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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/23/2025 has been entered.
Status of Claims
Claims 14, 16, 21, 24, 30 and 31 are currently pending and under examination in this office action.
Response to Arguments
Applicant’s Remarks filed 05/20/2025 have been fully considered, but they are NOT persuasive to overcome rejections under 35 U.S.C. §103 over Dekker in view of Fujii on the record.
Applicant’s argument is essentially the same as the Remarks filed December 18, 2024. The examiner’s response is the same as elaborated in the last office action mailed on 03/24/2025. Please see the Response in the following 35 U.S.C. §103 section.
Priority
This application 17/701,888 filed on 03/23/2022 claims benefit of US provisional application 63/164,872 filed on 03/23/2021.
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 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 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 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 14, 16, 21, 24, 30 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Dekker et al. (Journal of Agricultural and Food Chemistry, 1975, 23(4), 785-91, “Structure-Activity Relationships of Some Antifungal Indoles”), in view of Fujii et al. (Expert Opinion on Therapeutic Patents 29(6):439-453, 2019, "Androgen receptor modulators: a review of recent patents and reports” (2012- 2018)”, Applicant’s IDS dated 12/23/2022 under “Non-Patent Literature Documents”, Citation No. 4), and evidenced by STN database CAS# 2602281-10-5, CAS# 2437967-80-9 (entered in 2021, Aurora Fine Chemicals).
This103 rejection is directed to the elected species,
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having following structures
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, and non-elected compounds of Formula (IIb), wherein:
A is pyrazole;
R2 is CN
R1 is C1-C6 alkyl; n= 1 or 2
Regarding compound of formula II(b), Dekker et al. teaches structure-activity relationships of antifungal indole compounds (Experimental, Tables 2-3, pages 787-789).
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Dekker et al. explicitly teaches compound species 63 and 64 (Table 2 and 3, page 787 and 789) where R is
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or
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with following structures and CAS Registry number in CAS REGISTRY SM database.
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As elaborated above, Dekker teaches compound species comprising the core structure of pyrazolo-indole as instant compound of Formula IIb.
Dekker does not teach R2 is CN.
Fujii et al. provides an overview of androgen receptor modulators developed from 2012 to 2018 and teaches various AR-modulating compounds for androgen-dependent disorders (e.g. prostate cancer), including conventional antagonists, tissue-specific AR modulators (SARMs), degraders, and nonconventional AR-modulating compounds that target sites other than the ligand-binding domain (LBD), such as the N-terminal domain (NTD) or the DNA-binding domain (DBD) (abstract, Expert Opinion, page 439, Conclusion, whole paper). Fujii et al. teaches cyanophenyl/cyanopyridyl moiety in various AR modulating agent, for example, enzalutamide (13) and apalutamide (14), proxalutamide (GT-0918, 16), ODM-204 (17), enobosarm (18), EM-5854(21) (See Figures 3 and 4; last paragraph in the left column, second and third paragraph, right column, page 441).
Fujji specifically teaches cyanoaryl groups are the pharmacophoric motifs of most NSAAs targeting the LBD and teaches a variety of AR LBD binders bearing a cyanoaryl substructure including compounds developed by different pharmaceutical companies (2.1. Cyanoaryl or nitroaryl derivatives, second paragraph of left column, whole right column, page 442, Figures 5- 12, 14-18, 20). Fujji also teaches pyrazoline derivatives with cyanoaryl substructure as SARMs, such as compounds 39-40 (disclosed by WO 2013014627, Figure 9, left column, page 443) and compound 104 (disclosed by WO 2012143599) (See Figure 21 page 448) and cyanoindole derivatives, compounds 95 and 96 as SARMs (See last paragraph, right column, page 446, Figure 20).
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The collective teachings of Fujji establishes cyanoaryl moiety/substructure as a common pharmacophoric motif in nonsteroidal AR-modulating compounds targeting the AR LBD, therefore, provides motivation/incentive to further explore AR modulating agent comprising cyanoaryl moiety/substructure as promising therapeutic candidates for androgen-related diseases (Conclusion, page 450).
It is common practice in the pharmaceutical industry to further explore different therapeutic areas and/or repurposing pharmaceutical active compounds including pyrazole derivatives and indole derivatives. The Federal Circuit in Eisai makes it clear that from the perspective of the law of obviousness, any known compound might possibly serve as a lead compound: "Obviousness based on structural similarity thus can be proved by identification of some motivation that would have led one of ordinary skill in the art to select and then modify a known compound (i.e. a lead compound) in a particular way to achieve the claimed compound." Eisai, 533 F.3d at 1357, 87 USPQ2d at 1455. (MPEP 2143). In instant case, the pyrazolo-indole compounds taught by Dekker comprising both moieties of pyrazole and indole would have been qualified as lead compound for further modification. It would have been obvious for one of ordinary skill in the art before the effective filing date of the instant claimed invention to explore more pyrazolo-indole core structure taught by Dekker with the teachings of cyanoaryl moiety taught by Fujji, together with general knowledge of structural similarity and SAR of pharmaceutical active compounds, and arrive at the instant invention.
For example, compound 64 (CAS# 56366-46-2, 3-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-indole) taught by Dekker et al. can be modified to elected species
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, by simple modification of H to CN, Me to Et and H.
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Aurora Fine Chemicals catalog provides indole-7-carbonitriles (R2=CN) that are very similar to instant claimed species, e. g. CAS# 2602281-10-5, CAS# 2437967-80-9, etc. (See STN search note).
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As illustrated by structure above, compounds CAS# 2602281-10-5 and CAS# 2437967-80-9 comprising cyano group at 7-position and pyrazolyl at 3-position of indole, are very similar to instant elected species, compound 008, and would have anticipated instantly claimed Formula IIb except 2-methyl. Hydrogen and methyl are considered obvious variants, thus, the substitution of hydrogen for methyl on a known compound and vice versa, is not a patentable modification absent unexpected or unobvious results.
As elaborated above, the core structure of instant compound IIb including cyano group at 7-position and pyrazolyl at 3-position of indole ring is not novel. One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention. The teachings of cyanoaryl moiety as an important substructure in androgen receptor modulators by Fujji provides motivation /incentive to further explore compounds comprising cyanoaryl moiety/substructure as AR modulating agent for treating androgen-related diseases. Pyrazolo-indole compounds taught by prior art having the core structures of instant claimed Formula IIb are expected to exhibit similar biological activity as the instant claimed compounds in the absence of evidence to the contrary. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art.
Applicant repeated argument based on Otsuka Pharmaceutical Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280 (Fed. Cir. 2012) and argues lead compound analysis with “a reasoned identification of a lead compound” guided by evidence of its properties, such as activity and potency, pertinent to the claimed compound (Remarks, page 1).
RESPONSE: Applicant’s argument is based on the speculation that instant claimed compound of Formula IIb genus are androgen receptor modulator that are different from prior art. As indicated in 35 USC112(a) rejection on the record and discussed in the interview with the attorney, Brian C. Trinque, on 03/11/2025, instant specification only disclosed six compound species of formula IIb wherein one out of six tested compound species (cpd 10, R3 is OH) is inactive as shown in Table 3. As such, the variation of efficacies among tested examples do not support compound of Formula llb genus as alleged androgen receptor modulator.
Even though Dekker might be silent about modulating androgen receptor, pyrazolo-indole compounds having the core structures of instant claimed Formula IIb are construed to exhibit similar biological activity as the instant claimed compounds in the absence of evidence to the contrary. According to MPEP § 2144.09, A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. " A claimed compound may be obvious because it was suggested by, or structurally similar to, a prior art compound even though a particular benefit of the claimed compound asserted by patentee is not expressly disclosed in the prior art. It is the differences in fact in their respective properties which are determinative of nonobviousness. If the prior art compound does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, applicant’s recognition of the benefit is not in itself sufficient to distinguish the claimed compound from the prior art. In re Dillon, 919 F.2d 688, 693, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc).
Second, as MPEP 2143 (Example 10) states: “It should be noted that the lead compound cases do not stand for the proposition that identification of a single lead compound is necessary in every obviousness rejection of a chemical compound. For example, one might envision a suggestion in the prior art to formulate a compound having certain structurally defined moieties, or moieties with certain properties. If a person of ordinary skill would have known how to synthesize such a compound, and the structural and/or functional result could reasonably have been predicted, then a prima facie case of obviousness of the claimed chemical compound might exist even without identification of a particular lead compound”.
Regarding the reasons/motivation to select lead compound for further development, MPEP 2143 (Example 11) states: “the Federal Circuit stated that a "restrictive view of the lead compound test would present a rigid test similar to the teaching-suggestion-motivation test that the Supreme Court explicitly rejected in KSR . . . The district court in this case employed a flexible approach…that one of skill in the art would have used the more potent compounds of [Altana’s prior art] patent, including compound 12, as a starting point from which to pursue further development efforts… Id. at 1008, 91 USPQ2d at 1025”.
Applicant argues that “The 10-5 compound and the 80-9 compound are two catalogued compounds with no known properties or activity”. (Remarks, page 2)
RESPONSE: The Aurora catalog compounds are NOT lead compounds. The examiner does not dispute Aurora catalog compound have no known properties or activity. The Aurora catalog compounds are cited as evidence that instantly claimed core structure of compound of Formula IIb genus with simple substitution of alkyl group are not novel and commercially available. During the search in STN database, there are more commercially available compounds from Aurora catalog compounds that read on the pyrazole-indole core structure.
Applicant argues that Fujii teaches over 120 compounds as androgen receptor modulators and only two of which are indole compounds and Fujii compounds 13-18 do not have indole or pyrazoly ring. (Remarks, page 3)
RESPONSE, Fujii is cited as teaching reference that establishes cyanoaryl moiety/substructure as a common pharmacophoric motif in nonsteroidal AR-modulating compounds targeting the AR LBD, therefore, provides motivation/incentive to further explore AR modulating agent comprising cyanoaryl moiety/substructure as promising therapeutic candidates for androgen-related diseases. The cyanoindole structure are taught by Fujii compounds 95 and 96 while Fujii compounds 13-18 are only cited to demonstrate the cyanoaryl moiety as androgen receptor modulators.
Claims 14, 16, 21, 24, 30 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Berta et al. (US 2005/0032869 A1).
Berta teaches pyrazolyl-indole derivatives, compound of Formula I, as kinase inhibitors, preparation thereof, pharmaceutical composition and use in treatment for disease associated with dysregulated protein kinase (e.g. cancer) (See abstract, [0003], [0011], [0024]-[0031], Examples 1-18, claims 1-27).
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Berta’s pyrazolyl-indole compound wherein R is cyano, R1 is alkyl is considered as read on instant claimed formula IIb recited in instant claim 14.
Berta explicitly teaches compound species comprising cyno group with following structures (See Example 18, [0479]-0481], cpd 11-13):
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According to MPEP § 2144.09, A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. " A claimed compound may be obvious because it was suggested by, or structurally similar to, a prior art compound even though a particular benefit of the claimed compound asserted by patentee is not expressly disclosed in the prior art. It is the differences in fact in their respective properties which are determinative of nonobviousness. If the prior art compound does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, applicant’s recognition of the benefit is not in itself sufficient to distinguish the claimed compound from the prior art. In re Dillon, 919 F.2d 688, 693, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc). Please also note prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979).
In search for more kinase inhibitors for treatment of disease associated with dysregulated protein kinase (e.g. cancer), it would have been obvious for one of ordinary skill in the art before the effective filing date of the instant claimed invention to explore more pyrazolo-indole compound taught by Berta, together with general knowledge of structural similarity and bioisosteric modification of pharmaceutical active compounds, and arrive at the instant invention with reasonable expectation of success. For example, the cyano-indole compound taught by Berta could be modified to its positional/regional isomers followed by simple modification of H to Et and arrive at instant elected species, compound 008.
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Instant claim 14 is directed to compound of Formula IIb genus wherein the biological activity of a compound is direct result/property of its unique structure. Even though Berta might be silent about modulating androgen receptor, pyrazolo-indole compounds having similar core structures are construed as exhibiting similar biological activity as the instant claimed compounds in the absence of evidence to the contrary.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the teachings of prior art, together with general knowledge of structural similarity and bioisosteric modification of pharmaceutical active compounds. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
The reference made of record and not relied upon is considered pertinent to applicant's disclosure.
1. Toure et al. US 11,667,624B2 (Toure ‘624). Toure ‘624 has an earlier effective filing date than instant application.
Toure ‘624 teaches indole compound of Formula I to Formula X that bind to BF3 of an androgen receptor (AR) for treatment of androgen receptor AR associated diseases (e.g. prostate cancer, Kennedy's disease, etc.) (See abstract, Table 1, claims 1-19). Toure ‘624 teaches compound species comprising 7-CN indole moiety (See Table 1, claims 16-18).
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Toure ‘624 does not teach pyrazole ring attached to indole ring.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on (571)272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.M./ Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628