DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendments filed 08/22/2025 are acknowledged.
Claims 4, 6, 14-26, 29-30 and 34-41 are cancelled.
Claims 1-3, 5, 7-13, 27-28, 31-33 and 42 are pending and currently under consideration.
Claims 1 and 13 are independent claims. Claims 2-3, 5, 7-12, 31-33 and 42 depend from claim 1. Claims 27 and 28 depend from claim 13.
3. 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 371 of PCT/US2020/043900 filed 07/28/2020, which claims benefit of US provisional applications 63/001,136 filed 03/27/2020 and 62/880,014 filed 07/29/2019. Claims 1-3, 5, 7-13, 27-28, 31-33 and 42 have an effective filing date of 07/29/2019.
4. In view of applicant’s amendments, the previous rejection of claims 27 and 28 under 35 U.S.C. 112(b) is withdrawn because the newly amended claim set corrects for the prior lack of antecedent basis.
5. In view of applicant’s amendments, the following rejections are set forth.
Claim Rejections - 35 USC § 112
6. 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.
7. Claims 1-3, 5, 7-13, 27-28, 31-33 and 42 remain 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.
These claims stand rejected for essentially the same reasons outlined in the office action mailed 03/27/2025. Briefly, the instant claims are drawn to method of inducing Notch signaling in a tumor microenvironment comprising the administration of a bi-specific molecule comprising a cell-targeting domain that binds to a specific antigen of CD33, CD326, CD133 or mesothelin, AND a Notch-binding domain. As stated in the previous rejection, these claims are drawn to a genus of “bi-specific” molecules for which there is inadequate written description. Also outlined in the previous office action, the specification merely references only one specific species of a bi-specific protein that combines Notch ligand Delta 4 with an anti-CD33 molecule, which was disclosed in a previous prior art document (WO 2018/017827) (see specification pg. 4, last ¶ and the schematic on figure 2). Regardless of the breadth of the instant claims in regards to the bispecific molecule, it means little to invent a method if one does not have possession of the compound that is essential to practice the method. Without possession of the compound(s), there is no meaningful possession of the method.
8. Applicant's arguments filed 08/22/2025 have been fully considered but they are not persuasive.
Applicant argues that the guidance provided in the current disclosure, which consists of prior art teachings, including those of Bernstein et al (of record) are sufficient to show that the current inventors had possession of the method recited in the amended claims. Specifically, applicant argues that amended claims 1 and 13 limit the genus of claimed bi-specific agents to include only those with well-known cell-surface molecules for which antibodies or antigen binding agents have been previously developed and are well known in the art (CD33, CD326, CD133 or mesothelin) (remarks pg. 10, ¶ 1-3). The applicant also argues that the amendment reciting “wherein the Notch-binding domain comprises an extracellular domain of a Notch receptor ligand” further limits the genus of claimed agents (remarks pg. 10, ¶ 1-3). Based on these amendments, the applicant argues that the claimed cell-specific antigens and extracellular domains of Notch receptor ligands are well known in the art and that the disclosure of one single species suffices the written description requirement.
This was found to be unpersuasive because for the following reasons.
To begin, the instant amendments do not meaningfully limit the genus of bi-specific agents. Each of the cell-specific antigens recited in the bi-specific compound of the instant methods are highly divergent cell-specific markers that do appear to be interchangeable species, nor do they have any meaningful overlap with regards to function or conceptual role within the tumor milieu. For instance, CD33 is well known cell marker for hematopoietic cells (myeloid cells, monocytes, etc.,) while CD326 (EpCAM) is a marker for epithelial tissue; these markers are even used to differentiate between cell types in cancer screening (see abstract of Acosta et al. Cytometry B Clin Cytom. 2016 May;90(3):289-94. PMID: 26054018).
Regarding the amended limitation drawn to the “extracellular domain of a Notch receptor ligand”; this amendment does not sufficiently limit the genus of agents. As previously noted in the prior rejection, Notch signaling and the necessitated receptor-ligand interactions are incredibly intricate. For instance, mammalian ligands are complex, comprising three members of the Delta family (DLL-1, -3 and -4) and two members of the Jagged family (J-1 and -2) and there are a large number of extracellular Notch receptor domains that are known in the art (for instance see section 3 of Chillakuri et al; Semin Cell Dev Biol. 2012 Jun;23(4):421-8. doi: 10.1016/j.semcdb.2012.01.009. PMID: 22326375; see also table 1 of Chillakuri et al).
The potential number of bi-specific molecules one could design is large considering the possible number of combinations and permutations of these domains. Regardless of which antigen binding domain and notch receptor domain is chosen, there is no way of predicting whether the two domains will work as a cohesive molecule. For instance, there is no way of knowing whether the binding affinity for antigen “X” is suitable for anchoring the bi-specific molecule in order to facilitate trans-binding on a neighboring cell “Y”. As BERNSTEIN teaches, Notch signaling cascade is initiated by ligand binding that specifically results in a conformation change, exposing an S2 cleavage site in extracellular domain of the Notch receptor—this conformational change results from a mechanical “tug” (see pg. 2 lines 4-9). In order to determine if the selected antigen binding domain is capable of the required opposing force or is capable of binding long enough to induce signaling in a neighboring cell, one of ordinary skill would have to make and test the molecule. Further, it is not clear what other structural features are required for each combination of binding domains, such as length or number of linker domains. Therefore, it is clear that there are a large number of combinations and permutations of the claimed bi-specific molecule; this provides a very large genus of bi-specific molecules and the instant specification only discloses methods of administering a single species of said bi-specific molecule comprising the Notch ligand Delta 4 (DLL-4) and the affinity reagent that binds to the cell surface marker CD33. Based on the content of the current disclosure, one of ordinary skill in the art would not be able to predict the outcome of administering any of the other bi-specific molecules presently claimed.
For these reasons, the applicant’s arguments were not found to be persuasive.
Claim Rejections - 35 USC § 102 (maintained)
9. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
10. Claims 1-3, 5, 7-13, 27-28, 31-33 and 42 stand rejected under 35 U.S.C. 102(a)(1) as being anticipated by BERNSTEIN et al (WO 2018017827 A1; of record) as evidenced by HOSSAIN et al (Front Immunol. 2018 Jun 4;9:1288. PMID: 29915603; of record).
Presently amended base claim 1 is recited as follows (amendments are underlined):
“A method of inducing Notch signaling in a tumor microenvironment in an aggregation of cells comprising a first cell-type that expresses a cell-specific antigen and a second cell-type that expresses Notch, comprising:
administering to the tumor microenvironment a bi-specific molecule comprising a
cell-targeting domain that specifically binds to the cell-specific antigen, wherein the cell-specific
antigen is CD33, CD326, CD133, or mesothelin, and a Notch-binding domain that specifically
binds to Notch, wherein the Notch-binding domain comprises an extracellular domain of a Notch receptor ligand;
contacting the aggregation of cells in the tumor microenvironment with the bi-specific molecule comprising the cell-targeting domain that specifically binds to the cell-specific antigen, wherein the cell-specific antigen is CD33, CD326, CD133, or mesothelin, and the Notch-binding domain that specifically binds to Notch, wherein the Notch-binding domain comprises an extracellular domain of a Notch receptor ligand,
wherein binding of the bi-specific molecule in the tumor microenvironment to the cell-specific antigen on the first cell of the first cell-type and trans-binding to Notch on the second cell of the second cell-type causes Notch signaling in the second cell.”
Presently amended base claim 13 is recited as follows (amendments are underlined):
“A method of promoting a pro-inflammatory state in a tumor microenvironment comprising a tumor cell and a non-tumor cell, the method comprising:
administering to the tumor microenvironment a bi-specific molecule that comprises a cell-targeting domain that specifically binds to a cell-specific antigen expressed by the tumor cell, wherein the cell-specific antigen is CD33, CD326, CD133, or mesothelin, and a Notch-binding domain, wherein the Notch-binding domain comprises an extracellular domain of a Notch receptor ligand, that trans-binds to Notch expressed by a non-tumor cell in the tumor micro-environment, thereby inducing Notch signaling in the non-tumor cell.”
Regarding the amended base claims 1 and 13, BERNSTEIN teaches the exact same bi-specific molecule disclosed in the instant application: a bi-specific molecule comprising cell targeting domain that binds CD33 and DLL4, a notch binding domain (e.g. pages 1 and 4, last ¶; see also Fig. 1A). As discussed above, the instant application discloses only one species of the bi-specific molecule.
BERNSTEIN teaches methods of using the bi-specific compound for modulating Notch signaling in a cell-type of interest (i.e., cancer or tumor cells); the methods comprise contacting the cell-type of interest with said bi-specific compound (specification pg. 5, ¶3).
BERNSTEIN teaches that administering the bi-specific molecule to a patient with cancer, the molecule is coming in contact with heterogenous aggregations of cells (see BERNSTEIN page 21, lines 29-33). BERNSTEIN teaches that Notch signaling is initiated when NECD binds to an appropriate ligand presented on the surface of an opposing cells (or neighboring cell) (see pages 1 and 2), therefore, the teachings of BERNSTEIN indicate that contacting a heterogenous population of cells (i.e., a tumor) would result in cis-binding events (CD33 and Notch ligands bound on the same cell) AND it would also result in trans-binding events where the molecule binds CD33 the targeted cancer cell and Notch on another cell (either cancer cell or not).
As evidenced by HOSSAIN, the activation of Notch signaling in immune cells promotes immune responsive state in the TME, including promoting macrophage differentiation to an M1 phenotype and secretion of IL-12 and enhanced tumor immunity (page 5, right column, second ¶). HOSSAIN also teaches Notch signaling, initiated by peptides from the DSL (Delta-Serrate-LAG1) receptor-binding region of Jagged1, promotes the maturation of monocytes into myeloid dendritic cells (DCs) (page 4, left column, first ¶). HOSSAIN also teaches that myeloid DCs stimulated concurrently with both Notch and TLR ligands have a distinct cytokine profile and are more pro-inflammatory compared with myeloid DCs stimulated with either ligand alone (page 4, right column, second ¶). HOSSAIN also teaches that Notch signaling promotes differentiation of immune cell precursors toward anti-tumor phenotypes in a dose dependent manner, including NK cells, macrophages and/or T cell lineages (page 4, left column, first ¶). Therefore, the teachings of HOSSAIN describe the induction of a pro-inflammatory state in the TME.
The methods of administering the bi-specific molecule to treat cancer, as taught by BERNSTEIN (described above) in view of the complexities of Notch signaling and intracellular crosstalk involved in pro-inflammatory state of the tumor microenvironment described by HOSSAIN anticipate instant claims 1 and 13.
The teachings of BERNSTEIN include compositions and methods of using the bi-specific molecule for modulating Notch signaling in a cell type of interest, including cancer cells and cancer progenitor cells (page 5, lines 9-20). The pharmaceutical compositions and methods taught by BERNSTEIN are directed to inhibiting the development of several types of cancer including breast, prostate, lung, colorectal, etc., which are commonly known to form tumors (e.g. page 24, lines 19-26). By teaching the therapeutic use of the bi-specific molecule, BERNSTEIN anticipates the additional limitations recited in claims 2-3, 5 and 7. The cells and ligands involved in a binding event are dependent on the spatial context of the binding event within the tumor milieu. For instance a molecule binding CD33 on a cancer cell neighboring another cancer cell would induce Notch signaling in the same cell type. If the molecule bound to CD33+ cancer cell neighboring a non-cancer cell expressing notch (e.g. an immune cell), the Notch signaling would be induced in a difference cell type. Therefore, claims 2-5 and 7 are anticipated by BERNSTEIN.
The prior art methods of administering the same bispecific molecule would inherently achieve the same results including e.g. wherein Notch signaling in the immune cell promotes an immune-responsive states in the tumor microenvironment as recited in claims 8-13, 27, 28, 31-33 and 42.
As discussed above the bi-specific molecule taught by BERNSTEIN is identical to the molecule of the present invention. For instance the Notch binding domains taught by BERNSTEIN are mammalian Notch receptor ligands, including high affinity variants of the extracellular domain of delta protein (DLL4) or Jagged protein (see BERNSTEIN claims 11-13). BERNSTEIN teaches the variations of functional domains comprised by the Notch binding domain and the same binding affinities as presently claimed (see BERNSTEIN claims 14-15). BERNSTEIN teaches the cell surface antigen is a tumor cell marker (see BERNSTEIN claims 20-22). The bi-specific molecule taught by BERNSTEIN is a fusion polypeptide comprising binding domains that are non-naturally encoded (see BERNSTEIN claim 24). Therefore BERNSTEIN anticipates claims 13, 27-28, 31-33 and 42.
Therefore, the reference teachings anticipate the instant invention.
11. Applicant's arguments filed 08/22/2025 have been fully considered but they are not persuasive.
Applicant argues that Bernstein does not teach modulation of Notch other than the inhibition of Notch signaling in a target cell and that the bi-specific molecule of Bernstein was designed to bind to the cell-type of interest by way of the cell-targeting domain and bind to a Notch receptor also on the same cell of interest, cis-binding. Applicant argues that there is no teaching or suggestion in Bernstein of the bi-specific molecule binding a first cell by way of the cell-targeting domain and a second cell by way of the Notch binding domain, wherein the trans-binding to Notch of the second cell-type causes Notch signaling in the second cell (remarks pg. 14, ¶2). Further, the applicant argues that there is no disclosure or suggestion of administering the bi-specific molecule into the tumor microenvironment or that the bi-specific molecule will bind two cells and induce a trans-activation of Notch as required by the newly amended claims 1 and 13.
These arguments were not found to be persuasive for the following reasons.
First, the examiner recognizes that the examples and experimental evidence of BERNSTEIN are drawn to the inhibition of Notch signaling in CD33+ target cells without inhibiting Notch in the non-target cells (CD33-) via cis-binding. BERNSTEIN explains how regulation of Notch signaling is complex (pg. 2 ¶2); due in part to the number of canonical and noncanonical ligand-receptor pairs with varying binding affinities (pg. 2 lines 14-18), but it is also recognized as a function of the co-expression of a receptor ligand pair on the same cell—this results in a cis binding event thereby preventing that occupied receptor or ligand from trans binding on the neighboring cell. BERNSTEIN further explains that the general mechanism of Notch signaling operates with cell-to-cell contact and is even more complicated in the cellular milieu, playing a key role in divergent functions (cell proliferation VS cellular homeostasis) (pg. 2 ¶3). For instance, in the tumor microenvironment, Notch has been shown to further stimulate cell proliferation, prevent proper differentiation, and prevent apoptosis (pg. 2 ¶2); on the other hand, Notch also plays a role in the quiescence and/or maintenance of pluripotent cancer cells (pg. 3 ¶3). It is important to point out that BERNSTEIN discloses that the bi-specific molecule was expected to induce Notch signaling rather than inhibit it (pg. 7 lines 12-14). This clearly indicates that the molecule was initially expected to induce Notch signaling via canonical trans-binding modality.
While the examiner recognizes that much of the examples and experimental evidence of the BERNSTEIN are drawn to inhibiting Notch signaling in CD33+ target cells without inhibiting Notch in the non-target cells (CD33-) via cis-binding; it is important to point out that the experimental evidence borne out in the examples of BERNSTEIN was entirely generated in vitro with a cellular model (HL60 CD33+ human pro-myelocytic leukemia cells and REH CD33- human B-cell precursor leukemia cells). While all experimental models have limitations, the experiments disclosed by BERNSTEIN were not designed to investigate induction of Notch signaling, and would not be expected to reflect the outcome of contacting a heterogenous cell population in the tumor microenvironment in vivo. This is even more evident considering that BERNSTEIN discloses the cells were cultured in non-tissue treated cell culture wells requiring the cells to be immobilized in culture with a variety of peptides including different iterations of extracellular Notch receptor proteins (DLL1, DLL4, DLL4-E12 etc.,), the bi-specific molecule of invention, and IgG which was used as a “non-stimulating” control (see pg. 33, lines 19-24). Yet, the act of immobilizing cells induces Notch signaling, which is evident from the variability of the signal in the controls between experiments; in other words, the experiments were not designed to quantify to determine induced Notch signaling from a baseline, but were designed to quantify inhibition of Notch signaling in cells that were already stimulated (albeit to varying degrees).
Regardless of the limitations of the BERNSTEIN experiments, the prior art clearly teaches that the general mechanism of Notch signaling operates with cell-to-cell contact (trans binding events). BERNSTEIN also teaches that the regulation of Notch signaling is complex, not only in a developmental context (i.e., cell differentiation and niche formation, see pg. 2 beginning last ¶) but also in the context of disease states such as cancer (e.g., pg. 3, ¶2 through pg. 4, ¶1). This complexity was further evidenced by HOSSAIN (discussed in the rejection above). Owing to the canonical trans-binding activation of Notch taught by BERNSTEIN and the inventor’s initial expectations that the bi-specific molecule would induce Notch signaling, it would be unreasonable for a person of ordinary skill in the art to expect that trans-binding would not occur in the tumor microenvironment, especially in considering the scope of Notch signaling interplay between heterogenous cell populations.
As taught by BERNSTEIN and evidenced by HOSSAIN, it is well understood in the art that trans-binding activation and cis-binding inhibition of Notch is occurring simultaneously in developmental context as well as the tumor microenvironment; as HOSSAIN notes, “These findings highlight two general features of Notch signaling, namely, its context dependence and dose dependence. Notch signals do not appear to operate as an on/off switch. Rather, in many systems, these signals appear to operate based on an intensity gradient that modulates and is modulated by other pathways. Complete blockade of Notch signals is not always necessary to change cellular phenotypes, and small variations in signal intensity or duration may have major phenotypic consequences” (beginning on pg. 4, left column last ¶). One of ordinary skill in the art would not suspend this understanding, especially in consideration that neither BERNSTEIN nor the instant specification disclose any defined structure or feature of the claimed molecule that is capable of blocking trans-binding events.
Without a disclosed structure or feature of the bi-specific molecule that is capable of preventing a trans-binding event, one of ordinary skill in the art would expect both binding modalities to be occurring simultaneously in any cell population, let alone one as diverse as the tumor microenvironment. For instance, if BERNSTEIN disclosed that the bi-specific molecule was designed to include a peptide domain capable of sterically hindering a trans-binding event or a linker molecule that promoted only cis-binding events, a person reasonably skilled in the art might be surprised that the prior art molecule was capable of trans-binding induction of Notch. In the event that a cell comprising a target antigens also comprises a notch binding domain, it is not clear what structure of the claimed bi-specific molecule would prevent a cis-binding event, or even how it could happen.
In fact, from a structural perspective, Held et al., teaches that cell surface receptors are capable of binding in both cis and trans using identical binding sites, although it is not entirely clear how (see “structural basis for cis versus trans interaction” section of Held et al., Cell Mol Life Sci. 2011 Nov;68(21):3469-78. doi: 10.1007/s00018-011-0798-z. PMID: 21863376). Specifically, Held points out that the extracellular domains of Notch and Delta are composed of EGF-like domains that are thought to form extended and rigid structures; notwithstanding, structural and functional analyses suggest that Notch–ligand interactions use the same surfaces for cis and trans binding based on in silico docking of crystal structures of the binding domains of Notch with that of its ligand, Jagged, provided evidence for two distinct receptor–ligand complexes (section titled “Structural basis of cis versus trans interaction”). Held et al explains, that an anti-parallel engagement of receptor and ligand is thought to mediate a trans interaction, and unexpectedly, there is also the possibility of a parallel engagement that would allow cis binding. Held reasons that anti-parallel and parallel binding modes appear to be possible because the respective binding sites are symmetric. Held teaches that even though this model remains to be further tested, symmetry of binding sites does represent, in principle, an additional solution to the structural problem of how cell surface receptors can bind the same ligand in cis and trans (schematically shown in Fig. 1c of Held et al) (see “Structural basis for cis versus trans interaction” section, ¶5 of Held et al).
Taken together, the canonical understanding that Notch signaling occurs via trans-binding events between cells and the lack of a defined structure/feature that favors one binding modality over the other (cis vs trans), the teachings of BERNSTEIN as evidenced by HOSSAIN would lead a person of reasonable skill in the art to believe that the claimed bi-specific molecule is capable of inducing Notch signaling via cell-to-cell trans-binding events.
As such, applicant arguments are not found to be persuasive.
12. Applicant also argues the results disclosed in the instant application are a surprise and unexpected (remarks pg. 15, copied below):
“Applicant would also note that the inventors describe the results seen in this application as a surprise and unexpected. See paragraph [0034] of US2022/0267 437 wherein it is stated that the inventors conducted further investigations of the bi-specific reagents disclosed in WO 2018/017827 and surprisingly discovered the opposite effect in the context of tumor microenvironments when administered in vivo. They proposed that the surprising induction of Notch stimulation instead of inhibition is due to the close aggregation of cells in a tumor microenvironment, where the bi-specific reagent specifically binds to a cell specific marker on one cell and the Notch receptor of a neighboring cell.”
Applicant supports this argument by pointing out that BERNSTEIN was surprised by the effect that the bi-specific molecule had on Notch signaling in the CD33- cells (copied below):
“The Office further alleges that the prior art methods of administering the same bispecific molecule would inherently achieve the same results, including wherein Notch signaling in the immune cell promotes an immune-responsive state in the tumor microenvironment.
Contrary to the allegations and assertions of the Office, Bernstein teaches the promotion of methods for selectively targeting a target cell of interest while leaving the Notch signaling in non-target cells substantially unaffected. See, for example, page 7, lines 14-17 of WO 2018/017827. Bernstein even states that it was surprisingly found that the bi-specific molecule targeting CD33 on leukemic cells inhibited Notch signaling on the cells but not CD33- cells.”
The applicant also argues that the surprising results of the present application contradicts the notion that the bi-specific molecule (disclosed in the present specification AND taught by Bernstein) would modulate Notch signaling in the tumor environment because the instant application saw the opposite effect in the context of the tumor microenvironment in vivo, and cites paragraph [0034] of the instant application that it was "surprisingly discovered the opposite effect in the context of the tumor microenvironments when administered in vivo”; the applicant points out that the opposite effect being the induction of Notch signaling where only cis-binding of the bi-specific molecule prevented signaling (remarks pg. 16, first ¶).
The applicant also argues that BERNSTEIN does not disclose the administration of the bi-specific reagent to the tumor microenvironment and specifically intended for the prior art molecule to only achieve Notch inhibition via cis-binding events and the notion that the molecule would also be capable of trans-binding activation of Notch signaling on adjacent cells is speculative (remarks pg. 16, ¶2).
The applicant also argues that the evidence of HOSSAIN does not substantiate the allegation that trans-binding would occur upon administration of the bi-specific molecule to the tumor microenvironment, citing the HOSSAIN document points out the intricate cross-talk between different cell types in the tumor microenvironment modulates tumor immunity with Notch signaling playing multiple roles (remarks pg. 17, last ¶).
In summary, the applicant argues:
“Given the lack of teaching or suggestion that trans binding of the bi-specific molecule to the target cell and a second cell and the uncertainty of the effect of trans binding of the bi-specific molecule to the target cell and a second cell, such as an immune cell, in both Bernstein and the present application and the surprising result in the present application that Notch signaling is activated instead of inhibited as taught in Bernstein with cis binding of the bispecific molecule, Bernstein does not anticipate any of the pending claims.”
These arguments are not persuasive for the following reasons.
As discussed in response to earlier arguments (see above), BERNSTEIN establishes the canonical induction of Notch signaling is initiated by trans-binding of Notch receptor of one cell and a Notch ligand of another cell. BERNSTEIN teaches that Notch plays a multitude of key roles in various multicellular populations, including within the tumor microenvironment (also discussed above) and the teachings of HOSSAIN expand on the complexity and multifaceted role of Notch signaling and signal regulation in the tumor microenvironment. If a peptide is anchored to a cell (either embedded in the membrane via secretory pathway OR attached via a targeting domain) and said peptide comprises a Notch receptor ligand, one would reasonably expect both trans-binding induction of Notch and cis-binding inhibition—especially if said polypeptide did not include a structural aspect or feature that would favor one binding modality over the other (i.e., protein length, masking domain, steric hinderance, etc.,). As such, BERNSTEIN discloses that they were surprised by evidence of Notch inhibition because the initial expectation was signal induction (pg. 7, lines 12-14). Examiner notes that the BERNSTEIN document shares a number of the same inventors as the instant application; as the examiner understands the chain of unexpected results, BERNSTEIN was surprised by Notch inhibition of co-cultured cells in vitro because they were expecting an induction of Notch signaling. Then, following up this work in the present application, the inventors were surprised that their initial hypothesis were supported by experimental evidence in vivo.
The line of argument drawn to surprising results appears to be self-contradictory. Applicant points to lines 14-17 of BERNSTEIN which indicates the inventors were surprised by inhibition of Notch in target cells but not CD33- cells. However, the applicant fails to point out that the preceding sentence (lines 12-13) discloses that BERNSTEIN initially expected Notch activation instead of inhibition. The examiner does not find this convincing because BERNSTEIN initially expected the Notch binding molecules to induce signaling, then was surprised by the inhibition of signaling in vitro only to generate unexpected results in vivo with the exact same molecule.
For these reasons, the applicant’s arguments were not found to be persuasive.
13. Finally, the applicant also argues that the amendment to claim 1 comprises an additional step to the method of administering the bi-specific molecule to the tumor microenvironment (remarks pg. 16, ¶3 through pg. 17 ¶1).
This argument was not found to be persuasive for the following reasons.
Regarding the arguments drawn to the newly amended base claim methods that are alleged to comprise the additional step; base claim 1 now recites a first step of “administering” a bi-specific molecule to an aggregation of cells in the tumor microenvironment, followed by the step of “contacting” the aggregation of cells in the tumor microenvironment. As discussed in the 112(b) rejection for indefiniteness detailed above, the examiner does not understand whether these limitations are materially different from one another. The claimed bi-specific peptide comprises a cell-targeting domain and a Notch receptor ligand domain, both of which would be expected to facilitate “contact” to appropriate binding partners as a result of administering said molecule. Therefore, the base claim cannot be interpreted to comprise more than one step of administering the bi-specific compound.
As such, applicant’s argument was not found to be persuasive.
Conclusion
14. No claim is allowed.
15. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES L MCLELLAN whose telephone number is (703)756-1906. The examiner can normally be reached Monday - Thursday 7:30 am - 5:30 pm. *Compressed day off on first Friday of each Bi-week..
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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.
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/JAMES LYLE MCLELLAN/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641