shows the replacement of hydrogens 11 and 13 with methyl groups and the methyl group at atom 25 with a Ph ring in a TS structure for an Ir-catalyzed CH activation reaction").
Regarding claim 7, Ingman and Basith teach the methods of Claim 2 on which this claim depends/these claims depend, respectively. Basith also teaches the training is performed with supervision and binary labels are computed for each attachment location (Page 14 col 2 paragraph 2 "Descriptors are also required for this technique as features are necessary for building the models. As opposed to similarity-based screening where only a single query structure is required, machine learning-based search calls for a set of compounds, containing not only actives but also inactives, to build a reliable predictive model. Some of the frequently used supervised machine learning methods [204, 205] include support vector machines (SVM) [206, 207], decision trees (DT) [208], k-nearest neighbor (kNN) [209, 210], random forest (RF) [211], naïve Bayesian (NB) [212, 213], and artificial neural networks (ANN)" as active/inactive is a binary label).
Regarding claim 8, Ingman and Basith teach the methods of Claim 7 on which this claim depends/these claims depend, respectively. Basith also teaches the binary label computed is whether a hydrogen would be or would not be replaced by the atomic structure in the generated three-dimensional ligand compound structure, because the computational model in Basith is the same as the computational model in the claims, even if trained by a different process, and therefore reads on the claim (MPEP 2113 I. Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps).
Regarding claim 17-21, Ingman teaches the methods of Claim 1 on which this claim depends/these claims depend, respectively. Basith also teaches: iteratively repeating step (b), step (c) and step (d), resulting in an addition of another selected atomic structure to the ligand structure at another selected location at each iteration, wherein step (b), step (c) and step (d) are iteratively repeated until a final three-dimensional ligand structure is yielded; step (b), step (c) and step (d) are iteratively repeated until the generated three-dimensional ligand compound structure reaches a particular atomic weight; step (b), step (c) and step (d) are iteratively repeated until a selected number of iterations are performed; step (b), step (c) and step (d) are iteratively repeated until the generated three-dimensional ligand compound structure achieves a particular binding affinity for the target macromolecule structure; and step (b), step (c) and step (d) are iteratively repeated until a computational model predicts no further attachment points on the ligand structure, wherein the computational model is capable of interpreting 3D space of atomic structures and interactions between ligands and their associated macromolecule (lead optimization necessarily requires iterations until some threshold is reached, and Basith suggests using molecular weight and binding affinity on page 11 col 2 paragraph 2 "In contrast to intermediate to large compounds discovered as leads by current drug discovery methods, compounds with low molecular weight and simple structures are the main focus of FBDD, providing medicinal chemists with an excellent chance of controlling binding affinity and pharmacokinetic properties during lead optimization"). Additionally, repetition of previously recited steps and/or elements would have been prima facie obvious (MPEP 2143 E., Example 9 pertains).
Regarding claims 22-23, Ingman and Basith teach the methods of Claim 17 on which this claim depends/these claims depend, respectively. Basith also teaches: chemically synthesizing the final three-dimensional ligand structure to yield a chemically synthesized ligand; and the chemically synthesized ligand is utilized in a medicinal formula for treatment of a medical disorder or disease; wherein the chemically synthesized ligand is utilized as modulator in biochemical experimentation; or wherein the chemically synthesized ligand is utilized in an agricultural product (Page 12 col 1 paragraph 1 "Afterwards, they performed molecular docking to validate and select the best compounds to be synthesized for the assay tests. Consequently, they were able to obtain a lead compound with suitable activity against numerous cancer cell lines").
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Ingman as taught by Basith in order to integrate computational and experimental approaches for rapid discovery of novel therapeutics (page 1 abstract "Nowadays, the integration of experimental and computational approaches holds great promise in the rapid discovery of novel anticancer therapeutics"). One skilled in the art would have a reasonable expectation of success because both methods are concerned with in silico drug discovery.
Claims 3 and 10-14 rejected under 35 U.S.C. 103 as being unpatentable over Ingman et al. (Wiley Interdisciplinary Reviews: Computational Molecular Science 11.4 (2021): e1510) in view of Basith et al. (Current medicinal chemistry 24.42 (2017): 4753-4778) as applied to claims 1-2, 4-9, and 15-23 above, and further in view of Qiao et al. (WO-2021243106).
Ingman et al. in view of Basith et al. are applied to claims 1-2, 4-9, and 15-23.
Regarding claims 3 and 10, Ingman in view of Basith teach the method of Claims 2 and 9 on which this claim depends/these claims depend, respectively.
Ingman nor Basith explicitly teach the computational model is a neural network that is equivariant to rotation and translation.
However, Qiao teaches an equivariant neural network for molecule modeling (Para.0058 "In several embodiments, specific molecular system properties are utilized as inputs of an OrbNet process. [. . .]. In many embodiments, the input properties of the molecular system are a set of features based on symmetry-adapted atomic orbitals (SAAOs) and/or the derivatives of a set of SAAOs features. SAAOs are a set of atom-centered orbitals that satisfies one or more symmetries of the molecular system. SAAOs satisfy translational and rotational symmetry of the molecule, and permutational symmetry of the atoms" and para.0066 "OrbNet processes with AO based features integrate gauge symmetries in quantum interactions by formulating OrbNet as an equivariant map acting on tight-binding quantum operators [. . .] Certain embodiments provide that OrbNet processes with AO based features are equivariant with respect to non-orientation-preserving transformations through tracking the parity of spherical tensors, which may not be properly treated in SE(3) equivariant neural networks. The expressive power limitations present in many equivariant neural networks can be alleviated by normalization schemes, RepNorm in accordance with many embodiments. Several embodiments utilize a RepNorm normalization scheme to obtain more robust learning in OrbNet setups and/or other equivariant networks", as well as para.00104 and 00199).
Therefore, it would have been obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to modify the methods of Ingman and Basith as taught by Qiao in order to satisfy translational and rotational symmetry of molecules, and permutational symmetry of the atoms (Para.0058 "SAAOs [symmetry-adapted atomic orbitals] satisfy translational and rotational symmetry of the molecule, and permutational symmetry of the atoms"). Additionally, Qiao explicitly notes in para.00247 that " the above-mentioned concepts can be implemented in a variety of arrangements in accordance with embodiments of the invention. Accordingly, although the present invention has been described in certain specific aspects, many additional modifications and variations would be apparent to those skilled in the art. It is therefore to be understood that the present invention may be practiced otherwise than specifically described. Thus, embodiments of the present invention should be considered in all respects as illustrative and not restrictive". One skilled in the art would have a reasonable expectation of success because both methods are concerned with in silico drug discovery.
Regarding claims 11-13, Ingman, Basith, and Qiao teach the methods of Claim 10 on which this claim depends/these claims depend, respectively. Ingman also teaches: the particular atomic structure that has been selected to be added is an atom selected from: C, O, N, P, S, H, F, CI, or Br; the particular atomic structure that has been selected to be added is a small molecular structure selected from: an alkene, an alkyne, a carboxyl group, an amino groups, or a ring structure; and the small molecular structure has between 1 and 30 atoms (Page 7 last paragraph "The substitute command provides a flexible means of replacing any monovalent atom or substituent with a substituent from the built-in or user-defined libraries. To demonstrate this, Figure 2c shows the replacement of hydrogens 11 and 13 with methyl groups and the methyl group at atom 25 with a Ph ring in a TS structure for an Ir-catalyzed CH activation reaction").
Regarding claim 14, Ingman, Basith, and Qiao teach the methods of Claim 10 on which this claim depends/these claims depend, respectively. Basith also teaches the training is performed with supervision and labels can be computed for an additive state in which one label represents the correct additive state and a plurality of labels represents decoy states (Page 14 col 2 paragraph 2 "Descriptors are also required for this technique as features are necessary for building the models. As opposed to similarity-based screening where only a single query structure is required, machine learning-based search calls for a set of compounds, containing not only actives but also inactives, to build a reliable predictive model. Some of the frequently used supervised machine learning methods [204, 205] include support vector machines (SVM) [206, 207], decision trees (DT) [208], k-nearest neighbor (kNN) [209, 210], random forest (RF) [211], naïve Bayesian (NB) [212, 213], and artificial neural networks (ANN)" as "decoy" is interpreted from the instant specification as meaning inactive).
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Klei et al. "Ligand placement based on prior structures: the guided ligand-replacement method." Biological Crystallography 70.1 (2014): 134-143
Automated free energy perturbation calculations
Steinbrecher et al. "Accurate binding free energy predictions in fragment optimization." Journal of chemical information and modeling 55.11 (2015): 2411-2420
Free energy perturbation models for protein-ligand binding
Jespers et al. "QligFEP: an automated workflow for small molecule free energy calculations in Q." Journal of cheminformatics 11.1 (2019): 26
Automated free energy perturbation calculations
Conclusion
No claims are allowed.
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/R.A.P./Examiner, Art Unit 1686
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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