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 .
Current Status
This action is responsive to the amended claims of 01/05/2026. Claims 1, 5, 7, 11, 13, 15, and 33-40 are pending. Claims 11, 13, and 33-35 are withdrawn. Claims 1, 5, 7, 15, and 36-40 have been examined on the merits.
Election/Restrictions
The amendments of 01/05/2026 have overcome the outstanding rejections of 09/04/2025. Thus, the Markush search has been extended to the species below. This search returned prior art. Therefore, per Markush search practice, the Markush search will not be extended unnecessarily to additional species in this Office Action.
The extended species:
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. This species reads on claims 1, 5, 7, 15, and 36-40.
Claims 11, 13, and 33-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/21/2025.
Note: in the Non-Final Rejection of 09/04/2025 (¶8) it was mistakenly stated that the restriction requirement of 05/20/2025 was rendered moot by Applicant’s voluntary cancellation of the unelected Group II method claims (20-22, 24-26, 28-29, and 31). Please note, the restriction requirement is not withdrawn. If applicant cancels all the claims directed to a nonelected process invention before rejoinder occurs, the examiner should not withdraw the restriction requirement. This will preserve applicant’s rights under 35 U.S.C. 121. See MPEP 821.04(b).
Priority
The effective filing date remains: 04/23/2020 for claims 1, 5, 7, 15, 33-34, and 37-40; 02/02/2021 for claims 11, 13, and 35-36.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/05/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Examiner acknowledges receipt of and has reviewed the amendments and remarks of 01/05/2026; no new matter is found.
The objection to the drawings is withdrawn since Applicant has provided higher resolution figures.
The objection to the specification is withdrawn since Applicant has amended the specification to include higher resolution chemical structures.
The 112(a) rejection of claims 1, 7, 15, and 36-40 is withdrawn because Applicant has amended claim 1 to recite E3 ligase ligands for which the specification provides support. Thus, the scope of the claims now has written description support.
The 112(b) rejection of claims 1, 7, 15, and 36-40 regarding the attachment of the linker on the C17 of the estradiol is withdrawn. Applicant has amended claim 1 to clarify that the linker is coupled to the estradiol via the O atom which is bonded to the C17 of the estradiol. The claimed structure is now clear and definite.
Note: Applicant has responded to Examiner’s concern over “VHL-2 ligand 3” (¶18 of previous action) by removing this ligand from the claims.
The 102 rejection of claims 1, 7, and 36-37 over ITOH is withdrawn because Applicant has amended claim 1 to recite wherein the linker is coupled to estradiol via the O-C17. ITOH does not recite any compounds with this linker-estradiol configuration.
The 103 rejection of claims 1, 15, and 38-40 over ITOH in view of CREWS is withdrawn for the same reasons as above. This rejection simply provided a rationale to formulate the compound of ITOH in a pharmaceutical composition. Since ITOH no longer teaches a compound of claim 1, the rejection is withdrawn.
Response to Amendment
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 15, and 36-40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by PHAM (WO 2019/222272, provided IDS of 08/09/2023), evidenced by NALT (USDA NALT Concept Space, “Chemical Derivatives”, last modified 12/06/2013, retrieved from https://lod.nal.usda.gov/nalt/en/page/207583).
Note: this art was found incidental to the search for the expanded species above. It is applied here to promote compact prosecution but does not indicate that the Markush search has been fully extended.
Regarding claims 1 and 36, PHAM teaches the compound:
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(Pg 108 compound 2.22). The compound 2.22 of PHAM is understood to comprise 17β-estradiol coupled to a linker via the O atom on C17, wherein the linker comprises 1 PEG unit (-O-(CH2)2-O-) and the ligand is a derivative of the E3 ubiquitin ligase ligand CC-122 or TD-106. The instant specification does not define the word “derivative” therefore the definition reverts to that of the art. As evidenced by NALT, a derivative is a compound derived from a parent compound by a chemical reaction and having similar chemical structure (Definition). CC-122 and TD-106 share a similar bicycle containing a lactam-like ring (annotated) to the ligand on the compound of PHAM:
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(CC-122) and
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(TD-106). Due to these chemical similarities, the Examiner understands the ligand of PHAM’s compound 2.22 to be a derivative of the instantly claimed E3 ubiquitin ligase ligands CC-122 or TD-106. Thus, the compound of PHAM falls within the scope of the instantly claimed molecule.
Further, claim 1 recites the 17β-estradiol is a G-protein coupled estrogen receptor ligand. PHAM is silent as to this property of the estradiol. MPEP 2112.01.II states: "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). 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. Since PHAM teaches a compound of instant claim 1 comprising 17β-estradiol, it would be expected that the compound of PHAM (especially the estradiol) would have the same physical properties as the compounds in the instant application, namely that the compound is a G-protein coupled estrogen receptor ligand.
Regarding claim 36, this claim contains a limitation drawn to a property of the claimed compound: the molecule is a pan-estrogen receptor inhibitor. See MPEP 2112.01.II quotation above Since PHAM teaches a compound of instant claim 1 from which 36 depends and claim 36 does not further define any structural elements of the compound, it would be expected that the compound of PHAM would have the same physical properties as the compounds in the instant application, namely that the compound is a pan-estrogen receptor inhibitor.
Regarding claim 37, compound 2.22 comprises the linker
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which contains the 1 PEG unit and a further divalent alkyl group (-CH2-CH2-).
Regarding claims 15 and 38-40, PHAM teaches a pharmaceutical composition of the compound 2.22, above, further comprising a pharmaceutically acceptable excipient (Pg. 277 claim 29). PHAM teaches the pharmaceutical composition may take a form suitable for oral or parenteral administration (Pg. 170 Lines 24-25), thus, PHAM teaches an enteral and parenteral pharmaceutical composition.
This rejection is properly made FINAL as it is due to Applicants’ claim amendments.
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, 5, 7, 15, and 36-40 are rejected under 35 U.S.C. 103 as being unpatentable over:
CREWS (WO 2013/106643, provided IDS of 10/21/2022)
evidenced by
NALT (USDA NALT Concept Space, “Chemical Derivatives”, last modified 12/06/2013, retrieved from https://lod.nal.usda.gov/nalt/en/page/207583)
and further in view of
RODRIGUEZ (Rodriguez-Gonzalez, A. et al., Oncogene, 2008, 27, 7201-7211, provided IDS of 10/21/2022).
Determining the Scope and Contents of the Prior Art:
CREWS teaches compounds containing on one end a VHL ligand which binds to the VHL E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is degraded and inhibited by ubiquitin ligase (Pg. 1 ¶1). CREWS further teaches an exemplary compound
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(Pg. 386 claim 102) comprising 17β-estradiol coupled to a 12-atom linker comprising 2 PEG units and one divalent alkyl group (-(CH2)4-), further coupled to a VHL ligand (as annotated). The VHL ligand of CREWS is understood to be a derivative of the instant E3 ligase ligand VL285:
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. VL285 shares the outlined portion with the VHL ligand of CREWS’s compound. As evidenced by NALT, a derivative is a compound derived from a parent compound by a chemical reaction and having similar chemical structure (Definition). Due to the shared chemical structure between VL285 and CREWS’s VHL ligand, the VHL ligand of CREWS is understood to be a derivative of the instantly claimed ligand VL285. CREWS teaches the 17β-estradiol is an estrogen receptor ligand (Pg. 81 XIII.). CREWS also teaches the estradiol may be bound to a linker group or linker-VHL ligand group as is generally described in Rodriguez-Gonzalez et al., Oncogene, 2008, 27, 7201-7211 (Pg. 77 VII. 2.). Thus, CREWS points the artisan towards the secondary reference applied in this rejection.
CREWS further teaches pharmaceutical compositions comprising at least one compound of the invention (i.e., the above estradiol-linker-E3 ubiquitin ligase ligand compound) and a pharmaceutically effective amount of an excipient (Pg. 101 ¶3), i.e., a pharmaceutically acceptable excipient. CREWS teaches the compositions are preferably administered orally, intraperitoneally, or intravenously wherein intraperitoneally and intravenously are included under parenteral administration (Pg. 103 ¶2). CREWS further teaches sterile injectable forms of the composition (Pg. 103 last ¶) and orally acceptable dosage forms including capsules, tablets, aqueous suspensions or solutions (Pg. 104 ¶1). Note, Examiner understands oral administration as enteral administration. CREWS also teaches the estradiol-containing compounds are useful for treating diseases modulated by estrogen receptors such as breast cancer (Pg. 52 ¶2).
RODRIGUEZ teaches Protacs comprising a degron which binds to the VHL E3 ubiquitin ligase complex, linked to 17β-estradiol to target the estrogen receptor (Pg. 7201 Abstract). RODRIGUEZ teaches Protac B
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(Pg. 7202 Fig. 1) which led to ubiquitination and degradation of estrogen receptor alpha (Pg. 7202 Right Col. ¶1) and inhibited estrogen-dependent breast cancer cell lines with 16-50 uM IC50 (Pg. 7203 Right Col. ¶1).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
CREWS does not teach an exemplary compound wherein the linker is coupled via the O17 at the C17 of the estradiol.
RODRIGUEZ does not teach a compound wherein the linker comprises PEG.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a compound useful for degradation and inhibition of estrogen receptor and possesses the technical knowledge necessary to make adjustments to the compound to optimize/enhance the compound’s properties. Said artisan has also reviewed the problems in the art regarding estradiol-linker coupling strategies and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references CREWS (evidenced by NALT) and RODRIGUEZ.
Regarding claims 1, 5, 7, and 36-37, the artisan would find it obvious to modify the compound of CREWS, above (Pg. 386 claim 102), by moving the linker from the C7 to the oxygen atom on the C17 of the estradiol in view of the combined references. CREWS provides instructions directing the artisan to RODRIGUEZ (Pg. 77 VII. 2.). Further the compound taught in RODRIGUEZ is analogous in structure to the compound of CREWS – i.e., both comprise 17β-estradiol linked to a VHL ligand. Moreover, the two are analogous in function: CREWS teaches utility in treating breast cancer (Pg. 52 ¶2) via ubiquitin-mediated degradation of estrogen receptor (Pg. 1 ¶1 & Pg. 81 XIII.) and RODRIGUEZ teaches ubiquitin-mediated degradation of estrogen receptor (Pg. 7202 Right Col. ¶1) and inhibition of breast cancer cell lines (Pg. 7203 Right Col. ¶1). Due to this overlap in structure and function, and further in view of the instructions given by CREWS (Pg. 77 VII. 2.), the artisan would have a reasonable expectation of success that by modifying the linkage of the estradiol-linker to the C17 oxygen atom, the artisan would produce a compound with similar or improved ability to recruit and degrade estrogen receptor via the E3 ubiquitin ligase system. Thus, the artisan would find it obvious to arrive at the compound:
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wherein 17β-estradiol is a GPER ligand (CREWS Pg. 81 XIII.) coupled via O-C17 to a linker comprising PEG which is coupled to the derivative of the E3 ligase ligand VL285 (evidenced by NALT).
Further regarding claim 5, CREWS teaches the E3 ligand is a VHL ligand (Pg. 1 ¶1).
Further regarding claim 7, the resulting obvious compound has 12 linker atoms.
Further regarding claim 36, since CREWS teaches 17β-estradiol is a GPER ligand (CREWS Pg. 81 XIII.) and the compound degrades such target protein/receptor (Pg. 1 ¶1), the compound is understood to be a pan-estrogen receptor inhibitor.
Further regarding claim 37, the resulting obvious compound has a divalent alkyl group in the linker: i.e., (-(CH2)4-).
Regarding claims 15 and 38-40, since the compounds of both CREWS and RODRIGUEZ are useful for treating cancer (CREWS Pg. 52 ¶2; RODRIGUEZ Pg. 7203 Right Col. ¶1), the artisan would be motivated to formulate the resulting obvious compound in a pharmaceutical composition. The artisan would have a reasonable expectation of success since CREWS teaches pharmaceutical compositions comprising the estradiol-linker-E3 ubiquitin ligase ligand compound and a pharmaceutically acceptable excipient (Pg. 101 ¶3). The artisan would find success in formulating both enteral and parenteral compositions since CREWS teaches the compositions are preferably administered orally (i.e., enterally) or parenterally (Pg. 103 ¶2). Thus, the instant composition claims are found obvious.
Thus, claims 1, 5, 7, 15, and 36-40 are rejected as obvious.
This rejection is properly made FINAL as it is due to Applicants’ claim amendments.
Conclusion
Claims 1, 5, 7, 15, and 36-40 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA ELIZABETH BELL whose telephone number is (703)756-5372. The examiner can normally be reached Monday-Friday 9:00-5:30.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625