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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/CN2022/088615, filed on 04/22/2022.
Status of the Claims
Claims 1-14 and 17-20 are pending in the instant application and subject to examination herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/15/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 recites the limitation "the structural unit" shown below:
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68
116
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in the preamble of the claim: “The compound of pharmaceutically acceptable salts thereof according to claim 1, wherein the structural unit [structure drawing] is selected from the group consisting of”. There is insufficient antecedent basis for this limitation in the claim, because the structural moiety in claim 1 that bears the “R1” substituent is not limited to a pyridyl ring, but is rather as shown below:
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70
110
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wherein T1 is defined as “consisting of N and CH”. Thus, there is no antecedent basis for the assertion in claim 1 of the specific pyridyl “structural unit” disclosed in the preamble.
Claim 4 is further indefinite because the claim provides a Markush group of ring structures to be selected for the disclosed pyridyl “structural unit” that includes phenyl rings as well as pyridyl rings. A person of ordinary skill in the art would not understand the metes and bounds of the claims that require a pyridyl ring structure to further limited in a manner that includes both phenyl and pyridyl rings. The same limitation as found in claim 4 is also found in the instant Specification, on page 7; however, the Specification does not provide a new specific definition of a pyridyl ring, on page 7 or anywhere else, that would redefine the structure of a pyridyl ring from its common definition of a 6-membered heterocyclic aromatic ring containing 1 nitrogen atom, to also include the structure of a phenyl ring that is a 6-membered aromatic ring containing zero (0) nitrogen atoms.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 and 5-7 are anticipated by Tran.
Claims 1-2 and 5-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tran (Tran, et al.; Bioorganic & Medicinal Chemistry Letters, v17, pp5165-5170; 2007).
Claim 1 is drawn to a genus, designated as “formula (III)”, of pyrrolidinyl-carbonyl-piperazine compounds bearing additional pendant aryl rings and other limitations, as shown in the table below. Tran teaches a study in the synthesis and characterization of a series of potent agonists of human melanocortin-4 receptor, including a compound 141 that anticipates the genus of instant formula (III), as shown in the table below (page 5168, Table 1):
Claim Number(s) of Instant Application
Instant Application
Tran
1
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164
330
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wherein:
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312
432
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Thus, claim 1 is anticipated by the teaching of Tran.
Claim 2 further limits claim 1 to wherein Ra and Rb, when present, are selected from a Markush group consisting of hydrogen and methyl, and is met by the rejection above, as claim 2 does not require that Ra and/or Rb must be present.
Claim 5 further limits claim 1 to wherein R2, when present, is selected from a Markush group consisting of methyl and cyclopropyl, and is met by the rejection above, as claim 5 does not require that R2 must be present.
Claim 6 further limits claim 1 to wherein R3, when present, is selected from a Markush group that includes chloro, and is met by Tran’s compound 14 shown in the table above.
Claim 7 further limits claim 1 to wherein Rc, when present, is selected from a Markush group consisting of cyano and methyl, and is met by the rejection above, as claim 7 does not require that Rc must be present.
Thus, claims 2 and 5-7 are anticipated by the teaching of Tran.
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 1-3, 5-10 and 17-18 are unpatentable over Bakshi in view of Patani.
Claims 1-3, 5-10 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Bakshi (WO 2004/078716 A1) in view of Patani (Patani, G. A., LaVoie, E. J.; Chemical Reviews, v96, pp.3147-3176; 1996).
The limitations of claims 1-2 and 5-7 are discussed in the rejection above and hereby incorporated into the instant rejection.
Bakshi discloses N-acylated piperazine derivatives as agonists of human melanocortin-4 receptor, including a compound 20-52 that anticipates the genus of instant formula (III), as shown in the table below (page 59, Example 20):
Claim Number(s) of Instant Application
Instant Application
Bakshi
1
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164
330
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wherein:
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338
456
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Bakshi’s compound 20-5 differs from the genus of instant formula (III) in that the compound 20-5 has an ester group at the R1 position, whereas the Markush group of claimed R1 groups defined in claim 1 is limited to: halogen, C1-3alkyl, C1-3alkoxyl, amide, and amido-methyl groups. However, a person of ordinary skill in the art would have a reasonable expectation of success in making a using a derivative of the Bakshi’s compound 20-5, wherein the ester group is replaced with an N-methylamido group, and achieving similar biological activity, because ester and amido are interchangeable bioisosteric groups, per the teaching of Patani.
Patani reviews the practice of bioisosteric replacements as a methodology for the optimization of lead compounds in medicinal chemistry. In particular, nonclassical bioisosteres are capable of maintaining similar biological activity by mimicking the spatial arrangement, electronic properties, or some other physicochemical property of the molecule or functional group that is critical for retention of biological activity (page 3160). Patani specifically teaches that amide groups are a suitable replacement for ester groups, and remove the risk of undesirable in vivo metabolism by esterases (page 3163). Patani also teaches that the vice versa exchange of amide groups for esters has been widely used (page 3170).
Applicant’s invention is not patentable over the disclosure of Bakshi in view of the teaching of Patani, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of making and using a bioisosteric equivalent of Bakshi’s compound 20-5 wherein the ester group is replaced with an N-methylamido group and achieving comparable biological activity, because it was known in the art that ester and amide groups are bioisosterically interchangeable and the replacement of an ester group for an amide group can provide a metabolic stability advantage, per the teaching of Patani.
Thus, the invention was prima facie obvious at the time of filing.
Claim 2 further limits claim 1 to wherein Ra and Rb, when present, are selected from a Markush group consisting of hydrogen and methyl, and is met by the rejection above regarding the bioisosteric replacement of the ester group of Bakshi’s compound 20-5 with an N-methylamido group.
Claim 3 further limits claim 1 to wherein R1, when present, is selected from a Markush group consisting of F, Cl, CF3, N-methylamido and N-methylamidomethyl, and is met by the rejection above regarding the bioisosteric replacement of the ester group of Bakshi’s compound 20-5 with an N-methylamido group.
Claim 5 further limits claim 1 to wherein R2, when present, is selected from a Markush group consisting of methyl and cyclopropyl, and is met by the rejection above, as claim 5 does not require that R2 must be present.
Claim 6 further limits claim 1 to wherein R3, when present, is selected from a Markush group that includes fluoro (F), and is met by the rejection above regarding the bioisosteric replacement of the ester group of Bakshi’s compound 20-5 with an N-methylamido group.
Claim 7 further limits claim 1 to wherein Rc, when present, is selected from a Markush group consisting of cyano and methyl, and is met by the rejection above, as claim 7 does not require that Rc must be present.
Claim 8 further limits claim 1 to wherein R4 is selected from a Markush group that includes tert-butyl, and is met by the rejection above.
Claim 9 further limits claim 1 to wherein R4 is selected from a Markush group that includes tert-butyl, and is met by the rejection above.
Claim 10 further limits claim 1 to wherein the compound of formula (III) is within scope of any of a Markush group of formulae (I), (II-1), (II-2) and (II-3), which further limit the structure of the compound in regard to stereochemistry at the pyrrolidine ring, and is met by the rejection above regarding the bioisosteric replacement of the ester group of Bakshi’s compound 20-5 with an N-methylamido group, which matches the stereochemical requirements of formula (II-1) as shown in the table below:
Claim Number(s) of Instant Application
Instant Application
Bakshi
10
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154
312
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wherein:
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338
456
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Claim 17 is drawn to a method of treating a melanocortin-4 receptor (MC4R) agonist-related disease in a subject in need thereof, comprising administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to the subject. Claim 18 further limits claim 17 to wherein the MC4R agonist-related disease is selected from a Markush group consisting of male erectile dysfunction and female sexual desire disorder.
Bakshi discloses that the compounds of the present invention are effective as melanocortin receptor agonists and are particularly effective as selective MC4R agonists. They are therefore useful for the treatment and/or prevention of disorders responsive to the activation of MC4R, such as obesity, diabetes as well as male and female sexual dysfunction, in particular, male erectile dysfunction.
Applicant’s invention is not patentable over the disclosure of Bakshi in view of the teaching of Patani, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of making a bioisosteric equivalent of Bakshi’s compound 20-5 wherein the ester group is replaced with an N-methylamido group and achieving comparable biological activity, because it was known in the art that ester and amide groups are bioisosterically interchangeable and the replacement of an ester group for an amide group can provide a metabolic stability advantage, per the teaching of Patani, and using that bioisosterically equivalent derivative in the method disclosed by Bakshi for the treatment of male and female sexual dysfunction, in particular male erectile dysfunction.
Thus, the invention was prima facie obvious at the time of filing.
Claims Free of the Prior Art
Claims 4 and 11 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 12-14 and 19-20 are allowed. Prior art does not teach or reasonably suggest, alone or in combination, any of the specific compounds disclosed in claims 12-14, or any method of treating a melanocortin-4 receptor (MC4R) agonist-related disease in a subject in need thereof, comprising administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof to the subject, including wherein the MC4R agonist-related disease is selected from a Markush group consisting of male erectile dysfunction and female sexual desire disorder.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 1-[(3S,4R)-4-(4-chlorophenyl)-1-(propan-2-yl)pyrrolidine-3-carbonyl]-4-(2-
methoxyphenyl)piperazine
2 Ethyl 2-{4-[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carbonyl]piperazin-1-yl}benzoate