+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 .
Election/Restriction
Applicant timely traversed the restriction requirement in the reply filed on 22DEC2025 and upon further consideration as a result of amendments to the claims, the requirement for claims 2-4, 7, 9, and 14, and new claims 17-22 as set forth in the restriction requirement mailed on 06NOV2025 is hereby withdrawn. Therefore, claims 2-4, 7, 9, 14, and 17-22 will be rejoined to elected Invention II.
Applicant’s election of species without traverse of AARVIK-605, in the reply filed on 22DEC2025 is acknowledged.
Claims 2-4, 7, 9, 14, 17-20, and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species. Election was made without traverse in the reply filed on 22DEC2025.
Claim Status
Claims 2-4, 9, and 14 have been amended.
Claims 1, 5-6, 10-13, and 15-16 have been canceled.
Claims 17-24 are new.
Claims 2-4, 7-9, 14, and 17-24 are pending in the instant application (i.e., Claim(s) 7-8 is/are independent).
Claims 2-4, 7, 9, 14, 17-20, and 22 are withdrawn.
Claims 8, 21, and 23-24 are examined on the merits.
Priority
The present application claims the benefit of US Provisional Patent Application No. 63/266326, filed 01JAN2022. Applicant’s claim for the benefit of prior-filed applications is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 27JAN2023 is/are acknowledged and the references cited therein have been considered.
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.
Claim 21 is 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.
Claim 21 recites the limitation "the compound of claim 8, comprising the moiety [structure of AARVIK-605 (i.e., linker and drug with R groups selected, but without the Ab)]." In the instance of claim 8, the compound of Formula (VII) [structure of Formula (VII)], wherein Ab is antibody, and R groups are defined on the linker and drug, but not claimed as the moiety. Therefore, there is insufficient antecedent basis for this limitation in the claim.
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.
Written Description
Claim 24 is 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 claim(s) contains 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that 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, 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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
In this instance, Applicant has claimed a composition comprising a cell and a compound of claim 8, wherein the compound of claim 8 is an ADC comprising essentially any antibody which is linked to SN38 or an fluoro-analog of SN38, wherein the antibody is linked to the drug through a bifunctional linker which comprises two different types of cleavable linkers. While the specification has the written description support for the structure itself and pharmaceutical compositions thereof, the specification and working examples do not provide sufficient written description support for a generic composition comprising essentially any cell and the ADC of claim 8. Specifically, the term “pharmaceutical composition” refers to a composition comprising a pharmaceutical compound (e.g., drug) and a pharmaceutically acceptable carrier, which refers to a carrier that is compatible with the other ingredients of a pharmaceutical composition and can be safely administered to a subject (¶00075-00076), and is further clarified that the pharmaceutical compositions comprise a therapeutically effective amount of the ADC (¶000142) and may further comprise additional therapeutic agents, for example, antibodies, alkylating agents, etc., but does not include any mention of a cell (¶000148). Alternatively, the only mention of a generic composition is as another aspect, wherein the composition comprising a cell and a compound or conjugate herein, wherein in one embodiment the compound is bound to a surface of the cell, in another embodiment the compound is bound to an antigen present on the surface of the cell, in another embodiment the compound is within the cell, and in another embodiment the compounds drug and antibody are separate (¶00022). The prior art supports compositions of ADCs and alternative therapies (e.g., ADCs and tyrosine kinase inhibitors, DNA damage repair agents, checkpoint inhibitors, or bispecific T cell engagers), or compositions of ADCs and unconjugated antibodies for improved distribution; however there is no support which discusses a composition comprising ADCs and cells (Siu, et al., Annals of Onc, 2026, 37, 129-132 and Ponte, et al., Mol Cancer Ther, 2021, 20, 203-212). In this instance, claim 24 is unclear and as recited claims a composition product comprising the ADC and essentially any cell (i.e., blood cell, T cell, bacterial cell, etc.); however, based on the specification, the scope of the claim refers to the resulting composition product following administration of the ADC to a cell population. Therefore, in either interpretation, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of a composition comprising essentially any cell and the ADC nor the resulting product following administration of the ADC at the time the instant application was filed.
Claim Rejections - 35 USC § 103
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.
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 8, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over and King, et al., (Tet Letters, 2002, 43, 1987-1990), herein referred to as King, in view of WO 2020/236817 A2 (Novartis AG, et al., 26NOV2020, see OA.APPENDIX for paragraphs of interest), herein referred to as “‘817,” Yaegashi, et al., (Chem Pharm Bull, 1994, 42, 2518-2525), herein referred to as “Yaegashi,” and Kolakowski, et al., (Angew Chem, 2016, 55, 7948-7951), herein referred to as “Kolakowski.”
King teaches the facile synthesis of a maleimide-based bifunctional linker, wherein for each protein binding site there are two arms or ligand conjugation sites (see entire document, specifically see the bottom two structures in Fig 1). Furthermore, King teaches that this specific linker was designed for increasing the drug loading capacity in an ADC, wherein there are a discrete number of cysteines without causing aggregation and furthermore offers i) the presence of a water solubilizing amine functionality; ii) the ability to couple two components at a time, and iii) a straight-forward synthesis that can be modified to optimize the linker length (p 1988, col 1). Additionally, as a proof of concept, King teaches the conjugation of the Phe-Lys dipeptide and p-aminobenzyl group to each arm of the linker, which can then be further coupled to an NH2- or OH-containing cytotoxic drug (see scheme 4, p 1988, col 2, 3rd full paragraph).
However, they do not teach: the specific structures of each arm:
Top Arm comprises:
A dipeptide comprising ß-Ala and N-methyl-Gly (sarcosine);
ß-glucuronide-PAB; and
SN38 or the ring A, position 11, fluoro-analog of SN38; and
Bottom Arm comprises:
A dipeptide, wherein the first peptide residue position may comprise Gly, Ala, or Val and in the second peptide residue position may comprise Ala, Lys, Cit, or Val;
PAB; and
SN38 or the ring A, position 11, fluoro-analog of SN38.
Nevertheless, ‘817 teaches the Fmoc-Val-Lys(Boc)-PAB-PNP construct for further modification (i.e., the precursor for the synthesis of the bottom arm for conjugation of SN38 or the ring A, position 11, fluoro-analog of SN38) (¶443-445, see OA.APPENDIX).
Furthermore, Yaegashi teaches the synthesis of position 11, fluoro analog of SN38 (Fig 1) and its cytotoxicity in KB and L1210 cells of 0.3 and 2.2 ng/mL respectively (Table 1, compound 6z). Yaegashi further teaches solubilizing techniques, such as incorporation of a hydroxyl or amino group in the A-ring, such as SN-38 or 11-fluoro-substituted SN38 (p 2518, col 2), which was approximately 10 and 2 times more effective than camptothecin in KB and L1210 cells, respectively (compound number 1a) (p 2519, col 2, results and discussion section), and SN38 showed a DNA topo-I activity of < 1 μg/mL (Table III, compound number 1c).
Additionally, Kolakowski teaches the synthesis of the top arm, wherein the dipeptide comprises ß-Ala-ß-Ala-ß-glucuronide-PAB-PNP (i.e., an analogous precursor for the synthesis of the top arm for conjugation of SN38 or the ring A, position 11, fluoro-analog of SN38 (Fig 1 and scheme 1). Kolakowski teach that the design of a methylene alkoxy carbamate self-immolative moiety for ADCs centered on incorporating the payload alcohol oxygen atom in a stable manner to allow efficient release upon enzymatic processing. Furthermore, conjugation of compound 1 via maleimide to a cysteine of an antibody showed effective tumor growth inhibition at both 0.5 and 1.0 mg/kg compared to the IgG vehicle or untreated activity (Fig 2). Combined, Kolakowski teaches that the known methylene alkoxy carbamate self-immolative moiety and the enzyme cleavable linker, offers a solution for stable conjugation and efficient release of alcohol-based payloads for ADCs.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the generic bifunctional maleimide-based linker allowing for two ligand binding sites comprising two cleavable sites and further coupled to an NH2- or OH-containing cytotoxic drug drug disclosed by King by modifying the two ligand binding sites to comprise two different cleavable linkers and are further coupled to a known OH-containing drug, SN38 or the 11-fluoro-SN38 analog disclosed by ‘817, Yaegashi, and Kolakowski. One would have been motivated to do so, given the teachings of King that the bifunctional linker offered i) the presence of a water solubilizing amine functionality; ii) the ability to couple two components at a time, and iii) a straight-forward synthesis that can be modified to optimize the linker length. It is noted that Kolakowski utilizes a dipeptide comprising two ß-Ala; however, it is expected that a ß-Ala and methyl-Gly dipeptide would perform similarly and maintain a stable conjugation as well as efficient release of an alcohol-based payload from the ADC construct. There would have been a reasonable expectation of success, given the knowledge that linker modification utilizing known linker components, known drugs, and known chemistry would lead to a bifunctional linker comprising two different cleavage sites with increased delivery of the drug, improved topo-I inhibition compared to camptothecin, and facile synthesis, as taught by ‘817, Yaegashi, and Kolakowski.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641