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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The instant application claims foreign priority to an application filed in the People’s Republic of China, Chinese Patent Application No. 202310676316.1, filed on June 8, 2023. Receipt is acknowledged of a certified copy of foreign application. A certified copy of the translation of the foreign application has not been received.
Status of Claims
Claims 1-4 are pending.
Information Disclosure Statement
The Information Disclosure Statement (“IDS”) submitted on August 7, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4 are obvious over Bai 2012 in view of Murugesan 2005, EP’314, and WO’389
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Bai et al., “Synthesis and biological evaluation of 4’-[(benzimidazole-1-yl)methyl]biphenyl-2-sulfonamide derivatives as dual angiotensin II/endothelin A receptor antagonists,” Bioorganic & Medicinal Chemistry, vol. 20, no. 15, pp. 4661-4667 (2012), hereinafter referred to as “Bai 2012”, in view of Murugesan et al., “Dual Angiotensin II and Endothelin A Receptor Antagonists: Synthesis of 2′-Substituted N-3-Isoxazolyl Biphenylsulfonamides with Improved Potency and Pharmacokinetics,” J. Med. Chem., vol. 48, no. 1, 171-179 (2005), hereinafter referred to as “Murugesan 2005”, Hauel et al., European Patent specification No. EP0502314, dated May 20, 1998, hereinafter referred to as “EP’314”, and Murugesan et al., International Application Publication No. WO 00/01389, dated January 13, 2000, hereinafter referred to as “WO’389”.
Claim 1 of the instant application is directed to a dual-action receptor antagonist (a “DARA”) compound of formula I, having a core structure consisting of three parts:
an angiotensin II subtype 1 (AT1) receptor antagonist pharmacophore in the form of a {[4‐methyl‐6‐(1‐methyl‐1H‐1,3‐benzodiazol‐2‐yl)‐1H‐1,3‐benzodiazol‐1‐yl]methyl} moiety,1
a 2’-ethyoxymethyl substituted biphenyl linker, and
an endothelin subtype A (ETA) receptor antagonist pharmacophore in the form of an N-3-dimethylisoxazole sulfonamide moiety.
Claim 1 encompasses one disclosed example, for example, compound 1-10:
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(named 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide at page 9 of the Specification).
Bai 2012 discloses the structure of BMS-346567, which is referred to as compound 3 in the article, and describes it as a “potent dual-action receptor antagonist…,” Bai 2012 at 4661, with an ability to antagonize both AT1 and ETA receptors.
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Bai 2012 at 4662.
Similar to the exemplified embodiment of claim 1 of the instant application (see compound 1-10 above), the chemical structure of BMS-346567 incorporates a 2’-ethyoxymethyl substituted biphenyl linker, and an ETA receptor antagonist pharmacophore in the form of an N-3-dimethylisoxazole sulfonamide moiety.
Bai 2012 further teaches the general strategy for the design and optimization of DARAs in the field of dual AT1/ETA receptor antagonists. For example, Figure 2 of Bai 2012 illustrates the general design of a DARA, wherein the DARA combines an AT1 receptor antagonist pharmacophore of one known compound, with an ETA receptor antagonist pharmacophore of a second known compound, across a biphenyl linker (note that in the excerpted figure below, the illustrated example uses a benzimidazole-based AT1 receptor antagonist, a biphenyl linker, and an N-5 dimethylisoxazole sulfonamide-based ETA receptor antagonist):
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Bai 2012 at 4662.
Bai 2012 additionally teaches the motivation of the general strategy for the design and optimization of DARAs in the field of dual AT1/ETA receptor antagonists:
It is well-known that angiotensin II subtype 1 (AT1) receptor antagonists are clinically useful for the management of hypertension and heart failure,4,5 and endothelin subtype A (ETA) receptor antagonists show promising effects in the treatment of the similar indications.6 Interestingly, some of these two types of antagonists have close similarity in structure. Hence, lots of attempt has been made to hybridize both AT1 and ETA receptor antagonistic properties in one molecule. It is anticipated that drugs with dual AT1 and ETA receptor antagonistic action could be more effective than the current standard therapies for the treatment of hypertension.
Bai 2012 at 4661 (emphasis added).
As a proof of concept of the modularity of the general strategy for the design and optimization of DARAs in the field of dual AT1/ETA receptor antagonists that Figure 2 of Bai 2012 sets forth, Bai 2012 further teaches twelve DARAs developed that successfully antagonized both AT1 and ETA receptors:
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Bai 2012 at 4662.
Selection of the forms of a biphenyl linker and an ETA receptor antagonist pharmacophore
The general strategy for the design and optimization of DARAs in the field of dual AT1/ETA receptor antagonists Figure 2 of Bai 2012 illustrates, by example, a DARA incorporating a biphenyl linker and an ETA receptor antagonist in the form of a N-5-dimehtylisoxazole sulfonamide moiety. One of ordinary skill in the art would have a reasonable expectation of success in designing an AT1/ETA DARA that incorporates both 1) a 2’-ethyoxymethyl substituted biphenyl linker, and 2) an ETA receptor antagonist pharmacophore in the form of an N-3-dimethylisoxazole sulfonamide moiety, because Murugesan 2005 taught that such a linker and a pharmacophore imparted beneficial pharmacodynamic and pharmacokinetic properties in similar DARAs. See, e.g., Table 2 of Murugesan 2005, and nota bene that compound 7 is BMS-346567, or compound 3 of Bai 2012, which is discussed above.
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Murugesan 2005 at 174.2
As shown in the above table, selection of both the 2’-ethyoxymethyl substituted biphenyl linker and the N-3-dimethylisoxazole sulfonamide moiety offers optimal AT1 receptor antagonism pharmacodynamics, see AT1 Ki values for the entries highlighted in yellow, as well as pharmacokinetics superior to compounds 1 (irbesartan, an AT1 receptor antagonist) and 2 (BMS-193884, an ETA receptor antagonist), respectively, see oral AII and oral big ET pressor values highlighted in yellow.
Selection of the form of an AT1 receptor antagonist pharmacophore
The general strategy for the design and optimization of DARAs in the field of dual AT1/ETA receptor antagonists Figure 2 of Bai 2012 illustrates, by example, a DARA incorporating an AT1 receptor antagonist in the form of a benzimidazole moiety. One of ordinary skill in the art would have a reasonable expectation of success in designing an AT1/ETA DARA that incorporates an AT1 receptor antagonist pharmacophore in the form of a {[4‐methyl‐6‐(1‐methyl‐1H‐1,3‐benzodiazol‐2‐yl)-2‐propyl-1H‐1,3‐benzodiazol‐1‐yl]methyl} moiety (i.e., a bibenzimidazole), because Bai 2012 suggests using any AT1 receptor antagonist pharmacophore, and it would be obvious to try a pharmacophore from a well-known and FDA approved AT1 receptor antagonist, such as telmisartan.3
As background, telmisartan was disclosed EP’314. Its chemical structure is excerpted below from J. Fischer and C. Ganellin, Analogue-based Drug Discovery (2006) at 471 (the examiner annotated the corresponding {[4‐methyl‐6‐(1‐methyl‐1H‐1,3‐benzodiazol‐2‐yl)-2‐propyl-1H‐1,3‐benzodiazol‐1‐yl]methyl} moiety in blue):
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Telmisartan shares the exact same {[4‐methyl‐6‐(1‐methyl‐1H‐1,3‐benzodiazol‐2‐yl)-2‐propyl-1H‐1,3‐benzodiazol‐1‐yl]methyl} moiety of the exemplified embodiment of claim 1 of the instant application (see compound 1-10 above), as well as a biphenyl core feature. The structure of telmisartan itself suggests incorporation into an AT1/ETA DARA, because as Bai 2012 remarked regarding AT1 and ETA receptor antagonists, “some of these two types of antagonists have close similarity in structure.” Bai 2012 at 4661 (see also supra discussion of Bai 2012).
Use with salts and solvates
Claim 5 of EP’314 provides the chemical name for telmisartan and teaches its use with salts:
5. 4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid and the salts thereof with inorganic or organic acids or bases, particularly the physiologically acceptable salts thereof, prepared according to claim 1.
EP’314 at claim 5.
WO’389 teaches that BMS-346567 (see Example 227, WO’389 at 173) and other compounds of the disclosure may be in the form of salts and solvates (see, e.g., WO’389 at 10-12).
Claim 1, wherein the compound of formula I is compound 1-10, is obvious over the prior art
Given the general strategy for the design and optimization of DARAs in the field of dual AT1/ETA receptor antagonists taught by Bai 2012, and the teachings of Murugesan 2005, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing an AT1/ETA DARA that incorporated both 1) a 2’-ethoxymethyl substituted biphenyl linker and 2) an ETA receptor antagonist pharmacophore in the form of an N-3-dimethylisoxazole sulfonamide moiety because Murugesan 2005 taught that combination was known to impart optimal pharmacodynamic and pharmacokinetic properties. Moreover, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing an AT1/ETA DARA that incorporated an AT1 receptor antagonist pharmacophore in the form of a {[4‐methyl‐6‐(1‐methyl‐1H‐1,3‐benzodiazol‐2‐yl)-2‐propyl-1H‐1,3‐benzodiazol‐1‐yl]methyl} moiety because Bai 2012 suggests using any AT1 receptor antagonist pharmacophore, and it would be obvious to try a pharmacophore from a well-known and FDA approved AT1 receptor antagonist, such as telmisartan, that shared a biphenyl structural feature with BMS-346567 (i.e., compound 7 of Murugesan 2005, which is also compound 3 of Bai 2012). One of ordinary skill in the art would have a reasonable expectation of success in preparing the resulting compound as a salt because WO’389 and EP’314 taught that salts were known for similar compounds, such as telmisartan and BMS-346567. One of ordinary skill in the art would have a reasonable expectation of success in preparing the resulting compound as a solvate because WO’389 taught that solvates were known for similar compounds, such as BMS-346567.
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Therefore, one of ordinary skill in the art at the time of filing, who was following the teachings and suggestions of Bai 2012, Murugesan 2005, EP’314 and WO’389, and prepared a DARA from combining the AT1 receptor antagonist pharmacophore of telmisartan, with the 2’-ethoxymethyl substituted biphenyl linker of BMS-346567, and the ETA receptor antagonist pharmacophore of BMS-346567, would have a reasonable expectation of success in inhibiting both AT1 and ETA with the resulting DARA (i.e., the exemplified embodiment of claim 1, see compound 1-10). Table 1 of the Specification of the instant application, on pages 15-16, indicates that compound 1-10 behaved as expected.
Thus, claim 1 was prima facie obvious at the time of filing.
Claim 2 of the instant application is identical to claim 1, expect for that the general structure of the DARA has an ETA receptor antagonist pharmacophore in the form of an N-5-dimethylisoxazole sulfonamide moiety. Claim 2 encompasses one disclosed example, for example, compound 2-3:
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(named 4'-((1,7'-dimethyl-2'-propyl-1H,3'H-[2,5'-bibenzo[d]imidazol]-3'yl)methy1)-N-(3,4-dimethylisoxazol-5-yl)-2'-(ethoxymethyl)-[1,1'-bipheny1]-2-sulfonamide on page 11 of the Specification).
Bai 2012, Murugesan 2005, EP’314 and WO’389 are relied upon as above.
Selection of the forms of a biphenyl linker and an ETA receptor antagonist pharmacophore
Murugesan 2005 is further relied upon to teach the structure of compound 5, immediately depicted below and further listed below in Table 1, from Murugesan 2005 at 173. Similar to the exemplified embodiment of claim 2 of the instant application (see compound 2-3 above), the chemical structure of compound 5 of Murugesan 2005, incorporates a 2’-ethyoxymethyl substituted biphenyl linker, and an ETA receptor antagonist pharmacophore in the form of an N-5-dimethylisoxazole sulfonamide moiety.
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Compound 5 of Murugesan 2005
Table 1 of Murugesan 2005 provides the pharmacodynamic and pharmacokinetic properties of several DARAs possessing an ETA receptor antagonist pharmacophore in the form of an N-5-dimethylisoxazole sulfonamide moiety, including the aforementioned compound 5.
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Murugesan 2005 at 173.4
As shown in the above table, selection of both the 2’-ethyoxymethyl substituted biphenyl linker and the N-5-dimethylisoxazole sulfonamide moiety offers optimal AT1 receptor antagonism pharmacodynamics, see AT1 Ki values for the entries highlighted in yellow, as well as pharmacokinetics slightly better than compound 1 (irbesartan, an AT1 receptor antagonist), as well as the ability to antagonize the ETA receptor, see oral AII and oral big ET pressor values highlighted in yellow.
Claim 2, wherein the compound of formula II is compound 2-3, is obvious over the prior art
Given the general strategy for the design and optimization of DARAs in the field of dual AT1/ETA receptor antagonists taught by Bai 2012, and the teachings of Murugesan 2005, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing an AT1/ETA DARA that incorporated both 1) a 2’-ethoxymethyl substituted biphenyl linker and 2) an ETA receptor antagonist pharmacophore in the form of an N-5-dimethylisoxazole sulfonamide moiety because Murugesan 2005 taught that combination was known to impart optimal pharmacodynamic properties, and AT1 pharmacokinetics slightly better than irbesartan, while simultaneously antagonizing the ET-A receptor. Moreover, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in developing an AT1/ETA DARA that incorporated an AT1 receptor antagonist pharmacophore in the form of a {[4‐methyl‐6‐(1‐methyl‐1H‐1,3‐benzodiazol‐2‐yl)-2‐propyl-1H‐1,3‐benzodiazol‐1‐yl]methyl} moiety because Bai 2012 suggests using any AT1 receptor antagonist pharmacophore, and it would be obvious to try a pharmacophore from a well-known and FDA approved AT1 receptor antagonist, such as telmisartan, that shared a biphenyl structural feature with compound 5 of Murugesan 2005. One of ordinary skill in the art would have a reasonable expectation of success in preparing the resulting compound as a salt because WO’389 and EP’314 taught that salts were known for similar compounds, such as telmisartan and BMS-346567. One of ordinary skill in the art would have a reasonable expectation of success in preparing the resulting compound as a solvate because WO’389 taught that solvates were known for similar compounds, such as BMS-346567.
Therefore, one of ordinary skill in the art at the time of filing, who was following the teachings and suggestions of Bai 2012, Murugesan 2005, EP’314 and WO’389, and prepared a DARA from combining the AT1 receptor antagonist pharmacophore of telmisartan, with the 2’-ethoxymethyl substituted biphenyl linker of compound 5 of Murugesan 2005, and the ETA receptor antagonist pharmacophore of Compound 5 of Murugesan 2005, would have a reasonable expectation of success in inhibiting both AT1 and ETA with the resulting DARA (i.e., the exemplified embodiment of claim 2, see compound 2-3 above). Table 1 of the Specification of the instant application, on pages 15-16, indicates that compound 2-3 behaved as expected.
Thus, claim 2 was prima facie obvious at the time of filing.
Claim 3 depends from claim 1 and selects compounds 1-4, 1-7, 1-10, and 1-13. These compounds vary by the substituent at the 2-position of the telmisartan-based AT1 receptor antagonist, wherein the substituent is methyl, ethyl, propyl, and butyl, respectively.
Because claim 3 selects compound 1-10, and compound 1-10 is prima facie obvious over the references as explained above for claim 1, claim 3 is also prima facie obvious.
Regarding compounds 1-4, 1-7, and 1-13, claim 1 of EP’314 further teaches the generic chemical structure, reproduced below, that encompasses telmisartan and its C1-5-alkyl analogs:
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“R3 represents a C1-5-alkyl group or a C3-5-cycloalkyl group.” EP’314 at claim 1.
One of ordinary skill in the art would have a reasonable expectation of success in developing an AT1/ETA DARA that incorporated the methyl, ethyl, and butyl analogs of telmisartan as potential AT1 receptor antagonist pharmacophores because “[c]ompounds 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).” MPEP 2144.09. The AT1 receptor antagonist pharmacophores of compounds 1-4 (methyl), 1-7 (ethyl), and 1-13 (butyl) are homologous to the AT1 receptor antagonist pharmacophore of compound 1-10 (propyl), and are expected to possess similar properties relative to the pharmacophore of telmisartan. The same reasoning applies for the salts and solvates of compounds 1-4, 1-7, and 1-13, as explained above. Therefore, compounds 1-4, 1-7, and 1-13 are prima facie obvious over the references as well.
Thus, claim 3 was prima facie obvious at the time of filing.
Claim 4 depends from claim 2 and selects compounds 2-3 and 2-5. These compounds vary by the substituent at the 2-position of the telmisartan-based AT1 receptor antagonist pharmacophore, wherein the substituent is propyl and butyl, respectively.
Because claim 4 selects compound 2-3, and compound 2-3 is prima facie obvious over the references as explained above for claim 2, claim 4 is also prima facie obvious.
Regarding compound 2-5, it, and its salts and solvates, are also prima facie obvious using the same underlying reasoning that compounds 1-4, 1-7, and 1-13, and their salts and solvates, are obvious, explained above.
Thus, claim 4 was prima facie obvious at the time of filing.
Conclusion
No claims are allowed.
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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 The selected moiety has substitution at the 2-position of the base 1,3-benzodiazole, wherein the substituent is hydrogen, alkyl, cycloalkyl, or haloalkyl.
2 In Table 2 reproduced from Murugesan 2005, compounds 1 and 2 are irbesartan, an AT1 receptor antagonist, and BMS-193884, an ETA receptor antagonist, respectively.
3 Applicant describes telmisartan as “an AT1 receptor antagonist approved for marketing by the US FDA in 1998….” Specification at 15.
4 In Table 1 reproduced from Murugesan 2005, compounds 1 and 2 are irbesartan, an AT1 receptor antagonist, and BMS-193884, an ETA receptor antagonist, respectively.