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 .
Status of the Claims
Claims 1-2, 4-15, 23-26, and 33-34 and are pending.
Claim 1 is newly amended.
Claims 5, 10, 23-26, and 33-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-2, 4, 6-9, and 11-15 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn. Prior objections have been addressed by amendment.
The rejections under 35 USC 103 as being unpatentable over Fan et al. (US20190038671A1, 2019, on IDS 10/20/2021, previously cited) in view of Bayle et al. (US20170166877A1, 2017, on IDS 10/20/2021, previously cited) and Lim et al. (WO2016138034A1, 2016, previously cited) as evidenced by Qian et al. (Frontiers in Oncology, 2022, previously cited) and Das et al. (Current Gene Therapy, 2016) are maintained by modified the claims as amended.
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 1-2, 4, 6-9, and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Fan et al. (US20190038671A1, 2019, on IDS 10/20/2021, previously cited) in view of Bayle et al. (US20170166877A1, 2017, on IDS 10/20/2021, previously cited) and Lim et al. (WO2016138034A1, 2016, previously cited) as evidenced by Qian et al. (Frontiers in Oncology, 2022, previously cited) and Das et al. (Current Gene Therapy, 2016).
In regards to claims 1-2, 4, and 6-7, Fan teaches a therapeutic cell (such as a T cell) that expresses proteins (Title, Abstract; paragraph [0002]; claims 1 and 6). Fan teaches that the cell comprises a heterologous nucleic acid (claim 1), and thus a heterologous agent. Fan teaches that the heterologous nucleic acid (heterologous agent) encodes an immunomodulator (claim 1), which can be an immunoactivator (claim 25), which can be BCL-2 specifically (claim 28), which claim 4 indicates is an anti-apoptotic protein. Furthermore, as evidenced by Qian, BCL-2 is a known in the art as an “anti-apoptotic” BCL-2 family protein (The structural domains of BCL-2 family proteins, p02). Thus, the BCL-2 immunoactovator, as taught by Fan is a heterologous anti-apoptotic agent. Additionally, Fan teaches that immunomodulators can be operably linked to a promoter (claim 1), and thus are “heterologous inducible agents”.
In regards to whether expression of the heterologous anti-apoptotic agent prevents cell death, this is a property of the expression of a BCL-2 family protein. In the instant case, since as above, BCL-2 is a known in the art as an “anti-apoptotic” BCL-2 family protein and the therapeutic cell as taught by Fan expresses BCL-2, it would naturally prevent cell-death. Indeed, Fan explicitly teaches that overexpression of BCL-2 causes cells to become resistant to apoptosis (paragraph [0232]) and that expression of BCL-2 promotes persistence of these cells (paragraph [0407]).
While Fan teaches that the cell may comprise a second immunomodulator (thus, a second heterologous inducible agent) (paragraph [0138]), Fan does not explicitly teach that this agent is pro-apoptotic.
However, Bayle teaches that while therapeutic cells (such as T cells) can be used to treat cancers or blood disorders, these cells can induce adverse effects and that these is a need for rapid and near complete elimination of the therapeutic cells (paragraph [0005]). To do this, Bayle teaches that these cells can be engineered to express a “suicide gene” that can eliminate these cells in the event that they trigger serious adverse events (paragraphs [0005, 0273, 0484, etc.]).
Furthermore, Bayle also specifically teaches that suicide function should be preserved not only in malignant, transformed T-cell lines that express anti-apoptotic molecules, but also in subpopulations of normal T cells that express elevated anti-apoptotic molecules (such as therapeutic cells as taught by Fan) as part of the process to ensure long-term preservation of memory cells (paragraph [0484]).
Additionally, Bayle teaches that BCL-2 renders subpopulation of T cells (therapeutic cells), resistant to activation-induced cell death in response to cognate target or antigen-presenting cells, and that in several T-lymphoid tumors, the physiologic balance between apoptosis and survival is disrupted in favor of cell survival (paragraph [0497]). As a result, Bayle advises that a suicide gene should be used to delete substantially all transduced T cells (paragraph [0497]).
Therefore, a person of ordinary skill in the art would have been motivated to include a heterologous inducible pro-apoptotic agent in order to provide a kill switch for therapeutic cells in order ensure against adverse effects, especially when a therapeutic cell has been engineered with an anti-apoptotic agent.
Furthermore, since Bayle teaches that therapeutic cells can be engineered to comprise suicide genes, since Fan teaches that cells can be engineered to express other immunomodulators, and since Bayle and Fan are in the same technical field of using engineering immune cells to express heterologous proteins for therapeutic purposes, it could have been done with predictable results and a reasonable expectation of success.
While Bayle does not explicitly teach that the pro-apoptotic agent comprised a BCL-2 family protein specifically, the use of BCL-2 family proteins as pro-apoptotic gene switches was known in the art before the effective filing date.
For example, Lim teaches switch polypeptides for the induction of apoptosis in therapeutic cells such as T cells (paragraphs [0007, 0010, etc.]; claim 46), including specifically truncated BID (tBID) which Lim indicates is suitable for inducing apoptosis (paragraphs [00353, 00538]). As evidenced by Qian, BID is a known BCL-2 family pro-apoptotic protein (The structural domains of BCL-2 family proteins, p02).
In regards to wherein the expression of the pro-apoptotic agent in the cell is under the control of an inducible promoter, as taught by Lim, the pro-apoptotic agent (tBID) can be controlled by inducible tetracycline regulated promoters such as TetON (paragraph [00505]).
A person of ordinary skill in the art would have been motivated to choose a BCL-2 family protein (such as tBID, specifically) because Lim indicates that it is suitable for inducing apoptosis in the T cells of Fan in the event that they trigger serious adverse events (see from Bayle above). They would have been motivated to drive expression with a promoter such as TetON because Lim teaches that it is suitable as an inducible promoter (paragraph [00503]).
Furthermore, because Lim teaches that BCL-2 family proteins (such as tBID) are suitable for inducing apoptosis, that a promoter such as TetON can be used as an inducible promoter, and because Fan, Bayle, and Lim are all in the same technical field of using engineering immune cells to express heterologous proteins for therapeutic purposes, it could have been done with predictable results and a reasonable expectation of success.
In regards to whether uninduced expression of the heterologous inducible pro-apoptotic agent is sufficient to cause cell death, it is noted that this is a property of background expression of a particular BCL-2 family pro-apoptotic protein. Indeed, claim 2 suggests that background expression of tBID is sufficient to have this effect.
In the instant case, as evidenced by Das, the use of a TetON promoter (paragraph [00505]), results in low background expression (Improvements of the Tet-ON System, p158). Therefore, since the use of a TetON promoter would result in background expression of tBID, and the claims indicate that background expression of tBID is sufficient to allow uninduced expression of the heterologous inducible pro-apoptotic agent to cause cell death, the cells as taught by Fan, as modified, express background tBID, they would naturally have this property.
In regards to claim 8, as above, Fan teaches that the cell comprises heterologous nucleic acids (claim 1). Fan also teaches that the nucleic acid can be a CAR (paragraph [0011]; claim 8).
In regards to claim 9, a person of ordinary skill in the art would have recognized that the amino acid sequence of a therapeutic agent operably linked to a promoter (claims 1 and 8; paragraph [0011]) suggests that that the agent is “regulatable” since the function of promoters is to regulate gene transcription.
In regards to claim 11, as above, Fan teaches a therapeutic agent with an amino acid sequence operably linked to a promoter (claims 1 and 8; paragraph [0011]), which is understood in the art to be a “binding-triggered transcriptional switch.” Again, is also well-understood in the art that promoters control expression of genes.
In regards to claims 12-14, as discussed above, Lim teaches the TetON inducible promoter, which uses the ligand doxycycline to bind a binding-triggered transcription switch (i.e., tTA) to induce expression of the protein operably linked to a regulatory sequence (i.e., TRE) (paragraph [00503]).
In regards to claim 15, it is noted that the claims are drawn to a “therapeutic cell”, which is different composition than “non-target cells.” Thus, the limitation of “wherein the ligand is expressed by non-target cells” has been interpreted as an intended use of the therapeutic cell (meaning, if the therapeutic cell is used to treat non-target cells).
Product claims cover what a device is, not what a device does (see MPEP 2114(II)). A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim (see MPEP 2114).
To this end, because the cells of Lim are therapeutic cells applicable for cancer immunotherapy (Abstract) and because Fan demonstrates that the cell can interact with ligands on tumor cells (Fig. 7A), the cells of Fan are suitable for this intended purpose.
Response to Arguments
Applicant argues that none of the cited art teaches that the cell exhibit uninduced expression of the inducible pro-apoptotic agent (specifically an inducible BCL-2 family pro-apoptotic protein) at a level sufficient to cause cell death (Remarks, p6).
Applicant argues that none of the cited references teach that the expression of the anti-apoptotic agent prevents cell death that would have been caused by the uninduced expression of the pro-apoptotic agent (Remarks, p6).
Applicant’s arguments filed 01/15/2026 have been fully considered but are not found persuasive.
As discussed above, in regards to a cell that exhibits uninduced expression of the inducible pro-apoptotic agent (specifically an inducible BCL-2 family pro-apoptotic protein) at a level sufficient to cause cell death, as discussed above, it is noted that this is a property of background expression of a particular BCL-2 family pro-apoptotic protein. Indeed, claim 2 suggests that background expression of tBID is sufficient to have this effect.
In the instant case, as evidenced by Das, the use of a TetON promoter (paragraph [00505]), results in low background expression (Improvements of the Tet-ON System, p158). Therefore, since the use of a TetON promoter would result in background expression of tBID, and the claims indicate that background expression of tBID is sufficient to allow uninduced expression of the heterologous inducible pro-apoptotic agent to cause cell death, the cells as taught by Fan, as modified, express background tBID, they would naturally have this property.
In regards to whether the expression of the anti-apoptotic agent prevents cell death that would have been caused by the uninduced expression of the pro-apoptotic agent (see Remarks, p6), it is noted that the claims do not specifically require that the anti-apoptotic agent prevents cell death that would have been caused by the uninduced expression of the pro-apoptotic agent. Rather, the claim more generically, the anti-apoptotic agent “prevents cell death.”
Therefore, In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a specific causative relationship between the anti-apoptotic agent and the pro-apoptotic agent to prevent cell death) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
However, this is still a natural property of a cell that comprises a heterologous anti-apoptotic agent comprising a BCL-2 family anti-apoptotic protein, which may be BCL-2 specifically.
Thus, the claim suggests that expression of BCL-2 from a heterologous anti-apoptotic agent is sufficient to precent cell death (whether by the the uninduced expression of the pro-apoptotic agent, or otherwise). Indeed, as discussed above, as evidenced by Qian, BCL-2 is a known in the art as an “anti-apoptotic” BCL-2 family protein (The structural domains of BCL-2 family proteins, p02). Thus, expression of this protein from a heterologous anti-apoptotic agent would still prevent apoptosis. Moreover, as above, Fan explicitly teaches that overexpression of BCL-2 causes cells to become resistant to apoptosis (paragraph [0232]).
Therefore, as above, since the therapeutic cell of Fan expresses a heterologous nucleic acid (heterologous agent) that encodes BCL-2 (claims 1, 25, and 28), it would have the property of preventing apoptosis.
Applicant argues that they have discovered that expressing an anti-apoptotic agent in the same cell prevents death of a cell arising from the uninduced expression of a pro-apoptotic agent, and therefore, acts as a buffer against uninduced apoptosis (Remarks, p6-7).
Applicant’s arguments filed 01/15/2026 have been fully considered but are not found persuasive.
All of the claimed features where known in the prior art before the effective filing date, and according to MPEP 2145, Applicant's “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
While discussed in depth above, in brief, as taught by Fan, therapeutic immune cells can be engineered to exogenously express heterologous agents including at least BCL-2 (claims 1, 25, and 28). Indeed, Fan explicitly teaches that this exogenous or overexpression of BCL-2 enhances persistency of modified immune cells and make these cells resistant to apoptosis (paragraphs [0407]).
In regards to pro-apoptotic agents, immune cell “suicide genes” or “kill switches” were also known in the art before the effective filing date. Specifically, as discussed above, Bayle teaches that immune cells can be engineered to express suicide genes to suppress adverse effects that may be caused by therapeutic cells (paragraphs [0005, 0273, 0484, etc.]), while as above, Lim teaches that BCL-2 family protein, truncated BID (tBID), specifically can be used as an engineered therapeutic immune cell kill switch (paragraphs [0007, 0010, etc.]; claim 46), including specifically truncated BID (tBID)) induced by TetON (which is a known “leaky” promoter).
As above it would have been prima facie obvious to combine these elements, in order to create therapeutic immune cells that have persistence to apoptotic factors, but also can be readily killed when need be (such as to eliminate foreign cell or if they cause complications during therapeutic uses).
Furthermore, Fan teaches that therapeutic immune cells can be engineered to express multiple heterologous proteins, and since Bayle, Fan, and Lim are all in the same technical field of engineering immune cells to express heterologous proteins for therapeutic purposes, it could have been done with predictable results and a reasonable expectation of success.
In regards to the effects of uninduced expression of a heterologous pro-apoptotic agent to cause cell death, and expression of a heterologous anti-apoptotic agent to prevent cell death, again, these are all properties of an immune cell expressing heterologous BCL-2 and comprising a tBID kill switch driven by a leaky TetON promoter (which results in uninduced expression of tBID). Since the therapeutic cell as taught by Fan and as modified by Bayle and Lim is the same composition, it would naturally have these same properties.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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