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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Action is in response to the papers filed on 12/25/2025. Claims 1, 4-5, 18, 19, 27, 30-41, 43, 97, 110-111, 113, 125-126 are currently pending. Claims 1, 4, 5, 18, 19, 33 and 36 have been amended and claim 3 has been cancelled by Applicant’s amendment filed on 12/25/2025.
Election/Restrictions
Applicant's election of Group I, claims 1, 3-5, 18-19, 27, 30-41, and 43 drawn to an immunoresponsive cell expressing a modified pro-cytokine and a polynucleotide encoding the cytokine and the species of SEQ ID NO: 103 (claim 5); HMFG2 scFv (claim 35); ErbB heterodimers (claim 38); and TIE (claim 41), in the reply filed on 06/06/2025, was previously acknowledged. The election of species requirement for claims 38-40 was previously withdrawn.
Claims 33, 34, 97, 110-111, 113, 125 and 126 were previously withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Claims 33-34 were previously withdrawn from further consideration pursuant to 37 CPR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. The requirement for restriction was previously made final.
Therefore, claim 1, 4, 5, 18-19, 27, 30-32, 35-41 and 43 are currently under examination to which the following grounds of rejection are applicable. Claims 1, 43, 97, 110, 111, 113, 125 and 126 are independent claims.
Priority
The instant application is a 371 of PCT/GB2020/051934 filed on 08/13/2020, which claims priority to 62/886,065 filed on 08/13/2019.
Thus, the earliest possible priority for the instant application is 08/13/2019.
Withdrawn Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 101
The rejection of claims 1, 18-19, 27, and 43 under 35 USC § 101 is withdrawn in view of the amendments in the response filed on 12/25/2025. The amended claim now requires a cell that would not be a naturally occurring product, specifically the cell contains a modified pro-cytokine comprising SEQ ID NO: 26 (a non-natural cleavage sequence).
Claim Rejections - 35 USC § 112(a)
The rejection of claims 18 and 19 under 35 USC § 112(a) is withdrawn in view of the amendments in the response filed on 12/25/2025. Claim 18 has been amended to remove the recitation of “having at least 85% identity to SEQ ID NO:24” with the claim now only requiring SEQ ID NO:24. The specification provides support for a sequence having 100% similarity to SEQ ID NO:24.
Claim 19 has been amended to the recitation of “having at least 85% sequence identity to SEQ ID: 25 with the claim now reciting “The immunoresponsive cell of claim 1, wherein the pro-peptide is a polypeptide having at least 90% sequence identity to SEQ ID: 25, wherein a native caspase-1 cleavage site comprising an amino acid sequence of LESD of SEQ ID NO: 25 is replaced with the cleavage site of SEO ID NO: 26.” As the claim now requires the four amino acids of SEQ ID NO: 25 (cleavage site) to be replaced with the four amino acids of SEQ ID NO: 26 the similarity is ~91%. The specification provides support for this specific sequence substitution.
Applicants’ arguments with regard to a withdrawn objection/rejection are moot.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 18, 19, 27, 30, and 43 under 35 USC § 102 is withdrawn in view of the amendments in the response filed on 12/25/2025.
New rejections/objections in response to Applicants’ arguments or amendmentsClaim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 19 is newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
This rejection is necessitated in response to the claim amendments filed 12/25/2025.
Claim 19 recites “The immunoresponsive cell of claim 1, wherein the pro-peptide is a polypeptide having at least 90% sequence identity to SEQ ID NO: 25, wherein a native caspase-1 cleavage site comprising an amino acid sequence of LESD of SEQ ID NO: 25 is replaced with the cleavage site of SEQ ID NO: 26.” It is unclear what the applicants’ intended meaning for “cleavage site comprising an amino acid sequence of LESD of SEQ ID NO:25 is replaced with the cleavage site of SEQ ID NO: 26.” LESD is an amino acid sequence found within the sequence of SEQ ID NO: 25 and not the entire sequence of SEQ ID NO:25.
Further, a SEQ ID NO: is a placeholder and not a sequence (or a cleavage site) in and of itself. Therefore, it is unclear what “the cleavage site of SEQ ID NO: 26” is in reference to. It would, therefore, be proper to amend “the cleavage site of SEQ ID NO: 26” to instead recite “the amino acid sequence of SEQ ID NO: 26”.
Maintained and modified rejections in response to Applicants’ arguments or amendments
Allowable Subject Matter
Regarding claim 5, while various compositions comprising immunoresponsive cells expressing a pro-IL-18 cytokine and comprising a second generation chimeric antigen receptor (CAR) comprising a signaling region, a co-stimulatory signaling region, a transmembrane domain, and a first binding element that specifically interacts with a first epitope on a MUCl target antigen, and a chimeric co-stimulatory receptor (CCR) comprising a different costimulatory signaling region, a transmembrane domain, and a second binding element that specifically interacts with a second epitope on a second target antigen, as taught by Maher et al. (WO2017021701Al, 2017) and Wilkie et al. (Journal of Immunology, 2008, on IDS filed 03/10/2022), as discussed below, the prior art neither teaches nor suggests the combination of this immunoresponsive cell wherein the cell contains a polynucleotide engineered to encode both the pro-IL-18 cytokine and a TBB/H pCAR comprising the sequences of SEQ ID NOs: 103 or 111. Please note, the sequence corresponding to SEQ ID NO: 103 was the elected species. After it was found to be potentially allowable, examination was continued on the non-elected sequence corresponding to SEQ ID NO: 111.
Therefore, claim 5 remains objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 103
Claim 4 remains rejected and claims 1, 18-19, 27, 30 and 43 are newly rejected under 35 U.S.C. 103 as being unpatentable over Chmielewski et al. (Chmielewski M., Cell Rep. 2017, IDS filed on 02/11/2022) in view of Omoto et al. (Omoto Y, J Dermatol Sci., 2010, IDS filed on 12/17/2024) and Thornberry et al. (Thornberry NA, J Biol Chem., 1997).
This rejection has been modified in response to the claim amendments filed 12/25/2025.
Regarding Claim 1, 4, 19, 30, and 43, Chmielewski teaches an immunoresponsive CART cell engineered with an inducible IL-18 cytokine for cancer immunotherapy (Summary). Chmielewski teaches expression constructs/polynucleotides encoding IL-18 for expression in CAR-T cells (Pg. 3215, Section: Expression Constructs).
Although Chmielewski does teach an active IL-18 fragment, they do not expressly teach the IL-18 is expressed as a modified pro-cytokine of the IL-1 superfamily containing an engineered granzyme b cleavage site and a pro-peptide .
Omoto et al. teaches that pro-IL-18 is a known precursor of active IL-18 (Abstract) and granzyme B can cleave pro-IL-18 to produce active IL-18 in vivo (Pg. 133, 2nd column, 3rd Paragraph) and has a very stable structure and a much longer half-life compared to caspase-1. Specifically, they teach: "Caspase-1 achieves proIL-18 processing within 1 h with a very low enzyme/substrate ratio of 1:1000. GrB cleaved proIL-18 at the same position as did caspase-1. However, GrB required 6 h to complete processing with an enzyme/substrate ratio at 1:8. The present data implicate some different but specific roles of GrB in vivo. Caspase-1 processes IL-18 very rapidly, and it loses 50% of its enzymatic activity only within 5 min. In contrast, GrB takes a long time for processing, but it has a much longer half-life compared to caspase-1. GrB maintains its
enzymatic activity at 50% for 6 days and still retains 20% activity even after 15 days. GrB is therefore very stable and effective for a long time in vivo." (Pg. 133, 2nd column, 1st
Paragraph). Omoto et al. also teaches the use of an expression construct to express recombinant human pro-IL-18 cleavable by granzyme B (Pg. 130, Materials and Methods, Subsections 2.3-2.4).
GrB is a serine protease that requires the presence of an Asp residue at the Pl position (Pg. 133, 1st column, 1st Paragraph). However, the pro-IL-18 cleavage site overlaps with both GrB and the caspase-1 enzyme (see fig. 3 from Omoto below).
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With respect to GrB, the optimal cleavage sequence has been well described. Thornberry et al. teaches the GrB optimal cleavage sequence IEPD (see fig 2. below from Thornberry et al.). IEPD is the same as the instant application sequence corresponding to SEQ ID NO: 26 (Ile Glu Pro Asp) as recited in instant claims 1 and 19.
It would have been obvious to a person of ordinary skill in the art at the time of the instant application to modify the CAR T cell expressing an inducible IL-18 cytokine as taught by Chmielewski according to the teachings of Thornberry et and Omoto et al. by modifying the IL-18 construct to instead encode a pro-IL-18 comprising the known granzyme B cleave sequence IEPD, as taught by Thornberry, at the pro-cytokine cleavage region, in view of Omoto’s teaching that granzyme B processes pro-IL-18 to active IL-18 with favorable stability in vivo. Further, it would have been obvious to prepare a nucleic acid encoding the modified pro-IL-18 described above (reading on instant claim 43) because the sequences of pro-IL-18 and IEPD granzyme B cleavage motif were known and Omoto demonstrates successful use of pro-IL-18 gene construct. One of ordinary skill in the art would understand incorporation of known protease cleavage motifs into a polypeptides to confer protease sensitivity was a routine protein engineering strategy at the time of the instant application.
One would have been motivated to combine these teachings to provide an engineered CAR T cell that retains the anti-tumor benefits of inducible IL-18 while also allowing for active IL-18 production to depend upon proteolytic processing by granzyme B, which is released by activated cytotoxic T cells at the site of tumor cell killing. Moreover, the introduction of the IEPD cleavage site sequence from Omoto into the known sequence of the pro-IL-18 would allow one of ordinary skill in the art to arrive at the sequence corresponding to SEQ ID NO: 27 of claim 4.
One would have been further motivated to combine these teachings because Chmielewski is directed to using the engineered CAR T cells expressing IL-18 of their invention to treat tumors such as pancreatic cancer (Figure 3.) and a CART cell with GrB responsive pro-IL-18 expression would allow for stable/long-term production of IL-18 via cleavage by GrB in a spatially restricted manner (GrB released locally at tumor killing sites) compared to caspase-1.
There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results. Specifically, Omoto demonstrates that GrB cleaves pro-IL-18 at the same site as caspase-1, and Thornberry defines the optimal cleavage motif.
Regarding Claims 18, the combined teachings of Chmielewski, Omoto, and Thornberry above render obvious the cell of claim 1. Moreover, the pro-IL-18 taught by Omoto would yield a mature IL-18, which would inherently comprise the sequence set forth in SEQ ID NO:24. Therefore, the IL-18 would inherently consist of the amino acid sequences represented by SEQ ID NOs: 24, absent any factual evidence to the contrary.
Regarding Claim 27, Chmielewski does not specify whether their collected T cell population is either αβ T cells or γδ T cells, however one of ordinary skill in the art would recognize that the T cells isolated by Chmielewski are necessarily either αβ T cells or γδ T cells.
Regarding claim 30, the engineered T cell taught by Chmielewski in view of Omoto and Thornberry is an engineered CAR T cell (Abstract).
Response to Applicants’ Arguments as they apply to the modified rejection of claim 4 and the newly rejected claims 1, 18-19, 27, 30 and 43 under 35 U.S.C. 103
At pages 8-17 of the remarks filed on 12/25/2025, Applicants essentially argue the following: 1. Chmielewski alone does not teach pro-IL-18, 2. There are no teachings to engineer a GzB cleave site (IEPD), 3. There is no motivation to switch to a pro-cytokine and intracellular cleavage. 4. The unexpected results demonstrate a superiority to the sequence set forth in SEQ ID NO: 26 for a GzB cleavage site.
These arguments have been fully considered but have not been found persuasive.
With respect to point 1, applicant argues at pages 9-10 that “Chmielewski does not disclose or suggest a CAR T cell engineered to express a modified pro-cytokine, as claimed.”
The modified rejection of claim 1 in response to the amendments filed 12/25/2025 demonstrate the combined teaches of Chmielewski, Omoto, and Thornberry render obvious claim 1 as discussed in the 103 rejection above.
With respect to point 2, applicant argues at pages 12-13 that “Chmielewski alone or in combination with Omoto and Thornberry fails to teach or suggest a modified pro-cytokine with a GzB cleavage site of SEQ ID NO: 26”. Additionally, applicant asserts “Omoto does not teach a GzB cleavage site of SEQ ID NO: 26, or even suggest modifying pro-IL18 to change the cleavage site or propose alternative cleavage motifs to that of SEQ ID NO: 26, as claimed. There is no suggestion or guidance in Omoto to make such a modification to the native cleavage site, since Omoto fails to even identify that slow cleavage of pro-IL18 by GzB is a problem and does not connect the cleavage kinetics to reduced therapeutic efficacy.” With respect to Thornberry applicant asserts “Thornberry is a biochemical study aimed at understanding the specificities of
different proteases. In relation to GzB, it discusses that this enzyme may have a role as an upstream component in a proteolytic cascade that amplifies the death signal and concludes that this information could be exploited to produce selective, small molecule inhibitors that will help to further define the biological roles of these enzymes and may have clinical utility. However, Thornberry does not disclose or suggest that the preferred GzB cleavage motif should be introduced into other proteins, let alone a pro-cytokine comprising a biologically active IL18 fragment. Thornberry does not so much as touch on how such protein engineering might affect the cellular expression, folding, stability or therapeutic use. Hence, even if IEPD is preferred biochemically in Thornberry there is no teaching, suggestion or motivation to substitute the native cleavage site of pro-IL18 with IEPD to enhance activity in cells. Any attempt to apply Thornberry to pro-IL18 relies on hindsight, rather than a known teaching or predictable outcome. Thornberry is limited to biochemical characterization and cannot reasonably be combined with the other cited documents to motivate the claimed invention”
Applicants’ argument has not been found persuasive.
Protease specificity is determined by short amino acid recognition motifs, as characterized by Thornberry. Thornberry identifies IEPD as an optimal granzyme B cleavage sequence. It would have been obvious to incorporate such a known cleavage motif into a polypeptide substrate, such as pro-IL-18, to confer or enhance granzyme B-mediated cleavage, as incorporation of protease recognition sequences into proteins would be recognized to a person having ordinary skill in the art as a routine protein engineering strategy. Moreover, Omoto teaches that granzyme B cleaves pro-IL-18 at the same site as caspase-1, thereby establishing that pro-IL-18 is a suitable substrate from granzyme B. Thus, one of ordinary skill would have been motivated to optimize this cleavage using known optimized motifs such as IEPD.
With respect to point 3, applicants’ argument regarding lack of motivation is not persuasive.
Granzyme B is released by activated cytotoxic T cells at the site of target cell killing. Thus, engineering IL-18 to be activated by granzyme B would have predictably localized cytokine activation the tumor microenvironment. This spatial targeting would have been an advantage for therapeutic efficacy. Moreover, Omoto teaches granzyme B exhibits prolonged enzymatic stability relative to caspase-1, providing a predictable basis for sustained cytokine activation. One of ordinary skill in the art at the time of the instant application would therefore be motivated to utilize granzyme B-mediated processing to enhance the durability and localization of the IL-18 activity.
Applicants’ argument that at Pg. 13 that “Thornberry is limited to biochemical characterization and cannot reasonably be combined with the other cited documents to motivate the claimed invention.” is not found persuasive. While Thornberry characterizes protease specificity, such characterization directly informs the design of protease responsive substrates. Therefore, the teachings of Thornberry provide a specific sequence information that would be necessary to engineer an optimal granzyme B responsive protein.
With respect to point 4, in which applicant asserts unexpected results. Applicant’s evidence is not commensurate in scope with the claims and does not demonstrate unexpected results over the closest prior art. The comparison at pages 13-16 of remarks filed 12/25/2025 is between modified pro-IL-18 and unmodified pro-IL-18. Chmielewski teaches expression of active IL-18. The data provided does not establish that the claimed modified pro-IL-18 provides unexpected advantage of active IL-18 constructs of the prior art. Furthermore, improvements in cleavage efficiency or activity resulting from incorporation of an optimal protease recognition sequence would have been expected based on the teaching of Thornberry regarding granzyme B substrate preferences. Therefore, Applicants’ arguments are not considered persuasive and the claims remain rejected.
Claim 31 remains rejected under 35 U.S.C. 103 as being unpatentable over Chmielewski et al. (Chmielewski M., Cell Rep. 2017, IDS filed on 02/11/2022) and in view of Omoto et al. (Omoto Y, J Dermatol Sci., 2010, IDS filed on 12/17/2024) and Thornberry et al. (Thornberry NA, J Biol Chem., 1997) as applied to claim 1 above and 30 above and as evidenced by Tokarew et al. (Tokarew Nicholas et al., British journal of cancer, published 2018).
Regarding claims 1 and 30, the teachings of Chmielewski, Omoto, and Thornberry above render obvious the cell of claims 1 and 31, the content of which is incorporated herein, in its entirety.
Moreover, Chmielewski et al. teaches the composition of their CAR to contain “Lk, light chain kappa signal sequence; SCA431scFv (binding element), CEA-specific single chain (heavy and light) fragment variable (CEA is the specific epitope); IgG1, CH2-CH3 IgG1 ‘‘spacer’’-domain; CD4 transmembrane domain; CD28-CD3z, combined intracellular CD28 and CD3z signaling domain” (Figure 1c).
Chmielewski, Omoto, and Thornberry do not specifically teach their CAR is a second generation CAR, however it would have been obvious to one of ordinary skill in the art to seeking to develop an immunoresponsive, CAR expressing, IL-18 expressing cell to elect to express a 4th generation CAR (such as TRUCKs) as taught by Chmielewski versus an 2nd generation CAR. One would have been motivated to use the 4th generation CAR in place of the 2nd generation CAR as 4th generation CARs are based off of 2nd generation CARs with the additional characteristic of being able to inducibly or constitutively produce desired cytokines as evidenced by Tokarew et al (Fig 1. and corresponding figure legend of Tokarew et al.). Tokarew also describes additional benefits of these 4th generation CARs, including their capacity of transforming the immunosuppressive microenvironment into an immune-permissive one and pointing to inducible IL-18 specifically as capable of inducing enhancing proliferation and anti-tumour activity of monocytes and lymphocyte, without causing significant toxicity in clinical trials (Pg. 34, section: CAR T CELLS AS FACTORIES, Paragraphs 1-2).
As the goal of Chmielewski is the use of their cell for cancer therapy, exerting more control on the release of their cytokine of interest (IL-18) to enhance the capacity of the immune system to target a tumor would be more permissible with the 4th generation CAR versus the 2nd generation CAR.
Further, substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page1395. The modified method/composition of Chmielewski would thus result in an immunoresponsive CAR T cell wherein the 4th generation CAR has the additional capacity to regulate the expression of the cytokine of interest.
Claims 32 and 35 remain rejected under 35 U.S.C. 103 as being unpatentable over Chmielewski et al. (Chmielewski M., Cell Rep. 2017, IDS filed on 02/11/2022) in view of Omoto et al. (Omoto Y, J Dermatol Sci., 2010, IDS filed on 12/17/2024) and Thornberry et al. (Thornberry NA, J Biol Chem., 1997) as applied to claims 1 and 30-31 above and further in view of Wu et al. (Wu G, et al. Int J Mol Sci. 2018) and Wilkie et al. (Wilkie S, J Immunol. 2008).
Regarding Claims 32 and 35, the teachings of Chmielewski, Omoto, and Thornberry above render obvious the immunoresponsive cell of claim 1 and 30-31 as iterated above in the 103 rejections, the content of which is incorporated herein, in its entirety.
Chmielewski, Omoto, and Thornberry do not specifically teach the first epitope of their CAR to be a MUC1 target antigen. However, both MUC1 overexpression and immunotherapeutic targeting in cancer cells (including pancreatic cells) AND engineering CARs to have a first binding element targeting a MUC1 epitope to treat cancer were well established art in the art prior to the instant application.
Wu et al. teaches, “Mucins are known to be present in pancreatic cancer, with elevated expression of multiple MUC family including MUC1. MUC1 overexpression specifically has been linked to tumor progression, invasion and metastasis in breast and pancreatic cancer cells. In addition, MUC1 expression is associated with resistance to anti-cancer drugs, presumably leading poor patient prognosis. Studies have shown increased expression of MUC1 in pancreatic cancer in contrast to the low expression levels observed of MUC1 in the luminal surfaces of a normal control pancreases.”(Pg. 2, 2nd full paragraph of Wu et al.)
Additionally, Wilkie et al. teaches that MUC1 is a highly attractive immunotherapeutic target owing to increased expression, altered glycosylation, and loss of polarity in >80% of human cancers, and that CAR T cells engineered to target MUC1 proliferate vigorously upon repeated encounter with soluble or membrane-associated MUC1, mediate production of proinflammatory cytokines and elicit brisk killing of MUC1+ tumor cells (Abstract, p4901).
With respect to claim 35, Wilkie et al. demonstrated that an HMFG2 scFv incorporated into their CAR system (named H28z) resulted in successful binding to all tumor-associated glycoforms of MUC1 (Pg. 4904, 2nd column, 2nd full paragraph). Moreover, Wilkie demonstrated that their HMFG2 scFV CAR (for claim 35) had higher binding affinity and performed better overall than SM3 scFV CAR (Table 2; Discussion, 4th Paragraph). SM3 being an Ab renowned for its selectivity for tumor-associated MUC1 (Pg. 4903, Results, 1st Paragraph)
It would have been obvious to a person of ordinary skill in the art at the time of the instant application to modify the immunoresponsive cell from the combined teachings of Chmielewski, Omoto, and Thornberry discussed above to further include a binding element specific for an epitope of MUC1 based on the teachings of Wilkie et al. and Wu et al. One would have been motivated to combine these teachings because Chmielewski is directed to using the engineered CAR T cells of their invention to treat tumors such as pancreatic cancer (Figure 3.) and Wu et al. demonstrates MUC1 is overexpressed and readily accessible in pancreatic cancer while Wilke demonstrates the production of a CAR with a binding element directed at MUC1 (specifically, HMFG2- based scFV reading on instant claim 35) and its effectiveness as an immunotherapeutic. it would have been obvious to use the anti-MUC1 CAR because Wilke teaches that MUC1 upregulated in breast cancer (Introduction) and the anti-MUC1 CAR of Wilke effectively killed MUC1+ breast cancer cells (Results, p. 4905).
There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
Claims 36-41 remain rejected under 35 U.S.C. 103 as being unpatentable over Chmielewski et al. (Chmielewski M., Cell Rep. 2017, IDS filed on 02/11/2022) in view of Omoto et al. (Omoto Y, J Dermatol Sci., 2010, IDS filed on 12/17/2024) and Thornberry et al. (Thornberry NA, J Biol Chem., 1997) as applied to claims 1 and 30-31 above and in further view of Maher et al. (WO 2017/021701, IDS filed on 12/17/2024) and Larbouret et al. (Larbouret C, Neoplasia, 2012) as evidenced by Hughes-Parry et al. (Hughes-Parry HE, Int J Mol Sci., 2019)
Regarding Claims 36- 41, the teachings of Chmielewski, Omoto, and Thornberry above render obvious the immunoresponsive cell of claim 1 and 30-31 as iterated above in the 103 rejections, the content of which is incorporated herein, in its entirety.
Chmielewski, Omoto, and Thornberry together do not teach the immunoresponsive cell further comprises a chimeric co-stimulatory receptor comprising a second co-stimulatory signalling region; a transmembrane domain; and a second binding element that specifically interacts with a second epitope on a second target antigen (for claim 36) or that the second costimulatory domain is different from the first (for claim 37). Chmielewski, Omoto, and Thornberry also do not teach the second target antigen with a second epitope selected from ErbB heterodimers, including those containing EGFR and HER2, or that the second binding element comprises T1E (for claims 38 - 41).
ErbB heterodimers such as EGFR-HER2 overexpression and their recognition as therapeutic target in cancers (including pancreatic cells) AND engineering immune-responsive cells to have express both a CAR and CCR to treat cancer were established in the art prior to the instant application.
Larbouret et al. teaches overexpression of EGFR HER2 overexpression occurs in pancreatic cancers with EGFR/HER2 heterodimers playing role in these cancers and involvement in their malignant phenotypes leading to therapeutic strategies targeting them (Pg. 121-122, Introduction, 1st Paragraph).
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Maher et al. teaches an immunoresponsive cell that has a chimeric co-stimulatory receptor with the structural limitations of the instant claim 36 and 37 (see image below taken from pg. 3 of Maher et al.).
Moreover, Maher teaches a binding element of their invention may comprise ligands such as the TlE peptide which binds ErbB homo- and heterodimers (Pg. 11, Lines 26-27). Further, T1E is well established to bind all ErbB as evidenced by Hughes-Parry et al. who teaches T1E binds to ErbB1- and ErbB4-based homo- and hetero-dimers, and ErbB2/3 heterodimers, which would not have been possible using any other CAR format (Pg. 4-5, Section 2.4 of Hughes-Parry). This reads on the limitations of claims 38 - 41 respectively.
It would have been obvious to a person of ordinary skill in the art at the time of the instant application to modify the immunoresponsive cell taught by Chmielewski, Omoto, and Thornberry to further include a chimeric co-stimulatory receptor based on the teachings of Maher et al. and Larbouret et al. One would have been motivated to combine these teachings because Chmielewski’s teachings are directed to using the engineered CAR T cells of their invention to treat tumors such as pancreatic cancer (Figure 3.) and Larbouret et al. demonstrates EGFR and HER2 (ErbB1 and 2) are overexpressed and a therapeutic target in pancreatic cancer while Maher demonstrates the addition of a CCR with a T1E binding peptide to an engineered CAR T cell would allow the two constructs (CAR and CCR) to bind to their respective antigens with different binding affinities and this leads to a 'tumour sensing' effect that may enhance the specificity of the therapy with a view to reducing side effects (Pg.2, Lines 25-30), while maintaining the capacity for proliferation, cytotoxic potency and cytokine release over many repeated rounds of stimulation with antigen-expressing tumour cells (Pg. 4, 1st Paragraph).
There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
Conclusion
1, 4, 18-19, 27, 30-32, 35-41 and 43 are rejected.
Claim 5 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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/KODYE LEE ABBOTT/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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