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 .
Claim Objections
Claim 47 is objected to because of the following informalities: missing the H atom on the N of attached to the carbonyl-X3’ the structure of Formula (IVa). Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 22, 48 – 50, and 52 are 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.
Claim 22 recites, “the compound of claim 1, wherein the compound is selected from the group consisting of: […]
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” without ending in a period. Each claim begins with a capital letter and ends with a period. (MPEP 608.01(m)). Thus, the lack of a period at the end of the claim after the last structure renders the claim indefinite because it is unclear whether the claim comprises more structures than what is recited in the claim. Does the claim only require the compounds listed in the claim or does the claim encompass other unrecited structures? Consequently, one of ordinary skills in art would not be reasonably apprised of the scope of the invention. Specifically, one of ordinary skills in the art would not be reasonably apprised of what compounds are included within the scope of claim 22 and which are not. Therefore, given the uncertainty around what compounds or included in claim 22 due to the lack of ending punction; claim 22 is rejected under 35 U.S.C. 112(b).
Claim 48 recites, “the compound of claim 47, wherein the compound is selected from the group consisting of: […]
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” without ending in a period. Each claim begins with a capital letter and ends with a period. (MPEP 608.01(m)). Thus, the lack of a period at the end of the claim after the last structure renders the claim indefinite because it is unclear whether the claim comprises more structures than what is recited in the claim. Does the claim only require the compounds listed in the claim or does the claim encompass other unrecited structures? Consequently, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, one of ordinary skills in the art would not be reasonably apprised of what compounds are included within the scope of claim 48 and which are not. Therefore, given the uncertainty around what compounds or included in claim 48 due to the lack of ending punction; claim 48 is rejected under 35 U.S.C. 112(b).
Claim 49 recites the limitation " a compound represented by Formula (Va):
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[…] where W3 is hydrogen or carbonyl;" however, there is no W3 limitation is Formula (Va). Thus, there is insufficient antecedent basis for this limitation in the claim. Therefore, given the uncertainty around what W3 defines in claim 49; claim 49 is rejected under 35 U.S.C. 112(b). Additionally, claims 50 and 52 are included in the rejection since the claims are dependent on claim 49 but do not address the deficiency. For the sake of compact prosecution W3 = W3’; thus, any prior art reference that contains a compound of Formula (Va) where W3’ is either a H or carbonyl will be applied.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 23, 57, and 60 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Giordanetto et. al. ((2011), Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors, Bioorg. Med. Chem. Lett., 21, 5557 – 5561; cited on the IDS dated May 4th, 2026).
Regarding claims 1, 23, 57, and 60, Giordanetto et. al. teach that calcium influx across the cellular membrane is partly controlled by a family of transmembrane proteins termed voltage-gated calcium channels. See page 5557 column 1 paragraph 1. Giordanetto et. al. teach that the T-type class is characterized by fast inactivation (transient) and small conductance (tiny), and is composed of three members based on the different main pore-forming a1 subunit: Cav3.1 (a1G), Cav3.2 (a1H) and Cav3.3 (a1I); while Cav3.1 and Cav3.3 are mainly expressed in the brain, Cav3.2 is found in brain and peripheral tissues (e.g., heart, kidney, liver). See page 5557 column 1 paragraph 1. Moreover, Giordanetto et. al. teach that T-type channels were proposed as therapeutic targets for a number of cardiovascular afflictions including hypertension, angina pectoris, heart failure, and atrial fibrillation; and in the cardiovascular system, T-type calcium channels are mainly involve in cardiac pace making and vascular smooth muscle contraction regulation. See page 5557 column 1 paragraph 2.
Generally, Giordanetto et. al. teach compounds of general structures
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,
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, and
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which were used to create small libraries of compounds as described in Table 1, Tabl2, and Table 3 respectively. See page 5558 column 1 Table 1, column 2 Table 2; and page 5559 Table 3. Thus, Giordanetto et. al. suggest the ability to modulate the T-type calcium channel inhibitor scaffold. In particular, Giordanetto et. al. teach compound 16 of structure
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where B = -CH2CH2-; W1’ = W2’ = H; S1’ = S2’ = H; X2’ = absent; X3’ = 1-adamantyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 5. See claim 1 limitation for a compound of represented by Formula (Ia):
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where B = -CH2CH2-; W1’ = W2’ = H; S1’ = S2’ = H; X2’ = absent; X3’ = carbocyclyl; X1’ =
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where R2’ = R3’ = R4’ = R5’ = H; and R1’ = alkyl. Additionally, Giordanetto et. al. teach compound 18 of structure
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where B = -CH2-; W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CONH-; X3’ = 1-adamantyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 7. See claim 23 limitation for a compound of represented by Formula (IIa):
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where B = -CH2-; W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CO-NH-; X3’ = carbocyclyl; X1’ =
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where R2’ = R3’ = R4’ = R5’ = H; and R1’ = alkyl.
Giordanetto et. al. teach compound 4 of structure
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where W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CONH-; X3’ = 1-adamantyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 1. Furthermore, Giordanetto et. al. teach compound 13 of structure
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where W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CONH-; X3’ = 3,5-dichlorophenyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 2. Additionally, Giordanetto et. al. teach compound 15 of structure
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where B = -CH2CH2-; W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CONH-; X3’ = 3,5-dichlorophenyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 7.
Moreover, Giordanetto et. al. teach that compounds 4, 13, 15, 16, and 18 had a Cav3.2 IC50 values of 0.08 µM, 0.9 µM, 0.3 µM, 0.8 µM, and 0.9 µM respectively. See page 5559 Table 3 rows 1, 2, 4, 5, and 7 column 4. Additionally, Giordanetto et. al. teach that compounds were assayed in extracellular solution contained (mM): NaCl 145 mM, KCl 4 mM, CaCl2 2 mM, MgCl2 1 mM, HEPES 10 mM, glucose 10 mM (pH 7.4) and the intracellular (mM): KCl 120 mM, MgCl 21.75 mM, CaCl2 5.374 mM, EGTA 10 mM, HEPES 10 mM, Na2ATP 4 mM (pH 7.2). See page 5561 column 2 paragraph 2. See claim 57 limitation for a pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. See claim 60 limitation for a method of treating a disease or condition relation to aberrant function or activity of a T-type calcium channel in a subject. As a sequence of the relatively similar IC50 values for Cav3.2, Giordanetto et. al. suggest the ability to modulate the T-type calcium channel inhibitor scaffold while maintaining relative Cav3.2 potency.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Giordanetto et. al. ((2011), Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors, Bioorg. Med. Chem. Lett., 21, 5557 – 5561; cited on the IDS dated May 4th, 2026) as applied to claims 1, 23, 57, and 60 above, and further in view of European Patent Application EP 3150598 A1 to Masaki et. al. (Masaki’598).
The teachings of Giordanetto et. al. as they relate to claim 1, from which claim 22 depend, are given previously in this office action and are fully incorporated here.
However, Giordanetto et. al. fail to teach a compound of claim 1 where the compound selected is
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. See claim 22 limitation.
Nevertheless, Masaki’598 teach a substituted tropane derivative having antagonistic activity against T-type calcium channels, and a pharmaceutical agent containing the same. See page 3 paragraph 0001 lines 5 – 6. Moreover, Masaki’598 teach compounds that are useful as prophylactic or therapeutic agents for various diseases in which T-type calcium channels are involved, such as hypertension, arrhythmia, pain and cancer, which show antagonistic activity against which T-type calcium channels. See page 4 paragraph 0008 lines 29 – 31. Masaki’598 teach compounds represented by general formula (I) of structure
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. See page 4 lines 45 – 55. In particular, Masaki’598 teach example 4 of structure
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. See page 26 paragraph 0116 lime 16 – 24.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify compound 16 of Giordanetto et. al. in view of Masaki’598 that is to replace the
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with the
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. One of ordinary skill in the art would have been motivated to make the modification because the prior art of Masaki’598 taught that the structural modification was feasible. Moreover, one of ordinary skill in the art would have had a reasonable expectation of success because the prior art of Giordanetto et. al. suggest that modifications to the scaffold were tolerated with relatively similar Cav3.2 potency within the libraries of compounds.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Giordanetto et. al. ((2011), Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors, Bioorg. Med. Chem. Lett., 21, 5557 – 5561; cited on the IDS dated May 4th, 2026) as applied to claims 1, 23, 57, and 60 above, and further in view of European Patent Application EP 3150598 A1 to Masaki et. al. (Masaki’598).
The teachings of Giordanetto et. al. as they relate to claim 23, from which claim 41 depend, are given previously in this office action and are fully incorporated here.
As taught previously, Giordanetto et. al. teach compound 18 of structure
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where B = -CH2-; W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CONH-; X3’ = 1-adamantyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 7. Prior art compound 18 differs from the selected compound of examined claim 41 of structure
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with the introduction of an additional -CH2- group in the bridge. Given that one of only difference between the prior art compound 18 and the selected examined compound is a -CH2- group in the bridge these compounds are structural homologs of each other. As such compounds which are homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See MPEP 2144.09(II).
However, Giordanetto et. al. fail to teach a compound of claim 23 where the compound selected is
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. See claim 41 limitation
Nevertheless, Masaki’598 teach a substituted tropane derivative having antagonistic activity against T-type calcium channels, and a pharmaceutical agent containing the same. See page 3 paragraph 0001 lines 5 – 6. Moreover, Masaki’598 teach compounds that are useful as prophylactic or therapeutic agents for various diseases in which T-type calcium channels are involved, such as hypertension, arrhythmia, pain and cancer, which show antagonistic activity against which T-type calcium channels. See page 4 paragraph 0008 lines 29 – 31. Masaki’598 teach compounds represented by general formula (I) of structure
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. See page 4 lines 45 – 55. In particular, Masaki’598 teach example 4 of structure
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. See page 26 paragraph 0116 lime 16 – 24.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify compound 18 of Giordanetto et. al. in view of Masaki’598 that is to replace the
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with the
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and extend the bridge by a methyl unit. One of ordinary skill in the art would have been motivated to make the modification because the prior art of Masaki’598 taught that the structural modification was feasible. Moreover, one of ordinary skill in the art would have had a reasonable expectation of success because the prior art of Giordanetto et. al. suggest that modifications to the scaffold were tolerated with relatively similar Cav3.2 potency within the libraries of compounds.
Claims 42 is rejected under 35 U.S.C. 103 as being unpatentable over Giordanetto et. al. ((2011), Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors, Bioorg. Med. Chem. Lett., 21, 5557 – 5561; cited on the IDS dated May 4th, 2026) as applied to claims 1, 23, 57, and 60 above, and further in view of European Patent Application EP 3150598 A1 to Masaki et. al. (Masaki’598).
The teachings of Giordanetto et. al. as they relate to claims 1 and 23, are given previously in this office action and are fully incorporated here.
As taught previously, Giordanetto et. al. teach compound 15 of structure
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where B = -CH2CH2-; D = N; X2’ = -CONH-; and X3’ = 3,5-dichlorophenyl. See page 5559 Table 3 row 7.
However, Giordanetto et. al. fail to teach a compound represented by Formula (IIIa)
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where X1’ = alkyl. See claim 42 limitation.
Nevertheless, Masaki’598 teach a substituted tropane derivative having antagonistic activity against T-type calcium channels, and a pharmaceutical agent containing the same. See page 3 paragraph 0001 lines 5 – 6. Moreover, Masaki’598 teach compounds that are useful as prophylactic or therapeutic agents for various diseases in which T-type calcium channels are involved, such as hypertension, arrhythmia, pain and cancer, which show antagonistic activity against which T-type calcium channels. See page 4 paragraph 0008 lines 29 – 31. Masaki’598 teach compounds represented by general formula (I) of structure
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. See page 4 lines 45 – 55. In particular, Masaki’598 teach example 4 of structure
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. See page 26 paragraph 0116 lime 16 – 24.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify compound 15 of Giordanetto et. al. in view of Masaki’598 that is to replace the
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with the
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. One of ordinary skill in the art would have been motivated to make the modification because the prior art of Masaki’598 taught that the structural modification was feasible. Moreover, one of ordinary skill in the art would have had a reasonable expectation of success because the prior art of Giordanetto et. al. suggest that modifications to the scaffold were tolerated with relatively similar Cav3.2 potency within the libraries of compounds.
Claims 49 – 50, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Giordanetto et. al. ((2011), Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors, Bioorg. Med. Chem. Lett., 21, 5557 – 5561; cited on the IDS dated May 4th, 2026) as applied to claims 1, 23, 57, and 60 above, and further in view of European Patent Application EP 3150598 A1 to Masaki et. al. (Masaki’598).
The teachings of Giordanetto et. al. as they relate to claims 1 and 23, are given previously in this office action and are fully incorporated here.
As taught previously, Giordanetto et. al. teach compound 4 of structure
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where W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CONH-; X3’ = 1-adamantyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 1. Prior art compound 4 differs from the selected compound of examined claim 52 of structure
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with the introduction of an additional -CH2- group in the ring. Given that one of only difference between the prior art compound 4 and the selected examined compound is a -CH2- group in the ring; prior art compound 4 and the selected examined compound are structural homologs of each other. As such compounds which are homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See MPEP 2144.09(II).
However, Giordanetto et. al. fail to teach a compound represented by Formula (Va)
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where the compound selected is
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. See claims 49 – 50, and 52 limitation.
Nevertheless, Masaki’598 teach a substituted tropane derivative having antagonistic activity against T-type calcium channels, and a pharmaceutical agent containing the same. See page 3 paragraph 0001 lines 5 – 6. Moreover, Masaki’598 teach compounds that are useful as prophylactic or therapeutic agents for various diseases in which T-type calcium channels are involved, such as hypertension, arrhythmia, pain and cancer, which show antagonistic activity against which T-type calcium channels. See page 4 paragraph 0008 lines 29 – 31. Masaki’598 teach compounds represented by general formula (I) of structure
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. See page 4 lines 45 – 55. In particular, Masaki’598 teach example 4 of structure
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. See page 26 paragraph 0116 lime 16 – 24.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify compound 4 of Giordanetto et. al. in view of Masaki’598 that is to replace the
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and the increase the ring size by a methyl unit. One of ordinary skill in the art would have been motivated to make the modification because the prior art of Masaki’598 taught that the structural modification was feasible. Moreover, one of ordinary skill in the art would have had a reasonable expectation of success because the prior art of Giordanetto et. al. suggest that modifications to the scaffold were tolerated with relatively similar Cav3.2 potency within the libraries of compounds.
Claim 61 is rejected under 35 U.S.C. 103 as being unpatentable over Giordanetto et. al. ((2011), Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors, Bioorg. Med. Chem. Lett., 21, 5557 – 5561; cited on the IDS dated May 4th, 2026) as applied to claims 1, 23, 57, and 60 above, and further in view of Yang et. al. ((2008), Discovery of 1,4-Substituted Piperidines as Potent and Selective Inhibitors of T-Type Calcium Channels, J. Med. Chem., 51, 6471 – 6477).
The teachings of Giordanetto et. al. as they relate to claims 1 and 60, from which claim 61 depends, are given previously in this office action and are fully incorporated here.
However, Giordanetto et. al. fail to teach a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel in a subject where the disease or condition selected is essential tremors. See claim 61 limitation.
Nevertheless, Yang et. al. teach the discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. See page 6471 abstract. Moreover, Yang et. al. teach the through the initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. See page 6471 abstract. Furthermore, Yang et. al. teach that further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine compound 30 with a significantly improved selectivity profile. See page 6471 abstract. Additionally, Yang et. al. teach that compound 30 was evaluated in a rat harmaline model of essential tremor harmaline-induced tremor activity in the 6-12 Hz range was monitored and quantified to assess tremor suppression. See page 64755 column 1 paragraph 2. Yang et. al. teach that compound 30 was found to significantly reduce tremor activity in a dose-dependent manner (Figure 5a), highlighting the potential role of T-type antagonists as a novel treatment for movement disorders such as essential tremor. See page 64755 column 1 paragraph 2 and column 2 Figure 5. See claim 61 limitation for a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel in a subject where the disease or condition selected is essential tremors.
Therefore, it would have been obvious before the effective filing date of the instant application to use the invention of any of the compounds of Giordanetto et. al. in view of Yang et. al. that is to use in method of treating essential tremors. One of ordinary skill in the art would have been motivated to make this modification since Giodanetto et. al. taught the prior art compounds were capable of targeting the T-type calcium channel as antagonists. One of ordinary skill in the art would have had a reasonable expectation of success because the example T-type calcium channel antagonists compound 30 significantly reduce tremor activity in a dose-dependent manner in a rate model for essential tremors.
Claim 46 is rejected under 35 U.S.C. 103 as being unpatentable over Giordanetto et. al. ((2011), Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors, Bioorg. Med. Chem. Lett., 21, 5557 – 5561; cited on the IDS dated May 4th, 2026) and European Patent Application EP 3150598 A1 to Masaki et. al. (Masaki’598) as applied to claim 42 above, and further in view of Meanwell ((2011), Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design, J. Med. Chem., 54, 2529 – 2591).
The teachings of Giordanetto et. All. and Masaki’598 as they relate to claim 42, from which claim 46 depend, are given previously in this office action and are fully incorporated here.
However, Giordanetto et. al. and Masaki’598 fail to teach a compound of claim 42 where the compound selected is
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where D = C, B = -CH2OCH2- and one of the halogens is a Cl atom. See claim 46 limitation.
Nevertheless, Meanwell teach that in the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address several aspects associated with the design and development of drug candidates. See page 2529 column 1 paragraph 1. Additionally, Meanwell teach that bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. See page 2529 column 1 paragraph 1. Moreover, Meanwell teach that and -O-, -NH- ,and -CH2- are classical bivalent bioisosteres. See page 2530 column 1 Table 1. Thus Meanwell suggest the ability to substitute -CH2- for -NH- with a reasonable expectation that compounds with either -NH- or -CH2- would have similar biological properties. Furthermore, Meanwell teach that F and Cl are classical monovalent bioisosteres. See page 2530 column 1 Table 1. Thus Meanwell suggest the ability to substitute F for -Cl with a reasonable expectation that compounds with either Cl or F would have similar biological properties.
While the prior art fails to teach the limitation of claim 46 for a selected compound of
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where B = -CH2OCH2- the only difference between the bridge system taught by the prior art and the examined limitation is the addition of a -O- between the -CH2CH2- bridge. Moreover, as taught above the introduction of an additional -CH2- unit would make a compound species which would be a structural homolog to the selected examined compound. Moreover, as taught by Meanwell -O- can be substituted for the additional -CH2- unit of the bridge creating a compound species that is a structural homolog and bioisostere. Thus, given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a PharmD and PhD, it would be within the purview of such artisan to possible modify the bridge and substituents on the scaffold given the teachings of Giordanetto et. al. and Masaki’598 in view of Meanwell.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify compound 15 of Giordanetto et. al. in view of Masaki’598 that is to replace the
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with the
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and in further view of Meanwell, that is to substitute one of the Cl for a F atom, substitute the N atom in the ring for a C atom, and to modify the bridge by extended by a methyl unit before substituting with an O atom. One of ordinary skill in the art would have been motivated to make the modification because the prior art of Masaki’598 taught that the structural modification was feasible. Moreover, one of ordinary skill in the art would have had a reasonable expectation of success because the prior art of Giordanetto et. all. suggest that modifications to the scaffold were tolerated with relatively similar Cav3.2 potency within the libraries of compounds. Furthermore, one of ordinary skill in the art would be motivated to make this modification and have a reasonable expectation of success because both F and Cl are classical monovalent bioisosteres and -NH-, -CH2- , and -O- are classical bivalent bioisosteres and would be reasonably expected to at least have the same biological properties.
Claims 47 – 48 are rejected under 35 U.S.C. 103 as being unpatentable over Giordanetto et. al. ((2011), Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors, Bioorg. Med. Chem. Lett., 21, 5557 – 5561; cited on the IDS dated May 4th, 2026) and European Patent Application EP 3150598 A1 to Masaki et. al. (Masaki’598) as applied to claim 42 above, and further in view of Meanwell ((2011), Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design, J. Med. Chem., 54, 2529 – 2591).
The teachings of Giordanetto et. al. and Masaki’598 as they relate to the prior art rejections of claim 42, are given previously in this office action and are fully incorporated here.
However, Giordanetto et. al. and Masaki’598 fail to teach a compound represented by Formula (IVa)
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where X1’ = alkyl; X2’ = N; and X3’ = aryl. See claim 47 limitation. Furthermore, Giordanetto et. all. fail to teach a compound of claim 47 where the compound selected is
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. See claim 48 limitation.
Nevertheless, Meanwell teach that in the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. See page 2529 column 1 paragraph 1. Additionally, Meanwell teach that bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. See page 2529 column 1 paragraph 1. Furthermore, Meanwell teach that H, CH3, F and Cl are classical monovalent bioisosteres. See page 2530 column 1 Table 1. Thus, Meanwell suggest the ability to substitute F for Cl or H for a CH3 with a reasonable expectation that compounds with either Cl or F and H or CH3 would have similar biological properties.
While the prior art fails to teach the limitation of claims 47 – 48 for a selected compound of
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where the substituent is connected in the 3rd position of the ring; this structural limitation represents one of the only differences between compound 13 of the prior art and the selected examined compound these compounds are positional isomers. Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See MPEP 2144.09 (II). Moreover, given that the skill of one of ordinary skill in the pharmaceutical art is relatively high being that of a PharmD and PhD, it would be within the purview of such artisan to possibly modify the substituents on the scaffold given the teachings of Giordanetto et. al. and Masaki’598 in view of Meanwell.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify compound 13 of Giordanetto et. al. in view of Masaki’598 that is to replace the
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with the
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and in further view of Meanwell, that is to substitute one of the Cl for a F atom, substitute the H atom on free N atom for a CH3, and to modify the arrangement of the substituents. One of ordinary skill in the art would have been motivated to make the modification because the prior art of Masaki’598 taught that the structural modification was feasible. Moreover, one of ordinary skill in the art would have had a reasonable expectation of success because the prior art of Giordanetto et. al. suggest that modifications to the scaffold were tolerated with relatively similar Cav3.2 potency within the libraries of compounds. Furthermore, one of ordinary skills in the art would be motivated to make this modification and have a reasonable expectation of success because both F and Cl & H and CH3 are classical monovalent bioisosteres would be reasonable expected to at least have the same biological properties.
Claim 58 is rejected under 35 U.S.C. 103 as being unpatentable over Giordanetto et. al. ((2011), Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors, Bioorg. Med. Chem. Lett., 21, 5557 – 5561; cited on the IDS dated May 4th, 2026) as applied to claims 1, and 57, above, and further in view Perret et. al. ((2009), Targeting Voltage-Gated Calcium Channels for Neuropathic Pain Management, Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics, 6, 679 – 692).
The teachings of Giordanetto et. al. as they relate to claims 1, and 57, from which claim 58 depends, are given previously in this office action and are fully incorporated here.
However, the prior art of Giordanetto et. al. fail to teach a pharmaceutical composition further comprising a modified-release polymer. See claim 58 limitation.
Nevertheless, Perret et. al. teach that a recent survey has indicated that at least 50 million people in the United States suffer from chronic pain. See page 679 column 1 paragraph 1. Perret et. al. teach that voltage-gated calcium channels (VGCC) or their subunits are considered one family of molecules with therapeutic potentials in chronic pain management. See page 679 column 2 paragraph 2. Moreover, Perret et. al. teach that Based on their physiological and pharmacological properties, VGCC can be subdivided into low voltage-activated T-type (Cav3.1, Cav3.2, and Cav3.3), and high voltage activated L- (Cav1.1 through Cav1.4), N-(Cav2.2), P/Q- (Cav2.1), and R-(Cav2.3) types, depending on the channel forming Cavα subunits. See page 680 column 1 paragraph 2. Additionally, Perret et. al. teach that the binding of gabapentin and pregabalin to the Cavα2δ1 subunit of VGCC results in a reduction in the calcium-dependent release of multiple neurotransmitters, leading to efficacy and tolerability for neuropathic pain management. See page 685 column 2 paragraph 2. Moreover, Perret et. al. teach that gabapentin has been formulated as an extended-release (ER) form using polymer based AcuForm technology. See page 686 column 1 paragraph 2. See claim 58 limitation for a pharmaceutical composition further comprising a modified-release polymer. Furthermore, Perret et.al. teach that gabapentin ER once-daily dosing was found to produce higher maximum plasma concentrations compared with the TID gabapentin immediate-release regimen and twice-daily gabapentin ER dosing was found to result in less fluctuation in plasma concentrations. See page 686 column 1 paragraph 3. Additionally, Perret et. al. teach that extended release formulations would be ideal for patients requiring prolonged clinical exposure, such as patients with restless leg syndrome, using a single daily dose and that the use of the XR formulation may dramatically improve treatment compliance. See page 687 column 1 paragraph 1.
Therefore, it would have been obvious before the effective filing date of the instant application to formulate the compounds of Giordanetto et. al. in view of Perret et. al. that is in pharmaceutical compositions composing the modified release polymer AcuForm. One of ordinary skill in the art would have been motivated to make this modification to benefit patients requiring prolonged clinical exposure and to dramatically improve treatment compliance. One of ordinary skill in the art would have had a reasonable expectation of success because the example pharmaceutical gabapentin was successfully formulated with AcuForm which resulted in higher maximum plasma concentrations compared with the TID gabapentin immediate-release regimen.
Discussion of the Prior art
The closet prior art of Giordanetto et. al. ((2011), Discovery of N-(1-adamantyl)-2-(4-alkylpiperazin-1-yl)acetamide derivatives as T-type calcium channel (Cav3.2) inhibitors, Bioorg. Med. Chem. Lett., 21, 5557 – 5561; cited on the IDS dated May 4th, 2026) teach that calcium influx across the cellular membrane is partly controlled by a family of transmembrane proteins termed voltage-gated calcium channels. See page 5557 column 1 paragraph 1. Giordanetto et. al. teach that the T-type class is characterized by fast inactivation (transient) and small conductance (tiny), and is composed of three members based on the different main pore-forming a1 subunit: Cav3.1 (a1G), Cav3.2 (a1H) and Cav3.3 (a1I); while Cav3.1 and Cav3.3 are mainly expressed in the brain, Cav3.2 is found in brain and peripheral tissues (e.g., heart, kidney, liver). See page 5557 column 1 paragraph 1. Moreover, Giordanetto et. al. teach that T-type channels were proposed as therapeutic targets for a number of cardiovascular afflictions including hypertension, angina pectoris, heart failure, and atrial fibrillation; and in the cardiovascular system, T-type calcium channels are mainly involve in cardiac pace making and vascular smooth muscle contraction regulation. See page 5557 column 1 paragraph 2.
Generally, Giordanetto et. al. teach compounds of general structures
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,
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, and
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which were used to create small libraries of compounds as described in Table 1, Table 2, and Table 3 respectively. See page 5558 column 1 Table 1, column 2 Table 2; and page 5559 Table 3. In particular, Giordanetto et. al. teach compound 16 of structure
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where B = -CH2CH2-; W1’ = W2’ = H; S1’ = S2’ = H; X2’ = absent; X3’ = 1-adamantyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 5. Additionally, Giordanetto et. al. teach compound 18 of structure
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where B = -CH2-; W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CONH-; X3’ = 1-adamantyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 7.
Giordanetto et. al. teach compound 4 of structure
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where W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CONH-; X3’ = 1-adamantyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 1. Furthermore, Giordanetto et. al. teach compound 13 of structure
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where W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CONH-; X3’ = 3,5-dichlorophenyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 2. Additionally, Giordanetto et. al. teach compound 15 of structure
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where B = -CH2CH2-; W1’ = W2’ = H; S1’ = S2’ = H; X2’ = -CONH-; X3’ = 3,5-dichlorophenyl; R2’ = R3’ = R4’ = R5’ = H; and R1’ = -C(CH3)3. See page 5559 Table 3 row 7.
However, Giordanetto et. al. fail to teach a compound represented by Formula (VIa):
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. See claim 53 limitation for a compound where R3’ = aryl or heteroaryl. Moreover, Giordanetto et. al. fail to teach a compound of claim 53 where the compound selected is from a list. See claim 55 limitation. Furthermore, Giordanetto et. al. fail to teach a compound of the following structure:
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. See claim 56 limitation. Moreover, the prior art fails to provide a motivation for modifying the prior art to render the claims 53, and 55 – 56 obvious. Therefore, given that the prior art fails to anticipate or render obvious the structures as delineated in claims 53, and 55 – 56 are free of the prior art and allowable.
Conclusion
Claims 1, 22 – 23, 41 – 42, 46 – 50, 52, 57 – 58, and 60 – 61 are rejected. Claims 53, and 55 – 56 are allowable.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
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