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 .
DETAILED ACTION
1. This application is a 371 of PCT/US2022/044889 09/27/2022; PCT/US2022/044889 has PRO 63/249,316 09/28/2021.
Claims 1-11, 13, 15-17, 38-39, 68-70 are pending.
Response to Restriction Election
2. Applicant’s election of group I and the species, the first compound in claim 16:
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in the reply filed on August 6, 2026 is acknowledged. The election was made with traverse and the examiner finds the arguments unpersuasive. According to applicants’ representative claims 1-11, 13, 15-17 38-39, 68-70 read on the elected species, this compound reads on formula (I) where R1 is heterocycloalkyl (piperidine), m is 0, R4 is H, R3 is H, n is 0. Of the claims identified by applicants’ representative as reading on the elected species, only claims 1-11, 16 and 69 read on the elected species. As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. The search and examination was continued until prior art was found that anticipated or rendered obvious a non-elected species that falls within the scope of the generic Markush claim reading on the elected species. As per MPEP 803.02 II. C. “[T]he examiner must continue to search the species of the claim unless the claim has been found to be unpatentable over prior art.” The examiner “need not continue to search the claim if the claim is rejected over prior art”. [ibid. D.] Therefore, the search and examination is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claims 13, 15, 17, 38-39, 68, which do not read on the elected species are withdrawn. Claim 70 is withdrawn as being drawn to a non-elected invention.
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.
3. Claim(s) 1-11, 16, 69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Blumenkopf WO 9965909 A1 (cited on the IDS) in view of Schönherr “Profound Methyl Effects in Drug Discovery and a Call for New C-H Methylation Reactions" Angew. Chem. Int. Ed. 2013, 52, 12256 – 12267. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Blumenkopf WO’ 909 teaches the compounds of Formula 1 on page 1-3 that have the same utility as kinase inhibitors.
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These compounds correspond to the instant formula on page 2-3, where R3 is defined the same as R4, R3 is H, R2 is aryl (phenyl), A, E, B X and D are CR7R8, m = n = 1, where R7 and R8 are defined as instant R1/R2, which includes H, where instant n is 0, and those of R2 or those of where n is greater than 1 including but not limited to halogen, (C1-C6}alkyl, amino, hydroxy, (C1-C6)alkoxy, (C1-C6)alkylamino, ((C1-C6}alkyl)amino,(C1-C6}acylamino, (C1-C6)acyl(C1-C6)alkylamino, carboxy, (C1-C6)alkoxyacyl, (C1-C6)alkylaminoacyl, ((C 1-C6)alkylhaminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(C1 C6)alkyl, (C1-C6)alkyl (difluoromethylene), (C1-C3)alkyl(difluoromethylene)(C1-C3)alkyl, (C6-C10)aryl, (Cs-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkyl, (C6·C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C,-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C 1-
C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)acyloxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, piperazinyl(C1-C6)alkyl, (C1-C6)acylamino(C1-C6)alkyl, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)aryl(C1-C6)alkoxy(C1-Cs)alkyl, (C5-C9)heteroaryl(C1-C6)alkoxy(C1-Cs)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C6-C10)arylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C6-C10)arylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, R 13CO(C1-C6)alkyl or R 13CO(C3-C10)cycloalkyl wherein R13 is R200 or R20R21N wherein R20 and R21 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C6-C9)heteroaryl(C1-C6)alkyl; R14, R14(C1-C6)alkyl or R14(C3-C10)cycloalkyl wherein R14 is (C1-C6)acylpiperazino, (C6-C10)arylpiperazino, (C5-C9)heteroarylpiperazino, (C1-C6)alkylpiperazino,(C6-C10)aryl(C1-C6)alkylpiperazino, (C5-C9)heteroaryl(C1-C6)alkylpiperazino, morpholino,thiomorpholino, piperidino, pyrrolidino, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C6·C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C5-C9)heteroaryl(C1-C6)alkylpiperidyl or (C1-C6)acylpiperidyl.
R2 is defined as (C6-C10)aryl on page 5 line 13 which is substituted as described by instant R5 and the existing halogen (Cl), which is the first group listed:
aryl groups are optionally substituted by one to three halo, (C1-C6)alkyl,(C1-C6)alkyl-CO-NH-, (C1-C6)alkoxy-CO-NH-, (C1-C6)alkyl-CO-NH-(C1-C6)alkyl, (C1-C6)alkoxy-CO-NH-(C1-C6)alkyl, (C1-C6)alkoxy-CO-NH-(C1-C6)alkoxy, carboxy, carboxy(C1-C6)alkyl, carboxy(C1-C6)alkoxy, benzyloxycarbonyl(C1-C6)alkoxy, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy,(C6-C10)aryl, amino, amino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino, (C6-C10)aryl(C1-C6)alkoxycarbonylamino, (C1-C6)alkylamino, ((C1-C6)alkylamino, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, carboxy, carboxy(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, (C1-C6)alkoxy-CO-NH-,(C1-C6)alkyl-CO-NH-, cyano, (C5-C9)heterocycloalkyl, amino-CO-NH-, (C1-C6)alkylamino-CONH-,((C1-C6)alkyl)2amino-CO-NH-, (C6-C10)arylamino-CO-NH-, (C5-C9)heteroarylamino-CONH-,(C1-C6)alkylamino-CO-NH-(C1-C6)alkyl, ((C1-C6)alkylamino-CO-NH-(C1-C6)alkyl, (C6-C10)arylamino-CO-NH-(C1-C6)alkyl, (C5-C9)heteroarylamino-CO-NH-(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C6-C10)arylsulfonyl, (C6-C10)arylsulfonylamino, (C6-C10)arylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C5-C9)heteroaryl or (C2-C9)heterocycloalkyl
In support of this genus a number of groups are disclosed that mirror the instant examples including the base structure of claim 1.
Example 64 page 30 5-phenyl-4-(1-piperidinyl)-7H-Pyrrolo[2,3-d]pyrimidine,
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Example 73 on page 32 5-(3-chlorophenyl)-4-(1-piperidinyl)-7H-Pyrrolo[2,3-d]pyrimidine, has the requisite 3-Cl on the phenyl ring in the 5 position of the Pyrrolo[2,3-d]pyrimidine,
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Example 65 on page 32 5-(3-chloro-4-fluorophenyl)-4-(1-piperidinyl)- 7H-Pyrrolo[2,3-d]pyrimidine, has an additional halogen:
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Ascertainment of the difference between the prior art and the claims
The claimed genus and the prior art genus only differ semantically with different words and variable names used for the same structures. The claims simply add various groups to the known compounds shown above, which are provided for in the list of substituent groups R7/R8. The first compound on page 6 of claim 16 differs from the Example 73 only by the presence of a methyl group.
Claimed compound in claim 16 Vs. Blumenkopf Example 73
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Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
The generic claims only differ semantically from the prior art. The difference between the individual compounds of the prior art and of a compound of claim 16 is methyl group. One of ordinary skill would be motivated to make methylated compounds of Blumenkopf because he or she would expect the compounds to have similar properties since the methyl groups were suggested as substitutions in the broader disclosure of Formula (I). The interchangeability of hydrogen and methyl can create a case of prima facie obviousness. See In Re Herr 134 USPQ 176 (C.C.P.A. 1962), finding the presence of a methyl group failing to create a patentable distinction over the prior art (“The only structural distinction in appellant's compounds over those of Herr et al. is the presence of a methyl group in the 17 position of the claimed compounds. It is noted that the two compounds used as standards in the art have exactly the same structural difference. It therefore appears, as the board held, that the 17-methyl derivative of Herr et al. would be an obvious structural change to a chemist of ordinary skill in that field.”) See also In re Wood, Whittaker, Stirling, and Ohta, 199 USPQ 137 (C.C.P.A. 1978) and In re Lahr, 137 USPQ 548, 549 (C.C.P.A. 1963). However reliance on case law is not critical and the examiner submits Schönherr. Schönherr describes a number of reasons for methylation of the compounds of Blumenkopf as discussed in the abstract and page 12257:
The methyl group is one of the most commonly occurring carbon fragments in small-molecule drugs. This simplest alkyl fragment appears in more than 67% of the top-selling drugs of 2011 and can modulate both the biological and physical properties of a molecule. This Review focuses on so-called magic methyl effects on binding potency, where the seemingly mundane change of C-H to C-Me improves the IC50 value of a drug candidate more than 100-fold. This discussion is followed by a survey of recent advances in synthetic chemistry that allow the direct methylation of C(sp2)-H and C(sp3)-H bonds…
Methylation is used to optimize many properties of a drug candidate (Figure 2a). For example, methylating next to a metabolic hot spot, as in simvastatin (1), might sterically block metabolism and lengthen the half-life (t1=2).[4] Conversely if a drug candidate is longlived and excreted from the body at a rate too slow for the desired dosing regimen, for example one pill a day, a medicinal chemist may methylate to introduce a new metabolic hot spot and decrease the half-life, as was the case with etoricoxib (2).[5] Methylation can also have a favorable effect on solubility[6] or selectivity against off-targets (3).[7] Methylation can convert an agonist into an antagonist[8] or a partial antagonist into a negative allosteric modulator.[9] Indeed methylation can have a favorable effect on binding affinity, as in the case of the CETP inhibitor 4.[10] There are several reasons why an increase in methylation might affect biological activity. Fundamentally, one can consider that 6 of the 20 natural amino acids bear a methyl group, so proteins have various patterns of methylation.[11] It thus stands to reason that molecules designed to interact with biological systems will benefit from having various patterns of complementary methylation.
The compounds of the prior art are “molecules designed to interact with biological systems”, and as such they would benefit from methylation. Reasons for methylating are discussed in terms of so called ‘magic methyl effects'. These modifications give “increases in potency are far more than could be expected from the three- to tenfold potency boost based on desolvation effects, and are colloquially referred to as “magic methyl effects” in the medicinal chemistry community.” The experienced medicinal chemist, who would make applicants' compounds, would be motivated to prepare these analogs based on the expectation that such close analogs would have similar properties and even improved properties and upon the routine nature of such experimentation in the art of medicinal chemistry.
Blumenkopf already has shown this type of experimentation and shows that the change resulted in compounds with the same or similar activity.
The compound on page 40 in claim 4, 4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo[2,3-d]pyrimidine, has an unsubstituted piperidine in the 4 position:
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While Example 76 on page 33 5-(3-methylphenyl)-4-(2-methyl-1-piperidinyl)-7H-Pyrrolo[2,3-d]pyrimidine, has a methyl substituted variant.
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Conclusion
4. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
Prosecution Insights