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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/30/2026 has been entered.
Claims 1-9, 11-16 and 18-35 are currently pending and under consideration.
Claim Interpretation
The majority of the independent method claims recite the limitation a method of treating a disease or a condition in which activation of AT2 receptors is desired or required, but in which inhibition of CYPs is not desired. While the specification and claims (dependent ) appear to provides examples of diseases or conditions, this does not appear to be an exhaustive list. A careful review of the literature recognizes that CYP 450 metabolic enzymes are an important system for metabolism of drug substances in the body, wherein inhibition of these enzymes could lead to reduced metabolism of other drugs that might lead to unwanted side effects or toxicity. (See Mahalingam et al./Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS, specific citation to page 4571, 1st column, half way down bridging paragraph). Accordingly, it would see reasonable to interpret that CYP inhibition would not be desired for any disease or disorder. As such, the diseases or disorders are being interpreted as those in which AT2 action is desired or required.
Additionally, for clarity purposes, the examiner is interpreting the compounds as recited in claims 7 and 8 as having the following formula’s:
butyl(5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl )thiophen-2-yl)sulfonyl-carbamate
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butyl(3-(4-((2-ethyl-1H-imidazol-1-yl)methyl)phenyl)-5-isobutylthiophen-2-yl)sulfonyl-carbamate
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ethyl(5-isobutyl-3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl-carbamate:
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Rejections Maintained:
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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(s) 1-7, 13-16, 19-20, 22, 24-26, 28-29 and 31 remain rejected under 35 U.S.C. 103 as being unpatentable over Vicore Pharma AB (WO2016/139475A1, 9/9/2016, IDS) in view of Wan et al. (J. Med. Chem. 2004, 47, 5995-6008, IDS) and Mahalingam (Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS) as evidenced by Sica (Clin. Pharmacokinetics 2005; 44(8); 797-814).
Vicore Pharma teaches a method of treating pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (IPF), comprising administering to a person in need thereof a therapeutically effective amount of a compound capable of stimulating AT2 receptors (AT2 receptor agonists)(page 4, lines 11-19). With regards to the compound, the WO document teaches that the compounds are agonist of AT2 receptor where they bind selectively to the AT2 receptor in an affinity ration for the relevant compound (AT2:AT1) is at least 100:1, more preferably 10000:1 (page 14, lines 18-25). Specifically, the WO document teaches a compound referred to as C21 having the structure
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. which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (C21) vs. a C1-3 alkyl (compound of formula I) (Fig 1, page 4, lines 8-9). The WO document further teaches a pharmaceutical composition comprising a compound of the invention, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier (page 16, line 24 to page 17, line 1). Moreover, the WO document teaches that the compounds of the invention may also be administered in combination with other AT2 agonist that are known in the art, in combination with AT1 receptor antagonist such as losartan, ACE inhibitors, as well as, established therapies for IPF such as pirfenidone (page 17, lines 3-16). Lastly, the WO document teaches a kit of parts comprising components: (a) a pharmaceutical formulation comprising an AT2 receptor agonist, (b) a pharmaceutical formulation including an AT1 antagonist and/or an ACE inhibitor, which components (a) and (b) are provided in a form that is suitable for administration in conjunction with the other (page 18, lines 20 to page 19, line 4) . While the WO document does not specifically teach that losartan is a drug metabolized by a CYP enzyme, as evidenced by Sica, the major metabolic pathway for losartan is by the cytochrome P450 3A4, 2C9 and 2c10 isoenzymes (page 798, 1st full paragraph).
The WO document does not specifically teach that the AT receptor antagonist has a substantially similar structure to compound 21, wherein there is a C1-C3 alkyl, specifically a methyl, between the two nitrogen’s on the imidazole ring. Moreover, the WO document does not specifically teach that the kit of components contains pirfenidone in combination with the AT2 receptor agonist.
Wan et a. teaches the design, synthesis and biological evaluation of the first selective Nonpeptide AT2 receptor agonist (Title). Specifically, Wan et al. teach the first druglike selective angiotensin II receptor agonist referred to as compound 21 which has a Ki value of 0.4nM for the AT2 receptor and a Ki>10 mM for the AT1 receptor (Abstract). Compound 21 has the following formula:
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, which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound 21) vs. a C1-3 alkyl (compound of formula I). In addition to the compound of 21, Wan et al. teach other compounds having the core structure:
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which vary by the R substituent including wherein R is
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as well as their Ki values for AT1 and AT2. As such, Wan et al. teach a compound 20 which reads on the instantly claimed compound wherein R1 is a methyl (page 5998, Table 5).
Mahalingam et al. teach selective angiotensin II AT2 receptor agonist with reduced CYP450 inhibition (Title). Specifically, Mahalingam teaches that the first non-peptidic selective AT2 receptor agonist M024 has recently been reported, wherein the unsubstituted imidazole provided a good moiety to obtain high affinity, AT1/AT2 selectivity, as well as, agonist (page 4570, 2nd column, first full paragraph). Compound M024 has the structure
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which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound M024) vs. a C1-3 alkyl (compound of formula I) (Figure 1). Mahalingam further teaches that while M024 high affinity and selectivity towards the AT2 receptor, it was found to be an inhibitor of CYP 450 metabolic enzyme system which could lead to reduced metabolism of other drugs that might lead to unwanted side effects of toxicity (page 4571, 1st column (bridging paragraph). As such, Mahalingam teaches other compounds which have been modified at the imidazole in an attempt to eliminate the unwanted CYP 450 inhibition but maintain the other properties (page 4571, 1st column (bridging paragraph). For example, Mahalingam tested the binding affinities (Ki) for AT2 and At1, as well as, the CYP450 inhibition as shown below:
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Of interest, Mahalingam et al. teach that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring (page 4575, 1st column, 2nd paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute compound 21 within the method/pharmaceutical composition and kit taught by the WO document for compound 20 of Wan (previously Wu) et al. in view of the teachings of Wan (previously Wu) et al. and Mahalingam et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-The WO document teaches that ATII receptor antagonists suitable for the method of treatment include those which selectively bind AT2 receptor with an affinity over AT1 at 100:1, preferably 10,0000 to 1,
- Wan (previously Wu) et al. teach a an AT2 receptor agonist, compound 20, which is structurally similar to compound 21, wherein compound 20 has a selectively to AT2 over AT1 of >20,000 and,
- Mahalingam et al. reports that that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to have included pirfenidone in the kit in combination with the AT receptor agonist. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
- the WO document teaches that the compounds of the invention may also be administered in combination with other AT2 agonist that are known in the art, in combination with AT1 receptor antagonist such as losartan, ACE inhibitors, as well as, established therapies for IPF such as pirfenidone.
In response to this rejection, Applicants contend that Dahlof, Wan and Mahalingam alone or in combination do not teach or suggest that “compound 20” is a preferred alternative to Compound 21. For example, Applicants assert that while Wan teaches compound 20, Wan also teaches a plurality of other compounds with various substituents in the R1 position. Furthermore, Applicants contend that Wan teaches that the presence or absence of a methyl in the 2- position of the imidazole ring makes no significant difference in the affinity of the compound to bind to the AT2 or AT1 receptors. Regarding Mahalingam, Applicants contend that although the reference mentions alkylation of the imidazole ring, it does so in the context of alkylation at the 4-position of the imidazole ring. Accordingly, Applicants contend that there is no expectation from any of the cited art whether alkylation at the 2-position of the imidazole ring (corresponding to R1 position in Formula I) would lead to a reduction of CYP inhibition and an assertion, without support, that alkylation at the 2-position and 4-position of the imidazole ring leads to similar activity can only be made with the benefit of hindsight. Moreover, Applicants assert that according to Mahalingam, the imidazole moiety is responsible for the CYP450 inhibitory effect of compound 1 (i.e., C21 of Dahlof) and therefore, teaches away from the claimed compound by suggesting using compounds that do not have an imidazole moiety. Lastly, Applicants contend that, surprisingly, several of the disclosed compounds within the scope of Formula I are not only selective AT2 receptor antagonist, but are also more potent, have significantly improved stability to metabolic hydrolysis and/or exhibit less inhibition of CYP enzymes, compared to C21.
These arguments have been carefully considered, but are not found persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). As noted above, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute compound 21 within the method/pharmaceutical composition and kit taught by the WO document for compound 20 of Wan (previously Wu) et al. in view of the teachings of Wan (previously Wu) et al. and Mahalingam et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-The WO document teaches that ATII receptor antagonists suitable for the method of treatment include those which selectively bind AT2 receptor with an affinity over AT1 at 100:1, preferably 10,0000 to 1,
- Wan (previously Wu) et al. teach a an AT2 receptor agonist, compound 20, which is structurally similar to compound 21, wherein compound 20 has a selectively to AT2 over AT1 of >20,000 and,
- Mahalingam et al. reports that that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring.
As such, there is a reasonable expectation that compound 20 of Wan would have similar biological properties to compound 21 with a reduction in inhibition of CYP450. Assuming, arguendo, that Applicants arguments are meant to be in combination, the Examiner acknowledges that Wan et al. does not specifically teach that compound 20 is the preferred alternative to compound 21. However, the examiner recognizes that out of the 10 entries tested, both compounds 20 and compound 21 were the highest for their affinity for AT2 and had similar affinities for AT1 and AT2. Regarding Mahalingam, the examiner acknowledges that Mahalingam when referencing alkylation of the imidazole ring is in the context of alkylation at the 4-position of the imidazole ring vs. the 2-position as claimed or compound 20. However, there is nothing in the conclusion or discussion sections of Mahalingam et al. limiting the activity to only variables or positions substituted. In contrast, Mahalingam et al. suggest the CYP activity can be decreased by substitution of/on the imidazole generically. As such, in view of the totality of Mahalingam, it would appear that one of skill in the art would walk away with the reasonable expectation that any substitution, including the 2-position, of the imidazole ring would provide a decrease in CYP450 inhibition as compared to the unsubstituted compound, e.g. compound 21. For example, the non-substituted rings (compound 1, 62 and 60) inhibited the majority of the CYP450 enzymes vs. the substituted only inhibited 2, but to a lesser degree. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As noted above, in view of the totality of Mahalingam, it would appear that one of skill in the art would walk away with the reasonable expectation that any substitution, including the 2-position, of the imidazole ring would provide a decrease in CYP450 inhibition as compared to the unsubstituted compound, e.g. compound 21. In response to Applicants arguments of surprising results, the Examiner acknowledges that Applicants assert that surprising they have found that certain chemically modified compounds are not only selective AT2 receptor agonist, but are also more potent, have a significantly improved stability to metabolic hydrolysis and/or exhibit less inhibition of CYP enzymes, compared to C21 (see page 5, 4th full paragraph of specification as originally filed). However, Applicants have only provided one example, the methylated e.g. compound 20 of Wan et al.. As noted in the prior office action, compound 20 has already been shown in Wan et al. to have similar activity to compound 21, and further, in view of Mahalingam et al. it would be reasonably to expect a decrease in CYP activity because of the methyl substitution of the imidazole ring.
Claim(s) 8-9, 11-12, 23 and 32-35 remain rejected under 35 U.S.C. 103 as being unpatentable over Vicore Pharma AB (WO2016/139475A1, 9/9/2016, IDS) in view of Wan et al. (J. Med. Chem. 2004, 47, 5995-6008, IDS) and Mahalingam (Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS) as evidenced by Sica (Clin. Pharmacokinetics 2005; 44(8); 797-814), as applied to claims 1-7, 13-16, 19-20, 22, 24-26, 28-29 and 31 above, in further view of Wu et al. (J. Med. Chem. 2006, 49, 7160-7168).
The combination of Vicore Pharma AB referred to as the WO document in view of Wan et al. and Mahalingam as evidenced by Sica et al. has been described above and incorporated herein. In short, the combination teaches a method of treating pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (IPF), comprising administering to a person in need thereof a therapeutically effective amount of a compound capable of stimulating AT2 receptors (AT2 receptor agonists), wherein the compound is a compound having the formula
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The combination does not specifically teach that the methyl on the imidazole ring is an ethyl or separately that the ester is not a butyl, but instead an ethyl. Moreover, the combination does not specifically teach a method of making said compounds, wherein the process involves:
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Wu et al. teach structural modifications in the 2- and 5- positions of the first drug-like selective angiotensin II AT1 receptor agonist (1) have been performed (Abstract). Specifically, Wu et al. teach the synthesis of these compounds which involve the scheme below:
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, wherein to obtain compounds 5-9 deprotection of compound 4 by TFA or by BCl3 delivered the primary sulfonamide that was subsequently reacted with acyl chlorides or alkyl chloroformates, at ambient temperature, in pyridine with 4-pyrrolindin-1-ylpyridine nucleophilic catalyst, to afford the target compound 5-9 (page 7161, Scheme 1, 1st column). In summary, Wu et al. teaches that all variations gave good AT2 receptor affinities and retained high AT2/AT1 selectivity (page 7165, 1st column, Conclusion).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the length of the carbon chain on the imidazole or ester of compound 20 of the combination in view of the teachings of Wu et al.. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of similar properties, because:
- Wu et al. teaches that all variations gave good AT2 receptor affinities and retained high AT2/AT1 selectivity (page 7165, 1st column, Conclusion).
Moreover, compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or 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 also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.).
In response to this rejection, Applicants assert that the teachings and deficiencies of Dahlof, Wan and Mahalingam with respect to Formula I are noted above. Regarding Wu, Applicants contend that Wu teaches performing structural alterations in the 2- and 5-positions of the first drug-like selective angiotensin II AT2 receptor agonist. As such, Applicants contend that the Examiner’s conclusion is wholly insufficient because the PTO has only cited Wu for the modification of the sulfonamide groups and the PTO has in no way attempted to explain why a reasonable expectation of success would have existed for modifying the imidazole substituents defined by R1-R3 of Formula I.
These arguments have been carefully considered, but are not found persuasive.
Regarding Applicants arguments to Wu et al., the Examiner recognizes, as set forth above, that compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or 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 also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). As such, there would be a reasonable expectation that the lengthening of the carbon chain on the imidazole or ester of compound 20 would result in similar properties.
Claim(s) 18 and 27 remain rejected under 35 U.S.C. 103 as being unpatentable over Vicore Pharma AB (WO2016/139475A1, 9/9/2016, IDS) in view of Wan et al. (J. Med. Chem. 2004, 47, 5995-6008, IDS) and Mahalingam (Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS) as evidenced by Sica (Clin. Pharmacokinetics 2005; 44(8); 797-814), as applied to claims 1-7, 13-16, 19-20, 22, 24-26, 28-29 and 31 above, in further view of Vicore Pharma AB (WO02/096883A1, 5/12/2002, IDS) referred to herein as Vicore 2.
The combination of Vicore Pharma AB referred to as the WO document in view of Wan et al. and Mahalingam as evidenced by Sica et al. has been described above and incorporated herein. In short, the combination teaches a method of treating pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (IPF), comprising administering to a person in need thereof a therapeutically effective amount of a compound capable of stimulating AT2 receptors (AT2 receptor agonists), wherein the compound is a compound having the formula
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The combination does not specifically teach that the disease is chronic obstructive lung disease, pulmonary hypertension, myocardial infarction, autoimmune disorders, diabetes, diabetic nephropathy or myocardial infarction.
Vicore 2 teaches agonist of the AT2 receptor which are useful in the treatment of conditions where AT2 receptors are expressed and their stimulation is required (page 25, lines 19-21). Specifically, Vicore 2 teaches that such conditions include, but are not limited to, chronic obstructive lung disease, pulmonary hypertension, myocardial infarction, autoimmune disorders, diabetes, diabetic nephropathy or myocardial infarction (page 27, line 8 to page 28, line 22).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute pulmonary fibrosis as taught by the combination for another condition where AT2 receptors are expressed as described above in view of Vicore 2. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Vicore 2 teaches that such conditions are treatable with AT2 receptor agonists.
In response to this rejection, Applicants assert that the WO document fails to overcome the above-noted deficiencies of Dahlof, Wan, Mahalingam and Sica.
These arguments have been carefully considered, but are not found persuasive for the reasons set forth above and incorporated herein.
Claim(s) 21 and 30 remain rejected under 35 U.S.C. 103 as being unpatentable over Vicore Pharma AB (WO2016/139475A1, 9/9/2016, IDS) in view of Wan et al. (J. Med. Chem. 2004, 47, 5995-6008, IDS) and Mahalingam (Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS) as evidenced by Sica (Clin. Pharmacokinetics 2005; 44(8); 797-814), as applied to claims 1-7, 13-16, 19-20, 22, 24-26, 28-29 and 31 above, in further view of Fex et al. (US2022/0388994A1, Published 12/8/2022, priority to 11/20/2019).
The combination of Vicore Pharma AB referred to as the WO document in view of Wan et al. and Mahalingam as evidenced by Sica et al. has been described above and incorporated herein. In short, the combination teaches a method of treating pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (IPF), comprising administering to a person in need thereof a therapeutically effective amount of a compound capable of stimulating AT2 receptors (AT2 receptor agonists), wherein the compound is a compound having the formula
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The combination does not specifically teach that the disease is sarcoidosis.
Fex et al. teaches agonist of the AT2 receptor which are useful in the treatment of conditions where AT2 receptors are expressed and their stimulation is required (paragraph 0135). Specifically, Fex et al. teaches that such conditions include, but are not limited to, chronic obstructive lung disease, pulmonary hypertension, myocardial infarction, all which are currently claimed including sarcoidosis (paragraph 0161).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute pulmonary fibrosis as taught by the combination for another condition where AT2 receptors are expressed as described above in view of Fex et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Fex et al. teaches that such conditions are treatable with AT2 receptor agonists.
In response to this rejection, Applicants assert that Fex fails to overcome the above-noted deficiencies of Dahlof, Wan, Mahalingam and Sica.
These arguments have been carefully considered, but are not found persuasive for the reasons set forth above and incorporated herein.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
NOTE: All NSDP rejections have been maintained. Applicants request that these be held in abeyance until such time that claims 1-7 are otherwise identified as allowable.
Claims 1-7 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11123329 in view of in view of Wan et al. (J. Med. Chem. 2004, 47, 5995-6008, IDS) and Mahalingam (Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS).
U.S. Patent No. 11123329 claims a method of treating damage, injury or dysfunction of respiratory tract mucosal tissue caused by a severe acute respiratory syndrome (SARS) coronavirus in a subject in need of such treatment, which method comprises administering N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide which has the structure
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. which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (C21) vs. a C1-3 alkyl (compound of formula I) (claim 1). The patent further claims that the treating includes symptoms of the respiratory disease caused by SARS coronavirus (claim 8), wherein the symptoms include pneumonia (Claim 9).
The US Patent does not claim a compound of formula I, wherein R1 is a C1-C3 alkyl, specifically a methyl, between the two nitrogen’s on the imidazole ring.
Wan et a. teaches the design, synthesis and biological evaluation of the first selective Nonpeptide AT2 receptor agonist (Title). Specifically, Wan et al. teach the first druglike selective angiotensin II receptor agonist referred to as compound 21 which has a Ki value of 0.4nM for the AT2 receptor and a Ki>10 mM for the AT1 receptor (Abstract). Compound 21 has the following formula:
PNG
media_image5.png
186
217
media_image5.png
Greyscale
, which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound 21) vs. a C1-3 alkyl (compound of formula I). In addition to the compound of 21, Wan et al. teach other compounds having the core structure:
PNG
media_image6.png
71
154
media_image6.png
Greyscale
which vary by the R substituent including wherein R is
PNG
media_image7.png
437
413
media_image7.png
Greyscale
as well as their Ki values for AT1 and AT2. As such, Wan et al. teach a compound 20 which reads on the instantly claimed compound wherein R1 is a methyl (page 5998, Table 5).
Mahalingam et al. teach selective angiotensin II AT2 receptor agonist with reduced CYP450 inhibition (Title). Specifically, Mahalingam teaches that the first non-peptidic selective AT2 receptor agonist M024 has recently been reported, wherein the unsubstituted imidazole provided a good moiety to obtain high affinity, AT1/AT2 selectivity, as well as, agonist (page 4570, 2nd column, first full paragraph). Compound M024 has the structure
PNG
media_image8.png
202
161
media_image8.png
Greyscale
which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound M024) vs. a C1-3 alkyl (compound of formula I) (Figure 1). Mahalingam further teaches that while M024 high affinity and selectivity towards the AT2 receptor, it was found to be an inhibitor of CYP 450 metabolic enzyme system which could lead to reduced metabolism of other drugs that might lead to unwanted side effects of toxicity (page 4571, 1st column (bridging paragraph). As such, Mahalingam teaches other compounds which have been modified at the imidazole in an attempt to eliminate the unwanted CYP 450 inhibition but maintain the other properties (page 4571, 1st column (bridging paragraph). For example, Mahalingam tested the binding affinities (Ki) for AT2 and At1, as well as, the CYP450 inhibition as shown below:
PNG
media_image9.png
379
343
media_image9.png
Greyscale
PNG
media_image10.png
449
703
media_image10.png
Greyscale
Of interest, Mahalingam et al. teach that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring (page 4575, 1st column, 2nd paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the compound claimed in the US Patent for compound 20 of Wu et al. in view of the teachings of Wu et al. and Mahalingam et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Wu et al. teach a an AT2 receptor agonist, compound 20, which is structurally similar to compound 21 (compound claimed in the US Patent), wherein compound 20 has a selectively to AT2 over AT1 of >20,000 and,
- Mahalingam et al. reports that that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring.
Claims 1-7 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-23 of U.S. Patent No. 11,654,115 in view of in view of Wan et al. (J. Med. Chem. 2004, 47, 5995-6008, IDS) and Mahalingam (Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS).
U.S. Patent No. 11,654,115 claims a method of treating of interstitial lung disease which method comprises orally administering a pharmaceutical dosage form of N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide which has the structure
PNG
media_image4.png
316
288
media_image4.png
Greyscale
. which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (C21) vs. a C1-3 alkyl (compound of formula I) to a patient in need of such treatment (claim 21), wherein the interstitial lung disease is idiopathic pulmonary fibrosis (claim 22) or sarcoidosis (claim 23).
The US Patent does not claim a compound of formula I, wherein R1 is a C1-C3 alkyl, specifically a methyl, between the two nitrogen’s on the imidazole ring.
Wan et a. teaches the design, synthesis and biological evaluation of the first selective Nonpeptide AT2 receptor agonist (Title). Specifically, Wan et al. teach the first druglike selective angiotensin II receptor agonist referred to as compound 21 which has a Ki value of 0.4nM for the AT2 receptor and a Ki>10 mM for the AT1 receptor (Abstract). Compound 21 has the following formula:
PNG
media_image5.png
186
217
media_image5.png
Greyscale
, which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound 21) vs. a C1-3 alkyl (compound of formula I). In addition to the compound of 21, Wan et al. teach other compounds having the core structure:
PNG
media_image6.png
71
154
media_image6.png
Greyscale
which vary by the R substituent including wherein R is
PNG
media_image7.png
437
413
media_image7.png
Greyscale
as well as their Ki values for AT1 and AT2. As such, Wan et al. teach a compound 20 which reads on the instantly claimed compound wherein R1 is a methyl (page 5998, Table 5).
Mahalingam et al. teach selective angiotensin II AT2 receptor agonist with reduced CYP450 inhibition (Title). Specifically, Mahalingam teaches that the first non-peptidic selective AT2 receptor agonist M024 has recently been reported, wherein the unsubstituted imidazole provided a good moiety to obtain high affinity, AT1/AT2 selectivity, as well as, agonist (page 4570, 2nd column, first full paragraph). Compound M024 has the structure
PNG
media_image8.png
202
161
media_image8.png
Greyscale
which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound M024) vs. a C1-3 alkyl (compound of formula I) (Figure 1). Mahalingam further teaches that while M024 high affinity and selectivity towards the AT2 receptor, it was found to be an inhibitor of CYP 450 metabolic enzyme system which could lead to reduced metabolism of other drugs that might lead to unwanted side effects of toxicity (page 4571, 1st column (bridging paragraph). As such, Mahalingam teaches other compounds which have been modified at the imidazole in an attempt to eliminate the unwanted CYP 450 inhibition but maintain the other properties (page 4571, 1st column (bridging paragraph). For example, Mahalingam tested the binding affinities (Ki) for AT2 and At1, as well as, the CYP450 inhibition as shown below:
PNG
media_image9.png
379
343
media_image9.png
Greyscale
PNG
media_image10.png
449
703
media_image10.png
Greyscale
Of interest, Mahalingam et al. teach that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring (page 4575, 1st column, 2nd paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the compound claimed in the US Patent for compound 20 of Wu et al. in view of the teachings of Wu et al. and Mahalingam et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Wu et al. teach a an AT2 receptor agonist, compound 20, which is structurally similar to compound 21 (compound claimed in the US Patent), wherein compound 20 has a selectively to AT2 over AT1 of >20,000 and,
- Mahalingam et al. reports that that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring.
Claims 1-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of U.S. Patent No. 12,121,614 in view of in view of Wan et al. (J. Med. Chem. 2004, 47, 5995-6008, IDS) and Mahalingam (Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS).
U.S. Patent No. 12,121,614 claims a method of treating of pulmonary fibrosis comprising administering to the gastrointestinal tract of a patient a composition comprising N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide which has the structure
PNG
media_image4.png
316
288
media_image4.png
Greyscale
. which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (C21) vs. a C1-3 alkyl (compound of formula I) to a patient in need of such treatment (claim 1), wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (claim 10).
The US Patent does not claim a compound of formula I, wherein R1 is a C1-C3 alkyl, specifically a methyl, between the two nitrogen’s on the imidazole ring.
Wan et a. teaches the design, synthesis and biological evaluation of the first selective Nonpeptide AT2 receptor agonist (Title). Specifically, Wan et al. teach the first druglike selective angiotensin II receptor agonist referred to as compound 21 which has a Ki value of 0.4nM for the AT2 receptor and a Ki>10 mM for the AT1 receptor (Abstract). Compound 21 has the following formula:
PNG
media_image5.png
186
217
media_image5.png
Greyscale
, which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound 21) vs. a C1-3 alkyl (compound of formula I). In addition to the compound of 21, Wan et al. teach other compounds having the core structure:
PNG
media_image6.png
71
154
media_image6.png
Greyscale
which vary by the R substituent including wherein R is
PNG
media_image7.png
437
413
media_image7.png
Greyscale
as well as their Ki values for AT1 and AT2. As such, Wan et al. teach a compound 20 which reads on the instantly claimed compound wherein R1 is a methyl (page 5998, Table 5).
Mahalingam et al. teach selective angiotensin II AT2 receptor agonist with reduced CYP450 inhibition (Title). Specifically, Mahalingam teaches that the first non-peptidic selective AT2 receptor agonist M024 has recently been reported, wherein the unsubstituted imidazole provided a good moiety to obtain high affinity, AT1/AT2 selectivity, as well as, agonist (page 4570, 2nd column, first full paragraph). Compound M024 has the structure
PNG
media_image8.png
202
161
media_image8.png
Greyscale
which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound M024) vs. a C1-3 alkyl (compound of formula I) (Figure 1). Mahalingam further teaches that while M024 high affinity and selectivity towards the AT2 receptor, it was found to be an inhibitor of CYP 450 metabolic enzyme system which could lead to reduced metabolism of other drugs that might lead to unwanted side effects of toxicity (page 4571, 1st column (bridging paragraph). As such, Mahalingam teaches other compounds which have been modified at the imidazole in an attempt to eliminate the unwanted CYP 450 inhibition but maintain the other properties (page 4571, 1st column (bridging paragraph). For example, Mahalingam tested the binding affinities (Ki) for AT2 and At1, as well as, the CYP450 inhibition as shown below:
PNG
media_image9.png
379
343
media_image9.png
Greyscale
PNG
media_image10.png
449
703
media_image10.png
Greyscale
Of interest, Mahalingam et al. teach that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring (page 4575, 1st column, 2nd paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the compound claimed in the US Patent for compound 20 of Wu et al. in view of the teachings of Wu et al. and Mahalingam et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Wu et al. teach a an AT2 receptor agonist, compound 20, which is structurally similar to compound 21 (compound claimed in the US Patent), wherein compound 20 has a selectively to AT2 over AT1 of >20,000 and,
- Mahalingam et al. reports that that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring.
Claims 1-7 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-17 of U.S. Patent No. 11,844,868 in view of in view of Wan et al. (J. Med. Chem. 2004, 47, 5995-6008, IDS) and Mahalingam (Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS).
U.S. Patent No. 11,844,868 claims a method of treating of interstitial lung disease which method comprises administering a pharmaceutical dosage form of N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide which has the structure
PNG
media_image4.png
316
288
media_image4.png
Greyscale
. which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (C21) vs. a C1-3 alkyl (compound of formula I) to a patient in need of such treatment (claim 15), wherein the interstitial lung disease is idiopathic pulmonary fibrosis (claim 16) or sarcoidosis (claim 17).
The US Patent does not claim a compound of formula I, wherein R1 is a C1-C3 alkyl, specifically a methyl, between the two nitrogen’s on the imidazole ring.
Wan et a. teaches the design, synthesis and biological evaluation of the first selective Nonpeptide AT2 receptor agonist (Title). Specifically, Wan et al. teach the first druglike selective angiotensin II receptor agonist referred to as compound 21 which has a Ki value of 0.4nM for the AT2 receptor and a Ki>10 mM for the AT1 receptor (Abstract). Compound 21 has the following formula:
PNG
media_image5.png
186
217
media_image5.png
Greyscale
, which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound 21) vs. a C1-3 alkyl (compound of formula I). In addition to the compound of 21, Wan et al. teach other compounds having the core structure:
PNG
media_image6.png
71
154
media_image6.png
Greyscale
which vary by the R substituent including wherein R is
PNG
media_image7.png
437
413
media_image7.png
Greyscale
as well as their Ki values for AT1 and AT2. As such, Wan et al. teach a compound 20 which reads on the instantly claimed compound wherein R1 is a methyl (page 5998, Table 5).
Mahalingam et al. teach selective angiotensin II AT2 receptor agonist with reduced CYP450 inhibition (Title). Specifically, Mahalingam teaches that the first non-peptidic selective AT2 receptor agonist M024 has recently been reported, wherein the unsubstituted imidazole provided a good moiety to obtain high affinity, AT1/AT2 selectivity, as well as, agonist (page 4570, 2nd column, first full paragraph). Compound M024 has the structure
PNG
media_image8.png
202
161
media_image8.png
Greyscale
which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound M024) vs. a C1-3 alkyl (compound of formula I) (Figure 1). Mahalingam further teaches that while M024 high affinity and selectivity towards the AT2 receptor, it was found to be an inhibitor of CYP 450 metabolic enzyme system which could lead to reduced metabolism of other drugs that might lead to unwanted side effects of toxicity (page 4571, 1st column (bridging paragraph). As such, Mahalingam teaches other compounds which have been modified at the imidazole in an attempt to eliminate the unwanted CYP 450 inhibition but maintain the other properties (page 4571, 1st column (bridging paragraph). For example, Mahalingam tested the binding affinities (Ki) for AT2 and At1, as well as, the CYP450 inhibition as shown below:
Claims 1-7 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,819,494 in view of in view of Wan et al. (J. Med. Chem. 2004, 47, 5995-6008, IDS) and Mahalingam (Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS).
U.S. Patent No. 11,819,494 claims a method of improving lung function in a patient having idiopathic pulmonary fibrosis which comprises administering a pharmaceutical dosage form of N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide which has the structure
PNG
media_image4.png
316
288
media_image4.png
Greyscale
. which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (C21) vs. a C1-3 alkyl (compound of formula I) to a patient in need of such treatment (claim 21), wherein the interstitial lung disease is idiopathic pulmonary fibrosis (claim 22) or sarcoidosis (claim 23).
The US Patent does not claim a compound of formula I, wherein R1 is a C1-C3 alkyl, specifically a methyl, between the two nitrogen’s on the imidazole ring.
Wan et a. teaches the design, synthesis and biological evaluation of the first selective Nonpeptide AT2 receptor agonist (Title). Specifically, Wan et al. teach the first druglike selective angiotensin II receptor agonist referred to as compound 21 which has a Ki value of 0.4nM for the AT2 receptor and a Ki>10 mM for the AT1 receptor (Abstract). Compound 21 has the following formula:
PNG
media_image5.png
186
217
media_image5.png
Greyscale
, which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound 21) vs. a C1-3 alkyl (compound of formula I). In addition to the compound of 21, Wan et al. teach other compounds having the core structure:
PNG
media_image6.png
71
154
media_image6.png
Greyscale
which vary by the R substituent including wherein R is
PNG
media_image7.png
437
413
media_image7.png
Greyscale
as well as their Ki values for AT1 and AT2. As such, Wan et al. teach a compound 20 which reads on the instantly claimed compound wherein R1 is a methyl (page 5998, Table 5).
Mahalingam et al. teach selective angiotensin II AT2 receptor agonist with reduced CYP450 inhibition (Title). Specifically, Mahalingam teaches that the first non-peptidic selective AT2 receptor agonist M024 has recently been reported, wherein the unsubstituted imidazole provided a good moiety to obtain high affinity, AT1/AT2 selectivity, as well as, agonist (page 4570, 2nd column, first full paragraph). Compound M024 has the structure
PNG
media_image8.png
202
161
media_image8.png
Greyscale
which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound M024) vs. a C1-3 alkyl (compound of formula I) (Figure 1). Mahalingam further teaches that while M024 high affinity and selectivity towards the AT2 receptor, it was found to be an inhibitor of CYP 450 metabolic enzyme system which could lead to reduced metabolism of other drugs that might lead to unwanted side effects of toxicity (page 4571, 1st column (bridging paragraph). As such, Mahalingam teaches other compounds which have been modified at the imidazole in an attempt to eliminate the unwanted CYP 450 inhibition but maintain the other properties (page 4571, 1st column (bridging paragraph). For example, Mahalingam tested the binding affinities (Ki) for AT2 and At1, as well as, the CYP450 inhibition as shown below:
PNG
media_image9.png
379
343
media_image9.png
Greyscale
PNG
media_image10.png
449
703
media_image10.png
Greyscale
Of interest, Mahalingam et al. teach that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring (page 4575, 1st column, 2nd paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the compound claimed in the US Patent for compound 20 of Wu et al. in view of the teachings of Wu et al. and Mahalingam et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Wu et al. teach a an AT2 receptor agonist, compound 20, which is structurally similar to compound 21 (compound claimed in the US Patent), wherein compound 20 has a selectively to AT2 over AT1 of >20,000 and,
- Mahalingam et al. reports that that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring.
Claims 1-7 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 of U.S. Patent No. 12,128,029 in view of in view of Wan et al. (J. Med. Chem. 2004, 47, 5995-6008, IDS) and Mahalingam (Bioorg. Med. Chem. 18 (2010) 4570-4590, IDS).
U.S. Patent No. 12,128,029 claims a method of treating of idiopathic pulmonary fibrosis in a patient in need thereof administering a pharmaceutical dosage form of N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide which has the structure
PNG
media_image4.png
316
288
media_image4.png
Greyscale
. which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (C21) vs. a C1-3 alkyl (compound of formula I) to a patient in need of such treatment (claim 1).
The US Patent does not claim a compound of formula I, wherein R1 is a C1-C3 alkyl, specifically a methyl, between the two nitrogen’s on the imidazole ring.
Wan et a. teaches the design, synthesis and biological evaluation of the first selective Nonpeptide AT2 receptor agonist (Title). Specifically, Wan et al. teach the first druglike selective angiotensin II receptor agonist referred to as compound 21 which has a Ki value of 0.4nM for the AT2 receptor and a Ki>10 mM for the AT1 receptor (Abstract). Compound 21 has the following formula:
PNG
media_image5.png
186
217
media_image5.png
Greyscale
, which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound 21) vs. a C1-3 alkyl (compound of formula I). In addition to the compound of 21, Wan et al. teach other compounds having the core structure:
PNG
media_image6.png
71
154
media_image6.png
Greyscale
which vary by the R substituent including wherein R is
PNG
media_image7.png
437
413
media_image7.png
Greyscale
as well as their Ki values for AT1 and AT2. As such, Wan et al. teach a compound 20 which reads on the instantly claimed compound wherein R1 is a methyl (page 5998, Table 5).
Mahalingam et al. teach selective angiotensin II AT2 receptor agonist with reduced CYP450 inhibition (Title). Specifically, Mahalingam teaches that the first non-peptidic selective AT2 receptor agonist M024 has recently been reported, wherein the unsubstituted imidazole provided a good moiety to obtain high affinity, AT1/AT2 selectivity, as well as, agonist (page 4570, 2nd column, first full paragraph). Compound M024 has the structure
PNG
media_image8.png
202
161
media_image8.png
Greyscale
which differs from the instantly claimed compound of formula I, wherein R1 is a hydrogen (compound M024) vs. a C1-3 alkyl (compound of formula I) (Figure 1). Mahalingam further teaches that while M024 high affinity and selectivity towards the AT2 receptor, it was found to be an inhibitor of CYP 450 metabolic enzyme system which could lead to reduced metabolism of other drugs that might lead to unwanted side effects of toxicity (page 4571, 1st column (bridging paragraph). As such, Mahalingam teaches other compounds which have been modified at the imidazole in an attempt to eliminate the unwanted CYP 450 inhibition but maintain the other properties (page 4571, 1st column (bridging paragraph). For example, Mahalingam tested the binding affinities (Ki) for AT2 and At1, as well as, the CYP450 inhibition as shown below:
PNG
media_image9.png
379
343
media_image9.png
Greyscale
PNG
media_image10.png
449
703
media_image10.png
Greyscale
Of interest, Mahalingam et al. teach that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring (page 4575, 1st column, 2nd paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the compound claimed in the US Patent for compound 20 of Wu et al. in view of the teachings of Wu et al. and Mahalingam et al.. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Wu et al. teach a an AT2 receptor agonist, compound 20, which is structurally similar to compound 21 (compound claimed in the US Patent), wherein compound 20 has a selectively to AT2 over AT1 of >20,000 and,
- Mahalingam et al. reports that that the un-substituted imidazole lead structure 1 (M024) showed a significant inhibition to most of the tested CYP450, which could be decreased by introducing substituents on the imidazole ring.
Conclusion
Therefore, no claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626
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