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’s election without traverse of Invention I and/or species anti-TROP2_mcE104, in the reply filed on 21MAY2026 is acknowledged.
Claims 6, 9, and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species. Examiner notes that in the instances of claims 5 (dependent on claim 1), 10 (dependent on claim 4), and 12 (dependent on claim 10), the lack of definition of what Z1 and X2 are specifically, results in the claims being potentially drawn to nonelected species (i.e., wherein R1 is a C4 alkyl group, R2 and R3 are hydrogen, n is 1, Y is aryl, Z1 is -N(Rz)C(O)-, Z2 is absent, Rz is a hydrogen, X2 comprises a non-cleavable linker (i.e., C5 alkyl or L2) and a conjugation moiety (i.e., maleimide or L1)); however to facilitate compact prosecution claims 5, 10, and 12 will be evaluated on the merits with the following elections R1 is a C4 alkyl group, R2 and R3 are hydrogen, n is 1, Y is aryl, Z1 is -N(Rz)-, Z2 is absent, Rz is a hydrogen, and X2 comprises a non-cleavable linker (i.e.,
PNG
media_image1.png
46
70
media_image1.png
Greyscale
or L2) and a conjugation moiety (i.e., maleimide or L1). Election was made without traverse in the reply filed on 21MAY2026.
Claim Status
Claims 3, 8, 14-20, and 22-36 have been canceled.
Claims 1-2, 4-7, 9-13, and 21 are pending in the instant application (i.e., Claim(s) 1 is/are independent).
Claims 6, 9, and 11 are withdrawn.
Claims 1-2, 4-5, 7, 10, 12-13, and 21 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2022/070889, filed 01MAR2022, which claims the benefit of US Provisional Patent Application No. 63/155489, filed 02MAR2021. Applicant’s claim for the benefit of prior-filed application is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 28NOV2023, 31JAN2025, 11AUG2025, and 05MAY2026 is/are acknowledged and the references cited therein have been considered.
Drawings
The drawings are objected to because:
Fig 5 contains a typographical error in the x-axis
Fig 16, the legend reads Tras_mc_E104 rather than anti-HER2_mc_E104.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 4-5 and 21 are objected to because of the following informalities:
Claim 4 currently recites, “…L5 is carbonyl….” and should be updated to “…L5 is a carbonyl group….” or something of a similar nature.
Claim 5 contains a typographical error: The semicolon and space prior to the period should be deleted.
Claim 21 contains a typographical error: “…any claim 1…” should be corrected to “…claim 1…” in line 2 of the claim.
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 1-2, 4-5, 7, 10, 12-13, and 21 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “oxaalkyl” in claims 1 and 2 is used by the claim to mean “an ether or an alcohol, but not a carboxy group,” while the accepted meaning is “an ether.” For example the specification discloses that an oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen, examples include methoxypropoxy,…hydroxymethyl (i.e., -CH2OH), hydroxyethyl (i.e., -CH2CH2OH), etc., and that the term oxaalkyl is intended as it is understood in the art referencing Naming and Indexing of Chemical Substances for Chemical Abstract (¶196 without the restriction of ¶127(a)) or in this instance it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds), it does not refer to doubly bonded oxygen as would be found in carbonyl groups (¶0164 of the originally filed specification). With regards to naming compounds, ¶128 of Naming and Indexing of Chemical Substances for Chemical Abstract provides an example comparing “oxa” vs “oxy” vs “oxo” nomenclature:
PNG
media_image2.png
104
372
media_image2.png
Greyscale
, wherein “oxa” refers to the replacement of a carbon atom by an oxygen atom within a carbon chain so the oxygen atom is flanked on both sides by carbon atoms (i.e., ether or R-O-R’), “oxy” refers to an oxygen-linking bridge, for example between a carbon atom and a hydrogen atom (i.e., hydroxy or -O-H), and “oxo” indicates a doubly bonded oxygen atom (i.e., carbonyl group). In this instance, while the specification exemplifies an oxaalkyl to include hydroxy groups, the term as understood in the art does not include hydroxy groups. Therefore, the term is indefinite because the specification does not clearly redefine the term. Claims 4-5, 7, 10, 12-13, and 21 are also rejected since they depend from claim 1, but do not remedy this deficiency.
Claims 1-2, recite the phrase "optionally," which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(h)(II). Claims 4, 10, 12-13, and 21 are also rejected since they depend from claim 1, but do not remedy this deficiency.
Claim 5 recites the limitation "The compound according to claim 1, wherein said compound is of Formula (I), and: R1 is selected from n-butyl, -CH2OH, and -CH2OCH2CH3;…" however, per the discussion supra, an oxaalkyl is understood in the art to include R-O-R’ bonds (i.e., -CH2-O-CH2-CH3) and that a hydroxymethyl group belongs to the “oxy” nomenclature inclusive of -O-R bonds (i.e., CH2-O-H). Therefore there is insufficient antecedent basis for this limitation in the claim.
Claim 7 recites the structural limitation of -CH2OH for R1, in formula (Ib), (Id), (If), (Ih); however, per the discussion supra, an oxaalkyl is understood in the art to include R-O-R’ bonds (i.e., -CH2-O-CH2-CH3) and that a hydroxymethyl group belongs to the “oxy” nomenclature inclusive of -O-R bonds (i.e., CH2-O-H). 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
Claims 1-2, 4-5, 7, 10, 12-13, and 21 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 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.
Scope of the claimed genus:
Applicant has broadly claimed imidazoquinoline derivative compounds of Formula (I) or (II), which are conjugated via essentially any cleavable or non-cleavable linker to essentially any antibody or antibody fragment. The broadest claims do not require the antibody-drug conjugates (i.e., ADCs) comprising essentially any antibody conjugated via essentially any linker to the imidazoquinolines derivative compounds to have any function apart from being cleavable or non-cleavable and targeting essentially any antigen with an imidazoquinolines derivative, with dependent limitations adding additional functional limitations, such as the linker comprising a conjugation moiety and potentially a self-immolative spacer with no structure (i.e., claim 4), or wherein X2 is attached to Ab through a cysteine, lysine, or glutamine residue of Ab or wherein Ab is a tumor targeting antibody, an antibody fragment, a bispecific antibody or antibody fragment, a monoclonal antibody, a chimeric antibody, or a humanized antibody with no structure provided for X2 of claim 1, and no specific Ab structure for a tumor targeting antibody (i.e., claim 13). No claims recite any specific or particular structure of the full ADC construct (i.e., the claims as presently written disclose an entire “forest” of antibodies and linkers without disclosing a representative number of examples or common structural traits).
State of the relevant art:
McCombs, et al., teach that targeted drug conjugates or antibody drug conjugates (ADCs) have emerged as an important pharmaceutical class of drugs designed to harness the specificity of the targeting moiety or antibody with the potency of small molecule therapeutics (McCombs, et al., AAPS J, 2015, 17, 339-351, herein referred to as “McCombs”). McCombs further teaches that such targeted drug conjugates can potentially minimize dose-limiting toxicities while maximizing desired therapeutic effects. Yet, initial ADCs pairing standard anti-cancer agents, such as doxorubicin, were ineffective in clinical trials, which were linked to (1) the limited number of drug molecules that can be conjugated to one antibody without affecting antigen binding and (2) the limited number of antigens on target cell surfaces, preventing therapeutic levels of drug accumulation in cells (see introduction section). To date, the most successful approaches to overcome these challenges are improved linker technology and the selection of extremely potent drugs to the pair with the antibody. Innovations in linker design are focused on multiple issues ranging from serum stability to mechanism of release to drug to antibody ratio (DAR). At the most basic level, linkers provide a functional handle for efficient conjugation to antibodies through bioconjugation (see Linker section). More sophisticated linkers increase effector solubility, improve stability throughout the production process, prevent premature drug release, and facilitate the liberation of active drug at the target. Critical aspects of linker chemistry include the functionality that allows conjugation to antibody, the mechanism for drug release, and the physical properties of the linker itself. Ultimately the optimal combination of linker and conjugation chemistry must be uniquely tailored to correlate each unique facet: the targeting moiety or antibody, the drug molecule, and the profile of the disease to be treated. The greatest advantage of using non-cleavable linkers is their increased plasma stability when compared to many chemically labile linkers (see Non-cleavable linkers section). Despite the limited “bystander” effect, the resistance to cleavage outside of target cells may actually increase the specificity of drug release. One proposed mechanism for the decreased efficacy of non-cleavable linked ADCs is that drugs bearing charged amino acids suffer from decreased membrane permeability, limiting their ability to kill nearby cells. A major motivation for employing cleavable linkers is to improve this “bystander” effect.” Overall, enzymatically cleavable linkers (i.e., Val-Cit-PAB) provide antibody drug conjugates with plasma stabilities comparable to that of non-cleavable linkers while boasting a more defined method of drug release compared to disulfide-linked or acid-labile linkers (see Enzymatically cleavable linkers section). The ability to pair these linkers with self-immolative chemical groups (i.e., PAB) bestows the release of free drugs with minimal derivation; the main constraint being the requirement for the drug to bear an amine or hydroxyl group to conjugate with PAB. The selection of linker should depend on the application and conditions a given antibody is likely to encounter. The basic criteria for selecting the ADC payload are solubility, amenability to conjugation, and stability (see Payload section). Lipophilic drugs readily pass cell membranes and therefore have a greater potential to escape the lysosome after release. Conversely, a potential payload must be sufficiently soluble to allow for conjugation to the antibody in aqueous buffers as high concentrations of organic solvent lead to antibody scaffold denaturing. The low solubility of many candidate payloads may be balanced by hydrophilic linkers, such as those containing sulfonates or poly(ethylene glycol), allowing for higher DAR than hydrophobic linkers such as SMCC. Many potent drugs lack chemically functional handles that are necessary for conjugation. Modification to incorporate such handles can have deleterious effects on drug action. Likewise, conjugated drugs that are not released as the free, parent form may suffer decreased efficacy as is often seen when paired with non-cleavable linkers. Self-immolative linkers such as PAB facilitate the release of appended drugs back to the original unconjugated form; however, the PAB moiety itself is hydrophobic and may limit the use of certain payloads. As with solubility, a balance must be found between amending candidate drugs to allow conjugation and maintain efficacy. Following conjugation, the payload must remain stable in circulation, through cellular processing and release, to reach the cytosolic target. Su, et al., teaches the specific components of the linker which determine both efficacy and adverse effects of targeting drug conjugates or ADCs:
PNG
media_image3.png
259
693
media_image3.png
Greyscale
(Su, et al., Acta Pharm Sin B, 2021, 11, 3889-3907, see Abstract and Fig 1). Additionally, it is noted that there are a variety of self-immolative spacers (i.e., for use in cleavable linkers to release a payload from an antibody for example) inclusive of 1,4-, 1,6-, or 1,8-Elimination or cyclization, which can be triggered by chemical reagents, enzymes, or light, which each exhibits a wide scope of kinetic properties which affects the temporal and spatial delivery of a payload (Alouane, et al., Angew Chem, 2015, 54, 7492-7509, see entire document).
Furthermore, the prior art has recognized that antibodies in antibody drug conjugates require internalization to be effective drug vehicles. Chalouni teaches antigen binding, the anti-tumor potency of cytotoxic drugs and the favorable pharmacokinetic profile of the antibody are critical for the function of the ADC (Chalouni, et al., J Exp Clin Canc Res, 2018, 37, 1-12, herein referred to as “Chalouni”, see p 3, left column, ¶3). In addition, Chalouni teaches the efficacy of an ADC also relies on its internalization and processing, the release of the drug from the intracellular compartment to the cytosol and binding to its intracellular target to trigger cell death (p 3, left column, ¶3). Specifically, Chalouni teaches that ADC trafficking and processing in a classic model wherein: The ADC 1) binds to its surface antigen and 2) the complex is internalized, 3) it reaches lysosomes where its linker of the ADC is degraded leading to the release of the drug, 4) the drug passes from the intracellular compartment to the cytosol, and 5) binds to its target, DNA or tubulin resulting in apoptosis (Fig. 1b) and/or after release of the drug in the cytosol that the drugs may also be 6) effluxed into the microenvironment via pumps or passive transfer through the cell membrane and 7) enter a neighbor cancer cell resulting in the bystander effect (Fig. 1c).
The prior art further teaches that antibody drug conjugates can have unpredictable effects when combined, wherein the drug can affect antibody trafficking. Chalouni teaches that while the design of an ADC may rely on features specific to the trafficking of the parent antibody, this strategy can be challenging as the addition of a drug can result in subtle differences in these antibody properties such as preventing or inducing the internalization of a construct as seen for anti-CD19 antibody (p 4, left column, last paragraph).
Thus, antibody internalization is a requirement for an effective ADC and drugs may cause unpredictable effects on ADC internalization. Therefore, any antibody would not be expected to lead to an effective ADC.
Accordingly, the skilled artisan would be unable to envisage the ADC construct a priori given the current state of the ADC arts.
Description of representative species in the specification:
MPEP § 2163 states that “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.
To support such broad claims, the specification teaches the relative NFkB activation of four synthesized TLR7 and TLR8 agonists (i.e., E66, E75, E104, and E136) compared to four known agonists (i.e., GardiquimodTM, motolimod, imiquimod, resiquimod) and, of the eight tested compounds, E104, resiquimod, and E66 were the most effective at NFkB activation (Fig 1A). In this instance, E66, E75, and resiquimod meet the limitations of R1 in Formula (I), but do not meet the limitations of Z1 in Formula (I) and although E136 meets the limitations of Z1 of Formula (I), per the discussion supra that hydroxy is not inclusive in an oxaalkyl group, it does not meet the limitations of R1 in Formula (I), which leaves E104 as the only imidazoquinoline derivative compound that meets all claim limitations.
PNG
media_image4.png
102
65
media_image4.png
Greyscale
PNG
media_image5.png
135
81
media_image5.png
Greyscale
PNG
media_image6.png
122
74
media_image6.png
Greyscale
PNG
media_image7.png
139
88
media_image7.png
Greyscale
PNG
media_image8.png
379
255
media_image8.png
Greyscale
The specification teaches four different antibodies conjugated to E104 via two different linker constructs (¶0346). Specifically, the anti-RSV, anti-TROP2, anti-HER2, and anti-GCC antibodies are conjugated to either mcValCitPABC_E104 (i.e., comprising maleimide as a conjugation moiety, Val-Cit-PABC self-immolative spacer or a cleavable linker, and E104) or mc_E104 (i.e., comprising maleimide as a conjugation moiety,
PNG
media_image1.png
46
70
media_image1.png
Greyscale
or a non-cleavable linker, and E104)
(i.e.,
PNG
media_image9.png
174
327
media_image9.png
Greyscale
or
PNG
media_image10.png
176
163
media_image10.png
Greyscale
, respectively). In this instance, given the immense breadth of cleavable and non-cleavable linkers as described above as well as the immense breadth of antibodies used in ADCs, such a disclosure would not reasonably be considered representative of the genus: an ADC, which is only described by one out of three components (i.e., the drug is structurally defined, while the linker and antibody are functionally defined).
Identifying characteristics and structure/function correlation:
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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.
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017). In Amgen v. Sanofi, the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e., the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it. As such, knowledge of where an antibody binds provides no information as to what such an antibody necessarily looks like (i.e., its primary amino acid structure).
To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claim that essentially any cleavable or non-cleavable linker and essentially any antibody is biologically effective.
With regards to the full ADC construct, Example 32, Fig 16, and Fig 17 teach the anti-RSV, anti-TROP2, anti-HER2, and anti-GCC antibodies conjugated to either mcVALCitPABC_E104 or mc_E104
(i.e.,
PNG
media_image9.png
174
327
media_image9.png
Greyscale
or
PNG
media_image10.png
176
163
media_image10.png
Greyscale
, respectively) and their NFkB activation in coculture with A549 (NSCLC) or BXPC3 (pancreatic cancer) cells. The specification teaches that anti-Trop2 and anti-GCC ADCs and presumably the anti-RSV ADC (i.e., absorbance > 0.2 at 630 nm) of the mcValCitPABC_E104 constructs are able to stimulate macrophages in the presence of A549 cells or BXPC3 cells at a concentration of 30 μg/mL (i.e., the highest concentration); however, it appears that stimulation by any of the ADC constructs with mc_E104 is negligible (i.e., 0.1 absorbance at 630 nm) in the presence of A549 cells and minimal (i.e., slightly less than 0.2 absorbance at 630 nm) in the presence of BXPC3 cells at a concentration of 30 μg/mL (i.e., the highest concentration). In this instance, the differences in NFkB activation in the presence of different cancer cell lines, highlights how different antigen targets (i.e., antibodies) and linker constructs (cleavable vs non-cleavable) affect functionality, for example anti-HER2_mcValCitPABC_E104 was less effective in activating NFkB compared to the other three ADC constructs, but still more effective than any of the antibody_mc_E104 ADC constructs. Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the artisan cannot envision the detailed structure of the encompassed linkers and antibodies or fragments thereof.
Therefore, the specification provides neither a representative number of the encompassed linkers and antibodies of the ADCs, nor does it provide a descriptive of structural features that are common to the encompassed ADCs and thus the Applicant was not in possession of the instant claimed invention.
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 1-2, 4-5, 7, 10, 12-13, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over US 2016/0324983 (Li, et al., 10NOV2016, included in IDS), herein referred to as “’983” and in view of US 2014/0141033 (Vernejoul, et al., 22MAY2014, included in IDS), herein referred to as “’033” and US 2019/0151462 (Coffman, et al., 23MAY2019, included in IDS), herein referred to as “’462.”
‘983 teaches TM-L-AM constructs, wherein TM is a targeting moiety, L is a linker, and AM is an activating moiety that is capable of activating human immune cells, including but not limited to dendritic cells, macrophages, monocytes, myeloid-derived suppressor cells, NK cells, B cells, T cells, or tumor cells, or a combination thereof (¶0012). Furthermore, the AM is represented by the structure of:
PNG
media_image11.png
125
123
media_image11.png
Greyscale
, wherein the line from R1 represents the point to be connected to the linker (¶0126). Specifically, ‘983 teaches, the AM comprises imidazoquinoline derivatives represented by the structure:
PNG
media_image12.png
186
130
media_image12.png
Greyscale
, wherein R is -NH(R5), R5 is
PNG
media_image13.png
88
127
media_image13.png
Greyscale
wherein x is any integer from 1-10 and R8 is a peptide antigen moiety or a protein antigen moiety (i.e., TM) (¶0130) and pharmaceutical formulations thereof comprising the compounds and one or more pharmaceutically acceptable carriers (¶0270). ‘983 teaches that the TM binds to a tumor cell specifically or preferably in comparison to a non-tumor cell (¶0019) wherein exemplary targeting agents include antibodies (e.g., chimeric, humanized, and human) and antibodies may include antibody fragments, bispecific antibodies, or other antibody-based molecules (¶0136-0137). Furthermore, conjugation of a TLR7 and/or TLR8 agonist (i.e., AM) results in activation of T cells, NK cells, B cells, and myeloid DCs (¶0118) localized to the targeted antigen. ‘983 also teaches that ADCs have direct and indirect anti-cancer effect, wherein the antibody blocks or activates ligand/receptor signaling, induces apoptosis, and at the same time can present or deliver payload drug directly or indirectly (such as a drug, toxin, small interfering RNA or radioisotope) to the tumor cells (¶0011). Furthermore, therapeutic antibody drug conjugate utilizes dual characteristics of the antibody and the coupled drug, first is the binding function that it specifically binds to the target molecule, second is the tumor cell killing function of the antibody itself, and the third is the particular effect of the conjugated drug (¶0011). Current antibody-drug conjugates drugs are limited in how to kill tumor cells directly and because of the tough requirement of technologies in antibody, linker molecule, toxin molecules, and conjugation, as well as the limitation of bringing toxins within the tumor microenvironment molecules, resulting in the invention disclosed within (i.e., a construct which is able to target the tumor microenvironment and activate human immune cells) (¶0011-0012).
However, they do not teach: the compound of Formula (I), wherein Z1 is -NH rather than CH2NH and the antibody is anti-TROP2.
Nevertheless, ‘033 teaches conjugated compounds that mutually activate TLR7 and/or TLR8 and TLR2 receptors of the innate immune system (¶001). One of said compounds is CL552 having the structure of:
PNG
media_image14.png
184
286
media_image14.png
Greyscale
(¶0172), which comprises intermediate 39 having the structure:
PNG
media_image15.png
149
187
media_image15.png
Greyscale
, wherein the amino group (i.e., NH2 in the box of intermediate 39) was reacted with a carboxylic acid group (i.e., R-COOH) via peptide synthesis known in the art (¶0238) to form an amide bond (i.e., structure in the box of CL552).
Additionally, ‘462 teaches antibody-based cleavable conjugates of TLR7/8 agonists or imidazoquinoline derivative compounds comprising a conjugation moiety, a cleavable linker, and a self-eliminating linker, methods of preparation, uses for stimulating an effective immune response for the treatment of cancer (Abstract). Specifically, ‘462 teaches Toll-like Receptor 7/8 agonist compounds that are covalently conjugated to an agent, for example a tumor-specific targeting agent or a tumor microenvironment specific antigen antibody or a tumor cell surface marker antibody (i.e., TROP2), via a cleavable linker moiety to promote local release and/or local retention of a bioactive form of the TLR7/8 agonist, and reduce unwanted systemic pro-inflammatory cytokine responses (¶0002 and ¶0440).
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 ADC comprising a TLR7/TLR8 conjugate disclosed by ‘983 by utilizing a derivative of the TLR7/TLR8 conjugate and an anti-TROP2 antibody as disclosed by ‘033 and ‘462 because, the TLR derivative is able to also bind to TLR2 and because anti-TROP2 is a tumor cell surface marker, which allows for targeted delivery or the TLR conjugate for enhancing immune response. One would have been motivated to do so, given the teachings of ‘983 that the by conjugating a targeting moiety with a TLR7/8 agonist, one would be able to effectively activated human immune cells, including but not limited to dendritic cells, macrophages, monocytes, myeloid-derived suppressor cells, NK cells, B cells, T cells, or tumor cells, or a combination thereof in a tumor environment. There would have been a reasonable expectation of success, given the knowledge that the amine group of Intermediate 39 (i.e., TLR7 and/or TLR8 and TLR2 agonist) was able to be modified by a carboxylic acid group utilizing known peptide synthesis chemistry as taught by ‘033, such as the COOH/linker/maleimide construct of ‘983 and because anti-TROP2 is a known tumor-associated cell surface protein that is overexpressed in certain cancers as taught by ‘462 to promote local release and/or local retention of a bioactive form of a TLR7/8 agonist, and reduce unwanted systemic pro-inflammatory cytokine responses
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
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, Misook Yu can be reached at (571)272-0839. 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.
/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights