DETAILED ACTION
Claims 1-32, 36, 43-47, 53, 55-59, 61-63, 64 and 67-88 were/stand cancelled. Claims 33-35, 37-42, 48, 52, 54, 60, 64, 66 and 89-93 are pending.
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 .
Priority
This application is a CON of 17/025,607 (09/18/2020; PAT 11,564,947) which is a CON of 15/989,098 (05/24/2018; PAT 10,780,119) which claims benefit of 62/657,564 (04/13/2018) and claims benefit of 62/510,680 (05/24/2017).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on January 24 2023 were in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 33 is objected to because of the following informalities: The acronym “MNK” is not defined in the claims. When an acronym is used in a claim set, it should be defined the first time it appears in the claims. For the purposes of examination, the term “MNK” is interpreted to mean MAP-kinase interacting kinases. Appropriate correction is required.
Claim 60 is objected to because of the following informalities: The acronym “TCR” and “HLA” are not defined in the claims. When an acronym is used in a claim set, it should be defined the first time it appears in the claims. For the purposes of examination, the term “TCR” is interpreted to mean T cell receptor; “HLA” is interpreted to mean human leukocyte antigen. Appropriate correction is required.
Claim 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.
Claims 33-35, 37-42, 48, 52, 54, 60, 64, 66, 89 and 91-93 are 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.
The term “lower alkyl” in claims 33 and 37, is a relative term which renders the claim indefinite. The term “lower” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While the recitation ethyl, methyl, propyl, butyl, iso-propyl, sec-butyl or tert-butyl as set forth on page 81 of the instant specification are definite, the specification fails to provide a definition of lower alkyl such that one skilled in the art would understand at what point the alkyl is no longer considered “lower alkyl”. As evidenced in the art, this recitation can have different meanings/scope. For example, Rohloff et al. (USPGPUB No. 20160215013) indicates it is C1-C6 (claim 4); whereas Heo et al. (US Patent No. 11504349) indicates it is C1-C4 (claim 1); whereas Wang et al. (USPGPUB No. 20160007598) indicates it is C2-C6 (claim 4). Since the term is defined differently throughout the art and the instant specification provides no indication of the scope other than the specific recitations identified above, the recitation is indefinite.
Claims 34, 35, 37 and 40 all recite: “simultaneously, concurrently, sequentially”. While sequentially has a different meaning than the other choices, simultaneously and concurrently do not appear to have a different definition in the art. Merriam-Webster defines concurrent to mean operating or occurring at the same time. And even indicates simultaneous is a synonym. Merriam-Webster defines simultaneously as meaning at the same time: concurrently. Since these terms appear to be recited in the alternative (i.e. claims 34-35 recites “or”) it would imply they have different meanings. But the instant specification fails to provide any guidance as to how simultaneously and concurrently are of a different scope when the broadest reasonable interpretation is their normal definition in the art which suggests they mean the same thing.
Claim 37 as currently written is vague and indefinite. The claim recites the contacting step occurs “simultaneously, concurrently, sequentially” with the introduction of the transgene. There is no conjunction between concurrently and sequentially. Therefore, it isn’t’ clear if these are in the alternative. This creates confusion as to the contacting step.
Claim 40 as currently written is vague and indefinite. The claim recites the internal MNK-specific inhibitor is introduced into the T cell occurs “simultaneously, concurrently, sequentially” with the transgene. There is no conjunction between concurrently and sequentially. Therefore, it isn’t’ clear if these are in the alternative. This creates confusion as to the contacting step.
Claim 41 as currently written is vague and indefinite. The claim recites “and introducing an internal MNK-specific inhibitor” but the claim never indicates where the inhibitor is introduced. The wherein clause following the inhibitor recitation appears to just indicate the expression of MNK1, MNK2 or both is inhibited in the T cell but never actually indicates where the MNK-specific inhibitor is introduced. This is different than claim 40 which clearly states that the inhibitor is introduced into the T cell.
Claim 54 as currently written is vague and indefinite. The claim recites “an endonuclease selected from a CRISPR/Cas nuclease system..and a meganuclease”. The recitation “and” does not include the choices in the alternative. As set forth in MPEP 2117 proper Markush language is “selected from the group consisting of A, B and C” OR “selected from A, B or C”. Here, the claims use selected from but the conjunction “and”. Therefore, the species are not listed in the alternative. This suggests that the internal MNK-specific inhibitor is all of those at the same time which is confusing.
Claim 54 contains the trademark/trade name TALEN. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. While TALEN is a recognized abbreviation for transcription activator like effector nuclease, that does not preclude the fact that TALEN is a trademark (Registration number 4729507). It is suggested that the recitation TALEN be removed from the claims. If an abbreviation is desired, the abbreviation TALE nuclease or TAL-effector nuclease can be utilized.
Claims 38-39, 42, 48, 52, 60, 64, 66, 89 and 91-93 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
Claim Rejections - 35 USC § 103
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 37-38, 42, 48, 60, 64 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Cherkassky et al. (Oncology, 2016) in view of Webster et al. (USPGPUB No. 20160303124).
Applicant Claims
The instant application claims a method of generating a modified T cell, the method comprising contacting a T cell with a MNK-specific inhibitor; and introducing a transgene encoding an engineered antigen specific receptor into the T cell, wherein the contacting step occurs simultaneously, concurrently, sequentially with the introduction of the transgene encoding the engineered antigen specific receptor into the T cell, thereby generating the modified T cell, wherein the MNK-specific inhibitor is a compound according to Formula I.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Cherkassky et al. is directed to human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Investigation into whether programmed death-1–mediated (PD-1–mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells was conducted. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies (abstract; page 3141, right column). Exemplified is T cell isolation and gene transfer wherein the CAR sequence was inserted into a retroviral vector wherein peripheral blood mononuclear cells were transduced with the retroviral particles (methods page 3142). Taught is cotransduction with PD-1 shRNA which generated more than 60% PD-1 receptor knockdown at the protein level (page 3140, left column).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Cherkassky et al. suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies, Cherkassky et al. does not expressly teach administration to the T cell of a compound of formula I. However, this deficiency is cured by Webster et al.
Webster et al. is directed to inhibitors of immune checkpoint modulators and related methods. Claimed is a method of inducing or enhancing an immune response comprising administering a therapeutically effective amount of a MNK-specific inhibitor to a subject in need thereof (claim 1). The induced or enhanced immune response is an antigen-specific T cell response (claim 8). The method further comprises administering an inhibitor of an immunosuppressive component which can be an siRNA (claims 9-10). The method further comprises administering a therapy that induces or enhances an anti-cancer response which could be a vaccine, an inhibitor of an immunosuppression component, a B-Raf inhibitor, a MEK inhibitor, a VEGF inhibitor, a VEGFR inhibitor, a tyrosine kinase inhibitor, a cytotoxic agent, a chemotherapeutic, or any combination thereof (claim 17). The MNK-specific inhibitor and inhibitor of an immunosuppression component are administered simultaneously, concurrently, sequentially, or any combination thereof (claim 25). The MNK-specific inhibitor and therapy that induces or enhances an anti-cancer response are administered simultaneously, concurrently, sequentially, or any combination thereof (claim 25). The MNK-specific inhibitor reduces the expression of PD-1 (claim 27) wherein the expression of PD-1 is reduced in a T cell (claim 28). The MNK-specific inhibitor is of formula I which is the same as instantly claimed (claim 62).
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which clearly shows the compound is non-toxic (i.e. no cell death) but had significant effect on PD-1 (table 2A).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Cherkassky et al. and Webster et al. and administer the MNK-specific inhibitors of Webster et al. in combination with introducing a transgene encoding an engineered antigen specific receptor (aka the retroviral vector with the CAR sequence taught in Cherkassky et al.) into T-cells. One skilled in the art would have been motivated to contact a T-cell with the combination as Cherkassky et al. teaches PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies. Since the MNK-specific inhibitors taught in Webster et al. are expressly taught as inhibiting PD-1 and Webster et al. expressly teaches their administration can be combined with other therapies which enhance the anti-cancer effect, there is a reasonable expectation of success.
Regarding the claimed contacting step occurs simultaneously, concurrently or sequentially, Webster et al. teaches this same limitation (claim 25).
Regarding claim 38, Cherkassky et al. teaches T cells were subjected to ex vivo antigen stimulation (figure 4).
Regarding claim 42, Cherkassky et al. teaches a chimeric antigen receptor (CAR).
Regarding claim 38, Webster et al. teaches the same compound (compound 107).
Regarding claim 60, Cherkassky et al. teaches that the MBBz CAR T cells expressed less immunosuppressive cytokines such as IL-10 and TGF-beta (page 2141, left column) reading on inhibiting expression of an immunosuppression component gene.
Regarding claim 64, Cherkassky et al. teaches MSLN is a tumor-associated cell-surface antigen and the CARs are MSLN-targeted (introduction; Figure 1).
Regarding claim 66, Cherkassky et al. teaches CAR CD4+ or CD8+ T cells (page 3142, left column).
Claims 39-41, 52, 89 and 91-93 are rejected under 35 U.S.C. 103 as being unpatentable over Cherkassky et al. in view of Webster et al. as applied to claims 37-38, 42, 48, 60, 64 and 66 above and in further view of Grzmil et al. (US PGPUB No. 20110280886).
Applicant Claims
The instant application claims the method (claim 37 above) further comprising introducing an internal MINK-specific inhibitor into the T cell, wherein expression of endogenous MNK1,MNK2, or both is inhibited in the T cell.
The instant application claims a method of generating a modified T cell, the method comprising introducing a transgene encoding an engineered antigen specific receptor into a T cell, and introducing an internal MNK-specific inhibitor, wherein expression of endogenous MNK1,MNK2, or both is inhibited in the T cell, thereby generating the modified T cell.
Claims 35, 39-41, 52 and 54 all recite “introducing an internal MNK-specific inhibitor”. The instant specification teaches that this inhibitor include gene “knock out” and gene “knock down” that inactivates reduces or minimizes MNK1 activity, MNK2 activity or both (page 7).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Cherkassky et al. and Webster et al. are set forth above. Cherkassky et al. teaches an inhibitory nucleic acid, shRNA. Webster et al. teaches MNK inhibitors and the inhibitor can be combined with other inhibitors of an immunosuppression component.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Cherkassky et al. teaches an inhibitory nucleic acid, shRNA, Cherkassky et al. does not teach an internal MNK-specific inhibitor. However, this deficiency is cured by Grzmil et al.
Grzmil et al. is directed to treating cancer by modulating MNK. MNK can be modulated by an inhibitor such as a small molecule or an siRNA (claims 2, 3, 6). Figure 5 shows that MNK1-specific knockdown sensitizes cells to rapamycin (paragraph 0024). BS125 cells were transfected with duplex siRNA oligonucleotides against the MNK1 gene (paragraph 0025; 0163). “RNAi” is the process of sequence specific post-transcriptional gene silencing in animals and plants. It uses small interfering RNA molecules (siRNA) that are double-stranded and homologous in sequence to the silenced (target) gene. Hence, sequence specific binding of the siRNA molecule with mRNAs produced by transcription of the target gene allows very specific targeted knockdown’ of gene expression (paragraph 0107).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Cherkassky et al., Webster et al. and Grzmil et al. and additionally administer an siRNA (an inhibitory nucleic acid) to the T cell with the MNK inhibitor. One skilled in the art would have been motivated to utilize the siRNA to knockdown MNK expression as taught by Grzmil et al. in order to treat cancer. Since Cherkassky et al., Webster et al. and Grzmil et al. are all concerned with treating cancer and Webster et al. teaches that the MNK inhibitor can be administered with other compounds which produce an anti-cancer effect there is a reasonable expectation of success.
Regarding claim 89, Cherkassky et al. teaches a chimeric antigen receptor (CAR).
Regarding claim 91, Cherkassky et al. teaches that the MBBz CAR T cells expressed less immunosuppressive cytokines such as IL-10 and TGF-beta (page 2141, left column) reading on inhibiting expression of an immunosuppression component gene.
Regarding claim 92, Cherkassky et al. teaches MSLN is a tumor-associated cell-surface antigen and the CARs are MSLN-targeted (introduction; Figure 1).
Regarding claim 93, Cherkassky et al. teaches CAR CD4+ or CD8+ T cells (page 3142, left column).
Claims 33-35, 54, 60 and 90-91 are rejected under 35 U.S.C. 103 as being unpatentable over Cherkassky et al. in view of Webster et al. and in further view of Grzmil et al. as applied to claims 39-41, 52, 89 and 91-93, Bitter et al. (USPGPUB No. 20160362472, cited on PTO Form 1449), Wang et al. (Molecular Therapy Oncology, 2016) and Duran et al. (Targeted Oncology, 2016).
Applicant Claims
The instant application claims a method of generating a modified T cell, the method comprising introducing a transgene encoding an engineered antigen specific receptor into a T cell collected from a subject treated with a MNK-specific inhibitor, thereby generating the modified T cell, wherein the subject treated with the MNK-specific inhibitor was treated 1, 2, 3, 4, 5, 6, 7, 14,21, or 28 days prior to collection of the T cell from the subject, and wherein the MNK-specific inhibitor is a compound according to formula I.
The instant application claims the internal MNK-specific inhibitor is a chromosomal MNK gene knock out by chromosomal editing via an endonuclease selected from a CRISPR/Cas nuclease system, a zinc finger nuclease (ZFN), a Transcription Activator Like Effector nuclease (TALEN), and a meganuclease.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Cherkassky et al.,Webster et al. and Grzmil et al. are set forth above. Cherkassky et al. teaches an inhibitory nucleic acid, shRNA. Webster et al. teaches MNK inhibitors and the inhibitor can be combined with other inhibitors of an immunosuppression component. Grzmil et al. teaches the use of an inhibitory nucleic acid to knockdown MNK.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Cherkassky et al. teaches a transgene encoding an engineered antigen specific receptor into a T Cell, and Webster et al. teaches the use of the instantly claimed MNK inhibitors in a subject, Cherkassky et al. does not expressly teach the T cell is collected from a subject which was treated with an inhibitor. While Cherkassky et al. teaches an shRNA, Cherkassky et al. does not teach MNK gene knock out by chromosomal editing. However, these deficiencies are cured by Bitter et al., Wang et al. and Duran et al.
Bitter et al. is directed to cd20 therapies, cd22 therapies, and combination therapies with a cd19 chimeric antigen receptor (car)- expressing cell. It is taught an inhibitory nucleic acid such as a siRNA or shRNA, a clustered regularly interspaced short palindromic repeats (CRISPR), a transcription-activator like effect nuclease (TALEN) or a zinc finger endonuclease (ZFN) can be used to inhibit expression of a molecule that modulates or regulates (paragraph 0780). Modified T cells that lack expression of a functional TCR and/or HLA can be obtained by any suitable means, including a knock out or knock down of one or more subunit of TCR or HLA. For example, the T cell can include a knock down of TCR and/or HLA using siRNA, shRNA, clustered regularly interspaced short palindromic repeats (CRISPR) transcription-activator like effector nuclease (TALEN), or zinc finger endonuclease (ZFN) (paragraph 0835). Recent developments using chimeric antigen receptor (CAR) modified autologous T cell (CART) therapy, which relies on redirecting T cells to a suitable cell-surface molecule on cancer cells such as B cell malignancies, show promising results in harnessing the power of the immune system to treat B cell malignancies and other cancer (paragraph 0005). The cell expressing the CAR molecule is a cell described herein, e.g., a human T cell or a human NK cell, e.g., a human T cell described herein or a human NK cell described herein. In one embodiment, the human T cell is a CD8+ T cell. In one embodiment, the human T cell is a CD4+ T cell. In one embodiment, the human T cell is a CD4+/CD8+ T cell. In one embodiment the human T cell is a mixture of CD8+ and CD4+ T cells. In one embodiment, the cell is an autologous T cell (paragraph 0079). The cell expressing the CAR can further express another agent, e.g. an agent which enhances the activity of a CAR expressing cell (paragraph 0080).
Wang et al. is directed to the clinical manufacturing of CAR T cells: foundation of a promising therapy. The treatment of cancer patients with autologous T cells expressing a chimeric antigen receptor (CAR) is one of the most promising adoptive cellular therapy approaches. Adoptive cell therapy using naturally occurring endogenous tumor-infiltrating lymphocytes or T cells genetically engineered to express either T-cell receptors or chimeric antigen receptors (CAR) have emerged as promising cancer immunotherapy strategies. Adoptive cellular therapy involves the ex vivo enrichment and expansion of T lymphocytes (abstract). As a mostly autologous cell-based therapy, the CAR-T cell-manufacturing process starts from the collection of peripheral blood mononuclear cell from the patient, commonly achieved by a leukapheresis process. Consenting physicians choose the appropriate window for collection based on treatment regimens to ensure the presence of sufficient numbers of T lymphocytes (T-cell source).
Duran et al. is directed to resistance to targeted therapies in renal cancer, the importance of changing the mechanism of action. Renal cell carcinoma (RCC) is a complex disease characterized by mutations in several genes. Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a very common finding in RCC and leads to up-regulation of hypoxia-inducible factor (HIF)-responsive genes accountable for angiogenesis and cell growth, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Binding of these proteins to their cognate tyrosine kinase receptors on endothelial cells promotes angiogenesis. Promotion of angiogenesis is in part due to the activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway. Inhibition of this pathway decreases protein translation and inhibits both angiogenesis and tumor cell proliferation. Although tyrosine kinase inhibitors (TKIs) stand as the main first-line treatment option for advanced RCC, eventually all patients will become resistant to TKIs. Resistance can be overcome by using second-line treatments with different mechanisms of action, such as inhibitors of mTOR, c-MET, programmed death 1 (PD-1) receptor, or the combination of an mTOR inhibitor (mTORi) with a TKI (abstract). Fig. 1 shows where MNK is in the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR pathway. Strategies to prevent and overcome resistance is switching to an alternative drug and combination therapies (section 5).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Cherkassky et al.,Webster et al., Grzmil et al. Bitter et al., Wang et al. and Duran et al. and utilize CRISPR, TALEN or Zinc fingers to knockdown MNK. One skilled in the art would have been motivated to utilize these strategies as Grzmil et al. specifically teaches knockdown with an inhibitor nucleic acid, Bitter et al. teaches that inhibitory nucleic acids, CRISPR, TALEN or Zinc fingers can be used to inhibit expression of a molecule that modulates or regulates. Since they are all known ways in which expression of a gene can be modulated and Grzmil et al. teaches the motivation to knockdown MNK, one skilled in the art would have a reasonable expectation of success in substituting one known method with another with a reasonable expectation of success. Note: MPEP 2144. Rendering claim 54 obvious.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Cherkassky et al.,Webster et al., Grzmil et al. Bitter et al., Wang et al. and Duran et al. and utilize autologous T cells (i.e. T cells collected from the patient) which have been treated with a MNK-specific inhibitor prior to collection. Firstly, as taught by Duran et al. in situations of resistance, strategies to prevent and overcome resistance is switching to an alternative drug and combination therapies. Secondly, Cherkassky et al. recognizes that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies and Webster et al. teaches that the MNK-specific inhibitor can be utilized to block PD-1. Since Wang et al. teaches treatment of cancer patients with autologous T cells expressing a chimeric antigen receptor (CAR) is one of the most promising adoptive cellular therapy approaches, the use of T cells collected from a subject would have obvious. One skilled in the art would have been motivated to collect the T cells from a subject following treatment with a MNK-specific inhibitor to either switch to an alternative drug or drug combination in order to treat resistance as taught by Duran et al. or to allow for blockage of PD-1 which would then allow for improvement in the potency of the CAR T cell therapies as taught by Cherkassky et al. Wang et al. recognizes that consenting physicians choose the appropriate window for collection based on treatment regimens. Since Webster et al. teaches the same MNK-specific inhibitor, the combination suggests the limitations of claim 33.
Regarding claim 34, as established above, blockage of PD-1 which would then allow for improvement in the potency of the CAR T cell therapies as taught by Webster et al. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Cherkassky et al.,Webster et al., Grzmil et al. Bitter et al., Wang et al. and Duran et al. to continue to contact the T cells with the inhibitor at the same time as introduction of the transgene encoding the CAR in order to provide for continued improvement in the potency of the CAR T cell.
Regarding claim 35, as set forth above the use of an internal MNK-specific inhibitor is obvious. Since Duran et al. recognize the shift in treatment to include multiple different pathways to deal with resistance, one skilled in the art would have been motivated to administer a combination of different inhibitors which work in different ways in order to treat various cancers.
Regarding claim 90, compound 107 of Webster et al. is the same as instantly claimed.
Regarding claims 60 and 91, although addressed above, Bitter et al. also teaches modified T cells that lack expression of a functional TCR and/or HLA can be obtained by any suitable means, including a knock out or knock down of one or more subunit of TCR or HLA. For example, the T cell can include a knock down of TCR and/or HLA using siRNA, shRNA, clustered regularly interspaced short palindromic repeats (CRISPR) transcription-activator like effector nuclease (TALEN), or zinc finger endonuclease (ZFN). Thus, inhibiting expression of TCR and/ HLA is obvious and can be accomplished by various means as taught by Bitter et al.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636