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 .
Application Status
This action is written in response to applicant’s correspondence received on 07/28/2026. Claims 1-20 are currently pending. Claims 7, 9, 11, 17-19 are withdrawn from prosecution as being drawn to nonelected subject matter. Accordingly, claims 1-6, 8, 10, 12-16, 20 are examined herein. The restriction requirement mailed on 04/28/2026 is still deemed proper. Applicants elected Group I without traverse in the reply filed on 07/28/2026.
Election/Restrictions
Claims 7, 9, 11, 17-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group 2 or nonelected species, there being no allowable generic or linking claim. Regarding claim 7, the elected species has Y3 absent, here claim 7 requires Y3 to be a triazoyl fused with a BCN, hence does not read on the elected species. Regarding claim 10, the elected species includes an ODN set forth in SEQ ID NO: 4, which can form a hairpin structure with a double-stranded region, which is interpreted as the same as the recited “double band hairpin” under the broadest reasonable interpretation (BRI) via intradimerization (Page 62, line 20-22; FIG. 3D).
Applicant elected species: ULB is formula (II) shown on page 9; L1 = Formula (IVo) with Y1, Y3, Y8 absent, Y2 = triazolyl fused to bicyclo[6.1.0]nonane, Y4 = —CH2—, Y5 = —OC(O)—, Y6 = —NH—, Y7 = —(CH2)8—; ODN = SEQ ID NO: 4. The elected species is compound 16, dNF-κB #1 in Table 2 (Page 29), which is shown below. The underlined part, Y2, is the product of azide alkyne click reaction.
ODN (SEQ ID NO: 4)-triazolyl fused BCN-CH2-OC(O)-NH-(CH2)8-ULB (VH032 Me)
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 38 (https://string-db.org/). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms PROTAC, Agilent, Zorbax, Waters Acquity, Bruker, Phenomenex Luna, ENZO Life Sciences, Pierce, Calbiochem, Bio-Rad, Beckman Coulter, Thermo Fisher, Cell Signaling Technologies, Biolegend, Fisher Scientific, nanoEase, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a CON of PCT/US2022/031317 filed on 05/27/2022, and claims priority to PRO 63/245,506 filed on 09/17/2021, and PRO 63/194,917, filed on 05/28/2021.
Claim Objections
Claim 20 is objected to because of the following informalities: the recitation “... reacting a DNA oligomer… thereof; where said DNA oligomer protein is conjugated to an azide with a compound …” should 1) replace “;” with a “,”; 2) replace “where” with “wherein”; 3) insert a “,” between “azide” and “with”, because “reacting a DNA oligomer…, wherein …, with a compound …” appears to be the correct sentence. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-6, 8, 10, 12-16, 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, it is noted that the claim recites "ODN is a DNA oligomer protein comprising a transcription factor binding motif...". This language is considered to be indefinite because DNA oligomers and proteins are distinct classes of biomolecule. The phrase “DNA oligomer protein” creates ambiguity such that it cannot be determined whether it is an error for protein-binding DNA oligomer moiety, i.e. an aptamer, or it is intended as an actual DNA-protein chimera. The metes and bounds of ODN cannot be ascertained.
Claims 2-6, 8, 10, 12-16, 20 are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
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 2-5, 8 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.
Claims 2-5, and 8 are rejected as failing to further limit claim 1's L1 requirement, i.e. "a linker comprising an azide/alkyne cycloaddition reaction product".
Claim 2 recites "a strained click chemistry reaction product" without structural limitation. Per the specification's own disclosure, "click chemistry reaction product" is a broader genus including non-azide/alkyne chemistries, e.g. strain-promoted alkyne-nitrone cycloaddition (SPANC), alkene-tetrazine inverse-demand Diels-Alder, alkene-tetrazole photoclick reactions, Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction product (e.g., a divalent triazole), and thiol-based Michael additions/substitutions (Page 19, line 18 – Page 20, line 5). Claim 2 as drafted encompasses broader scope than claim 1 upon which it depends, thereby not further limiting claim 1.
Claim 3 (Formula IV, -Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-) permits embodiments where every Yn (n=1-8) position to be independently selected from only non-ring linkages (—C(O)—, —O—, —OC(O)—, —NRa—, —N(Ra)C(O)—, plain alkylene, PEG-type spacer, —S—S—) or "absent". Some embodiments of claim 3 do not contain any cycloaddition-derived structure at any Yn position, only some embodiments do, thus claim 3 does not incorporate all the limitations of claim 1. As written, claim 3 does not require “an azide/akyne cycloaddition reaction product” mandated by claim 1 for embodiments that contain L1.
Claim 4 also suffers the same defect as claim 3 because it permits embodiments where “an azide/akyne cycloaddition reaction product” is not required for L1.
Claim 5 is rejected under 112(d) because its Markush structure for the click-derived moiety includes Z1 = —N— or —CR3—, which encompasses both a triazole, i.e. the required azide/alkyne-derived click chemistry product, and a dihydroisoxazole, a strain-promoted alkyne-nitrone cycloaddition (SPANC) product (Page 19, lines 22-23), which is not an azide/alkyne chemistry derived product, thereby failing to further limit claim 1 regarding L1’s limitation.
Claim 8 is also rejected for depending from claim 3 and failing to remedy the defect therein.
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 § 112 Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 8, 10, 12-16, 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The independent claim 1 directs to an extremely broad genus of "ULB is a ubiquitin ligase binding moiety" variants without structural limitation. The claimed product genus relies on a functional limitation “ubiquitin ligase binding moiety. In another word, it claims what the product does instead of what the product is. By doing so, the claim reads on any moiety binding any of the hundreds of structurally and mechanistically distinct known E3 ubiquitin ligases (VHL, CRBN, MDM2, IAP family members, and others.
The specification discloses ULB only limited types “selected from the group consisting of von Rippel Lindau (VHL) E3 ubiquitin ligase, ß-Transducin Repeat Containing (ß-TRCP) E3 Ubiquitin Protein Ligase, Mouse Double Minute 2 (Mdm2) E3 Ubiquitin Protein Ligase, and a Cereblon (CRBN) E3 Ubiquitin Ligase” (Page 3, lines 22-24) focusing primarily on Formula (II) or (III) species (Pages 9-12), wherein Formula (II) is a variant of a well-known building block in the synthesis of proteolysis-targeting chimeras (PROTACs) a von Hippel–Lindau (VHL) ligand VH-032 commercially available for synthesizing ULBs for a wide range of pharmaceutical applications involving E3 ubiquitin ligase-based protein degraders. The specification also confirms that VH-032 is used for the synthesis and conjugation of the linkers (Page 63, lines 6-8). And Formula (III) is also a well-known molecular glue targeting the CRBN (Cereblon) E3 ubiquitin ligase, called Thalidomide analogues / IMiDs, another known building block of PROTACs in the art. The specification admits these well-established routine structures in the art from page 3 (line 20) to page 19 (line 4), and credits prior publications in the art for these known structures (Page 11, lines 1-8).
Regarding the state of the art, Ishida (SLAS Discov. 2021 Apr;26(4):484-502) teaches a broad genus of structurally orthogonal, non-interchangeable ULB chemotypes, e.g. hydroxyproline-based VHL ligands, glutarimide-based CRBN ligands (IMiDs), bestatin-derived IAP ligands, and nutlin-based MDM2 ligands, each species engaging its target through a distinct, non-predictive binding mode (Figures 2-6).
The disclosure of insufficient species of a broad genus, the high degree of variation in the art, and the failure to disclose correlation between structure in the specification and the claimed function led to the determination that claim 1 is overly broad with insufficient evidence of possession at the time of filing to one skilled in the art. Thus, claim 1 does not meet the written description requirement, and the specification demonstrates a clear lack of possession of the full genus as claimed.
Claims 2-6, 8, 10, 12-16, 20 are also rejected for depending from the rejected claim 1 and failing to remedy the lack of written description therein.
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.
Claim interpretation: “DNA oligomer protein” is interpreted as DNA oligonucleotide.
Claims 1-6, 8, 10, 12-15, 20 are rejected under 35 U.S.C. 103 as being unpatentable over Shao (bioRxiv 2021.03.08. 434493; Cited on IDS filed on 11/27/2023; Supporting information listed in PTO-892), in view of Hu (J Med Chem. 2019 Feb 14;62(3):1420-1442) as evidenced by Tocris (Me VH 032, amine, CAS #2504950-56-3; Tocris_Me VH032 .pdf is listed in PTO-892), further in view of Shibuya (Biochem Biophys Res Commun. 2002;298(1): 10-16), Jin (WO2019173516 A1, published on 09/12/2019), Heightman (WO2017212329A1, published on 12/14/2017), as evidenced by MCE (MCE_SRS AHPC-C8-NH2.pdf and MCE_endo-BCN-NHS.pdf listed in PTO-892), and Fomich (Org Lett. 2014;16(17):4590-3).
Shao (2021 march) teaches a general architecture of a transcription factor (TF)-PROTAC compound molecule combining a TF binding oligodeoxynucleotide (ODN), a linker, and a ubiquitin E2 ligase binding moiety, i.e. a ULB, named O’PROTAC (Page 11, Figure 1). Shao also teaches exploring different ULB types, linker types and linker lengths (Scheme S1; Page 2, right column, 2nd ¶, lines 22-25).
Shao does not teach: 1) the elected species of ULB; 2) the elected species of a NF-κB binding motif ODN set forth in SEQ ID NO: 4; 3) the elected species of a click chemistry product-containing alkyl carbamate linker (See Election/Restriction above).
However, Hu (2019) teaches a Methyl modified VH032, a widely used ubiquitin E3 ligase binding moiety in the art, which has identical structure to the ULB structure of the elected species, which has a CAS registry number: 2504950-56-3 (Entered STN on 05 Nov 2020; See STN structure search history), as evidenced by a commercial product sheet from Tocris (above).
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Hu also does not teach 2) and 3) listed above.
However, Shibuya (2002) teaches 2), an NF-κB decoy ODN, named NF-κB31 (Page 10, Abstract), which is the identical to the elected ODN: Query: Shibuya NF-κB31; Sbjct: Instant SEQ ID NO: 4.
Querr: 5’-TGGGGACTTTCCAGTTTCTGGAAAGTCCCCA-3’
|||||||||||||||||||||||||||||||
Sbjct: 5’-TGGGGACTTTCCAGTTTCTGGAAAGTCCCCA-3’
Shibuya also does not teach 3).
However, Jin (2019) teaches various strategies to synthesize PROTACs including using a building block containing the VH-032, non-methyl version of a ULB attached with a C8 alkyl with a terminal amine, i.e. –(CH2)8-NH2, which is a routine PROTAC building block with its own CAS registry number: 2376139-49-8 (Entered STN on 20th June 2019; See STN structure search history), as evidenced by MCE (MCE_SRS AHPC-C8-NH2-HCl.pdf listed on PTO-892). Jin does not teach the linker groups Y2 (a triazoyl fused with a bicyclo[6.1.0]nonane, or BCN), Y4 (a -CH2-), and Y5 (a OC(O)-), or the click chemistry product of azide-alkyne reaction between the ODN-azide and the BCN functionalized carbamate linkage, i.e. BCN-CH2-O-C(=O)-NH-(CH2)8-.
However, Heightman (2017) teaches a variety of click chemistry-based linker conjugation strategies, including methods to prepare the click chemistry-based, i.e. SPAAC-based conjugation methods using BCN click handles as strained-alkyne click-chemistry functionality in the construction of a PROTAC degrader, CLIPTAC (Figure. 1; Claims 10-13). The use of BCN-NHS carbonate reagents to yield BCN-functionalized E3 ligase precursors is evidenced by the commercially available reagent, CAS registry: 1493802-77-9 (Entered STN: 12/12/2013 based on STN structure search; See Search History), as evidenced by MCE (See MCE_exo-BCN-NHS.pdf in PTO-892). Fomich (2014) teaches the strategy to add azide-based click handles on oligonucleotides for downstream click chemistry, i.e. SPAAC, based conjugations (Page 4590, Abstract; Pages 4591-4593, Schemes 1-3). Hence, Heightman and Fomich collectively teach methods to formulate BCN-CH2-O-C(=O)-NH-(CH2)8-[VH032 Me], and ODN-Azide modules for the bifunctional PROTAC molecule of an ODN-L1-ULB construct via Strain-promoted azide-alkyne cycloaddition (SPAAC) click chemistry reaction to form the claimed species.
Regarding the elected species, compound 16, dNF-κB #1, of Table 2, it would have been obvious to persons having ordinary skills in the art (PHOSITAs) before the effective filing date (EFD) of the claimed invention to have further modified the transcription factor degrader according to the same general architecture taught by Shao (2021, March), ODN-linker-ULB, via simple substitutions of known improvements of similar functional modules that include:
1) substituting with a different ULB: a chiral methyl modified VH032 ULB module, published and CAS registered before the EFD as taught by Hu and evidenced by Tocris, because Hu shows more potent protein degrading effect for the variant with a chiral methyl on the benzyl group of the VH032 base structure (Page 1427, Figure 8, compound 15 has chiral methyl group whereas compound 42 doesn’t, the latter showing poor ER degrading effect in Figure 8B; Page 1428, left column, first 2 lines). Shao further explored VH032 as an alternative, interchangeable ULB module (Page 5, Design of O’PROTACs, line 5).
2) substituting the LEF1- or ERG-targeting ODNs of Shao with a NF-κB specific ODN taught by Shibuya to target NF-κB, also published before the EFD; This substitution is simply necessitated by the target of choice which differs from Shao’s LEF1 and ERG;
3) substituting the linker of Shao (Page 12, Table 1; Shao_2021_O'PROTAC_supp.pdf listed in PTO-892) with a known click chemistry functionalized linkage via a linker already conjugated to a VH032 variant, which is also published before the EFD, as taught by Jin, Heightman, and Fomich.
It would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results because these substitutions maintain the same functional architecture of the O’PROTAC of Shao, and each substituted element has been known as alternative interchangeable in the art. One would have been motivated to do so because Hu (2019) teaches that these the chiral methyl modification of the VH032 ULB results in increased potency of target protein degradation action (Page 1427, Figure 8; Page 1428, right column, lines 1-3). Shao further teaches it is necessary to explore and compare different linkers or ULB modules to optimize the desired TF degradation (Page 5, last 4 lines; Page 6, first 2 lines). One would have reasonable expectations of success because Shao describes successful TF degradation for 2 distinct TFs with different ODNs and teaches that “O’PROTAC is desirable due to its readily predictability and superior stability” (Page 11, lines 4-5) and “… possible to target any TF…” and “that the efficacy of O’PROTACs can be further optimized by altering the lengths and types of a linker and the E3 ligase ligand” (Page 10, lines 10-12).
Regarding claim 1, the elected species rejected above reads on this claim and is a compound having the structure of formula (I): ODN-L1-ULB (I) wherein ULB is a ubiquitin ligase binding moiety; L1 is a linker comprising an azide/alkyne cycloaddition reaction product; ODN is a DNA oligomer protein comprising a transcription factor NF-κB binding motif that binds to the transcription factor NF-κB.
Regarding claim 2, the elected species rejected above reads on this claim and has a L1 linker comprising a Y2, triazoyl-fused bicyclo[6.1.0]nonane, which is a SPAAC click chemistry product.
Regarding claims 3 and 8, the elected species rejected above reads on this claim and comprises a L1 having the structure of formula (IV): -Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8- (IV)
wherein Y1 is absent, Y2 is a five membered heteroarylene (triazoyl) fused with a bicyclic cycloalkyl (bicyclo [6.1.0] nonane), Y3 is absent, Y4 is methylene (-(CH2)-), Y5 is -OC(O)-, Y6 is NH, and Y7 is -(CH2)8- and Y8 is absent (formula IVo), thereby rendering both claims 3 and 8 obvious.
Regarding claim 4, the elected species rejected above reads on formula IVo.
Regarding claim 5, the elected species rejected above reads on this claim, wherein Y2 is a strained click chemistry reaction product having the structure: Z1=C, R3=C8 ring, p=1,
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, thereby rendering the claim obvious.
Regarding claim 6, the elected species rejected above reads on this claim, wherein Y2 is a strained click chemistry reaction product having the structure:
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, thereby rendering the claim obvious.
Regarding claims 10, 12, the elected species rejected above reads on this claim as the elected ODN set forth in the claimed SEQ ID NO: 4 was shown by Shibuya (2002) that “that this ‘hairpin’ structure confers resistance to exonucleases” (Page 11, left column, 3rd ¶, lines 3-6).
Regarding claim 13, Shao further teaches that the linker and ULB module, i.e. phosphoramidites (P1-P6, equivalent structure of L1-ULB) in Shao were attached to the ODN on the 5’ end of one of the strands of an oligo duplex that contain the TF binding motif (Shao, page 6, lines 2-5; Support information, Table S1 on pages 12-13), which is equivalent of the 5’ end of a hairpin ODN that comprise both the forward and reverse sequences containing the TF binding motif in a single oligonucleotide. Fomich (2014) further teaches strategies to functionalize ODNs with azide-based click handles on the 5’ end of oligos (Page 4592, Table 1, Scheme 3).
Regarding claim 14, the elected species rejected above is compound 1 (dNF-κB #16).
Regarding claim 15, Jin further teaches “pharmaceutical composition” for using the PROTAC protein degraders (Page 73-75, under Pharmaceutical Composition).
Regarding claim 20, the elected species rejected above reads on the product made by the claimed method, and it can be formed by reacting a DNA oligomer ODN comprising a transcription factor binding motif that binds a transcription factor, a NF-κB ODN taught by Shao (2021) and Shibuya (2002), wherein said ODN is conjugated to an azide, taught by Fomich (2014), with a compound having the structure of formula VI: Y2-Y3-Y4-Y5-Y6-Y7-Y8-ULB, wherein ULB is a ubiquitin ligase binding moiety VH032-Me, taught by Hu (2019), Y2 is a bicyclic cycloalkynyl, i.e. a bicyclo[6.1.0]nonane/BCN, Y3 and Y8 are absent, Y4 is methylene (-(CH2)-), Y5 is -OC(O)-, Y6 is NH, and Y7 is -(CH2)8-. This is the same component of the elected species prior to a SPAAC reaction between the azide and the cycloalkynyl, i.e. BCN groups between the ODN part and the ULB part, taught by Hu (2019), Jin (2019), and Heightman (2017). Both Fomich and Heightman teach SPAAC click reaction between an azide and an alkyne, components of SPAAC click chemistry reactions (Fomich, page 4590, Abstract; Left column, 2nd ¶, lines 2-3; Heightman, claim 11). At least one method described above based on the combined teachings of Shao, Hu, Shibuya, Jin, Fomich, and Heightman involving routine optimization, simple combination, and simple substitutions, as illustrated below:
substitution VH032, Me of Hu
[AltContent: roundedrect] NF-κB ODN of Shibuya ODN – L1 – ULB NH2-C8-VH032 of Jin
substitution Formula of Shao substitution
Azide click handle on ODN BCN click handle on alkyl(C8)-ULB
combining Fomich SPACC combining Heightman
NF-κB ODN-
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Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Shao (2021), in view of Hu (2019), as evidenced by Tocris (see above), Shibuya (2002), Jin (2019), Heightman (2017), as evidenced by MCE (see above), and Fomich (2014), further in view of Desantis (US20200139430A1, published on 07/30/2020).
The teachings of Shao, Hu, Shibuya, Jin, Heightman, and Fomich have been discussed above as applied to claims 1-6, 8, 10, 12-15, 20. None of Shao, Hu, Shibuya, Jin, Heightman, and Fomich teaches formulating the compound of claim 1 in a liposome.
However, Desantis (2020) teaches pharmaceutical compositions of a claimed PROTAC degrader compound can be formulated in a liposome (Page 61,¶[0216], lines 12-13).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the pharmaceutic composition teachings of Desantis with the elected species already rejected above based on the combined teachings of Shao, Hu, Shibuya, Jin, Heightman, and Fomich. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results because using liposomes as delivery vehicles has been known as alternative interchangeable pharmaceutical composition strategies in the art. One would have been motivated to do so because Desantis (2020) teaches that liposomes may help targeted delivery in certain cell types (Pages 61-62, ¶[0218], lines 6-8). One would have reasonable expectations of success because using the liposome formulations taught by Desantis does not rely on any specific features of PROTACs, hence there is reasonable expectation of success for liposomes to perform similarly across the same PROTAC class of compounds that Desantis also teaches, compared with the PROTAC compounds of the instant applications.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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