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 .
Applicant’s amendment, filed on 4/14/2026, is acknowledged.
Claims 1-13 are currently pending.
Claim 1 is the only independent claim.
Election/Restrictions
Applicants’ election without traverse of Group I, claims 1-8, directed to a prodrug comprising an effector molecule and a protecting group, filed on 4/14/2026, is acknowledged.
Claims 9-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
Claims 1-8 are under examination as directed to a prodrug comprising an effector molecule and a protecting group.
Priority
Applicant’s claim for the benefit of a prior-filed U.S. Provisional Patent Application No. 63/162,208, filed on March 17, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/14/2024 and 8/15/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in their entireties.
Claim Interpretation
The instant specification discloses generation of “allosteric antibodies”. The instant specification discloses “allosteric antibodies” as antibodies that have been modified to not bind to its antigen unless it is in the presence of a small molecule that restores antigen binding (pg. 9-10):
“Allosteric antibodies which can be bound by the effector molecules of the instant invention to increase or restore the binding activity of the allosteric antibody… The use of the effector molecule allows for spatial and/or temporal control of the activity (e.g., antigen binding) of the antibody”
For the purposes of examination, the term “allosteric antibody” has been interpreted to be an activatable antibody that has reduced binding to its cognate antigen until an effector molecule binds to an allosteric site on the antibody to restore antigen binding.
Claim Rejections - 35 USC § 112
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 1-8 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 applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
Claims 1-3 and 5-7 encompass a broad genus of substrates with no recited structure and the function of “substrate for a cleaving enzyme” (claims 1 and 5-7), an enzyme upregulated in the tumor microenvironment (claim 2), or a substrate for cathepsin B (claim 3).
Claims 1-5 and 8 encompass a broad genus of linkers with no recited structure and the function of “self-immolating linker”.
Claims 1-4, 6, and 8 encompass a broad genus of effector molecules with no recited structure and the function of “binds an allosteric antibody and increases or restores its binding activity”.
However, the specification fails to provide adequate written description support for a genus of substrates with little to no recited structure and the function of “substrate for a cleaving enzyme”; a genus of linkers with little to no recited structure and the function of “self-immolating linker”; or a broad genus of effector molecules with little to no structure and the function of “binds an allosteric antibody and increases or restores its binding activity”.
The claims are not supported by a description that satisfies 35 U.S.C. § 112(a) or 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Phanns., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).
A "sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Id. at 1350. "[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.
"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Id.
"A sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
Regarding the broadly claimed genus of substrates with the function of “substrate for a cleaving enzyme” (claims 1-3 and 5-7), the instant specification discloses different types of peptide sequences that act as substrates for different proteases (Table 1):
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One example each of a substrate that is cleaved by β-glucuronidase, β-galactosidase, and DT diaphorase (NQO1) are also disclosed (Fig 1D).
One working example of an enzyme cleavable substrate as part of a prodrug was disclosed, which is the Val-Cit dipeptide sequence that is recognized and enzymatically cleaved by cathepsin B (Example 1, Fig. 1, annotated below):
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Regarding the broadly claimed genus of linkers with no recited structure and the function of “self-immolating linker” (claims 1-5 and 8), the specification discloses that self-immolative linkers have the general function of reacts to self-cleave after an activating event (pg. 4): “[a] self-immolating linker (also known as a self-immolative linker) is a linker that upon some activation event…results in a reaction (typically a cascade of reactions) which results in the removal of the linker from another group (e.g., effector molecule), leaving no residual atoms on the other group…”
The only example of a self-immolative linker that is disclosed is p-aminobenzyloxycarbonyl (PAB), which is also the only working example of a structure with this function (Fig. 1, annotated below):
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Regarding the broadly claimed genus of effector molecules with no recite structure and the function of “binds an allosteric antibody and increases or restores its binding activity”, the instant specification discloses that effector molecules are designed to fit into an engineered “allosteric antibody” that does not fold into a functional antibody unless bound by the effector molecule (pg. 3 and 4): “…the instant invention describes allosteric antibodies and prodrugs of effector molecules which 1) bind the allosteric antibody and increase or restore the binding activity of the allosteric antibody, and 2) have tumor environment selectivity.”
The instant specification further discloses that specific effector molecules need to have a specific structure to work with an allosteric antibody (pg. 4): “[e]ffector molecules such as JK43 (also known as Stitch3) bind to a fully-enclosed site of the allosteric antibody. As such, modest or even minor perturbations to the shape can completely abrogate rescue of the allosteric antibody…”
The instant specification discloses one example of an effector molecule, JK43 or Stitch3, that can specifically bind to an engineered pocket in an scFv with a specific triple mutation in the framework region (Example 1, pg. 23-24): “…a triple-mutant antibody (SGS 3 'M (Rip3) - the SGSWT scFv with the triple mutation (VLF98G/VHV37A/VHW110G)…[a]s seen in Figure 2, the addition of Stitch3 rescues the activity of the triple mutant scFv variant (Rip3)”.
With respect to representative number of species, see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014). Also, see MPEP 2163 Il(A)(3)(a))(ii):
A representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See Abb Vie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
Regarding the broadly claimed genus of substrates with the function of “substrate for a cleaving enzyme” (claims 1-3 and 5-7), the small number of examples does not sufficiently represent the broadly claimed genus of substrates with any structure with the recited functions. For example, the instant claims encompass non-peptide structures that can serve as enzyme cleavable substrates, however there are no representative species of such substrate structures disclosed, and how to determine which enzymes cleave such substrates. Furthermore, regarding peptide substrates that are cleaved by proteases such as cathepsin B, there is no guidance in the instant specification nor the prior art to allow one with ordinary skill in the art to determine which peptide structures other than the ones disclosed would be cleaved by cathepsin B, or how to distinguish peptide with this function from ones without.
Regarding the broadly claimed genus of linkers with no recited structure and the function of “self-immolating linker” (claims 1-5 and 8), the one disclosed example of a PAB self-immolative linker does not sufficiently represent the claimed genus of linkers with no recited structure and the function of “self-immolative linker or bond”, which encompasses any structure with the recited function.
Regarding the broadly claimed genus of effector molecules with no recite structure and the function of “binds an allosteric antibody and increases or restores its binding activity”, the instant specification discloses one specific example of an effector molecules, stitch3, that will only act with a specific type of modified scFv with a triple mutation in the framework region. This one specific effector molecule that binds to a specific modified scFv does not sufficiently represent the broadly claimed genus of effector molecules of any structure that increases/restores binding activity of any allosteric antibody structure.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed substrates, linkers, and effector molecules to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the broadly claimed classes of substrates, linkers, and effector molecules, and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed classes of substrates, linkers, and effector molecules, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163.
Regarding the broadly claimed genus of substrates with the function of “substrate for a cleaving enzyme” (claims 1-3 and 5-7), the instant specific discloses that different proteases will recognize and cleave specific peptide sequences (Table 1), however neither the instant specification nor the prior art provides sufficient guidance to determine a structure function relationship between a substrate’s structure (which can also be non-peptide structures) and the function of “substrate for a cleaving enzyme”, other than listing specific examples of peptide structures with this function. Undue experimentation would be required by one with ordinary skill to determine what other substrate structures, include peptides and non-peptide structures, would retain the ability to be cleaved by enzymes such as cathepsin B.
Regarding the broadly claimed genus of linkers with no recited structure and the function of “self-immolating linker” (claims 1-5 and 8), the instant specification discloses one example of a self-immolative linker, which is PAB (Fig. 1). Neither the instant specification nor the prior art provides sufficient structure-function relationship between a linker’s structure and the function of “self-immolative linker or bond”.
For example, Xu et al. (Eur J Med Chem. 2024 Dec 5;279:116928. doi: 10.1016/j.ejmech.2024.116928. Epub 2024 Sep 30) teaches principles of design of self-immolative linkers used in prodrugs (Section 2): “[a]t the heart of the design of self-immolative prodrugs lies the incorporation of a trigger moiety, a chemical entity that initiates the cascade of decomposition reactions leading to drug release…the trigger moiety must be carefully tailored to ensure selective activation within the target tissue while minimizing off-target effects… the design of self-immolative prodrugs encompasses the selection of appropriate drug payloads and linker chemistries to achieve optimal pharmacokinetic and pharmacodynamic properties”. Xu et al. further teaches that specific self-immolative linker structures differ based on the cleavable substrate that they are incorporated in and the specific payload/therapeutic that is used. For example, different self-immolative linkers have been found to function in cathepsin-B cleavable prodrugs based on the drug that is intended to be released (Section 4.2.1, Fig. 1), while PABC has been found to act as a self-immolative linker in MMAE-based prodrugs (Section 4.2.3, Fig. 2). Thus, undue experimentation would be required by one with ordinary skill in the art to determine which structures in the broadly claimed genus would have the function of “self-immolative linker”, or how to distinguish between structures with this the function and those without.
Regarding the broadly claimed genus of effector molecules with no recite structure and the function of “binds an allosteric antibody and increases or restores its binding activity”, the instant specification nor the prior art provides sufficient structure-function relationship between an effector molecule’s structure and the function of “binds an allosteric antibody and increases or restores its binding activity”. In fact, the instant specification discloses that even minor alterations to an effector molecule’s structure can abolish its function (pg. 4): “[e]ffector molecules such as JK43 (also known as Stitch3) bind to a fully-enclosed site of the allosteric antibody. As such, modest or even minor perturbations to the shape can completely abrogate rescue of the allosteric antibody…”
Additionally, the prior art teaches that there are specific pairings of activatable antibodies and the small molecules that restore the antibody’s specific binding capabilities. Khowsathit et al. (ACS Cent Sci. 2020 Mar 25;6(3):390-403. doi: 10.1021/acscentsci.9b01065. Epub 2020 Mar 11) teaches that a specific triple mutation (VLF98G/VHV37A/VHW110G) in the framework of an scFv molecule creates a cavity that prevents the VH and VL from forming a functional scFv unless the specific small molecule stitch-3 is present to bind to the engineered cavity (Fig. 1):
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Khowsathit et al. further teaches that even slight alterations to the stitch-3 molecule can abolish the function, as the stitch-3 molecule needs to be complementary to the engineered pocket that was formed in the engineered scFv (Fig. 4):
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Khowsathit et al. additionally teaches that this Stitch-3 activatable switch via three point mutations in the variable framework regions can only be applied to other scFvs that share a specific type of structural similarity (pg. 397, emphasis added): “[t]o test the transferability of our design, we selected from this group another antibody with readily assayed activity… the framework regions of 4D5Flu and 8B10 are very different: they share only 56% sequence identity (Figure S5b). Unsurprisingly, given their different antigens and origins, the CDR loops in these two antibodies differ in both their lengths and their conformations. Despite these differences, however, both share the precise arrangement of the residues comprising the Rip-3 constellation (Figure 5b), suggesting that 8B10 could also be modulated using precisely the same Rip-3/Stitch-3 pairing… our characterization of the Rip-3/Stitch-3 pair in the context of 4D5Flu allowed us to rapidly generate an analogous switch in an unrelated antibody framework, by virtue of the structural conservation of the mutated constellation. These results confirm that this mutation/ligand pairing is indeed transferrable, provided that the target antibody framework harbors these conserved residues in precisely the same geometry as in 4D5Flu.”
Khowsathit et al. further teaches that there is uncertainty that antibody formats other than a scFv would also be able to be engineered to be an activatable antibody due the presence of the constant regions (pg. 398, emphasis added): “…we have not extended testing of the Rip-3/Stitch-3 pairing beyond the scFv format and, thus, cannot yet confirm applicability to a Fab (or IgG) context. We anticipate that, in such a context, the dissociated (mutant) variable domains may be more restricted by the presence of the constant regions: this, in turn, may lead to retention of higher background in the absence of Stitch-3. While further studies are undoubtedly necessary to define the applicability of the Rip-3/Stitch-3 pairing in this setting, we expect that this constraint will behave in a manner analogous to an scFv with intrinsically strong VH/VL interaction…”
Thus, the prior art teaches that the relationship between an “allosteric antibody” and an effector molecule that can activate the allosteric antibody (i.e., “binds an allosteric antibody and increases or restores its binding activity”) is a precise relationship between an engineered scFv that has conserved variable framework regions that have a specific geometry, which can be substituted with other residues to introduce a cavity that blocks the scFv formation into a functional antibody unless a particular small molecule structure that mimics the precise structure that was eliminated from the scFv binds and restores proper VH and VL pairing (see Fig. 1 supra). Due to this specific relationship between the structure of an effector molecule and the function of restoring an allosteric antibody’s function, undue experimentation would be required by one with ordinary skill in the art to generate other effector structures that increase the activity of any “allosteric antibody” regardless of structure or how that allosteric antibody was generated.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of substrates, linkers, and effector molecules thereof falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 1-8 do not meet the requirements of 35 U.S.C. 112(a) for written description.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
To resolve this issue, it is recommended to amend claim 1 to recite specific substrates, linkers, and effector molecule structures that have the recited functions (i.e., the one working example of a prodrug that is disclosed, which is stitch-3 bound to Val-Cit via a PAB linker; wherein stitch-3 binds to an allosteric antibody comprising the VLF98G/VHV37A/VHW110G triple mutation). This includes the enzyme that cleaved the recited substrate, given that specific peptide sequences are cleaved by specific enzymes. This also includes the allosteric antibody structure that the effector molecule restores activity to, given that specific effector molecules will only restore binding activity to specific scFv structures that have an engineered cavity via the introduction of point mutations.
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 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Khowsathit et al. (ACS Cent Sci. 2020 Mar 25;6(3):390-403. doi: 10.1021/acscentsci.9b01065. Epub 2020 Mar 11, supra) in view of Dubowchik et al. (Bioconjug Chem. 2002 Jul-Aug;13(4):855-69. doi: 10.1021/bc025536j), as evidenced by Pubchem CID11535911 (pubchem.ncbi.nlm.nih.gov/compound/11535911).
Claim 1 encompasses a prodrug comprising an effector molecule that binds to an allosteric antibody, and an enzyme cleavable substrate linked to the effector molecule by a self-immolating group.
Khowsathit et al. teaches the development of a scFv (Rip-3) with cavity forming amino acid substitutions in the VH and VL framework regions that inactivates the scFv unless an effector ligand (Stitch-3) is present (Fig. 1A):
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Khowsathit et al. used a computational modeling strategy to identify this designs of scFv cavity-forming mutations and small molecules that fit into said cavity from hundreds of millions of potential candidates (Results, Fig. 1B):
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Khowsathit et al. further teaches that the Stitch-3 compound successfully activates the mutated Rip-3 scFv to restore antigen binding to its antigen fluoresceine in a dose-dependent manner (Fig. 2A):
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Khowsathit et al. teaches an effector molecule that binds an allosteric antibody and increases it binding activity.
Khowsathit et al. further teaches (Discussion): “…were determined to create a robust and transferrable allosteric antibody switch, that can be selectively activated using a bio-orthogonal ligand with druglike physicochemical properties… we acknowledge that inducing antigen-recognition through binding of Stitch-3 is not itself sufficient for selectively activating an antibody in a specific microenvironment, such as in the vicinity of a tumor. In contrast to an antibody that responds directly to a selected stimulus (e.g., the presence of matrix metalloproteases found in the tumor microenvironment), the modularity of our strategy allows for the future design of many diverse responsive derivatives. In particular, drawing from the fact that Stitch-3 is completely enclosed in the Rip-3 cavity, and the fact that our SAR studies demonstrate that rescue is sensitive to the exact complementarity of the ligand for this cavity, one can easily envision a broad set of labile handles that might be attached to Stitch-3 to prevent activity until triggered by the intended stimulus. We expect that the wealth of extant knowledge in designing prodrugs for activation in highly specific in vivo environments can now begin to be applied for controlling antibody activity.”
Khowsathit et al. does not teach the effector molecule in a prodrug format, wherein the effector molecule is linked to an enzyme-cleavable substrate through a self-immolating linker (i.e., the limitations of instant claim 1). However, Khowsathit et al. provides suggestion and motivation to make such an activatable prodrug to allow for site-specific restoration of antibody binding.
Dubowchik et al., in the same field of endeavor, teaches that the enzyme cathepsin B is ubiquitously expressed in lysosomes, however is found to be expressed extracellularly in pathological conditions such as metastatic cancer (Introduction): “[c]athepsin B is a ubiquitous
cysteine protease whose properties do not differ very much from species to species. It is never found extracellularly, except in pathological conditions such as metastatic tumors…”
Dubowchik et al. teaches that enzyme-activated prodrugs can be developed that link a cathepsin B cleavable peptide to a drug (in this case, doxorubicin) via a PABC self-immolating linker (Scheme 1):
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Dubowchik et al. teaches one of these prodrug moieties can be Z-Val-Cit-PABOH (pg. 857 and compound 22), and can be bound to drugs to generate Z-Val-Cit-PAB-Drug (pg. 859 and compound 42).
The Z-Val-Cit-PABC-drug prodrug was found to release the drug in the presence of both cathepsin B and in the presence of rat liver lysosomes in vitro, however no drug release was observed in human plasma in vitro (Table 2).
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the teachings of Khowsathit et al. in view of Dubowchik et al. to generate a Z-Val-Cit-PAB-Stitch3 prodrug that allows for site-specific cleavage of the prodrug at cathepsin B expressing tumor microenvironments (i.e., the limitations of instant claim 1), leading to binding of Stitch3 to a modified scFv such as Rip-3 and site-specific restoration of antibody binding with a reasonable expectation of success, as Dubowchik et al. teaches methods of binding Z-Val-Vit-PAB to drugs such Dox that one with ordinary skill in the art would be able to apply to Stitch3. One would have been motivated to make this change because Khowsathit et al. teaches that such prodrugs are required to prevent restoration of antibody binding at unwanted sites, leading to site-specific antibody binding. In this instance, given that the Rip-3 scFv binds to fluoresceine, this specific antibody-effector setup could be used in an in vitro proof-of-concept assay to determine if such a prodrug would be able to restore Rip-3 binding to fluoresceine only in the presence of cathepsin B.
Regarding claim 2-4, Dubowchik et al. teaches that cathepsin B is upregulated in metastatic tumor sites, and the Val-Cit dipeptide is cleaved by cathepsin B, meeting the claim limitations.
Regarding claim 5, Pubchem CID11535911 is provided as an evidentiary reference that the Stitch3 compound is 6-phenylmethoxy-1H-indazole (Sections 2.1.1 and 1.1), meeting the claim limitations:
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Regarding claims 6-8, the self-immolating Val-Cit-PAB linker taught by Dubowchik et al. has the p-aminobenzyl self-immolating linker (“PAB”), and comprises Val-Cit. The combined references teach Z-Val-Cit-PAB-Stitch3 (supra), meeting the claim limitations.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 12,465,637 (Pat ‘637) in view of Khowsathit et al. (ACS Cent Sci. 2020 Mar 25;6(3):390-403. doi: 10.1021/acscentsci.9b01065. Epub 2020 Mar 11, supra) and Dubowchik et al. (Bioconjug Chem. 2002 Jul-Aug;13(4):855-69. doi: 10.1021/bc025536j, supra).
Pat ‘637 claims effector molecules such as 6-phenylmethoxy-lH-indazole (claim 19) that bind to allosteric antibodies to restore their activity (claim 1).
Pat ‘637 does not teach the effector molecule in a prodrug format, wherein the effector molecule is linked to an enzyme-cleavable substrate through a self-immolating linker (i.e., the limitations of instant claim 1).
Khowsathit et al. provides suggestion and motivation to make such an activatable prodrug to allow for site-specific restoration of antibody binding (Discussion): “…were determined to create a robust and transferrable allosteric antibody switch, that can be selectively activated using a bio-orthogonal ligand with druglike physicochemical properties… we acknowledge that inducing antigen-recognition through binding of Stitch-3 is not itself sufficient for selectively activating an antibody in a specific microenvironment, such as in the vicinity of a tumor. In contrast to an antibody that responds directly to a selected stimulus (e.g., the presence of matrix metalloproteases found in the tumor microenvironment), the modularity of our strategy allows for the future design of many diverse responsive derivatives. In particular, drawing from the fact that Stitch-3 is completely enclosed in the Rip-3 cavity, and the fact that our SAR studies demonstrate that rescue is sensitive to the exact complementarity of the ligand for this cavity, one can easily envision a broad set of labile handles that might be attached to Stitch-3 to prevent activity until triggered by the intended stimulus. We expect that the wealth of extant knowledge in designing prodrugs for activation in highly specific in vivo environments can now begin to be applied for controlling antibody activity.”
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘637 in view of Khowsathit et al. and Dubowchik et al. for the same reasons discussed in the 35 U.S.C. § 103 rejection supra.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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