DETAILED ACTION
Applicant’s response, filed 22 October 2025, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 11-14, 18, 21, 25, 26, and 28-31 are pending and examined herein.
Claims 33-40 have been canceled.
Claims 11-14, 18, 21, 25, 26, and 28-31 are rejected.
Priority
The instant application does not claim priority to any earlier filed applications. Thus, the effective filling date of claims 11-14, 18, 21, 25, 26, and 28-31 is 20 November 2022.
Claim Interpretation
Claim 11 recites “screening the third molecule with the third bioisostere to determine whether the third molecule with the third bioisostere is a drug candidate having a desired biological activity” which is interpreted as being a physical wet lab step for screening the third molecule. The instant disclosure states on page 16 that the screening process to determine potential drug candidates can be conducted according to any method known to those of ordinary skill in the art such as, for example, using high-throughput screening arrays. Further, the instant disclosure only provides support for physical steps of screening such as the high-throughput arrays and the instant disclosure does not provide support for any virtual screening techniques of the third molecule for determining a drug candidate. Lage et al. (Marine drugs 16.8 (2018): 279; newly cited) is a review that shows different methodologies of screening bioactive compounds. These screening approaches are physical wet lab steps. Further, this review shows that one of ordinary skill in the art would recognize that screening the third molecule in the instant application is a physical wet lab step which is supported on page 16 of the instant disclosure as screening through high-throughput arrays and does not encompass “virtual screening” or “computational screening”.
Claim Rejections - 35 USC § 112
The rejection on the ground of 112/b of claim 25 for reciting “wherein the method is used to discover new bioisosteres of the first molecule having one or more functionalities selected from the group consisting of…” in Office action mailed 18 April 2025 is withdrawn in view of the amendment of “wherein the method is used to discover new bioisosteres of the first molecule having one or more uses selected from the group consisting of…” received 22 October 2025.
112/d
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The rejection below is newly recited necessitated by amendment.
Claims 14 and 25 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 14 does not limit the subject matter of claim 11 in which it depends from because claim 11 recites screening the third molecule with the third bioisostere to determine whether the third molecule with the third bioisostere is a drug candidate having a desired biological activity which is a further investigation the third molecule as a pharmaceutical of interest. Thus, claim 14 does not further limit claim 11 because further investigation of the third molecule as a pharmaceutical of interest is performed in claim 11. Claim 25 does not limit the subject matter of claim 11 in which it depends from because claim 11 recites steps including the newly added screening limitation which inherently has the use of “1) identifying, generating, discovering, and creating new bioisosteres containing the additional sets of atoms having a desired biological activity for treating a specific disease”. Further, claim 25 recites “the method is used to discover new bioisosteres of the first molecule having one or more uses selected from…” and the arguments provided that “one skilled in the art would recognize the limitations of claim 25 are clearly descriptive as to what the method may be used for” (Reply p. 11) provide that claim 25 recites intended uses of the method which do not limit the claimed invention of the method (see MPEP 2111.02(II)).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
The rejection on the ground of 101 of claims 11-14, 18, 21, 25, 26, 28-31, and 33-40 in Office action mailed 18 April 2025 is withdrawn in view of the amendment of “screening the third molecule with the third bioisostere to determine whether the third molecule with the third molecule with the third bioisostere is a drug candidate having a desired biological activity” received 22 October 2025. The judicial exceptions are now integrated into a practical application because the judicial exceptions interact with the additional element of screening the third molecule with the third bioisostere in a manner that provides an improvement (i.e. speeding up the wet-lab process and saving resources by prefiltering out candidates that are not promising) which is realized in the additional element of screening the third molecule.
Claim Rejections - 35 USC § 103
The rejection on the ground of 103 of claims 32-40 as being unpatentable over Arabi (Future Med Chem 2020, 12(12), pgs. 1111-1120; previously cited) in view of Kumari et al. (J. Med. Chem. 2020, vol. 63, pgs. 12290-12358; previously cited) in Office action mailed 18 April 2025 is withdrawn in view of the amendment which cancels claims 32-40 received 22 October 2025.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The rejection below has been modified necessitated by amendment.
Claims 11-14, 18, 21, 25, 26, and 28-31 are rejected under 35 U.S.C. 103 as being unpatentable over Arabi (Future Med Chem 2020, 12(12), pgs. 1111-1120; previously cited) in view of Kumari et al. (J. Med. Chem. 2020, vol. 63, pgs. 12290-12358; previously cited).
Independent claim 11 is directed to selecting a first molecule of interest having a first bioisostere, replacing the first bioisostere with a second bioisostere to obtain a second molecule with the second bioisostere
Arabi discloses a method for evaluating quantitative similarities between nonclassical bioisosteres using an average electron density (AED) tool (abstract). Arabi et al. discloses that carboxylic acid groups of commonly found in active molecules and frequently replaced by bioisosteres in drug design (pg. 1112, para. 1). Arabi et al. discloses that the purpose of the paper is to investigate the similarities in the average electron densities of carboxylic acid and nonclassical bioisosteres of carboxylic acid with different kinds of capping groups (pg. 1112, para. 1). Therefore, the carboxylic acid corresponds to the first molecule of interest and the isoxazole, tatrazol-5-one, oxadiazole, oxazolidinedione and thiazolidinedione correspond to the second molecule having the second bioisostere.
completing quantum mechanics (QM) simulations to obtain optimized geometries having no imaginary frequencies for the first and second molecules containing the first and second bioisosteres as docked in a receptor or as not docked in a receptor
Arabi et al. show optimizing each of the molecules using G16 with B3LYP/6 311++G(d,p) //B3LYP/6-311++G(d,p) level of theory (pg. 1113, para. 1), which corresponds to completing a quantum mechanics simulation for the first and second molecules containing the first and second bioisosteres. Further, Arabi et al. shows performing a vibrational frequency analysis to confirm that the optimized geometries have no imaginary frequencies (pg. 1113, para. 1).
evaluating average electron density values, using an average electron density tool, corresponding to the first and second bioisosteres in the first and second molecules as docked in the receptor
Arabi then discloses determining the AEDs for each bioisosteric group with five different capping groups (Table 1; Figs. 2-3; pg. 1113, para. 2 to pg. 1115, para. 2). Arabi et al. suggest testing the average electron densities for drug molecules docked in their receptors as next steps for the AED tool testing (pg. 1118, para. 3). It would have been obvious to one of ordinary skill in the art to have used the AED tool in this manner. Since Arabi earlier discloses that equivalent AED values indicate bioisosterism, it would be obvious to one of ordinary skill in the art that the same equivalence would be required to identify molecules as bioisosteric even when docked into their receptors based on the teachings of Arabi regarding the equivalence of the AED values being indicative of bioisosterism.
confirming experimentally observed bioisosterism between the first and second bioisosteres based on the calculated AED values
Arabi then discloses that nonclassical bioisosteres have very similar AEDs that demonstrate insignificant changes in AEDs of the bioisosteric group (pg. 1112, para. 1; pg. 1113, para. 2 to pg. 1115, para. 2; pg. 1118, para. 2; Table 1), which confirms the experimentally observed bioisosterism for carboxylic acid, isoxazole, tatrazol-5-one, oxadiazole, oxazolidinedione and thiazolidinedione.
identifying those calculated AED values equivalent between the first and second bioisostere, wherein the equivalent calculated AED values have a difference no more than 10%, identifying additional sets of atoms having calculated AED values corresponding to the calculated AED values equivalent between the first and second bioisosteres, wherein the corresponding calculated AED values have a difference of no more than 10% from the equivalent calculated AED value of the first bioisostere,
Arabi et al. shows identifying AED values that are within 10% of each other with the additional sets of atoms which the AED values were derived from (Arabi et al. pg. 1113 Table 1). Further, Arabi et al. shows in column 1 of this table that the AED values for each bioisostere are all within 10% of each other (Arabi et al. pg. 1113 Table 1 in column 1).
computationally replacing the first bioisostere of the first molecule of interest with one of the identified additional sets of atoms to obtain a third molecule with a third bioisostere
Arabi et al. further shows that AED provides quantitative information that could be useful for predicting new bioisosteres (Arabi et al. pg. 1113 pg. 1118, paras. 2-3). Arabi et al. discloses that carboxylic acid groups of commonly found in active molecules and frequently replaced by bioisosteres in drug design (pg. 1112, para. 1).
Arabi does not show the first bioisostere being an amide group and the second bioisostere being a 1,2,3-triazole group and screening the third molecule with the third bioisostere to determine whether the third molecule with the third bioisostere is a drug candidate having a desired biological activity
Like Arabi, Kumari et al. shows analyzing bioisosteres. Kumari et al. shows that the amide functional group plays a key role in the composition of biomolecules, including clinically approved drugs and the bioisosterism is widely employed in the rational modification of lead compounds (abstract). Kumari et al. discloses that because of the very labile nature of the amide functional group, amide bond bioisosteres that improve metabolic stability are of great interest (Kumari et al. pg. 12292, col. 1, para. 3). Kumari et al. further discloses that nonclassical bioisosteres possess more advanced mimicry of their emulated counterparts than classical isosteres (pg. 12291, col. 2, para. 2 to pg. 12292, col. 1, para. 1). Kumari et al. further discloses that 1,2,3-triazole is considered an excellent nonclassical bioisostere for amide groups (pg. 12292, col. 2, para. 2). Kumari et al. further discloses that other nonclassical bioisosteres for amide groups include oxadiazoles (pg. 12296, col. 2, para. 3 to pg. 12297, col. 2, para. 2), imidazole (pg. 12301, col. 2, para. 2), and tetrazole (pg. 12306, col. 1, para. 3). Kumari et al. discloses performing in vitro screening of synthesized molecules with bioisosteres to determine biological activities that a promising for drug candidates (Kumari et al. page 12294 left col., para. 2, page 12295 right col. para. 2, and page 12296 left col. para. 2).
Clam 12 is directed to wherein the simulated third molecule with the third bioisostere is further evaluated to determine any commonalities in biological activity of the first molecule of interest having the first bioisostere. Claim 13 is directed to wherein the simulated third molecule with the third bioisostere shares common biological activity with the molecule of interest having the first bioisostere.
Arabi discloses that bioisosteric replacement changes the chemical properties of the molecule significantly while the biological activity remains intact (pg. 1111, para. 1 to pg. 1112, para. 1). Therefore, molecules that are found to have the same AED are considered to be bioisosteres, as discussed above in regards to claim 11, and therefore would be expected to have the same biological activity given that common biological activity is a standard for bioisosteres.
Claim 14 is directed to wherein the third bioisostere of the third molecule is further investigated as a pharmaceutical of interest.
Kumari et al. discloses various investigations into suggested bioisosteres as pharmaceuticals of interest (pg. 12297, col. 2, para. 3 to pg. 12298, col. 1, para. 2).
Claim 18 is directed to wherein each bioisostere can be considered in any isomeric form of the respective bioisostere
Kumari et al. discloses 1,2,3-triazole can also mimic the configuration of the trans or cis conformation abound the amide bond depending on the substitution pattern of the triazole (pg. 12292, col. 2, para. 2; Fig. 2). Kumari et al. discloses that the 1,4-disubstituted 1,2,3-triazole is isosteric to the trans amid bond and the 1,5-disubstituted 1,2,3-triazole moiety mimics the cis amide bond (pg. 12292, col. 2, para. 2; Fig. 2).
Claims 21 is directed to wherein the calculated average electron density (AED) values are calculated as a sum of electron population divided by a sum of volumes of all atoms in the first or second bioisostere.
Arabi shows that the average electron density of a bioisosteric group is given by the sum of the electron population of each atom divided by the sum of the volume of each atom (Arabi pg. 1112, para. 1).
Claim 25 is directed to a description of the use of the method such as identifying, generating, discovery, designing, and creating new molecules have desired biological activity common to a first molecule.
This is a description of what the method may be used for (i.e. not active steps of the method). However, Arabi shows a methodology that would allow for this process.
Claim 26 is directed to completing a QM simulation for the third molecule, partitioning the third molecule into atoms, delimiting the partitioned atoms by zero-flux surfaces to obtain interatomic basins, delimiting an outer limit of the atomic basins with three difference isodensity envelopes, obtaining atomic basins and performing atomic integrations on the partitioned atoms of the third molecule, extracting data for each of the partitioned atoms in the third molecule, segregating a bioisosteric group of the third molecule from the other atoms in the third molecule, and calculating AED values of the bioisosteric group of the third molecule.
Arabi shows performing QM simulations on molecules (Arabi page 1113 para 1).
Arabi shows the use of the AIMAII package for atomic integrations based on QTAIM. Arabi shows the interatomic basins are delimited by zero-flux surfaces, and the outer limit of the atomic basins are defined by three different isodensity envelopes of 0.0004, 0.001, and 0.002 a.u. (Arabi page 1113 para 2). The use of this process extracts data for each of the partitioned atoms because it performs operations of the atomic basins. Arabi shows that the AED tool is based on the partitioning of the molecule into atomic basins using quantum theory of atoms in the molecule (QTAIM) partitioning scheme which is then used to calculate the AED of a bioisosteric group by summing the properties of the atoms constituting this group (Arabi pg. 1112 paras 1-2).
Claim 28 is directed to determining a first additional sets of atoms, replacing the set of atoms of the first molecule of interest with the first additional set of atoms to obtain one or more isomeric forms of a first potential candidate molecule,
Arabi shows that the purpose of the paper is to investigate the similarities in the average electron densities of carboxylic acid and nonclassical bioisosteres of carboxylic acid with different kinds of capping groups (pg. 1112, para. 1). Therefore, the carboxylic acid corresponds to the first molecule of interest and the isoxazole, tatrazol-5-one, oxadiazole, oxazolidinedione and thiazolidinedione correspond to the second molecule having the second bioisostere.
completing a QM simulation for the first potential candidate molecule,
Arabi shows performing QM simulations on molecules (Arabi et al. page 1113 para 1).
partitioning the first potential candidate molecule into atoms, delimiting the partitioned atoms by zero-flux surfaces to obtain interatomic basins, delimiting an outer limit of the atomic basins with three difference isodensity envelopes, obtaining atomic basins and performing atomic integrations on the partitioned atoms of the first potential candidate molecule, extracting data for each of the partitioned atoms in the first potential candidate molecule,
Arabi shows the use of the AIMAII package for atomic integrations based on QTAIM. Arabi shows the interatomic basins are delimited by zero-flux surfaces, and the outer limit of the atomic basins are defined by three different isodensity envelopes of 0.0004, 0.001, and 0.002 a.u. (Arabi page 1113 para 2). The use of this process extracts data for each of the partitioned atoms because it performs operations of the atomic basins.
segregating a bioisosteric group of the first potential candidate molecule from the other atoms in the first potential candidate molecule, and calculating AED values of the bioisosteric group of the first potential candidate molecule,
Arabi shows that the AED tool is based on the partitioning of the molecule into atomic basins using quantum theory of atoms in the molecule (QTAIM) partitioning scheme which is then used to calculate the AED of a bioisosteric group by summing the properties of the atoms constituting this group (Arabi pg. 1112 paras 1-2)
confirming that the AED values of the first additional set of atoms of the first potential candidate molecule and the AED values corresponding to the first bioisostere in the first molecule are different from one another by no more than a predetermined 10%,
Arabi shows that nonclassical bioisosteres have very similar AEDs that demonstrate insignificant changes in AEDs of the bioisosteric group (Arabi pg. 1112, para. 1; pg. 1113, para. 2 to pg. 1115, para. 2; pg. 1118, para. 2; Table 1), which confirms the experimentally observed bioisosterism for carboxylic acid, isoxazole, tatrazol-5-one, oxadiazole, oxazolidinedione and thiazolidinedione correspond to the second molecule having the second bioisostere.
and repeating these steps for one or more further additional set of atoms of each of one or more further potential candidate molecule until one or more potential candidate molecules, including the first potential candidate molecule, having identified additional sets of atoms having calculated AED values different by no more than a predetermined 10% of the calculated AED values of the first bioisostere is obtained.
Arabi shows performing this analysis for each of the bioisosteres under investigation of the AED values (Arabi page 1113 para. 1-3).
Claim 29 is directed to wherein the calculated AED values of the first bioisostere and each of the additional sets of atoms are equivalent to one another, irrespective of any groups to which the first bioisostere and each of the additional sets of atoms are attached. Claim 30 is directed to wherein the calculated AED values of the first bioisostere and each of the additional sets of atoms have capped groups.
Arabi discloses that the calculated AEDs for each bioisostere group are equivalent to one other regardless of five different capped groups that were tested (Arabi pg. 1113, para. 4 to pg. 1115, para. 2; Figs. 2-3). Arabi et al. further shows the AED tool determines the similarity among them irrespective of the bioisostere chosen or its capping group (Arabi pg. 1113, para. 4 to pg. 1115, para. 2; Figs. 2-3).
Claim 31 is directed to wherein the step of completing a QM simulation for the first potential candidate molecule and each of the further potential candidate molecules optimizes the geometries, computes the frequency, and generates a wavefunction from which volumes and electron densities are extracted.
Arabi shows the use of a QM simulation that optimizes molecular geometries, computes a frequency, and generates a wavefunction which volumes and electron densities are extracted (Arabi pg. 1113 para 1).
An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Arabi discloses an AED tool that can be used to identify bioisosteric groups based on an equivalence of AED values in the group (abstract). Arabi further discloses that AED tool has been tested in several cases, including tetrazole, methylaquarate and sulphonamide as well as numerous different nonclassical bioisosteres for carboxylic acid (Arabi pg. 1112, para. 1). Arabi also discloses that carboxylic acid groups are frequently replaced by bioisosteres in drug design (Arabi pg. 1112, para. 1). In addition, Arabi discloses that the AED tool is more precise and less ambiguous for evaluating bioisosteres than other tools (Arabi pg. 1118, para. 2). Kumari et al. discloses that bioisosteric replacements for amide groups are of great interest in drug design (Kumari et al. pg. 12292, col. 1, para. 3) and that 1,2,3-triazole is one such bioisostere for amide as well as many other possibilities (Kumari et al. pg. 12292, col. 2, para. 2 to pg. 12312, col. 2, para. 2). Kumari et al. discloses in vitro testing of bioisostere for screening molecules for a desired biological activity (Kumari et al. page 12294 left col., para. 2, page 12295 right col. para. 2, and page 12296 left col. para. 2). Therefore, one of ordinary skill in the art would have been motivated to utilize the AED tool taught by Arabi to evaluate the various possible bioisosteres of the amide group, including 1,2,3-triazole in order to confirm the bioisosterism of the groups with a precise tool for determining bioisosterism, as taught by Arabi and further performing in vitro screening of identified molecules with bioisosteres that are deemed similar to both the molecules with the amide and 1,2,3- triazole groups. Furthermore, one of ordinary skill in the art would predict that AED tool taught by Arabi could be readily applied to the amide group, 1,2,3-triazoles and their bioisosteres with a reasonable expectation of success because Arabi discloses that the tool has been tested and successfully applied to numerous different kinds of nonclassical bioisosteres previously (pg. 1112, para. 1). Furthermore, one of ordinary skill in the art could apply the method to both of the disclosed cis and trans isomers of the amide groups as well as their 1,2,3-triazole scaffold counterparts disclosed in Kumari et al. in order to fully investigate all possible bond conformations and their effects for amide bond substitutions and pursue all known potential solutions for the amide bond bioisosteric substitutions. Furthermore, one of ordinary skill in the art would predict that AED tool taught by Arabi could be readily applied to the bioisosteres of both amides and to identify a third molecule having a closely related bioisostere.
Response to Arguments
Applicant's arguments filed 23 June 2025 have been fully considered but they are not persuasive.
Argument 1
Applicant argues the Arabi et al. does not satisfy the claim requirement of “identifying those calculated AED values equivalent between the first and second bioisostere, wherein the equivalent calculated AED values have a difference of no more than 10% between one another” because the bioisosteres refer specifically to a 1,2,3-triazole (second bioisostere) as a bioisostere of an amide (first bioisostere) are not included, there is no discussion on % difference in the AED or linking the threshold of 10% to obtain a suitable drug candidate having a desired biological activity (Reply p. 33). Applicant argues a person of ordinary skill in the art would have had no reason to replace the carboxylic acid by Arabi with a 1,2,3-triazole and an amide and a person of ordinary skill in the art would have had no motivation to pick the bioisosteric pair of 1,2,3-triazoles and an amide a 1,2,3-triazole and an amide (Reply p. 34). Applicant argues that the choice of the specific 1,2,3-triazole and amide bioisosteric pair required by the present claims is truly not trivial nor obvious (Reply p. 36).
These arguments have been fully considered but found to be not persuasive.
Arabi does not disclose triazole and amide bioisostere pair but Kumari et al. discloses the use of an amide and 1,2,3-triazole along with providing reasons to use this pair. Kumari et al. discloses that “The triazole moiety has repeatedly shown potential application in refining the therapeutic ability of amide bond-containing molecules and therefore is considered an excellent non-classical bioisostere. Most importantly, the triazole motif is proficient in mimicking the configuration of the trans amide bond; either a trans or a cis conformation can be achieved around the heterocycle depending on the substitution pattern of the triazole. (Kumari et al. page 12292 right col.). Kumari et al. provides motivation for the use of this specific bioisosteric pair due to Kumari et al. disclosing the triazole moiety is considered an excellent non-classical bioisostere along with the “widespread use” of 1,4-disubstituted 1,2,3-triazole scaffold for its proficiency in mimicking the configuration of the trans amide bond. Thus, the bioisostere pair is obvious in the context of drug discovery due to repeatedly showing application in refining therapeutic ability of molecules and being considered an excellent non-classical bioisostere.
Arabi shows that the AED tool is capable of identifying bioisosteres that are within 10% of each other (Arabi et al. pg. 1113 Table 1 in column 1). Chemical properties such as bonding and dipole moments stem from electron density and therefore bioisosteres that have similar electron densities as disclosed in Arabi (i.e. bioisosteres with values that are within 10% of each other) would indicate similar properties. Further, Kumari et al. shows the bioisosteric pair of amide/ 1,2,3-trazole along with stating these isosteres have comparable fundamental properties such as dipole moment and hydrogen bonding properties which stem from how they distribute electrons which would indicate comparable electron densities.
Kumari et al. further states that several fundamental properties, such as planarity, dipole moment and hydrogen bonding properties of the 1,2,3-triazole, are comparable to those of an amide and the dipole moment of the amide and 1,2,3-triazole is not significantly different due to the similarity in the electronic distribution with the triazole moiety possessing lone pairs of electrons that play a similar role as the oxygen atom in the amide and the CH bond within the triazole exhibiting a strong dipole moment and therefore can function as a hydrogen bond donor, analogous to the amide NH (see Kumari et al. 12292 right col.). Thus, the bioisosteric pair of 1,2,3-triazole and amide having fundamental properties that are comparable to each other such as electronic properties of a dipole moment and hydrogen bonding properties which are properties that arise from the electron density can be detected with the AED tool for identifying electron distributions within a certain percentage.
Argument 2
Applicant argues in the present application, the tool is used on two isomers of amide (cis and trans) and two isomers of 1,2,3-triazole (1,4 and 1,5 isomers). There is no mention or any hint whatsoever in the cited Arabi reference about the AED tools and isomers of bioisosteres, and therefore, logically speaking, based on Arabi, it is not trivial at all to think of using the AED tool for isomerism of bioisosteres, let alone entangling two different isomerism types: cis/trans isomerism crisscrossed with 1,4/1,5 disubstituted isomerism. It would not have been trivial, even to one of ordinary skill in the art, to expect that the tool would perform consistently the same for the different isomers of the chosen bioisosteres (Reply p. 36). Applicant argues that cis/trans isomerism and 1,4/1,5 isomerism cause drastic changes (Reply p. 36).
These arguments have been fully considered but found to be not persuasive.
Arabi shows using an AED tool to quantify the similarity among nonclassical bioisosteres. Although Arabi does not disclose information about isomers, Kumari et al. states that “the triazole motif is proficient in mimicking the configuration of the trans amide bond; either a trans or a cis conformation can be achieved around the heterocycle depending on the substitution pattern of the triazole. The 1,4-disubstituted 1,2,3-triazole scaffold is isosteric to the trans amide bond and has gained widespread use… The 1,5-disubstituted 1,2,3-triazole moiety mimics the cis amide bond, and its use is much less common” (Kumari et al. page 12292 right col.) which shows that particular isomers of the 1,2,3-trazole are isosteric to particular isomers of the amide. Therefore, one of ordinary skill in the art would have recognized that the AED tool which is used to quantify similarity among nonclassical bioisosteres should focus on the isomers that are an isosteric pair (e.g., trans amide isomer with the 1,4-disubstituted 1,2,3-triazole isomer).
Applicant provides references that show amide cis/trans isomerization has an effect on molecular structure (along with its properties) and that show two different drug molecules with the only difference between them being the structural isomerism of 1,4 vs. 1,5-triazole. It is noted these references show the changes of molecules due to different isomers of the same moiety. However, the claim is focused on replacing an amide group with a corresponding isosteric substituted 1,2,3-triazole group that accounts for the isomer effect (i.e. substituting an isomer of one moiety with an isosteric isomer of a different moiety). Kumari et al. shows that particular isomers of the 1,2,3-trazole are isosteric to particular isomers of the amide and have comparable fundamental properties (Kumari et al. page 12292 right col.).
Argument 3
Applicant argues that one of ordinary skill in the art would be highly discouraged from considering any other bioisosteres, let alone the presently recited amide/triazole pair because Kumari stats that “The introduction of a bioisostere… can be either favorable or detrimental to biological activity”. Applicant argues that one of ordinary skill in the art would have had no expectation of obtaining a suitable drug candidate having a desired biological activity by using the 1,2,3-triazole/amide bioisosteric pair (Reply p. 37-38).
These arguments have been fully considered but found to be not persuasive. The statement by Kumari et al. indicates that certain bioisosteres are better than others since some may be favorable to biological activity. Kumari et al. states “The triazole moiety has repeatedly shown potential application in refining the therapeutic ability of amide bond-containing molecules and therefor is considered an excellent nonclassical bioisostere” (Kumari et al. page 12292 right col.). Further, Kumari et al. states “Successful replacement of the amide bond within bioactive scaffolds with a 1,2,3-triazole has led to the discovery of many potent bioactive molecules, including approved marketed drugs to combat human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), bacterial infections, cancer, and neurological disorders” (Kumari et al. page 12293 left col.) which shows that the bioisosteric pair of 1,2,3-triazole/amide has been successfully used in several drug applications.
Argument 4
Applicant argues since Kumari et al. states the introduction of a bioisostere leads to structural changes in the electronic distribution it is discouraging/contradictory to using the AED tool for bioisosteres. This is because the AED tool is related to the average distributions of electrons per unit volume (AEDs), and unlike Kumari’s statement, the present application reports that the electronic distribution measured by the AEDs of bioisosteres are similar (Reply p. 38).
This argument has been fully considered but found to be not persuasive. The Arabi discloses using this AED on bioisosteres to quantify the similarity among nonclassical bioisosteres. Further, Kumari et al. discloses the bioisosteric pair of amide/ 1,2,3-trazole along with stating these isosteres have comparable fundamental properties such as dipole moment and hydrogen bonding properties which stem from how they distribute electrons which would indicate that they would have comparable electron densities. Thus, it would have been obvious to one of ordinary skill to use an AED tool for quantifying the similarity among nonclassical bioisosteres and the use of a nonclassical bioisostere pair which have comparable fundamental electronic properties.
Argument 5
Applicant argues it would not have been obvious that because the AED tool shows similarities between carboxylic acid and its bioisosteres as shown by Arabi that it would consistently show similarities between amides and triazoles; especially since amides and triazoles have two R groups as opposed to only the one R group in carboxylic acid. This difference is substantial enough not only make an amide and triazole pair as recited in the instant claims a non-trivial one, but on the contrary, to exclude the amide and triazole pair (Reply p. 39-43).
This argument has been fully considered but found to be not persuasive. Kumari et al. states “The triazole moiety has repeatedly shown potential application in refining the therapeutic ability of amide bond-containing molecules and therefor is considered an excellent nonclassical bioisostere” (Kumari et al. page 12292 right col.). Further, Kumari et al. states “Successful replacement of the amide bond within bioactive scaffolds with a 1,2,3-triazole has led to the discovery of many potent bioactive molecules, including approved marketed drugs to combat human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), bacterial infections, cancer, and neurological disorders” (Kumari et al. page 12293 left col.) which shows that the bioisosteric pair of 1,2,3-triazole/amide has been successfully used in several drug applications. Applicant points to several different molecules to discuss the effects of multiple R groups and molecules have enantiomers to show one of ordinary skill would not choose this bioisosteric pair. However, Kumari et al. recites reasons for the use of the triazole and amide bioisosteric pair such as repeatedly showing potential application in refining therapeutic ability, several successful replacements of an amide with a 1,2,3-triazole, and disclosing that an amide and a 1,2,3-triazole have comparable fundamental properties such as dipole moments and hydrogen bonding properties which stem from how they distribute electrons. Therefore, it would have been obvious to one of ordinary skill in the art to have applied the AED tool to the bioisosteric pair of an amide and a 1,2,3-triazole.
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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/J.E.H./Examiner, Art Unit 1685
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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