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 the Claims
Claims 1, 7, 9-10, 12-16, and 26-35 are pending.
Claims 2-6, 8, 11, and 17-25 are cancelled.
Claims 9-10, 13-15, and 28-32 are withdrawn.
Priority
Applicant’s claim for benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. This application is a national stage entry of and claims priority to Application Serial No. PCT/US2020/027412, filed 04/09/2020; and further claims priority to provisional Patent Application numbers 62/884422 and 62/831952, filed on 08/08/2019 and 04/10/2019, respectively.
Information Disclosure Statement
All references from IDS(s) received 10/05/2021, 04/10/2023, 08/02/2023, 09/20/2024, 02/13/2025, 3/18/2025, 6/16/2025, and 09/29/2025 have been considered unless marked with a strikethrough.
Response to Arguments
Applicant's arguments filed 9/29/2025 have been fully considered but they are not persuasive.
In a non-final dated 07/03/2025, Claims 1, 7, 12, 16, 20, 26-27, and 33 were examined upon their merits.
In a non-final dated 07/03/2025, Claims 1, 7, 12, 16, 20, 26-27, and 33 were rejected under 35 U.S.C. 103. In response, Applicant amended claims 1 and 26. Applicant also added claims 34-35 and cancelled claims 17 and 20, so any previous rejection for these claims is moot.
With respect to the 103 rejection for claims 1, 7, 12, 16, 26-27, and 33-35, the Examiner does not find the argument persuasive. The applicant argues that, although they agree that FGFR2 and AR degraders are different, the art points to the unpredictability of PROTACs and therefore it would not be obvious to a person skilled in the art. The Applicant provides an explanation of the nature of PROTACs under the assumption the Examiner has misinterpreted PROTAC art. The Applicant points back to the art provided in the response filed 2/13/2025. More specifically, the Applicant quotes art by Nandave that in summary says the selection of the POI ligand is crucial and linker selection involves multiple synthetic design rounds to achieve the desired length for efficacy selectivity and pharmacokinetics of PROTACs. The Applicant seems to use this art to argue that not all parent compound POI inhibitors are well suited to be ligands for small molecule degraders. Further, the applicant argues that Caponigros teaching of allowing the FGFR2 compound to be a “prodrug” is not the same as the active group would be only temporarily masked. The Examiner argues that although she agrees with the general point made by the Applicant, the FGFR2 targeting ligand (also known as infigratinib) is known to have the nitrogen of the piperazine ring permanently “masked” with an ethyl group. Therefore, it would be reasonable to expect that any addition changes to the ethyl group or general substitution on the piperazine nitrogen would not significantly change the activity of the compound. As evidence, the Examiner points to Zheng, J. et al. (Front. Chem., 2022. Sec. Chemical Biology. doi.org/10.3389/fchem.2022.860985) Figure 7 showing no significant binding interactions for the ethyl off the piperazine ring.
The Examiner maintains the argument with respect to predictability, the field of medicinal chemistry is considered generally unpredictable because, for example, the design of compounds that need to bind to binding pockets. However, within the field, bioconjugate chemistry is considered more predictable because it is the combination and conjugation of two compounds whose structure and function are known in the art and their conjugation to achieve a “two-birds, one-stone” effect would be considered obvious to one skilled in the art at the time. The Examiner previously pointed out that to make a bifunctional compound unpredictable, data would have to show that if both the targeting ligand and degron were added at the same time they would not have the same activity as if they were bound together. Along the same line, if a certain class of linkers improved or inhibited this activity.
In response, the Applicant pointed to data specific to compound 6 (and compound 20 in the interview). The Examiner agrees that the data provided for compounds 6 and 20 would be considered unexpected results and would provide reason for unpredictability for those specific compounds. However, the rejection is maintained because the data does not encompass the rest of the claimed compounds. Often, if data for a few compounds can represent a larger genus then it would be considered enough to represent other compounds in the claims. However, in the instant case, the Applicant has pointed out and provided data to show that compound 7, which is a stereoisomer of compound 6, does not have the activity of compound. Therefore, if a small change such as stereochemistry makes such a large difference, data would need to be provided to argue that if the stereochemistry remains the same but the linker changes that the activity is not severely affected.
The Applicant also argues that the Examiner said that compound 6 does not have a linker and points out that there is a linker: a CH2 group. The Examiner reiterates her point in the office action that the linker is of “insignificant” length of 0-1 carbons. Therefore, a linker length so short would be obvious in view of Han.
Accordingly, the 103 rejection is maintained for the previously presented claims. With respect to the new claims, the same rejection applies because it includes the limitation of “stereoisomers.” The Examiner notes that as mentioned in the interview, if the applicant were to put claims 34 and 35 in independent form, strike through stereoisomer, and make the method claims dependent on independent claims 34-35 that these claims would be in condition for allowance.
MAINTAINED/NEW REJECTIONS
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 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, 7, 12, 16, 26-27, and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Caponigro et al. (WO 2011/075620 A1; “Caponigro”) in view of Han et al (J. Med. Chem. Jan. 2019; “Han”) and Bradner, J. et al. (US9694084B2; “Bradner”).
The instant application describes a bispecific compound that is designed to target FGFR2, through a specific targeting ligand, as well as to degrade the VHL protein, through a specific degron component. The two main components, FGFR2 targeting ligand and the VHL protein degron ligand, are connected through a linker, which in the case of the elected species is a single CH2 group.
Caponigro teaches a variety of FGFR2 ligands, including the one in the elected species as required by instant claims 1 and 7, shown below.
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(Caponigro, where R4 is N′-(2,6-Dichloro-3,5-dimethoxyphenyl), R3 is methyl, Y and Z are N, R1 a phenyl para-substituted with 1-piperazinyl, and R5 is H; listed as “3-(2,6-dichloro-3,5-dimethoxy- phenyl)-1 -methyl-1-[6-(4-piperazin-1-yl-phenylamino)-pyrimidin-4-yl]-urea” in Examples of Compounds (Page 8).. would result in the same structure as below.)
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(Targeting ligand of the elected species, N′-(2,6-Dichloro-3,5-dimethoxyphenyl)-N-methyl-N-[6-[[4-(1-piperazinyl)phenyl]amino]-4-pyrimidinyl]urea)
Caponigro fails to teach the conjugation of the FGFR2 targeting compound specifically to a VHL degron. However, Caponigro does teach the concept of using the FGFR2 targeting compound as a prodrug, therefore there is an expectation of success for using it in a “prodrug” fashion, including conjugating it to a moiety with a different function.
Han teaches the degron as shown in the elected species (see below) as a VHL-b degron ligand (referred to in the art as an E3 ligand) that is known to degrade the VHL protein, as required by instant claim 20.
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(Figure 3)
Han also teaches the degron ligands linked to a specific targeting ligand, in this case, a compound that targets the androgen receptor. Therefore, Han teaches the concept of a bispecific (referred to in the art as heterobifunctional) compound, as required by instant claim 1 (Introduction, p.3).
Han does not teach the degron linked to a FGFR2 targeting ligand, as required by the instant application.
However, Bradner teaches bispecific compounds/PROTACS including FGFR2 targeting ligands. Therefore, it would have been obvious to any skilled person in the art at the time to link the FGFR2 targeting ligand taught by Caponigro and the VHL degron ligand taught by Han to achieve a bispecific compound, as taught by Bradner.
With respect to instant claims 12 and 16, the elected species and compound used as a representative example has an insignificant linker of 0-1 carbons between the targeting and degron ligands. Further, Han teaches varying length of the alkyl linker between the VHL degron and the targeting ligand, as well as, that the change in length does not significantly impact the function (Table 1). Therefore, it would be presumed that there is not significant chemical or biological activity designated to the linker of the elected species and its only role is to conjugate the targeting and degron ligands.
With respect to the combination at least the following rationale applies.
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (A), it would have been prima facie obvious to extract the method of Han and Bradner to design a FGFR2 PROTAC using the targeting ligand taught by Caponigro and the degron taught by Han. A skilled artisan would have had a reasonable expectation that conjugating a compound that targets FGFR2 to a VHL protein degron would result in a bispecific compound that recruits E3 ligase and results in the degradation of FGFR2. Therefore, claims 1, 7, 12, 16, 26-27, and 33-35 would have been obvious to a person who is skilled in the art prior to the effective filing date.
Conclusion
Claims 1, 7, 12, 16, 26-27, and 33-35 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/N.M.B./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621