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 .
Application History
Claims 1-4 were originally presented on the filing of the instant application, 08/17/2023. Claims 1-4 were rejected in a non-final rejection mailed 12/10/2025. Applicant’s amendments to the claims and responses to the rejections were received on 04/09/2026.
Status of Claims
The amendments to the claims received on 04/09/2026 are acknowledged and entered. Claims 1-2 were canceled and claims 3-4 were amended. The amendments affect the following changes. See Remarks received 04/09/2026, at 1:
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Remarks received 04/09/2026, at 1.
Accordingly, claims 3-4 are pending.
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.
Claim 3 is obvious over Bai 2012 in view of Murugesan 2005, EP’314, and WO’389
Claim 3 is 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”.
The rejection of claim 3 as stated in the non-final rejection mailed 12/10/2025 is maintained. The rejection of claim 4 is withdrawn. The text of the entire the non-final rejection of claims 1-4 under 35 U.S.C. 103, mailed 12/10/2025, is reproduced under the following Response to Arguments section. See section titled Restated Rejections Mailed 12/10/2025.
Accordingly, claim 3 is rejected as obvious over Bai 2012 in view of Murugesan 2005, EP’314, and WO’389.
The reasons for maintaining the rejection of claim 3 over Bai 2012 in view of Murugesan 2005, EP’314, and WO’389 are discussed in the following Response to Arguments section.
Response to Arguments
The examiner has fully considered Applicant’s Remarks received 04/09/2026, some of which are persuasive. While the scope of the claims have changed by Applicant’s amendments, the same art and rejections apply to the same embodied species of the invention (with acknowledgement that compound 1-4 is deleted from claim 3), and reference is made to those art and rejections which were mailed 12/10/2025. For the following reasons, the rejection of claim 3 is maintained, and the rejection of claim 4 is withdrawn. The examiner will begin with the discussion of claim 4, and then turn to the discussion of claim 3.
Claim Rejections under 35 USC 103
Applicant’s arguments, see pages 8-9, filed 04/09/2026, with respect to claim 4 have been fully considered and are persuasive. The rejection of claim 4 has been withdrawn.
However, the examiner strongly disagrees with a few of Applicant’s statements. See Remarks received 04/09/2026, at 8:
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Remarks received 04/09/2026, at 8.
First, one of ordinary skill in the art at the time of filing would have expected the selection of the biphenyl linker and the ETA receptor antagonist pharmacophore disclosed for Compound 5 of Murugesan 2005 to result in significantly lower ETA Ki values relative to telmisartan. Telmisartan is not an ETA receptor antagonist. However, the compounds of Murugesan 2005, and those built using its teachings for constructing such compounds, are dual ETA/AT1 receptor antagonists. Further, the instant compounds 2-3 and 2-5 are built using the teachings of Murugesan 2005, and use its linkers and ETA receptor antagonists. The instant compounds 2-3 and 2-5 were expected to exhibit ETA antagonism. Therefore, the statement that “[a] person of ordinary skill in the art could not have reasonably expected that the resulting compound would exhibit significantly reduced … ETA Ki value[] relative to telmisartan”, is not accurate.
What was unexpected, upon re-reviewing Applicant’s disclosed data in light of the helpful Remarks received 04/09/2026, at 8-9, was that the instant compounds 2-3 and 2-5 exhibited a decrease in AT1 Ki values relative to the AT1 standard telmisartan in rats. Applicant’s Table 1 data derive from rats. Murugesan 2005 teaches that introducing the biphenyl linker and the ETA receptor antagonist pharmacophore disclosed for Compound 5 of Murugesan 2005 resulted in an increase in AT1 Ki relative to the AT1 standard irbesartan in rats (compound 5, AT1 Ki = 1.4 ± 0.5 nM irbesartan, AT1 Ki = 0.8 ± 0.2 nM; the ratio of the mean Kis = 1.75 relative to the standard), see Murugesan 2005 at 173, Table 1, under the AT1/Rat column.
Contrary to that trend, Applicant’s data from rats for the instant compounds 2-3 and 2-5 show a significant decrease in AT1 Ki relative to the AT1 standard telmisartan in rats. See, e.g., Instant Table 1 (compound 2-3, AT1 Ki = 2.1 ± 0.6 nM, telmisartan, AT1 Ki = 9.5 ± 1.5 nM; the ratio of the mean Kis = 0.22 relative to the standard). That result was not expected in rats.
The examiner disagrees with Applicant’s characterization regarding homologous compounds (e.g., ethyl, propyl) for at least two reasons. First, Bai 2012 at 4663, Table 1 teaches that homologous compounds ib, ic, id, ie (methyl, ethyl, propyl, and butyl) affect the same receptor AT1 in the same way, i.e., as antagonists. It further teaches that the receptor has a preference for a linear alkyl chain length around propyl or butyl. Applicant’s data are consistent with these trends, particularly in view of the relatively large standard of error in the data.
Second, telmisartan represents a known API that antagonizes the same AT1 receptor and is approved for medicinal use. It has a known SAR and the inventors of telmisartan selected an alkyl chain length of propyl based off of optimization of its activity.
Therefore, the examiner cannot agree with Applicant’s characterization regarding homologous compounds as they contradict at least Bai 2012.
With that stated, Applicant’s Remarks received 04/09/2026, at 8-9, pointing to the significant decrease in AT1 Ki relative to the AT1 standard telmisartan in rats for compounds 2-3 and 2-5 have overcome the rejections for claim 4.
Applicant’s arguments, see pages 6-8, filed 04/09/2026, with respect to claim 3 have been fully considered but they are not persuasive. The rejection of claim 3 is maintained.
Following the same logic discussed with respect to claim 4, the comparator in Murugesan 2005 is its disclosed compound 7 and the AT1 standard irbesartan. Murugesan 2005 teaches that introducing the biphenyl linker and the ETA receptor antagonist pharmacophore disclosed for Compound 7 of Murugesan 2005 resulted in a decrease in AT1 Ki relative to the AT1 standard irbesartan in rats (compound 7, AT1 Ki = 0.4 ± 0.2 nM irbesartan, AT1 Ki = 0.8 ± 0.2 nM; the ratio of the mean Kis = 0.5 relative to the standard), see Murugesan 2005 at 174, Table 2, under the AT1/Rat column.
Consistent with that trend, Applicant’s data from rats for the instant compound 1-10 show a decrease in AT1 Ki relative to the AT1 standard telmisartan in rats. See, e.g., Instant Table 1 (compound 1-10, AT1 Ki = 3.4 ± 1.1 nM, telmisartan, AT1 Ki = 9.5 ± 1.5 nM; the ratio of the mean Kis = 0.36 relative to the standard). That result was consistent with the teachings of Murugesan 2005, particularly in view of the relatively large standard of error in the data.
Accordingly, compound 1-10 exhibited an AT1 Ki consistent with the teachings of Murugesan 2005.
As stated previously, the examiner disagrees with Applicant’s characterization regarding homologous compounds (e.g., ethyl, propyl). Bai 2012 at 4663, Table 1 teaches that homologous compounds ib, ic, id, ie (methyl, ethyl, propyl, and butyl) affect the same receptor AT1 in the same way, i.e., as antagonists. It further teaches that the receptor has a preference for a linear alkyl chain length around propyl or butyl. Indeed, methyl has poor binding. Applicant’s data are consistent with these trends, particularly in view of the relatively large standard of error in the data.
Therefore, the examiner cannot agree with Applicant’s characterization regarding homologous compounds as they contradict at least Bai 2012.
However, compounds 1-7 and 1-13 do exhibit characteristics that are perhaps unexpected. The AT1 Ki of compound 1-7 matches telmisartan and theoretically could be dosed similarly. A claim drawn to the compound 1-7 would be allowable. Likewise, a claim drawn to compound 1-13 would be allowable, in view of its significant decrease in AT1 Ki, even in view of Bai 2012 teaching that butyl is slightly better than propyl.
With that stated, Applicant’s Remarks received 04/09/2026, at 6-8, pointing to the decrease in AT1 Ki relative to the AT1 standard telmisartan in rats for the compound 1-10 have not overcome the rejections for claim 3.
Restated Rejections Mailed 12/10/2025
The following text is an exact copy of the 35 USC § 103 rejections of claims 1-4 mailed 12/10/2025. The text is provided herein for reference purposes. As discussed above, the rejection of claim 3 is maintained. The rejection of claim 4 is withdrawn. Claims 1-2 were canceled by the amendments received on 04/09/2026.
The Conclusion section that follows this section is the conclusion for this office action.
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
Claim 4 is allowed. Claim 3 is rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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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.
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