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 .
Office Action Overview
Claim Status
Canceled:
2
Pending:
1 and 3-21
Withdrawn:
none
Examined:
1 and 3-21
Independent:
1
Amended:
1, 3, 4, 13, 17, 19
New:
None
Allowable:
None
Objected to:
None
Rejections applied
Abbreviations
112/b Indefiniteness
PHOSITA
"a Person Having Ordinary Skill In The Art before the effective filing date of the claimed invention"
112/b "Means for"
BRI
Broadest Reasonable Interpretation
112/a Enablement,
Written description
CRM
"Computer-Readable Media" and equivalent language
112 Other
IDS
Information Disclosure Statement
X
102, 103
JE
Judicial Exception
X
101 JE(s)
112/a
35 USC 112(a) and similarly for 112/b, etc.
101 Other
N:N
page:line
Double Patenting
MM/DD/YYYY
date format
Priority
As detailed in the 06/13/2025 filing receipt, this application is a bypass continuation of PCT/KR2024/014763, filed 09/27/2024, which claims benefit of priority to KR10-2024-0039328, filed 03/21/2024.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 (see paper entered 06/29/2025).
Overview of Withdrawal/Revision of Interpretations/Objections/Rejections
In view of the amendment and remarks received 11/12/2025:
• The objection to claim 17 is withdrawn.
• The interpretation of claim 2 is no longer asserted. Claim 2 has been canceled.
• The 112(b) rejections of claims 3-6, 10 and 13-15 are withdrawn. The clarity issues of claims 3, 4, and 13 have been corrected by amendment. Applicant's remarks regarding claim 10 are persuasive.
• The 101 rejection of claims 1 and 3-21 is maintained with revision.
• The 103 rejection of claims 1 and 3-21 is maintained with revision.
Claim Interpretation
The last two lines of claim 1 recite "generating the hit compound derivative, wherein the method is executed on a computational system." The generating of the hit compound derivative is interpreted as a virtual process which is performed by applying the abstract idea of generating the hit compound derivative on a computational system.
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 and 3-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 details the following framework to analyze Subject Matter Eligibility:
• Step 1: Are the claims directed to a category of statutory subject matter (a process, machine, manufacture, or composition of matter)? (see MPEP § 2106.03)
• Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. an abstract idea, a law of nature, or a natural phenomenon? (see MPEP § 2106.04(a)). Note, the MPEP at 2106.04(a)(2) & 2106.04(b) further explains abstract ideas and laws of nature are defined as: • mathematical concepts, (mathematical formulas or equations, mathematical
relationships and mathematical calculations);
• certain methods of organizing human activity (fundamental economic practices
or principles, managing personal behavior or relationships or interactions between
people); and/or
• mental processes (procedures for observing, evaluating, analyzing/ judging and
organizing information).
• laws of nature and natural phenomena are naturally occurring principles/ relations that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature.
• Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application? (see MPEP § 2106.04(d))
• Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept? (see MPEP § 2106.05)
Step 1: Yes, the claims are directed to a method, and therefore to a category of statutory subject matter. (See MPEP § 2106.03).
Step 2A, Prong One: The claims recite mathematical concepts and mental processes, as follows:
Independent claim 1 recites mental processes as follows:
• (A) selecting a substitutable portion and a scaffold excluding the substitutable portion in a chemical structure of the hit compound;
• (B) setting a target space within the target protein, around a region where the selected substitutable portion of the hit compound binds; and
• (C) selecting a substituent that can replace the substitutable portion of the hit compound within the set target space of the target protein, and generating the hit compound derivative.
Dependent claims 3-21 further limit the abstract ideas as follows:
Claim 3 recites a mental process of selecting the substitutable portion based on an indicator showing lower binding interaction between the hit compound and the target protein. Claim 4 recites mental processes and mathematical concepts of determining the binding interaction by cleaving individual bonds; selecting a substitution candidate portion; and calculating an average binding energy. Claim 5 further limits the abstract ideas by reciting the substitution candidate portion comprises 1 to 12 atoms. Claim 6 recites the mental process of filtering the substitution candidate portion based on the number of constituent atoms.
Claim 7 further limits the abstract idea of claim 1 in reciting the target space in step (B) being set to accommodate the selected substitutable portion.
Claim 8 recites a mental process and mathematical concept of further determining the region of the target protein constituting the target space by stepwise classification based on interaction energy. Claim 9 further limits the abstract idea of claim 8 in reciting the interaction energy is classified into three to five levels.
Claim 10 recites a mental process and mathematical concept of wherein regions with relatively lower level of the interaction energy are clustered, and the clustered regions of the target space to be used for generating the hit compound derivative are further selected based on proximity to the scaffold of the hit compound and size of the clustered regions.
Claim 11 recites mental processes and mathematical concepts of extracting the region of the target protein constituting the target space as a spatial filter; setting marker points (dots) arranged at equal intervals in the spatial filter; and stepwise classifying the marker points based on interaction energy between atoms of the target protein.
Claim 12 further limits the abstract idea of claim 11 in reciting the spatial filter is a spherical, rectangular, cylindrical, or amorphous filter.
Claim 13 recites mental processes and mathematical concepts of (B1) extracting the region of the target protein constituting the target space as a cylindrical filter form, setting marker points (dots) arranged at equal intervals in the cylinder filter, and stepwise classifying the marker points based on the interaction energy between atoms of the target protein; and (B2) approaching the scaffold of the hit compound to the cylindrical filter, excluding regions where interaction energy exceeds a preset threshold from the cylindrical filter, and then clustering the remaining marker points into spatial units.
Claim 14 recites a mental process and mathematical concept of (B3) selecting a part of the clustered regions as the target space to be used for generating the hit compound derivative, based on proximity between marker points in the clustered regions and the size of the clustered regions.
Claim 15 recites a mental process and mathematical concept of clustering is performed based on the density of regions with relatively lower level of the interaction energy, or by using Gaussian Mixture Model (GMM) clustering.
Claim 16 recites a mental process and mathematical concept of step (C) is performed by replacing the substitutable portion that binds to the scaffold of the hit compound, selected in step (A), with a substituent selected from a substituent group database, which can be accommodated within the target space of the target protein set in step (B).
Claim 17 recites mental processes and mathematical concepts of the substitutable portion in the chemical structure of the hit compound in step (A) is selected based on an indicator showing lower lever of the binding interaction compared to other chemical structures, as determined from the interaction profile between the hit compound and the target protein, wherein the selection of the target space to be used for generating the hit compound derivative of the target protein in step (B) is performed by the steps of: (B 1) extracting the region of the target protein constituting the target space as a cylindrical filter form, setting marker points (dots) arranged at equal intervals in the cylindrical filter, and stepwise classifying the marker points based on the interaction energy between atoms of the target protein, (B2) approaching the scaffold of the hit compound to the cylindrical filter, excluding regions where the interaction energy exceeds a preset threshold from the cylindrical filter, and then clustering the remaining marker points into spatial units, and (B3) selecting a portion of the clustered regions based on the proximity between marker points (dots) in the clustered regions and the size of the clustered regions, and wherein the derivative generation in step (C) is performed by selecting substituents that can be accommodated within the target space selected in step (B).
Claim 18 recites mental processes and mathematical concepts of (i) the derivative having multiple different binding conformations is generated for the same substituent by varying the binding position within the substituent that binds to the scaffold of the hit compound; (ii) the derivative having multiple different binding poses is generated for the substituents with the same binding conformation by varying the binding between the substituents and the scaffold of the hit compound ; or (iii) the derivative having multiple different binding poses is generated for the substituents with the same binding conformation by varying the binding angle between the substituents and the scaffold of the hit compound.
Claim 19 recites mental processes and mathematical concepts of cleaving individual bonds within the hit compound that interact with the target protein; selecting a substitution candidate portion that includes atoms at the cleaved site; and calculating average binding energy between each atom constituting the substitution candidate portion and the target protein.
Claim 20 recites a mental process and mathematical concept of (D) filtering the generated derivatives.
Claim 21 recites mental processes and mathematical concepts of (D) filtering the generated derivatives, wherein step (D) comprises: at least one or more of (i) filtering the binding angle between the substituent and the scaffold of the hit compound compared with a real compound database; and (ii) filtering the derivatives based on degrees of atomic clash between the derivative and the target protein atoms, which occurs within the target space set in the derivatives in step (B), according to the binding pose of the substituents.
Step 2A Prong One summary: The claims recite abstract ideas of mental processes and mathematical concepts. When considering the broadest reasonable interpretation (BRI) of the claims, the mental processes recited in independent claim 1 (e.g., " selecting a substitutable portion and a scaffold", "setting a target space", "selecting a substituent", "generating the hit compound derivative") include embodiments directed to steps which may be performed in the human mind, or with pen and paper, as one could mentally analyze a chemical structure of a hit compound to perform the steps of claim 1 as the claim does not include any additional details about how the selecting(s), setting, and generating are accomplished. Additionally, the claims are considered to recite mathematical concepts, both explicitly (e.g., in the calculating steps recited in claims 4 and 19) and inherently, e.g., cleaving bonds (claims 4 and 19, discussed at Specification [0099], [0125-0126], [0172-0176]); clustering (claim 10, discussed at Specification [0140-0141]); stepwise classification and extracting (claims 8, 11, 13, and 17, discussed at Specification [0138-0140]), etc. It is noted the method of claim 1 has been amended to recite execution on a computational system, however, although such analysis performed mentally, or with paper and pencil, may take considerable time and effort, and although a general-purpose computer can perform these calculations at a rate and accuracy that can far exceed the mental performance of a skilled artisan, the nature of the activity is essentially the same, and therefore constitutes an abstract idea. (See MPEP § 2106.04(a)(2)(III)(C)). Therefore, the claims recite elements that constitute a judicial exception in the form of an abstract idea. (Step 2A, Prong One: Yes.)
Step 2A, Prong Two: In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs). Here at Step 2A, Prong Two, any remaining steps and/or elements not identified as JEs are therefore in addition to the identified JE(s), and are considered additional elements. Because the claims have been interpreted as being directed to judicial exceptions (abstract ideas in this instance) then Step 2A, Prong Two provides that the claims be examined further to determine whether the judicial exception is integrated into a practical application [see MPEP § 2106.04(d)]. A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
MPEP § 2106.04(d)(I) lists the following five example considerations for evaluating whether a judicial exception is integrated into a practical application:
(1) An improvement in the functioning of a computer or an improvement to other technology or another technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a).
(2) Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2).
(3) Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b).
(4) Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c).
(5) Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
The additional element(s) of the instant claims are as follows:
Additional elements of computer components: Claim 1 recites an additional element of a computational system. The claims require only generic computer system, which does not improve computer technology, and do not integrate the recited judicial exception into a practical application (see MPEP 2106.04(d)(1) and MPEP 2106.05(f)).
Step 2A Prong Two summary: Referring to the Step 2A, Prong Two considerations listed above, none of (1) an improvement, (2) treatment, (3) a particular machine, or (4) a transformation is clear in the record, such that here in Step 2A, Prong Two, no additional step or element, alone or in combination, clearly demonstrates integration of the JE(s) into a practical application. The additional elements are further discussed below in Step 2B. (Step 2A, Prong Two: No).
Step 2B analysis: Because the additional elements of the claim do not integrate the abstract idea into a practical application, claim 1 is further examined under Step 2B, which evaluates whether the additional elements, individually and in combination, amount to significantly more than the judicial exception itself by providing an inventive concept. An inventive concept is furnished by an element or combination of elements that is recited in the claim in addition to the judicial exception, and is sufficient to ensure that the claim, as a whole, amounts to significantly more than the judicial exception itself (see MPEP 2106.05).
Additional elements of computer components: The additional element of a computational system of claim 1 does not cause the claims to rise to the level of significantly more than the judicial exception; this is a conventional computer system, which may include a computer as discussed at Specification [0106], and does not provide an inventive concept.
Further regarding the conventionality of additional elements, the MPEP at 2106.05(b) and 2106.05(d) presents several points relevant to conventional computers and data gathering steps in regard to Step 2A Prong 2 and Step 2B, including:
• A general purpose computer that applies a judicial exception, such as an abstract idea, by use of conventional computer functions, does not qualify as a particular machine (see 2106.05(b)(I)), as in the case of claim 1, which executes the abstract ideas on a conventional computational system.
• Integral use of a machine to achieve performance of a method may integrate the recited judicial exception into a practical application or provide significantly more, in contrast to where the machine is merely an object on which the method operates, which does not integrate the exception into a practical application or provide significantly more (see 2106.05(b)(II). In the instant claims, the recited computational system acts only as a tool to perform the steps of the abstract ideas for selecting, setting, and generating, and does not integrate the exception into a practical application or provide significantly more.
• Use of a machine that contributes only nominally or insignificantly to the execution of the claimed method (e.g., in a data gathering step or in a field-of-use limitation) would not integrate a judicial exception or provide significantly more (see 2106.05(b)(III). The computational system of the claims does not impose meaningful limitations on the claims.
All limitations of claims 1 and 3-21 have been analyzed with respect to Step 2B, and none of these claims provide a specific inventive concept, as they all fail to rise to the level of significantly more than the identified judicial exception, and thus do not transform the judicial exception into a patent eligible application of the exceptions. Step2B: NO. Therefore, claims 1 and 3-21, when the limitations are considered individually and as a whole, are rejected under 35 U.S.C. § 101 as reciting non-patent eligible subject matter.
Response to Applicant Arguments - 35 USC § 101
Applicant's arguments regarding the 101 rejection (remarks, p.9-12) filed 11/12/2025 have been fully considered but they are not persuasive.
Regarding Applicant Arguments for Step 2A Prong One
Applicant asserts (emphasis added):
• …the presently claimed method recites steps…that cannot be practically performed by the human mind (p.10, ¶ 2).
• … the method requires a series of interdependent, non-generic computational and biological steps that culminate in a tangible, functional hit derivative molecule (p.10, ¶ 3).
•…the Specification includes embodiments where "generating" may include a computerized implementation (see, e.g., para. [0124])…However, Applicant submits that this is non-limiting embodiment, as indicated by the word "may" (p.10, ¶ 4).
• …Examples 3 and 4 demonstrate that the methods described in the instant application also encompass design and production of the physical molecules. … the Specification consistently supports both digital design and physical implementation. (bridging p.10-11).
• under the principles of the broadest reasonable interpretation, the term "generating" should not be limited to an abstract, computational output (p.11, ¶ 2).
The arguments regarding Step 2A Prong One are not yet persuasive for the following reasons:
First, the claimed steps do not include details that would prevent analysis in the mind or with pen and paper. It is noted the method of claim 1 has been amended to recite execution on a computational system, however, although such analysis performed mentally, or with paper and pencil, may take considerable time and effort, and although a general-purpose computer can perform these calculations at a rate and accuracy that can far exceed the mental performance of a skilled artisan, the nature of the activity is essentially the same, and therefore constitutes an abstract idea.
MPEP § 2106.04(a)(2)(III)(C) discusses a claim that requires a computer may still recite a mental process, and presents three situations (similar to claim 1, which executes the method on a computational system) in which the claim is considered to recite a mental process, although the claim requires a computer: Performing a mental process on a computer; performing a mental process in a computer environment; and using a computer as a tool to perform a mental process.
Further, the instant claims do not recite any step for synthesis of real compounds. Claim 1 recites the method is executed on a computational system, and the generating of hit compound derivatives has been interpreted (above in "Claim Interpretation" section) as being as a virtual process which is performed by applying the abstract idea of generating the hit compound derivative on a computational system.
Regarding Applicant Arguments for Steps 2A Prong Two and 2B
Applicant asserts (emphasis added):
• …under Step 2A, Prong Two, claim 1 recites features that clearly improve technology or a technological field, thereby integrating the judicial exception (remarks p.12, ¶ 1).
• … claim 1 as a whole integrates these steps into a specific, practical application with a real-world solution, namely, the generation of a hit derivative that provides a significant improvement in the efficacy and/or pharmacokinetic properties of hit compounds… the generated derivatives have improved binding affinity with the target protein (para. [0023]), demonstrate improvement in pharmacokinetic properties (para. [0062]), have an enhanced effect on the activity of the target protein (para. [0064]) and demonstrate superior efficacy (para. [0193], [0198]). Specifically, the claimed method enables the development of hit derivatives with improved inhibitory effects as shown in Tables 2 and 3 (remarks p.12, ¶ 2).
• …Step 2B would also be satisfied, as claim 1 … recites limitations that confine the claim to a particular useful application that amounts to significantly more than the judicial exception itself (remarks p.12, ¶ 4).
The arguments regarding Steps 2A Prong Two and 2B are not persuasive for the following reasons:
The claims are directed to an abstract idea, even when considering the claims as a whole, as the additional element of a computational system is not sufficient to integrate the abstract idea into a practical application at Step 2A Prong two, nor does it provide significantly more at Step 2B.
With respect to the five considerations listed at MPEP § 2106.04(d)(I) for integrating the judicial exception into a practical application, it appears that two of these considerations might be pertinent regarding the instant claims: an improvement to technology and a transformation. At present, there is not yet an improvement to technology shown, nor is there yet a transformation shown.
However, if the instant claims were appropriately amended, possibly to recite step(s) of synthesizing the hit compound derivative which includes the selected substituent, this may possibly be a step toward reciting a transformation, in that the synthesis of the compound would be informed by selecting and setting steps which constitute the judicial exception, and therefore the judicial exception identified at Step 2A Prong One would be integrated into a practical application at Step 2A Prong Two. .
The following Applicant remarks are acknowledged as pointing in the right direction for showing improvement (p,12, ¶ 2) ("the generated derivatives have improved binding affinity with the target protein (para. [0023]), demonstrate improvement in pharmacokinetic properties (para. [0062]), have an enhanced effect on the activity of the target protein (para. [0064]) and demonstrate superior efficacy (para. [0193], [0198]). Specifically, the claimed method enables the development of hit derivatives with improved inhibitory effects as shown in Tables 2 and 3") (italic emphasis added). However, the argument regarding improvement is not yet persuasive because the improvement is to the abstract idea, even when considering the claim as a whole. Possibly reciting the real world step of synthesis (which also might add a transformation) in addition to building on the presented improvement arguments (at p,12, ¶ 2) may be a step to showing improvement to technology.
Regarding showing an improvement to technology, a detailed explanation of a technical improvement may help to overcome a 101 rejection, (see MPEP 2106.04(d) and (d)(1), regarding the first consideration, showing an improvement to technology, at Step 2A Prong Two of the 101 analysis, as well as MPEP 2106.05(a)). The explanation might include a concise statement of the improvement, including improvement over the previous state of the technology field; identification of the technology field; explanation of how the claims deliver the improvement and that reasonably all embodiments within the claim scope also will result in the asserted improvement, and extension of the explanation to persuasively demonstrate the nexus of integration of the judicial exceptions into a practical application. As further examples, argument may clearly and adequately explain cause and effect leading to improvement or, for example when such cause and effect explanation is not possible, then may include evidence (e.g. experimental data) comparing a claimed result to conventional results. Also, arguments and evidence may be extrinsic to the original disclosure, including references available after the priority date, as long as it is clear that an argument applies to all embodiments of a properly supported claim.
Regarding showing an improvement to technology in the instant claims, it is considered that the synthesis of the hit compound derivative is likely needed to show an improvement to technology. Therefore overall, with respect to the instant claims, the considerations for an improvement to technology and a transformation appear to be intertwined, such that as a possible step toward overcoming the 101 rejection, it may be helpful to put forth a detailed explanation for improvement while possibly amending the claims to recite a transformation in synthesis of the hit compound derivative.
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.
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.
Claims 1 and 3-21 are rejected under 35 U.S.C. 103 as being unpatentable over Jin, (Journal of Medicinal Chemistry, vol. 66(15), pages 10808-10823 (2023); cited on the 08/12/2025 form PTO-892), in view of Bekker, (Journal of Chemical Theory and Computation, vol. 13(6), pages 2389-2399 (2017); cited on the 08/12/2025 form PTO-892).
Independent claim 1 recites a method for generating a hit compound derivative from a hit compound for a target protein, (A) selecting a substitutable portion and a scaffold excluding the substitutable portion in a chemical structure of the hit compound; (B) setting a target space within the target protein, around a region where the selected substitutable portion of the hit compound binds; and (C) selecting a substituent that can replace the substitutable portion of the hit compound within the set target space of the target protein, and generating the hit compound derivative; and executing the method on a computational system.
Claim 3 further recites the substitutable portion in step (A) is selected based on an indicator showing lower binding interaction compared to other chemical structures, as determined from an interaction profile between the hit compound and the target protein. Claim 4 further recites the binding interaction is determined by: cleaving individual bonds within the hit compound that interact with the target protein, selecting a substitution candidate portion that includes atoms at the cleaved site for each cleaved bond, and calculating an average binding energy between each atom constituting the substitution candidate portion and the target protein. Claim 5 further recites the substitution candidate portion comprises 1 to 12 atoms. Claim 6 further recites filtering the substitution candidate portion based on the number of constituent atoms.
Claim 7 further recites a size of the target space within the target protein in step (B) is set to accommodate the selected substitutable portion of the hit compound in the chemical structure of the hit compound binding to the target protein.
Claim 8 further recites the setting in step (B) comprises determining the region of the target protein constituting the target space by stepwise classification based on interaction energy between atoms of the target protein present in the region. Claim 9 further recites the interaction energy is classified into three to five levels. Claim 10 further recites regions with relatively lower level of the interaction energy are clustered, and the clustered regions of the target space to be used for generating the hit compound derivative are further selected based on proximity to the scaffold of the hit compound and size of the clustered regions. Claim 11 further recites the classification of interaction energy between atoms of the target protein in step (B) is performed by: extracting the region of the target protein constituting the target space as a spatial filter, setting marker points (dots) arranged at equal intervals in the spatial filter, and stepwise classifying the marker points based on interaction energy between atoms of the target protein. Claim 12 further recites the spatial filter is a spherical, rectangular, cylindrical, or amorphous filter. Claim 13 further recites the selection of clustered regions of the target space to be used for generating the hit compound derivative in step (B) comprises: (B1) extracting the region of the target protein constituting the target space as a cylindrical filter form, setting marker points (dots) arranged at equal intervals in the cylinder filter, and stepwise classifying the marker points based on the interaction energy between atoms of the target protein; and (B2) approaching the scaffold of the hit compound to the cylindrical filter, excluding regions where interaction energy exceeds a preset threshold from the cylindrical filter, and then clustering the remaining marker points into spatial units. Claim 14 further recites the selection of clustered regions of the target space to be used for generating the hit compound derivative in step (B) further comprises (B3) selecting a part of the clustered regions as the target space to be used for generating the hit compound derivative, based on proximity between marker points in the clustered regions and the size of the clustered regions. Claim 15 further recites clustering is performed based on the density of regions with relatively lower level of the interaction energy, or by using Gaussian Mixture Model (GMM) clustering.
Claim 16 further recites step (C) is performed by replacing the substitutable portion that binds to the scaffold of the hit compound, selected in step (A), with a substituent selected from a substituent group database, which can be accommodated within the target space of the target protein set in step (B).
Claim 17 further recites the substitutable portion in the chemical structure of the hit compound in step (A) is selected based on an indicator showing lower lever of the binding interaction compared to other chemical structures, as determined from the interaction profile between the hit compound and the target protein, wherein the selection of the target space to be used for generating the hit compound derivative of the target protein in step (B) is performed by the steps of: (B1) extracting the region of the target protein constituting the target space as a cylindrical filter form, setting marker points (dots) arranged at equal intervals in the cylindrical filter, and stepwise classifying the marker points based on the interaction energy between atoms of the target protein, (B2) approaching the scaffold of the hit compound to the cylindrical filter, excluding regions where the interaction energy exceeds a preset threshold from the cylindrical filter, and then clustering the remaining marker points into spatial units, and (B3) selecting a portion of the clustered regions based on the proximity between marker points (dots) in the clustered regions and the size of the clustered regions, and wherein the derivative generation in step (C) is performed by selecting substituents that can be accommodated within the target space selected in step (B). Claim 18 further recites (i) the derivative having multiple different binding conformations is generated for the same substituent by varying the binding position within the substituent that binds to the scaffold of the hit compound; (ii) the derivative having multiple different binding poses is generated for the substituents with the same binding conformation by varying the binding between the substituents and the scaffold of the hit compound; or (iii) the derivative having multiple different binding poses is generated for the substituents with the same binding conformation by varying the binding angle between the substituents and the scaffold of the hit compound. Claim 19 further recites the binding interaction is determined by: cleaving individual bonds within the hit compound that interact with the target protein, selecting a substitution candidate portion that includes atoms at the cleaved site, and calculating average binding energy between each atom constituting the substitution candidate portion and the target protein.
Claim 20 further recites (D) filtering the generated derivatives.
Claim 21 further recites (D) filtering the generated derivatives, wherein step (D) comprises: at least one or more of (i) filtering the binding angle between the substituent and the scaffold of the hit compound compared with a real compound database; and (ii) filtering the derivatives based on degrees of atomic clash between the derivative and the target protein atoms, which occurs within the target space set in the derivatives in step (B), according to the binding pose of the substituents.
Regarding claim 1: Jin presents a generative model for drug design, "FFLOM", a flow-based fragment-to-lead optimization model inspired by previous flow-based models on molecule generation (p.10808, abstract; p. 10810, col.2). Jin teaches R-Group Optimization using a case study of Dabrafenib, a clinical anticancer drug that acts as a kinase B-Raf inhibitor. Dabrafenib was discovered to potently activate the human nuclear receptor pregnane X receptor (PXR), leading to unexpected clearance of various chemicals and drugs. A selective potent kinase B-Raf inhibitor, Compound 4c, was designed (by Schneider et al. 65) that barely binds to PXR. By analyzing the crystal structure of dabrafenib binding to PXR or to a B-Raf single mutant (V600E), the t-Butyl group of dabrafenib was elaborated, and the subsequently derived novel lead compounds had comparable inhibitory activity (IC50 2−6 nM) against BRaf-V600E and much lower agonist activity (EC50 > 5 μM) toward PXR. For the case study, compound 4c was taken as the ground-truth molecule. The t-Butyl group of dabrafenib was removed, and 5000 molecules were generated for each R-group size between 4 and 6 atoms. (p.10817, col.1). As such, Jin shows the hit compound (dabrafenib), the substitutable portion (tert-butyl group of dabrafenib), the scaffold (dabrafenib without t-butyl group), and hit compound derivative(s) (the 5000 molecular derivatives of dabrafenib with tert-butyl replaced) of claim 1.
Regarding claims 3-6, 16, and 19-21: Jin shows docking scores to both B-Raf-V600E (and PXR) of 527 hit compound derivatives (of a "database" of 15,000 molecules generated by the method, FFLOM), in the lower right panel of fig.6, p.10817, and cols.1-2, p.10817). A zoom-in panel (upper left panel of fig.6, p.10817) shows six example molecules with R-group highlighted, and binding interaction, as calculated docking scores to B-Raf-V600E, on the X-axis (of both panels fig.6, p.10817). Jin shows 510 unique molecules had SC (similarity score) fragment scores of above 0.7, while 295 unique molecules got RMSD scores of less than 0.5 Å, indicating that the original substructures were able to adopt the required conformation. 527 compounds that passed the 2D filters were docked to the B-Raf-V600E. Intuitively, the molecules with larger R-groups (i.e., more atoms) would have better docking scores; and compared with the ground-truth compound (docking score −11.85 kcal/mol), 77 molecules with 6-atom R-groups had better docking scores; in addition, 52 unique molecules with 5-atom R-groups and 26 unique molecules with 4-atom R-groups had better docking scores than the ground-truth molecule (p.10817, bridging cols.1-2). (Showing lower binding interaction as compared to other chemical structures of claim 3; determining binding interaction regarding individual bonds, a substitute candidate portion including atoms at the bond site, calculating average binding energy of claim 4 and 19; substitution candidate portion is 1 to 12 atoms of claim 5; filtering by number of atoms of claim 6, and filtering the generated derivatives of claim 20 and 21.)
While Jin shows a target space in a target protein, Jin does not specifically show selecting a target space in target protein of claim 1 step (B).
Jin does not specifically show: the size of a target space to accommodate the selected substitutable portion of the hit compound of claim 7; nor the determining of region space based on interaction energy of target protein of claim 8; nor the interaction energy in 3-5 levels, of claim 9; nor the target space based on proximity to scaffold and size of clustered regions of claim 10; nor the target protein region as spatial filter, marker points based on interaction energy of claim 11; nor the spatial filter of claim 12; nor the cylindrical filter, marker points, approaching scaffold with hit compound of claim 13 and 17 step (B1 and 2); nor the selecting of clustered regions based on proximity of marker points and size of regions of claim 14 and 17 step (B3); nor clustering by region density and lower interaction energy of claim 15; nor the varying binding position of claim 18. These limitations are shown by Bekker as follows:
Bekker presents a method that combines multicanonical molecular dynamics (McMD) simulation and thermodynamic integration (TI) as a general drug docking method in accurately predicting both binding complex structure and affinity.
Regarding claims 1 step (B), 7-15, 17 steps (B1-3), and 18, Bekker shows (at p.2391 col.1-2 and fig.1, thru p.2392) selecting a target space in a target protein using McMD by estimating of a space restraining cylinder using a naive method, in which spherical surface grid points were generated at an increasing radius R at constant intervals ΔR (e.g., 1 Å) starting from the center of a given pocket, with a density of surface grid points at approximately 1 Å-2. Among the grid points for each radius R, they defined the point h⃗(R)max which is the furthest from the all the heavy atoms of the receptor. Among these points, they selected only those points such that the distance was between Rg + 2 Å and Rg + d Å, where Rg is the radius of gyration of the ligand molecule and d is a value representing a buffer distance between the receptor and the ligand in the bulk. Using linear least-squares fitting of the selected points h⃗(R)max and the given center of the pocket, a straight line connecting the pocket and the bulk was generated, which formed the basis for their space restraints. Finally, the ligand was positioned at the end of the vector λ (p.2391-2392). Bekker shows calculating the Potential of Mean Force (PMF) from the probability distribution of the sampled structures, such that the Free Energy Landscape (FEL) is displayed as the PMF distribution by one or more principal components; and that the Thermodynamic Integration method (TI) is another one to compute the binding free energy, where the average force is calculated by the force field along a binding or unbinding path (p.2390, col.1). Bekker shows a strategy which involves picking a representative structure at the predicted global minimum from the FEL along λ, to predict the native binding configuration. After calculating the Free Energy Landscape (FEL) on λ at 300 K, all the structures near the global minimum were selected. These structures were then clustered based on their relative RMSD (root mean square deviation) within 0.1 Å. The cluster with the largest contribution to the PMF (which would correspond to the most stable one) was taken, after which the structure that was the closest to the average structure in this cluster was chosen as the representative structure. This is followed by picking structures to make a new path ξ, as shown schematically in Figure 2, which shows schematic representation of the generation of the path ξ for TI (Thermodynamic Integration method) by binning along λ (i.e., 5 different levels of interaction energy) (p.2392, col.1, and fig. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the deep generative method for drug design including R-group optimization of Jin, with method of molecular docking using cylindrical filter space in structural prediction of a target protein and ligand of Bekker, to come to a method for generating a hit compound derivative, because Bekker provides motivation to combine by discussing that to overcome higher computing costs, they teach a combination of the McMD (multicanonical molecular dynamics) simulation with TI (Thermodynamic Integration) to accurately predict both the binding complex and the affinity (Bekker, p. 2390, col.2), while Jin states their results demonstrated that the FFLOM model could accurately recover the ground-truth molecules while efficiently generating novel molecules with better docking scores than the original molecules (Jin, p.10818 col.1). One of ordinary skill would have had a reasonable expectation of success in combining, as Jin and Bekker are generally drawn to related teaching, and one of ordinary skill in the art would have understood how to and would have been motivated to combine the teachings of Jin and Bekker and as such, the combination would have been obvious.
Response to Applicant Arguments - 35 USC § 103
Applicant's arguments filed 11/12/2025 regarding the 103 rejection over Jin in view of Bekker (remarks, p.13-15) have been fully considered but they are not persuasive.
Regarding Jin, Applicant asserts:
• … Jin discloses a method wherein after generating a large number of candidate compounds by creating a vast library of R-groups (with a 4-6 atom range) using FFLOM, the candidates are evaluated and selected subsequently using 2D filters, similarity, RMSD, and docking scores. This method enables the large-scale generation of diverse and novel molecular structures based on the extensive chemical patterns inherent in the training data (see Jin et al., p.10811, left column, last paragraph) (remarks, bridging p.13-14; original emphasis).
• In contrast, the instant claims employ a pre-selection method where the substitutable portion of the hit compound is identified before generating the derivatives. The objective of the present invention is to improve an existing hit compound with confirmed or derived efficacy in terms of its medicinal effects or pharmacokinetics…This is achieved by analyzing the interaction with the target protein from an early stage to prospectively identify a portion with relatively low binding interaction as the substitutable part. Therefore, the present invention is clearly distinct from Jin in its objective and technical approach (remarks, p.14, ¶ 2; original emphasis).
The arguments regarding Jin are not yet persuasive because Jin shows by analyzing the crystal structure of dabrafenib (i.e., the hit compound) binding to the human nuclear receptor pregnane X receptor (PXR) or to a B-Raf single mutant (V600E), the t-Butyl group (i.e. the substitutable portion) of dabrafenib was elaborated…The t-Butyl group of dabrafenib was removed, and 5000 molecules (i.e., hit compound derivatives) were generated for each R-group size between 4 and 6 atoms (p.10817, col.1 ). This shows selecting a substitutable portion and a scaffold before generating the hit compound derivative(s) of claim 1.
Regarding Bekker, Applicant asserts:
• … Bekker relates to a simulation method for predicting how an entire ligand molecule binds to a target protein and what its total binding strength (binding free energy) will be. Contrary to the assertions made in the Office Action, Bekker does not define a limited space for a part of the ligand; rather, it constrains the dynamic movement of the entire molecule by confining its center of mass (COM) within a cylinder (see e.g., description of Figure 1 in Bekker).
• …While Bekker constrains the movement of the entire ligand molecule to predict its overall binding energy to the protein, the present invention focuses on a specific, predefined space for substitution. This represents a fundamental difference (remarks, p.14, ¶ 4; original emphasis).
• …Applicant submits that no reference teaches or suggests the limitation selecting a
target space in the target protein as required by the instant claims (remarks, p.14, ¶ 5).
The arguments regarding Bekker are not yet persuasive because Bekker was not relied upon for teaching "selecting a substitutable portion and a scaffold excluding the substitutable portion in a chemical structure of the hit compound"; this was taught by Jin as stated above.
Regarding the target space in a target protein, Bekker shows "setting a target space within a target protein" of claim 1 step (B) using McMD by estimating of a space restraining cylinder using a naive method, in which spherical surface grid points were generated at an increasing radius R at constant intervals L1R ( e.g., 1 A) starting from the center of a given pocket (i.e. a target space) (Bekker, p.2391, col.1, last paragraph).
Additionally, it is noted there is no size limitation put on the substitutable portion of claims 1 step (A).
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.
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/M.A.V./Examiner, Art Unit 1687
/G. STEVEN VANNI/Primary patents examiner, Art Unit 1686