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 .
Status of claims
Pending claims 1-3, 7-9, 11-12, 14-28 have been examined on the merits.
New Grounds of Rejection due to new IDS 01/27/2026
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.
Claims 1-3, 7-9, 11-12, 14-20, and 24-28 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. PLoS One. 2016 Sep 12;11(9):e0162491 (IDS01/27/2026), Blanchard et al. WO-2007058626, Kania in view of Patani et al., Chemical Reviews 96, no. 8 (January 1, 1996): 3147–76.
Regarding claim 1-3, 7-9, 11-12, 14-20, and 24-27, Wu (page 3) teaches anti-cancer drug LY2874455 interacts with the kinase domain of FGFR4, having the following structure,
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wherein A1, A2 and A3 are CH; L is CH=CH; B2 is imidazole with a hydroxyethyl group; X1 and X2 together is -OCH(CH3)-; B1 is pyridine with chlorine substituted R4. While Wu does not teach linker -OCH2-, however, it is well established that the substitution of a lower alkyl for a hydrogen atom on a known compound is not a patentable modification absent unexpected or unobvious results. In re Lincoln, 53 U.S.P.Q. 40 (C.C.P.A. 1942), In re Druey, 138 USPQ 39 (C.C.P.A. 1963), In re Wood, 199 U.S.P.Q. 137 (C.C.P.A. 1978) and In re Lohr, 137 U.S.P.Q. 548, 549 (C.C.P.A. 1963). The motivation to make the claimed compounds derives from the expectation that structurally similar compounds would possess similar activity (i.e., anticancer therapeutics). Also see MPEP §2144.09(II). Therefore, a POSITA would have it obvious to modify -OCH(CH3)-; to arrive at the claimed linker -OCH2-, as replacing a methyl with a hydrogen group is a routine and predictable isostere substitution. This is also supported by Patani (p. 3162, section 4) teaches hydrogen and methyl groups are bioisosteric replacement for each other.
Furthermore, Blanchard (abstract) also teaches indazole compounds to treat proliferative disorders such as cancer, comparable to the instant claim. Blanchard (page 122-123) discloses comparable genus of linker chemistry such as alkyl, heteroalkyl, alkylsulfonyl, alkylamino, as an example. For example, Blanchard (page 142) discloses various indazole-based therapeutic compounds with the following linker groups. This demonstrate that comparable variations of the linker composition were already known in the art before the effective filing date of the claimed invention. This is further supported
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by Kania’s teachings (page 1-3) on indazole compounds or pharmaceutical compositions as prophylactic or treatment against cancer (solid tumor); and further reinforces that a wide range of linker moieties were conventionally used in indazoles-based therapeutic compounds. For example, Kania (abstract; p.4, [0034] and [0046]) discloses linker options which overlap and structurally equivalent to that of the instant claims:
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Therefore, it would have been obvious to a POSITA to combine the teachings of Wu in view of Blanchard and Kania to substitute such linkers into indazole derivatives, as part of routine medicinal chemistry strategies aimed at expanding the therapeutic candidate library in the search of a lead compound, with a reasonable expectation of retaining or improving the drug therapeutic benefits. Furthermore, selecting from among these known linker options would have been a routine optimization of known variables, with reasonable expectation of success to arrive at the claimed invention.
It is important to note that Wu (page 3) discloses that pyridine moiety (B1 ring) attaches to the indazole core at the 4-position, Kania (page 82 and 84-88) discloses attachment at 3-, and 4-position, and Blanchard (page 131-133) discloses the attachment at 2-, 3-, and 4-position. thus, the combined teachings of Wu, Kania and Blanchard demonstrate that the position attachment on the pyridine ring is not fixed and serves as a variable for routine optimization. Therefore, a POSITA would have been motivated to explore alternative attachment positions, including the 3-position on the pyridine as part of routine structure-activity relationships (SAR) to arrive at the claimed invention. This is because, Blanchard (page 118-119, compound 204 and 209) discloses that 3-position provides better inhibitory activity than the 4-position, thus selecting 3-position provides a reasonable expectation of improved or at least comparable biological activity.
It is further significant that Blanchard (page 68) and Kania (page 81) explicitly disclose B1 ring as being either a phenyl ring or a pyridine ring, which would lead a POSITA to recognize B1 could be substituted interchangeably with either ring.
Regarding substituents on benzene ring and pyridine ring with substituents, the instant claim recites a benzene ring or pyridine ring with substituents (e.g., with a fluorine at the 3-position, and other substituents independently selected from and not limited to halogen, methyl and amino) and because Kania’s substituents fall within the range of the instant claim but only differs in position, thus, it would have been obvious to a POSITA to vary the position of such substituents knowing that positional isomers are routine optimization method, and such modifications can influence biological activity and pharmacokinetic properties. See MPEP 2144.09. Thus, a POSITA would recognize that the claimed invention is an extension of the combined teachings of Kania, Wu and Blanchard as part of expanding and optimizing a therapeutic drug library to improve efficacy or reduce side-effects.
Regarding bioisosteric replacement, Patani (p. 3162, section 4) teaches hydrogen, fluorine, amino, or methyl groups are bioisosteric replacement for each other, thus, a POSITA would reasonably expect that substituents such as hydrogen, fluorine, amino, or methyl groups could independently or optionally be substituted for one another on a benzene ring, and being placed at various positions to achieve similar molecular properties or biological effects. Therefore, it would have been obvious with a reasonable expectation of success to a POSITA at the time of filling of the instant application to modify Wu’s teachings in view of Kania, Blanchard with the disclosure of Joshi and Patani to arrive at the claimed invention, because the modification would expect to retain or potentially improve biological activity of the indazole derivatives. Therefore, it would have been obvious for a POSITA to modify Kania’s teachings by replacing the amino group at position 5 with a fluorine, as Patani (page 3152) teaches that fluorine often improves IC50 values compared to an amino group. Additionally, substituting a methyl group at 4-position with a hydrogen is also a predictable modification, as methyl and hydrogen are recognized bioisosteres (Patani, page 3149-3152). Furthermore, relocating the fluorine to position 3 is a common positional isomerism strategy frequently used to optimize activity and pharmacokinetics. Thus, the claimed compound, which combines these routine and predictable modifications, would have been obvious in view of Patani to arrive at the claimed invention. Especially, since the core structure as presented by Kania’s teachings is the same and all the benzene ring substituents are comparable to those in the instant claims.
Therefore, modifying Wu’s compound in view of Blanchard and Kania would lead to the compounds of the instant claims, as an example.
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Claim 28, Blanchard (page 30) teaches the treatment is effective against including but not limited to breast cancer and thyroid cancer.
Claim Objections
Claims 21-23 are objected and free of the art of record. The closest prior art is Wu et al. PLoS One. 2016 Sep 12;11(9):e0162491 in view of Kania et al., US 2004/0171634, Blanchard et al. WO-2007058626; however, these reference do not explicitly teach or fairly suggest the various options for R6, R7, as an example. The claims are not allowed because of the 103 rejection. As a result, until this issue is remedied or resolved, the claims cannot be subject of allowance.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622