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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3-2-26 has been entered.
Claims 60-62 are pending and under examination.
The prior rejections under 35 USC § 103 based on the teachings of Roybal et al. (2016, Cell 164, 770–779, cited on an IDS) in view… have been withdrawn upon reconsideration.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Knowledge of the Prior Art
The rejections under 35 U.S.C. §§102(a)(2)/103 are set forth below in the context of the following prior art teachings which illustrate the knowledge in the prior art regarding FAP expression by cancer associated fibroblasts (CAFs) of the tumor microenvironment (TME), e.g., the expression of FAP by breast cancer associated fibroblasts, as well as prior art disclosure of anti-FAP antibodies, and in turn anti-FAP CAR-T cells, and their use in targeting FAP expressing stromal cells, i.e., FAP expressing fibroblasts, of the tumor microenvironment.
Tchou et al. (Human Pathology (2013) 44, 2549–2557, cited previously) taught that fibroblast activation protein (a.k.a., “FAP”) was an antigen known prior to applicant’s earliest filing date to be widely expressed in the tumor microenvironment (TME) of all stages of Her2+ breast cancer (see page 2551-52 bridging paragraph to page 2552 col. bridging paragraph, and in the first two Discussion paragraphs).
The production of anti-FAP antibodies, and in turn anti-FAP CAR-T cells, was known prior to applicant’s earliest filing date to readily bind FAP-expressing stromal cells associated with carcinoma tumors, such as the breast cancer (see, e.g., June et al., 20140099340, cited previously, at, e.g., paragraphs 11, 99, 100, 105, 121, 181, 184, 222, 308, 310 and 361).
Additionally, the expression of FAP by a wide variety of cancer CAFs (colon, ovarian, pancreatic, hepatocellular and breast), but not by normal fibroblasts, made FAP expression by CAFs a well-recognized target for delivery of a therapeutic agent to the tumor microenvironment (see Sounni et al., Clinical Chemistry 59:1, 85-93 (2013), cited herewith, at page 89 col. bridging paragraph).
Finally, as evidenced by Morgan et al. (Molecular Therapy vol. 18 no. 4, 843–851 apr. 2010, cited previously), prior to applicant’s earliest filing date anti-Her2/ErbB2 directed CAR T-cells were known to have adverse effects in the lung due to on-target, but off tumor binding of Her2/ErbB2-expressing normal lung tissue (see page 848, right col., 1st full paragraph; page 848-49 bridging paragraph - 1st full paragraph).
Claims 60-62 are rejected under 35 U.S.C. 102(a)(2) as anticipated by Lim et al. (20160264665), or, in the alternative, under 35 U.S.C. 103 as obvious over Lim et al. (20160264665) in view of Tchou et al. (Human Pathology (2013) 44, 2549–2557)(all cited previously).
Lim teaches a "binding-triggered transcriptional switch polypeptides" based on a chimeric Notch receptor polypeptide comprising an extracellular antigen binding domain (first member of a specific binding pair) and an intracellular domain, “…wherein the first member of the specific binding pair is heterologous to the Notch receptor polypeptide, and wherein binding of the first member of the specific binding pair to a second member of the specific binding pair induces cleavage of the Notch receptor polypeptide at the one or more ligand-inducible proteolytic cleavage sites, thereby releasing the intracellular domain,” and in one embodiment the released intracellular domain is a “transcriptional activator” that binds to a "transcriptional control element," and wherein a chimeric antigen receptor (CAR) is "operably linked" to said "transcriptional control element." (see, e.g., at paragraphs 5-8 and Figs. 1, 5, 7-9A, 10, 11, 15, 113A-C).
In working Example 1 drawn to “Generation and Characterization of Chimeric Notch
Receptor Polypeptides,” paragraph 623 teaches (emphasis added):
“T cells engineered to express artificial T cell receptors known as Chimeric Antigen receptors (CAR) are effective as therapeutics for certain B cell cancers. However, a major concern with CAR T cell cancer immunotherapy is off-target effects, where the therapeutic T cells destroy normal tissue leading to serious side effects and even death. A potential strategy to mitigate such problems is for therapeutic T cells to only express the CAR when in the tumor microenvironment providing more localized T cell responses. To implement such a strategy, it was reasoned that Chimeric Notch could be used in therapeutic T cells to first detect the tumor by binding a tumor-specific cell surface antigen and initiate expression of a CAR to a second tumor-specific antigen only in the tumor. Effectively, this provides both dual antigen control over T cell activity and a tumor-localized response. Proof of principal in vitro data are presented in Jurkat cells.”
Related teachings appear in working Example 4 drawn to “Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors,” paragraphs 709, 712 and 713 teach (emphasis added):
“[0709] Another important component of future T cell therapeutics is to engineer T cells with new capabilities that allow them to deliver customized therapeutic payloads, even ones that are non-native. Natural T cells or CAR T cells directly recognize infected cells or cancer cells and kill them through the delivery of lytic granules (FIG. 100A). However, natural T cell responses are often insufficient or too extreme to eradicate disease safely. Custom delivery of therapeutic payloads by T cells, such as secreted biologics could aid in difficult to treat diseases by, for example, locally enhancing cytotoxic activity or by priming the site of disease to be recognized and killed by the immune system.”
“[0712] Overall, these findings suggest that synNotch T cells can be efficient and effective delivery agents for therapeutics such as TRAIL. Any biologic agent that has been ineffective or toxic when systemically delivered, might be more effective and safer if locally delivered in this manner synNotch engineered T cells have the potential to locally deliver any genetically encoded therapeutic agents for enhanced effectiveness and reduced systemic OFF-target toxicity.”
“[0713]…[w]hile the ability of synNotch T cells to infiltrate these tumors could still be improved, these data clearly show that synNotch receptors can target T cells to primary tumors and selectively induce production of a therapeutic agent in a local manner. Thus synNotch engineered T cells could prove effective for delivery of a wide-range of genetically encodable therapeutics that could benefit from local delivery both to enhance effectiveness and reduce toxicity of systemic administration.”
The final sentences of Lim Example 4 (see page 90, left col.) are reproduced below for reference (emphasis added):
“FIG. 102. SynNotch Receptors are Versatile Regulators that
Allow T Cells to Monitor and Selectively Modulate their
Microenvironment.
[0726] (A) synNotch receptors are versatile regulators of T
cell response: synNotch receptors can drive diverse behaviors
in primary human T cells. synNotch receptors can drive
custom cytokine production profiles, effectively deliver nonnative
therapeutics, and control T cell differentiation, all in
an antigen-dependent and T cell activation independent
manner (B) synNotch are sufficient to target T cells in vivo
to locally produce a therapeutic payload.”
Fig 102 of Lim is also reproduced below:
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At paragraphs 218-221, Lim proposes the “first member of the specific binding pair” of the Notch receptor polypeptide comprising one or more ligand-inducible proteolytic cleavage sites can be “an antigen to which an antibody specifically binds,” and further that the “second member of the specific binding pair,” i.e., an antibody, can be “an antibody specific for a cancer-associated antigen…where cancer-associated antigens include, e.g….FAP….”
Elsewhere Lim teaches “In some cases, a chimeric Notch polypeptide specifically binds an antigen; e.g., the second member of the specific binding pair is an antigen. Examples of such antigens include, e.g., tumor antigens; cancer cell-associated antigens; hematological malignancy antigens; solid tumor antigens; cell surface antigens ( e.g., cell surface antigens targeted by a T cell receptor (TCR); intracellular antigens; and the like…Examples of solid tumor antigens include, e.g.,… FAP† (as expressed in e.g., Cancer associated fibroblasts)…. FAP (gene symbol FAP)….” (see paragraph 472).
At paragraph 440, Lim teaches activation of the chimeric Notch receptor comprising, e.g., via binding of the second member of the specific binding pair to a “cancer cell-associated antigen” via the “first member of the specific binding pair,” such as an antibody that binds the FAP antigen (see paragraphs [0221] and [0472] above), induces proteolytic cleavage of the Notch intracellular domain which, in turn, “…induces production of a CAR in a cell that expresses the chimeric Notch polypeptide. The CAR in some cases comprises a domain that specifically binds an antigen. Examples of such antigens include, e.g., tumor antigens; cancer cell-associated antigens; hematological malignancy antigens; solid tumor antigens….ErbB2(HER2) (as expressed in e.g., Breast, lung, prostate, glioma),….”
The ordinarily skilled artisan knew FAP expressing CAFs were present in the tumor microenvironment (TME) of a widely variety of cancers, including in all stages of Her2+ breast cancer (see Tchou at page 2551-52 bridging paragraph to page 2552 col. bridging paragraph, and in the first two Discussion paragraphs).
Furthermore, anti-FAP antibodies, and in turn anti-FAP CAR-T cells, were known prior to applicant’s earliest filing date to readily bind FAP-expressing cells of the breast cancer microenvironment (see, e.g., June at, e.g., paragraphs 99, 100, 105, 121, 181, 184, 222, 308). Finally, as evidenced by Morgan, prior to applicant’s earliest filing date anti-Her2/ErbB2 directed CAR T-cells were known to have adverse effects in the lung due to on-target, but off tumor binding of Her2/ErbB2-expressing normal lung tissue (see page 848, right col., 1st full paragraph; page 848-49 bridging paragraph - 1st full paragraph).
Thus, claim 173 of Lim drawn to a “method of treating cancer in an individual, the method comprising administering to the individual the cell which is genetically modified to produce a chimeric polypeptide, wherein the chimeric polypeptide comprises:
a) an extracellular domain comprising a single-chain Fv (scFv) or nanobody that specifically binds to an antigen;
b) a Notch receptor polypeptide comprising one or more proteolytic cleavage sites and having at least 85% amino acid sequence identity to any one of SEQ ID NOs:131, 132 and 135-137; and
c) an intracellular domain comprising a transcriptional activator, wherein binding of the scFv or the nanobody to the antigen induces cleavage of the Notch receptor polypeptide at the one or more proteolytic cleavage sites, thereby releasing the intracellular domain,
wherein the antigen is a cancer-associated antigen, and
wherein release of the intracellular domain causes the transcriptional activator to induce expression of a heterologous gene product in the cell,”
would be understood by the ordinarily skilled artisan to encompass in its breadth a method of treating, e.g., breast cancer, by administering to a patient in need thereof a cell, e.g., a cytotoxic T-cell, which is genetically modified to produce a chimeric polypeptide comprising an extracellular domain that specifically binds a cancer-associated antigen, e.g., the FAP antigen, wherein FAP-binding induces the chimeric Notch receptor polypeptide to undergo proteolytic cleavage thereby releasing its intracellular domain which is a transcriptional activator that induces expression of a heterologous gene product in the cell, e.g., a CAR that has an extracellular Her2/ErbB2-binding domain capable of binding Her2+ breast cancer cells.
The skilled artisan would understand from the teachings of Lim set forth above that having the extracellular portion of the chimeric Notch receptor bind to FAP+ CAFs found in the breast cancer microenvironment ensures that Notch-induced proteolytic cleavage of the intracellular transcription factor which mediates expression of the heterologous CAR that has an extracellular Her2/ErbB2-binding domain occurs in the vicinity of the breast cancer cells to be treated, thereby inhibiting “on-target but off-tumor” toxicity as occurs with conventional Her2/ErbB2-binding CAR T-cells (see Morgan).
Note in this regard that SEQ ID NOs: 132 and 137 recited in Lim claims 167/171/173 comprise ADAM protease and γ-secretase cleavage sites as recited in claim 62.
Insofar as applicant disagrees that the teachings of Lim anticipate the claimed invention, the claimed invention is additionally obvious over the teachings of Lim in view of Tchou as described further below.
One tumor type those of ordinarily skill in the art had attempted to treat with CAR T-cells prior to applicant’s earliest filing date was breast cancer expressing the Her2/ErbB2 antigen. That said, a limiting feature of CAR T-cells in general, and ErbB2-directed CAR T-cells in particular, was that they were known to cause “on target, off tumor” toxicity. For example, prior to applicant’s earliest filing date it was known in the art that anti-Her2/ErbB2 directed CAR T-cells had adverse effects in the lung due to on-target, but off tumor binding of Her2/ErbB2-expressing normal lung tissue, as evidenced by Morgan at page 848, right col., 1st full paragraph; page 848-49 bridging paragraph - 1st full paragraph.
However, the teachings of Lim provide an obvious solution for this challenge.
As described above, Lim teaches a chimeric Notch polypeptide can be made to bind to a “Tissue-specific antigen,” such as FAP expressed by CAFs, wherein binding of the FAP antigen to the chimeric Notch polypeptide “induces cleavage of the Notch receptor polypeptide at the one or more ligand-inducible proteolytic cleavage sites, thereby releasing the intracellular domain,” that eventually gives rise to “Local Delivery of Therapeutic Agents,” such as an ErbB2-binding CAR.
Indeed, it would have been obvious to one of ordinary skill in the art to link:
(i) recognition of the expression of FAP by breast CAFs in particular, to
(ii) chimeric Notch-inducible expression of an ErbB2-binding CAR, because
(iii) FAP was well known to be CAF specific, and to be widely expressed in the tumor microenvironment (TME) of all stages of Her2+ breast cancer (as evidenced by the teachings of Tchou above).
Furthermore, anti-FAP antibodies, and in turn anti-FAP CAR-T cells, has been previously produced and shown to bind to FAP expressing cells of the breast cancer microenvironment (see the teachings of June above).
Thus, given the teachings of Lim in view of Tchou as evidenced by the knowledge of the prior art, it would have been obvious to the ordinarily skilled artisan to kill breast cancer cells in an individual, the method comprising: administering a genetically modified, cytotoxic immune cell to the individual, wherein the genetically modified cytotoxic immune cell comprises: (a) a nucleic acid encoding a chimeric antigen receptor (CAR) that that is activated by binding to epidermal growth factor receptor 2 (ERBB2) on another cell; and (b) antigen-triggered polypeptide that comprises an extracellular domain that binds to fibroblast activation protein a (FAP), a transmembrane domain, and an intracellular domain comprising a transcriptional activator, wherein the antigen-triggered polypeptide comprises one or more protease cleavage sites that are cleaved when the antigen-triggered polypeptide binds to FAP on another cell, and wherein cleavage of the antigen-triggered polypeptide at the one or more protease cleavage sites results in release of the transcriptional activator and expression of the CAR.
With respect to claim 62, claim 173 of Lim is drawn to a “method of treating cancer in an individual, the method comprising administering to the individual the cell which is genetically modified to produce a chimeric polypeptide, wherein the chimeric polypeptide comprises:
a) an extracellular domain comprising a single-chain Fv (scFv) or nanobody that specifically binds to an antigen;
b) a Notch receptor polypeptide comprising one or more proteolytic cleavage sites and having at least 85% amino acid sequence identity to any one of SEQ ID NOs:131, 132 and 135-137; and
c) an intracellular domain comprising a transcriptional activator, wherein binding of the scFv or the nanobody to the antigen induces cleavage of the Notch receptor polypeptide at the one or more proteolytic cleavage sites, thereby releasing the intracellular domain,
wherein the antigen is a cancer-associated antigen, and
wherein release of the intracellular domain causes the transcriptional activator to induce expression of a heterologous gene product in the cell,”
which would be understood by the ordinarily skilled artisan to encompass in its breadth a method of treating, e.g., breast cancer, by administering to a patient in need thereof a cell, e.g., a cytotoxic T-cell, which is genetically modified to produce a chimeric polypeptide comprising an extracellular domain that specifically binds a cancer-associated antigen, such as the FAP antigen, wherein FAP-binding induces the chimeric Notch receptor polypeptide to undergo proteolytic cleavage thereby releasing its intracellular domain which is a transcriptional activator that induces expression of a heterologous gene product in the cell, e.g., a CAR that has an extracellular Her2/ErbB2-binding domain capable of binding Her2+ breast cancer cells.
The ordinarily skilled artisan would understand from the teachings of Lim in view of Tchou as evidenced by the knowledge in the art set forth above that having the extracellular portion of the chimeric Notch receptor bind to FAP+ CAFs found in the breast cancer microenvironment ensures that Notch-induced proteolytic cleavage of the intracellular transcription factor which mediates expression of the heterologous CAR that has an extracellular Her2/ErbB2-binding domain occurs in the vicinity of the breast cancer cells to be treated, thereby inhibiting “on-target but off-tumor” toxicity as occurs with conventional Her2/ErbB2-binding CAR T-cells (see Morgan).
Note in this regard that SEQ ID NOs: 132 and 137 recited in Lim claims 167/171/173 comprise ADAM protease and γ-secretase cleavage sites as recited in claim 62, and thus it would further be obvious to one of ordinary skill in the art to prepare the chimeric Notch polypeptides as described above to comprise SEQ ID NOs: 132 or 137 as recited in Lim claims 167/171/173, said sequences comprising ADAM protease and γ-secretase cleavage sites as recited in claim 62.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. 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.
Response to Applicant’s Arguments
A primary focus of applicant’s arguments is that Lim fails to teach or suggest a method of treating cancer using a genetically modified immune cell that comprises an antigen-triggered polypeptide having an extracellular domain that binds to “FAP on a non-target cancer-associated fibroblast,” wherein the chimeric antigen receptor (“CAR”) produced in response to FAP binding is one that will bind a different cell, i.e., bind a breast cancer cell.
For example, applicant asserts / argues:
“…Lim does not disclose a single modified immune cell that binds FAP on a non-target cancer-associated fibroblast and ERBB2 on a target breast cancer cell (i.e., two different cells).”
“First, ‘expressing CAR in the tumor microenvironment’ merely describes the general concept of limiting T-cell activation to a particular location, not a specific method for doing so. Lim only discloses methods for localizing T cell activity in which both antigens are expressed on the same cell.”
“FAP is expressed on cancer-associated fibroblasts, while ERBB2 is expressed on breast cancer cells. Lim is silent with respect to targeting antigens on separate cells and does not specifically disclose the combination of FAP/ERBB2.”
“Given that there is nothing in Lim that clearly and unequivocally indicates a T cell configured to bind to antigens on different cells, Lim does not teach this element of the claims.”
“As Wilkie discloses only targeting breast cancer cells that co-express MUC1 and ERBB2, it is clear that targeting the "tumor microenvironment" includes targeting multiple antigens expressed on the same cancer cell.”
“Accordingly, there is no teaching or suggestion that would lead one of skill in the art to "cause localization of a CART-cell to the noncancer cells of the tumor microenvironment" as suggested in the Office Action.”
“The absence of any explicit teachings in Lim with respect to targeting antigens on two different cells is discussed above….The Office Action has not identified a single instance in which Lim describes simultaneously targeting an antigen on a non-target cell and an antigen on a target cell, and as such, Applicants submit that the interpretation of ‘expressing CAR in the tumor microenvironment’ as teaching this element would only have been possible using impermissible hindsight in view of the Applicants' own disclosure.’”
Applicant’s arguments have been considered but are not found convincing, essentially for the reasons set forth above.
The skilled artisan would understand from the teachings of Lim set forth above that having the extracellular portion of the chimeric Notch receptor bind to FAP+ CAFs found in the breast cancer microenvironment ensures that Notch-induced proteolytic cleavage of the intracellular transcription factor which mediates expression of the heterologous CAR that has an extracellular Her2/ErbB2-binding domain occurs in the vicinity of the breast cancer cells to be treated, thereby inhibiting “on-target but off-tumor” toxicity as occurs with conventional Her2/ErbB2-binding CAR T-cells (see Morgan).
Example 4 / Figs. 102A-B of Lim teach that a “Tissue-specific antigen” can provide “the second member of the specific binding pair” that is bound by “the first member of the specific binding pair,” and this binding event “induces cleavage of the Notch receptor polypeptide at the one or more ligand-inducible proteolytic cleavage sites, thereby releasing the intracellular domain,” that eventually gives rise to “Local Delivery of Therapeutic Agents,” such as an ErbB2-binding CAR.
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By contrast to applicant’s assertion / arguments (i)-(vii) above, the ordinarily skilled artisan would understand the teachings of Lim at paragraph 189, and as illustrated above to draw a clear distinction between an epitope present “in a tissue-specific antigen" versus an epitope present “in a disease-associated antigen."
More particularly, the ordinarily skilled artisan would understand from the above that "an epitope present in a tissue-specific antigen" may very well occur locally to an epitope present “in a disease-associated antigen," and using FAP expression by CAFs as such a tissue-specific antigen was well understood in the prior art as illustrated by the teachings Sounni.
As described above, an advantage of the system described by Lim is that by targeting an epitope present in a tissue-specific antigen, such as FAP expressed by breast cancer associated fibroblasts (CAFs), via a chimeric FAP-binding synNotch receptor one can control T-cell expression of the CAR which binds an epitope present “in a disease-associated antigen," such as ErbB2-expressing breast cancer cells, thereby inhibiting “on-target but off-tumor” toxicity that occurs with conventional Her2/ErbB2-binding CAR T-cells (see Morgan).
Notably, additional teachings of Lim which are consistent with the above are also set forth at paragraph 0754:
“FIG. 108. synNotch Receptors for Combinatorial Antigen Sensing in T Cells
[0754] (A) CAR or tumor-specific TCR T cells generally target single antigens, thereby often causing OFF-target tissue damage[.] Improved therapeutic T cells will require multiple sensors that recognize combinations of both tumor antigens and tissue-specific antigens, allowing the cells to assess their environment and make more precise decisions on when to activate. Such therapeutic cells would be better equipped to distinguish target diseased tissue from normal tissue. (B) New types of receptors that sense combinations of antigens and regulate T cell signaling and transcription must be built to allow for sophisticated cellular decision-making and more precise therapeutic T cell responses. (C) synNotch receptors are engineered with a custom extracellular ligand-binding domain such as an scFv or nanobody directed towards an antigen of interest (e.g. tumor or tissue specific antigen). Upon ligand recognition by the synNotch receptor, an orthogonal transcription factor (e.g. TetRVP64 or Gal4VP64) is cleaved from the cytoplasmic tail that regulates a custom genetic circuit. (D) Design of a synNotch AND-gate circuits, which requires T cells to sense two antigens to activate. This AND-gate signaling circuit works in two sequential steps: 1) A synNotch receptor allows the T cell to recognize the first antigen A and 2) the T cell expresses a CAR directed towards a second tumor antigen B. If A and B are present, the T cells can activate and kill the target tumor.”
Further to applicant’s arguments that Lim fails to teach or suggest a method of treating cancer using a genetically modified immune cell that comprises an antigen-triggered polypeptide having an extracellular domain that binds to “FAP on a non-target cancer-associated fibroblast,” wherein the chimeric antigen receptor (“CAR”) produced in response to FAP binding is one that will bind a different cell, i.e., bind a breast cancer cell, applicant asserts:
“The Office Action further asserts that an FAP binding protein will inherently bind FAP wherever it is expressed, whether on the same cell or a different cell (pg. 6). However, FAP is expressed on cancer-associated fibroblasts, while ERBB2 is expressed on breast cancer cells. As FAP and ERBB2 are only found on separate cells, and as the T cells of Lim must target a dual positive cell expressing both markers, Lim cannot disclose a T cell targeting the combination of FAP and ERBB2. In other words, even if Lim discloses a T cell targeting FAP, Lim's FAP-targeting T cell would not be configured to also target ERBB2, because ERBB2 would only be present on a different cell (or vice versa). Thus, because a T cell targeting both FAP and ERBB2 on the same cell is impossible, Lim accordingly does not disclose a T cell that binds to both FAP and ERBB2.” (see page 6-7 bridging paragraph, emphasis added).
It appears that applicant is referring to page 6, 1st paragraph of the Final rejection mailed 12-3-2 (emphasis in the original):
“Finally, note that while local delivery of a Her2/ErbB2-binding CAR expressing T-cell to the breast cancer cell microenvironment via chimeric Notch receptor binding to the breast cancer-associated antigen FAP in the context of a FAP+ breast cancer cell microenvironment may occur due to binding to FAP expressed by a “cancer-associated fibroblast;” alternatively, given that a a chimeric Notch receptor comprising a FAP binding domain will inherently bind FAP wherever it is expressed, such a chimeric Notch receptor may also bind to FAP expressed by breast cancer cells (see Shi et al., World J Gastroenterol 2012 February 28; 18(8): 840-846, cited on an IDS, at page 844-45 bridging paragraph).”
The undersigned maintains a chimeric Notch receptor comprising a FAP binding domain will inherently bind FAP wherever it is expressed, whether that be by CAFs in the breast cancer micoenvironment, or by breast cancer cells per se (see above).
Be that as it may, given the knowledge in the prior art regarding the importance and well-established prevalence of FAP expressing CAFs in the microenvironment of various cancers, including breast cancer, it is the opinion of the undersigned that the teachings of Lim would be understood by the ordinarily skilled artisan as being focused on targeting FAP expressed by CAFs, not the perhaps remote possibility that primary breast cancer cells may express FAP by analogy to certain breast cancer cell lines.
With respect to applicant’s arguments that the teachings of Lim at paragraph [0753] “…teach[] that binding to separate cells is undesirable,” see Remarks at page 10, this is not found convincing as stated in the Final Office Action mailed 12-3-25 at page 7-8 bridging paragraph – 1st full paragraph on page 8:
“‘…by contrast to the experiment described in [0753] of Lim, other teachings of Lim emphasize the importance of making expression of the CAR that has the potential for on-target but off-tumor toxicity, e.g., the ERBB2-binding CAR, dependent on the T-cell comprising said ERBB2-binding CAR being localized to the tumor microenvironment, e.g., with a chimeric Notch receptor having specificity for the breast cancer-associated antigen FAP which was known to be present in the breast cancer microenvironment (e.g., see page 4, 1st full paragraph to page 6, 1st full paragraph of the prior Office Action).
Thus, the teachings of Lim at [0753] are not relevant to the prima facie case of obviousness because as set forth in the prior Office Action at page 7, 1st full paragraph, ‘[t]he skilled artisan would understand from the teachings of Lim set forth above that having the extracellular portion of the chimeric Notch receptor bind to the breast cancer-associated antigen FAP ensures that Notch-induced proteolytic cleavage of the intracellular transcription factor which mediates expression of the heterologous CAR that has an extracellular Her2/ErbB2-binding domain occurs in the context of a FAP+ breast cancer cell microenvironment.’” (emphasis in the original)
Applicant further sets forth the following argument at page 12, last paragraph, of their Remarks:
“….At the time of the invention, T cell activation was understood to occur via the two-signal model, according to which full T cell activation, and subsequent killing of an antigen presenting cell (APC), requires that the T cell bind to an antigen-specific signal and a co-stimulatory molecule, both of which are expressed on the APC. As such, one of skill in the art would have reason to expect CART cells to be able to bind two different antigens expressed on the same cell and to kill that cell. However, one of skill in the art would have no expectation of success in developing a CART cell capable of binding to an antigen on a first non-target cell, then binding to an antigen on a second target cell, and finally killing the target cell. "Trans-killing", the process in which a T cell is primed by one cell and kills a different target cell bearing the killing antigen but lacking the priming antigen, is not described in the cited prior art….As such, at the time of the invention, there was simply no evidence in the art that would provide the skilled person with a reasonable expectation of success in modifying Wilkie and/or Lim to produce a CART cell that binds to an antigen on a non-target cell and an antigen on a target cell as presently claimed.”
Applicant’s argument has been considered but is not found convincing for the reasons set forth above, i.e., as described above Lim teaches, or in the alternative given the teachings of Lim in view of Tchou it would have been obvious to one of ordinary skill in the art that a chimeric Notch polypeptide can be made to bind to a “Tissue-specific antigen,” such as FAP expressed by breast CAFs, wherein binding of the FAP antigen to the chimeric Notch polypeptide “induces cleavage of the Notch receptor polypeptide at the one or more ligand-inducible proteolytic cleavage sites, thereby releasing the intracellular domain,” that eventually gives rise to “Local Delivery of Therapeutic Agents,” such as an ErbB2-binding CAR which can activate breast cancer killing.
Note that by contrast to applicant’s argument, one of ordinary skill in the art would understand that by linking a chimeric Notch receptor to a transcription factor which is released upon binding of the chimeric Notch to its cognate ligand, and that can then enter the nucleus to induce expression of a nucleic acid encoding a singular therapeutic CAR (see, e.g., Lim Figs. 102A and 108C), the teachings of Lim would necessarily imply to one of ordinary skill in the art prior to applicant’s filing date that the encoded CAR must have both a co-stimulatory domain and a primary signaling CD3z domain (see, e.g., Lim at paragraph [0517]). The understanding that optimum CAR mediated killing of cancer cells generally depends on the combined action of one or more co-stimulatory domains and a CD3z signaling element was reflected, e.g., in the teachings of Morgan (2010) at page 843-844 bridging paragraph. Thus, by contrast to applicant’s argument (“one of skill in the art would have no expectation of success in developing a CART cell capable of binding to an antigen on a first non-target cell, then binding to an antigen on a second target cell, and finally killing the target cell”), it is the opinion of the undersigned that the ordinarily skilled artisan would readily understand Lim to teach such an embodiment.
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. § 716.01(d).
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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