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 .
Claims 1-20 are pending in the present application.
Applicant's election with traverse of Group I in the reply filed on 07/30/2026 is acknowledged. Applicant also elected with traverse the following species: (i) in vivo; (ii) a Src kinase inhibitor; (iii) an Lck inhibitor; (iv) a T cell; (v) a genetically modified cell; (vi) genetically modified to express one or more natural immune receptors or a synthetic immune receptor that target one or more predefined antigens; and (v) CD19. With respect to the elected Lck inhibitor, the Examiner has rejoined and examined Dasatinib as an Lck inhibitor.
I. With respect to Group restriction, the traversal is on the ground(s) that claims 18-20 have been placed in Invention I but incorporate every limitation of claim 12, which has been placed in Invention II. Thus, examination of claims 18-20 requires consideration of the composition of claim 12, and the requirement does not avoid the search and examination burden it is directed to avoiding.
This is not found persuasive because: (i) Claims 18-20 are broad method claims that encompass a method of adoptive cell therapy of Invention I; (ii) As stated in the Restriction Requirement dated 06/02/2026, Inventions II and I are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case, the composition of Invention II can be used at least in an in vitro screening assay for therapeutic agents that are useful for an adoptive cell therapy; and (iii) The product of Invention II is much broader than the product used in the method of Invention I, and therefore it would have require undue burden for the Examiner to search and/or consider the patentability (examination) of both Inventions I-II in a single patent application. Moreover, the examiner has required restriction between product and process claims. Where applicant elects claims directed to the product, and a product claim is subsequently found allowable, withdrawn process claims that depend from or otherwise include all the limitations of the allowable product claim will be rejoined in accordance with the provisions of MPEP § 821.04. Process claims that depend from or otherwise include all the limitations of the patentable product will be entered as a matter of right if the amendment is presented prior to final rejection or allowance, whichever is earlier. Amendments submitted after final rejection are governed by 37 CFR 1.116; amendments submitted after allowance are governed by 37 CFR 1.312.
II. With respect to species restriction, the traversal is on the ground(s) that the alternatives recited in claim 9 are not mutually exclusive and are not distinguished on the basis that each of the recited species is distinct structurally one from the other, as well as having different properties one from the others. Additionally, Applicant argued that an Lck inhibitor is a sub-genus that encompasses the remaining Dasatinib, Ponatinib and A-77041 as species of Src kinase inhibitor; and the four recited alternatives are not mutually exclusive. Applicant further argued that the successive species requirement do not correspond to a distinct search and examination burden because a search directed to the elected subject matter, namely, use of a Src family kinase inhibitor in connection with an adoptive cell therapy employing genetically modified immune effector cells, would in the ordinary course encompass the recited species. Moreover, Applicant argued that patent applications would be found in A61K 40/0 and A61P 35/00, and relevant scientific publications are addressed in a common body of non-patent literature.
This is not found persuasive because:
(i) With respect to the species restriction in claim 9, at least an in vitro contact of an immune cell or an immune effector cell with an agent is distinct from an in vivo contact of an immune cell or an immune effector cell with an agent in a method of adoptive cell therapy; and they would require different technical considerations to attain the desired end-results (e.g., prevent and/or treat one or more toxicities and/or complications associated with adoptive cellular therapies, see dependent claim 11);
(ii) With respect to the species restriction for a Src kinase inhibitor, at least Dasatinib, Ponatinib and A-990041 are distinct structurally and have different properties one from the others. This is evident at least by different blocking efficiencies of CD19-CAR-T cell induced cell death by Dasatinib and Ponatinib as shown in Fig. 36 of the present application. Additionally, a reference disclosing Dasatinib does not necessarily also disclose Ponatinib as evidenced at least by the prior art in the form of Fraser et al (Experimental Hematology 37:256-265, 2009), and Schade et al (Blood 111:1366-1377, 2008).
(iii) Although patent applications would be found in A61K 40/0 and A61P 35/00, and relevant scientific publications in a common body of non-patent literature, it is nevertheless undue burden for the examiner to search and/or consider the patentability (examination) of a plethora of species encompassed by the claims of the present application. For example, the prior art in the form of Fraser et al (Experimental Hematology 37:256-265, 2009) and Schade et al (Blood 111:1366-1377, 2008) do not disclose at least the species Potaninib, let alone all other species recited by claims of the present application.
The requirement is still deemed proper and is therefore made FINAL.
Accordingly, claims 12-17 were withdrawn from further consideration because they are drawn to a non-elected invention.
Thus, claims 1-11 and 18-20 are examined on the merits herein with the above elected species.
Claim Objections
Claims 2 and 4 are objected to because of the term “A-77041” which appears to be a typo. It should be - - A-770041 - -.
Claims 18 and 20 are objected to because they are dependent on claim 12 which is drawn to a non-elected invention.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-11 and 18-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A. A method of adoptive cell therapy comprising contacting an immune effector cell with an agent selected from the group consisting of: Dasatinib, Ponatinib and A-770041, wherein said immune effector cell is an autologous or allogeneic immune effector cell; and
B. A method comprising administering to a subject a composition comprising at least an agent selected from the group consisting of: Dasatinib, Ponatinib and A-770041, and an autologous or allogeneic immune effector cell to a subject; and
C. A method of controlling the activity of an adoptive cell therapy and/or treating toxicities and/or complications associated with an adoptive cellular therapy comprising administering a therapeutically effective amount of a composition comprising at least an agent selected from the group consisting of: Dasatinib, Ponatinib and A-770041, and an autologous or allogeneic immune effector cell to a subject, wherein the toxicities and/or complications associated with an adoptive cellular therapy are selected from the group consisting of:
i) cytokine release syndrome;
ii) neurological complication;
iii) capillary leak syndrome;
iv) hemophagocytic lymphohistiocytosis (HLH);
v) Macrophage Activation Syndrome (MAS); and
vi) any combinations of (i)-(v);
does not reasonably provide enablement for other methods as claimed broadly. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors to be considered in the determination of an enabling disclosure have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art and the breadth of the claims. Ex parte Forman, (230 USPQ 546 (Bd Pat. Appl & Unt, 1986); In re Wands, 858 F.2d 731, 8 USPQ 2d 1400 (Fed. Cir. 1988)).
When read in light of the instant specification, the sole purpose for a method of adoptive cell therapy comprising contacting an immune cell or an immune effector cell with an agent selected from the group consisting of an inhibitor of T cell mediated target cell killing, an inhibitor of NK cell mediated target cell killing, an inhibitor of cytokine production and any combination thereof or a method comprising administering to a subject a composition comprising at least a Src kinase inhibitor and/or an Lck inhibitor with an immune cell or an immune effector cell is to control or terminate the activity of said immune cell or said immune effector cell (see at least paragraphs [00574]-[00577], [00749]-[00759], and Figs. 35-38 and 41). The instant specification is not enabled for the instant broadly claimed invention for the reasons discussed below.
1. The breadth of the claims
Claims 1-11 encompass a method of adoptive cell therapy comprising contacting an immune cell or an immune effector cell with any agent as long as it is selected from the group consisting of an inhibitor of T cell mediated target cell killing, an inhibitor of NK cell mediated target cell killing, an inhibitor of cytokine production and any combination thereof, including any Src kinase inhibitor or any Lck inhibitor, and not necessarily limited to Dasatinib, Ponatinib and A-770041; and that the immune cell or the immune effector cell is autologous, allogeneic and/or xenogeneic cell in the adoptive cell therapy. Claims 18-19 encompasses a method comprising administering a composition comprising at least any Src kinase inhibitor and/or any Lck inhibitor with an immune cell or an immune effector cell derived from any source (e.g., autologous, allogeneic and/or xenogeneic sources) to a subject. Claim 20 encompasses a method of controlling the activity of an adoptive cell therapy and/or preventing and/or treating toxicities and/or any complications associated with adoptive cellular therapies comprising administering a therapeutically effective amount of a composition comprising at least any Src kinase inhibitor and/or any Lck inhibitor with an immune cell or an immune effector cell derived from any source.
2. The state and the unpredictability of the prior art
Before the effective filing date of the present application (03/18/2016), little was known about the use of any Src kinase inhibitor and/or any Lck inhibitor, not necessarily limited to Dasatinib, Ponatinib and A-770041, to treat one or more toxicities and/or complications associated with adoptive cellular therapies as evidenced at least by the teachings of Ivan (WO 2017/025638) in view of Fraser et al (Experimental Hematology 37:256-265, 2009), Fraser et al (Experimental Hematology 37:256-265, 2009), Schade et al (Blood 111:1366-1377, 2008) and Zhao et al (WO 2016/069283). Moreover, physiological art is recognized as unpredictable (MPEP 2164.03).
3. The amount of direction or guidance provided
Apart from disclosing Dasatinib, Ponatinib and A-770041 are capable of blocking at least CD19-CAR-T cells induced target cell death in vitro, and Dasatinib also blocks cytotoxicity induced parental NK92MI cells and those modified to express a CAR in vitro (paragraphs [00752], [00754]-[00755], [00758]-[00759], and Figs. 35-38 and 41); the instant specification failed to provide sufficient guidance for an ordinary skilled artisan on how to make and use any other Src kinase inhibitor and/or any other Lck inhibitor in an adoptive cell therapy, particularly to prevent and/or treat one or more toxicities and/or complications associated with adoptive cell therapies, not necessarily limited to those recited in the Markush group in claim 11, in a subject as claimed broadly by the instant claims. Particularly, the instant specification also disclosed specifically that unlike A-770041, Saracatinib which is another Lck inhibitor had no significant effect on blocking CAR-T cells induced death of RAII-pLenti-Gluc cells (paragraph [00759] and Fig. 41B). There is also no evidence of record indicating or suggesting that apart from exemplary immune effector cells (e.g., T-cells, CAR-T cells, NK cells and CAR-NK cells) whether Dasatinib, Ponatinib and A-770041 have any effect on other immune cells, let alone any Src kinase inhibitor and/or any Lck inhibitor as encompassed broadly by the instant claims. Moreover, none of the in vitro data presented for Dasatinib, Ponatinib and A-770041 in Figs. 35-38 and 41 demonstrated that any of these Lck inhibitors is capable of blocking completely induced cell death and/or induced cytotoxicity in CAR T cells/CAR NK cells, and/or NK cells; let alone to prevent toxicities and/or complications associated with adoptive cellular therapies in a subject using any Src kinase inhibitor and/or any Lck inhibitor as encompassed broadly by claims 11 and 20. Furthermore, the instant specification also failed to provide sufficient guidance for an ordinary skill in the art on how to make and use any xenogeneic immune cell or xenogeneic immune effector cell in any adoptive cell therapy in a subject, including in a human subject; particularly these xenogeneic cells would elicit potent and vigorous rejection immune responses in a recipient subject. There is no evidence of record indicating or suggesting that any Src kinase inhibitor and/or Lck inhibitor are capable of treating, let alone preventing, toxicities and/or complications generated by the adverse xenogeneic rejection immune response in a subject.
Since the prior art before the effective filing date of the present application failed to provide sufficient guidance regarding the above issues, it is incumbent upon the present application to do so. Given the state of the prior art, coupled with the lack of sufficient guidance provided by the present application, it would have required undue experimentation for a skilled artisan to make and use the instant invention as claimed broadly.
As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires:
That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.
Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maizel.).
Accordingly, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state and unpredictability of the relevant art, and the breadth of the instant claims, it would have required undue experimentation for one skill in the art to make and use the instant broadly claimed invention.
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 2 is 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 2 recites the broad recitation “a Src kinase inhibitor”, and the claim also recites “optionally an Lck inhibitor; optionally selected from the group of Dasatinib, Ponatinib, and A-77041” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5, 9-11, 18 and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fraser et al (Experimental Hematology 37:256-265, 2009).
Claims 1-5, and 9-11 encompass a method of adoptive cell therapy comprising contacting an immune cell or an immune effector cell with a dasatinib which is an Lck inhibitor or a Src kinase inhibitor. Claim 18 encompasses a method comprising administering a composition comprising a Src kinase inhibitor and/or a Lck inhibitor and an immune cell or an immune effector cell. Claim 20 encompasses a method of controlling the activity of an adoptive cell therapy comprising administering a therapeutically effective amount of a composition comprising a Src kinase inhibitor and/or a Lck inhibitor and an immune cell or an immune effector cell.
Fraser et al already disclosed at least a method comprising adoptively transferring CFCE-labeled OT-I or OT-II mouse T cells (transgenic CD8+ T cells and transgenic CD4+ T cells that recognize a chicken OVA peptide in the context of H-2Kb and I-Ab, respectively) into recipient mice that were treated with dasatinib via oral gavage, which were then immunized with either OVA257-264 or OVA323-339 peptides, respectively (see at least Abstract; Sections titled “Mice”, “Drug preparation” and “Dsatinib inhibits antigen-specific in vivo expansion of CD8+ and CD4+ transgenic T cells in a dose-dependent manner” at pages 257 and 259; and Figs. 1A-B). Fraser et al found that when OT-I T cell recipients were immunized with peptide (50 ng), the proliferative response was halved in the 25 mg/kg dasatinib-treated group and was consistently lower in the 10 mg/kg group (Fig. 1A). Fraser et al disclosed that the proliferation of OT-II T cells in response to peptide immunization (5 ug) was inhibited more potently, with significant levels of inhibition of 40% and 50% observed at doses of 10 mg/kg and 25 mg/kg, respectively (Fig. 1B). Fraser et al also stated “Furthermore, drugs such as dasatinib may prove effective for the treatment of diseases associated with aberrant immune function. Potent Lck inhibitors have been proposed as therapeutic agents for T-cell-mediated pathologies, including rheumatoid arthritis, graft-vs-host disease and psoriasis [5]. This is supported by the studies herein, which demonstrate comparable inhibitory effects of dasatinib on T-cell proliferation and function relative to that mediated by cyclosporine, an immunosuppressant commonly used to treat these disorders [46]” (left column, last paragraph at page 264). With respect to dependent claim 11, since the adoptive cell transfer method of Fraser et al has the same single method step and starting materials as the presently claimed invention, it is inherently that dasatinib in the disclosed method is also capable of treating cytokine release syndrome associated with adoptive cellular therapies via its therapeutic immunosuppression.
Accordingly, the teachings of Fraser et al meet every limitation of the instant claims. Thus, the reference anticipates the instant claims.
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, 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.
Claims 1-5, 9-11 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Ivan (WO 2017/025638) in view of Fraser et al (Experimental Hematology 37:256-265, 2009) and Schade et al (Blood 111:1366-1377, 2008).
Claims 1-5, and 9-11 encompass a method of adoptive cell therapy comprising contacting an immune cell or an immune effector cell with a dasatinib which is an Lck inhibitor or a Src kinase inhibitor. Claims 18-19 encompass a method comprising administering a composition comprising a Src kinase inhibitor and/or a Lck inhibitor and an immune cell or an immune effector cell. Claim 20 encompasses a method of controlling the activity of an adoptive cell therapy comprising administering a therapeutically effective amount of a composition comprising a Src kinase inhibitor and/or a Lck inhibitor and an immune cell or an immune effector cell.
Ivan already disclosed at least a method for treating undesirable effects (e.g., cytokine release syndrome (CRS) or symptoms associated with gastrointestinal inflammation) occurring in conjunction with T cell-mediated therapies using an inhibitor of NFAT activation (e.g., cyclosporine, cyclosporine derivatives) in a patient (see at least Abstract; Brief Summary of the Disclosure; particularly paragraphs [0027], [0030], [0033]-[0038], [0048]-[0050], [0057]-[0068], [0083]-[0104] and [00111]-[00113]). Ivan also taught that T cell-mediated therapy is co-administered with a composition comprising an inhibitor of NFAT activation, and wherein the composition is administered simultaneously, sequentially or separately to the therapy (paragraph [0027]), and the composition is preferably administered via oral administration (paragraph [0030]). Ivan also taught specifically that T-cell mediated therapies include direct infusion of immune cells such as T cells that find, recognize, and kill cancer cells directly; and genetically modified immune cells such as T cells that are genetically modified to express tumor specific CARs, including CAR-engineered T cells targeting the B cell antigen CD19; and the administered immune cells can be autologous or allogeneic (paragraphs [0033]-[0038]). Ivan also disclosed that in patients with leukemias, infused CAR-T cells may be intensively activated after encountering a large amount of cancer cells in the peripheral blood, and the CAR-T cells will proliferate which may potentiate CRS or add to the risk of CRS (paragraph [0061]).
Ivan did not teach explicitly a method for treating undesirable effects such as cytokine release syndrome (CRS) occurring in conjunction with T cell-mediated therapies using dasatinib (a Src kinase inhibitor and/or an Lck inhibitor) in a patient.
Before the effective filing date of the present application (03/29/2016), Fraser et al already demonstrated that dasatinib (a small molecule Src/Abl tyrosine kinase inhibitor) inhibited antigen-specific proliferation of murine CD4+ and CD8+ transgenic T cells and NK-cell cytolytic activity in vitro and in vivo (see at least Abstract; Table 1 and Figs. 1-5). Fraser et al stated explicitly “Furthermore, drugs such as dasatinib may prove effective for the treatment of diseases associated with aberrant immune function. Potent Lck inhibitors have been proposed as therapeutic agents for T-cell-mediated pathologies, including rheumatoid arthritis, graft-vs-host disease and psoriasis [5]. This is supported by the studies herein, which demonstrate comparable inhibitory effects of dasatinib on T-cell proliferation and function relative to that mediated by cyclosporine, an immunosuppressant commonly used to treat these disorders [46]” (left column, last paragraph at page 264).
Additionally, Schade et al also demonstrated that dasatinib which is an oral small molecule inhibitor of Abl and Src family tyrosine kinase (SFK), including p56Lck (Lck), inhibits TCR-mediated signal transduction, cellular proliferation, proinflammatory cytokine production, and in vivo T-cell response (see at least Abstract; sections titled “Proinflammatory cytokine production is inhibited by dasatinib” and “”In vivo inhibition of T-cell proliferation” at pages 1370-1372 and page 1373, respectively; and Fig. 4). Schade et al also stated “In addition, dasatinib combined with cyclosporine A or rapamycin led to a much more potent inhibition of T-cell activation, suggesting that targeted inhibition Lck could be a useful adjunct for immunomodulation. In combination with currently available immunomodulatory agents, SFK inhibition could potentially increase immunomodulatory efficacy while minimizing toxicity of individual agents” (last two sentences in the Abstract).
Accordingly, it would have been obvious for an ordinary skilled artisan to modify the teachings of Ivan by also selecting and using dasatinib in a method for treating undesirable effects such as cytokine release syndrome (CRS) occurring in conjunction with T cell-mediated therapies, in light of the teachings of Fraser et al and Schade et al as presented above.
An ordinary skilled artisan would have been motivated to carry out the above modifications because: (i) Fraser et al already demonstrated that dasatinib inhibited antigen-specific proliferation of murine CD4+ and CD8+ transgenic T cells and NK-cell cytolytic activity in vitro and in vivo; and inhibitory effects of dasatinib on T-cell proliferation and function are comparable to those mediated by cyclosporine; and (ii) Schade et al also demonstrated that dasatinib inhibits TCR-mediated signal transduction, cellular proliferation, proinflammatory cytokine production, and in vivo T-cell response, as well as the combination of dasatinib and cyclosporine A led to a much more potent inhibition of T-cell activation, suggesting that targeted inhibition Lck could be a useful adjunct for immunomodulation. Please also note that the primary Ivan reference already taught using cyclosporine and cyclosporine derivatives, including cyclosporin A, in a method for treating undesirable effects (e.g., cytokine release syndrome (CRS) or symptoms associated with gastrointestinal inflammation) occurring in conjunction with T cell-mediated therapies.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Ivan, Fraser et al and Schade et al; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified treatment method resulting from the combined teachings of Ivan, Fraser et al and Schade et al as set forth above is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Ivan (WO 2017/025638) in view of Fraser et al (Experimental Hematology 37:256-265, 2009) and Schade et al (Blood 111:1366-1377, 2008) as applied to claims 1-5, 9-11 and 18-20 above, and further in view of Zhao et al (WO 2016/069283).
The combined teachings of Ivan, Fraser et al and Schade et al were presented above. However, none of the cited references teach or suggest specifically using CAR-T cells that are deficient in endogenous T cell receptor chains.
Before the effective filing date of the present application (03/29/2016), Zhao et al already taught using a modified T cell for adoptive therapy to treat a condition such as cancer, wherein the modified T cell has an endogenous gene expression selected from the group consisting of TCR alpha chain, TCR beta chain, beta-2 microglobulin, a HLA molecule, CTLA-4, PD1, and FAS being downregulated or knockdowned, and said modified T cell further comprising a nucleic acid encoding a chimeric antigen receptor (CAR), including a CAR that binds to CD19 (see at least Abstract; Summary of the Invention; sections titled “Knockdown of endogenous gene expression” and “Chimeric Antigen Receptor (CAR)” starting at pages 36 and 43, respectively). Zhao et al stated specifically “For example, downregulating expression of endogenous TCR, MHC or beta-2 microglobulin genes removes surface presentation of alloantigens on the T cell that could cause rejection by the host immune system. Also, downregulating an endogenous gene that regulates inhibitory signaling pathways in T cells, such as CTLA-4, PD1, and/or FAS, enhances anti-tumor efficacy of the modified T cell when exposed to an immunosuppressive microenvironment” (last paragraph at page 36 continues to first paragraph at page 37).
Accordingly, it would have been obvious for an ordinary skilled artisan to further modify the combined teachings of Ivan, Fraser et al and Schade et al by also using CAR-T cells that are at least deficient in endogenous T cell receptor chains, in light of the teachings of Zhao et al as presented above.
An ordinary skilled artisan would have been motivated to further carry out the above modification because Zhao et al already taught using a modified T cell for adoptive therapy to treat a condition such as cancer, wherein the modified T cell has an endogenous gene expression selected from the group consisting of TCR alpha chain, TCR beta chain, beta-2 microglobulin, a HLA molecule, CTLA-4, PD1, and FAS being downregulated or knockdowned, and said modified T cell further comprising a nucleic acid encoding a chimeric antigen receptor (CAR), including a CAR that binds to CD19; and particularly at least downregulating expression of endogenous TCR, MHC or beta-2 microglobulin genes removes surface presentation of alloantigens on the T cell that could cause rejection by the host immune system. Thus, the administered modified CAR-T cells would be less likely to be rejected by the immune system of a recipient in need of treatment.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Ivan, Fraser et al, Schade et al and Zhao et al; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified treatment method resulting from the combined teachings of Ivan, Fraser et al, Schade et al and Zhao et al as set forth above is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/
Primary Examiner, Art Unit 1631
