DETAILED ACTION
This office action is in response to applicant’s filing dated May 5, 2026.
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
Claims 1, 3-6, 8-11, 13-16 and 20-27 are pending in the instant application. Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on May 5, 2026 are acknowledged. Claims 20 – 22 remain withdrawn, as being drawn to an unelected invention or specie. Acknowledgement is made of Applicant's amendment of 1, 3-6, 8-11 and 13-15; cancelation of claims 2, 7, 12, 17-19 and addition of new claims 23-27. Newly added claims 24 – 26 are withdrawn from consideration as related to non-elected invention (see Restriction/Election requirement, sent on 09/17/2025).
Claims 1, 3-6, 8-11, 13-16, 23 and 27 are under consideration in the instant office action.
Objections and/or Rejections and Response to Arguments
Acknowledgement is made of the Applicant’s amendment of claim 11. The amendments as shown herein:
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Accordingly, the rejection of claim 11 under 35 USC § 112(b) as reciting indefinite language is withdrawn.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
Claim Objections
Claim 15 is objected to because of the following informalities: some chemical structures are not fully visible due to images cropping, e.g.:
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. Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 11 and 13 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 11 recites variables Ak1, Ak2 and Ak3 having a structure
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, which structure is not a possible variant of Ak1, Ak2 and Ak3 as recited in claim 1, from which claim 11 directly or indirectly depends. Claim 13 recites fragment B of structure
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, which structural element is not recited in claim 4, from which claim 13 directly or indirectly dependents. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 3-5, 8-11, 13-16 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Andersen et al (WO 2020/198711 A1, hereinafter Andersen).
Instant claims are directed to a compound of general formula B-L-K, where the bifunctional compound of formula B-L-K binds to both, targeted protein AR and E3 ubiquitin ligases, and acts as an androgen receptor (AR) degrader. The compound of formula B-L-K has the following structural fragments:
B is androgen receptor (AR) binding moiety having a structure e.g.:
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, where Rb11 is halogen, CF3 or NC; and Rb12 is H, OCH3, OCH2CH3 or OCH2CH2Cl; such as
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.
L is a linker of structure e.g.:
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where Ak1, Ak2, Ak3 are each independently -CH2-, -OCH2-, - OCH2CH2-, -C(=O)-, -NRL- (RL is H); Cy1, Cy2, Cy3 and Cy4 are each independently selected from:
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,
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,
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,
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. Furthermore, L can have a structure e.g.:
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,
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or
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.
K is a E3 ligase binding moiety of structure e.g.:
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,
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or
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.
The exemplary compounds of formula B-L-K are:
,
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,
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,
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,
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. Instant claims are further drawn to a pharmaceutical composition comprising compound of formula B-L-K and pharmaceutically acceptable carrier.
Andersen teaches PROTAC compounds of formula : PLM-LI-PTC, such as formula (W-VIA):
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(page 35, [197]), where PLM is E3 ligase binding group, LI is a linker and PTC is androgen receptor binding group (page 6, [18] – [22]). Andersen teaches compounds, where PTC has a structure e.g.:
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(page 78, [247]), such as
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(page 87, [256]), where X is -(CR5R6)- , R5 and R6 is C1-C3 alkyl (methyl is a C1 alkyl); W is -CH2-; Y and Z is -O-; V is -CH2- or -CH2CH2-; L is hydrogen or halogen; C is
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R3 is hydrogen; R1 is hydrogen; R2A and R2B are each independently halogen, -CN, -CF3, or methyl. One of the examples of PTC taught by Andersen is:
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(page 128, A121). The exemplary structure of PTC fragment is provided herein for illustrative purposes only. Although exemplary structure of PTC has an amino group in pyrimidine ring, this substituent is not required by the description of ring “C” as set forth above.
LI has a structure of -LI-LII(q)-, where LI and LII is a bond or group, covalently bounded to PLM or PTC, and q >0 (page 45, [219]), such as -LI-LII(q)- is a polyethylene glycol chain from 1 to 12 polyethylene glycol units, -CH2-, -O-(CH2)i-, -(CH2)i-N-(CH2)i-, CO, C=C, where i is 1 – 10; C3-11 heterocyclyl, where heterocyclyl is a monocyclic, bicyclic or tricyclic, including fused or bridged ring systems, e.g.: morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl; aryl. The exemplary linkers are:
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,
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,
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(pages 48 – 50, Table 2).
PLM has a structure e.g.:
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,
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(page 216),
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, where R is an atom, covalently joined to a LI and n is 1 – 4 (pages 221 – 222).
One of the exemplary compounds of formula PLM-LI-PTC, taught by Andersen is
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(page 296, example 53). Andersen is also teaching a pharmaceutical composition comprising compound of formula PLM-LI-PTC and a pharmaceutically acceptable carrier (page 14, [98]).
Thus, Andersen teaches bifunctional compounds, PROTACs, selectively degrading androgen receptor (AR) protein, where the compound consists of ligands binding AR and E3 ligase, connected via bivalent linker, where the structure of all the fragments is equivalent to the structures of corresponding fragments of instantly claimed compounds.
Thus, since prior art teaches compounds, whose chemical structure includes all the structural elements of instantly claimed compounds, and where the compounds taught by prior art are useful for the same purpose (targeted AR degradation), it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to combine the structural elements known in the art (E3 ligase binding ligand, AR binding ligand and appropriate linker), by known methods, with no change in their respective functions to yield heterobifunctional compound with predictable properties to arrive at claimed compounds. The one of ordinary skills would be motivated to do so in search of an agent applicable for targeted AR degradation with improved desired properties, with the reasonable expectation of success.
Claims 6 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Andersen et al (WO 2020/198711 A1) as applied to claims 1, 3-5, 8-11, 13-16 and 23 above, and further in view of Crew et al (US 2018/0099940 A1, hereinafter Crew).
Andersen teaches all the limitations of claims 6 and 27 as discussed supra and are applied here in the same manner, except where the linker has a structure:
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,
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,
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or
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.
However, Crew teaches bifunctional (PROTAC) compounds having a structure PTM-L-CLM, where PTM is an AR binding moiety, L is a linker, and CLM is a cereblon E3 ubiquitin ligase binding moiety. PROTACs taught by Crew are capable of modulating targeted ubiquitination of an androgen receptor (page 2, [0012]). Crew further teaches linker structures such as:
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(Fig. 3, ex. 129),
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(Fig. 3, ex. 198) and
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(Fig.3, ex. 203).
Thus, combined prior art references teach compounds, where all the structural elements are identical to those of instantly claimed compounds, and are known to be used for the same purposes.
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues:
- Neither the Office Action nor the cited references provide any reason or motivation to prepare or arrive at the currently claimed compounds by replacing the linker LI disclosed in Andersen with the linker L recited in instant claim 1. Andersen is entirely silent regarding the structurally distinct linker now claimed and fails to provide any teaching or motivation to make the claimed modifications.
- Andersen only reports androgen-induced PSA luciferase activity associated with its PTCs, and is completely silent as to any biological activity of PROTAC molecules themselves (see Biological Assays section of Andersen). The compounds of the present invention demonstrated significant inhibitory activity against 22RV1 cell proliferation as well as favorable oral pharmacokinetic properties. These unexpected and advantageous technical effects are neither disclosed nor fairly suggested by Andersen and further confirm that a person of ordinary skill in the art would not have been motivated to modify the teachings of Andersen to arrive at the presently claimed compounds with the claimed activities.
Examiner’s response:
Applicant's arguments have been fully considered but they are not persuasive because: as set forth above the instantly claimed compounds have a linker of structure anything from:
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, where Ak1, Ak2, Ak3 are anything from:-CH2-, -OCH2-, - OCH2CH2-, -C(=O)-, -NRL- (RL is H), and Cy1, Cy2, Cy3 and Cy4 are anything from: azetidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl or aryl.
Andersen teaches a linker of structure: -LI-LII(q)-, where LI and LII is a bond or group, covalently bounded to PLM or PTC, and q >0, such as LI and LII is a -CH2-, -O-(CH2)i-, -(CH2)i-N-(CH2)i-, CO, C=C, where i is 1 – 10; C3-11 heterocyclyl, where heterocyclyl is a monocyclic, bicyclic or tricyclic, including fused or bridged ring systems, e.g.: morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl; aryl. Thus, if linker, taught by Andersen, has a structure where LI and LII are both C3-11 heterocyclyl (e.g. morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl) or aryl and q = 2, this structure of linker corresponds to instantly claimed linker of structure
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. Moreover, the exemplary linker structures taught by Andersen are identical to those incorporated into PROTAC structures of claim 15. Another reference (Crew et al), applied herein, teaches AR PROTACs, where structures of linkers are identical to structures disclosed in claims 6, 15 and 27 (see above). Thus, linkers taught by prior art and instantly claimed linkers are structurally identical, not distinct.
Regarding the argument about biological properties of claimed compounds, this is not persuasive, because since prior art teaches compounds of the same structure, all the properties are necessarily present, even if prior art is silent as to those properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) (see MPEP 2112.01).
Therefore, Applicant’s arguments are not persuasive and the rejection of claims 1, 3-5, 8-11, 13-16 and 23 as obvious over teachings of Andersen, as well as rejection of claims 6 and 27 as obvious over teachings of Andersen and Crew is maintained.
Conclusion
Claims 1, 3-6, 8-11, 13-16, 23 and 27 are rejected. Claim 15 is objected to.
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELENA V VISHNYAKOVA whose telephone number is (571)272-3781. The examiner can normally be reached 7:30am - 5pm ET.
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/E.V.V./ Examiner, Art Unit 1691
/SAVITHA M RAO/ Primary Examiner, Art Unit 1691
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