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 .
Restriction/Election
Applicant’s election without traverse of the following species in the reply filed 05/12/2025 is acknowledged:
a single PD-1 inhibitor: Pembrolizumab
a single EGFRvlll-specific CAR:
EGFRvlll binding domain: defined by heavy/light chain CDRs of SEQ ID
NO: 68.
transmembrane domain of CD28
intracellular signaling domain of CD3 zeta
Claim Status
Claims 2, 7, 10, 12, 17, 25, 29, 31, 34, 37-38, 41-42, 45, 52, 54, 56, 61, 63-64, 68, 70-71 ,76, 78, 84, and 86-87 are pending. Claims 37, 38, 41, 42, and 84 are withdrawn for being directed to a non-elected anti-PD-1 species.
Claims 2, 7, 10, 12, 17, 25, 29, 31, 34, 45, 52, 54, 56, 61, 63-64, 68, 70-71 ,76, 78, 84 and 86-87 are under examination.
Drawings
The drawings are objected to because the graph of Fig.1 does not have a legend identifying the experimental groups. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 12, 34, 45, 52, and 78 are objected to because of the following informalities:
Claim 12 is objected to for the typo “as not have CRS” (line 5) which should be corrected to --as not having CRS--.
Claim 52 is objected for a misplaced colon at the end of line 5 and for a missing conjunction (“or”) at the end of line 5.
Claim 78 is objected to for the colon as the end of line 3, which should be a semicolon and for a missing conjunction (“and” or “or”) at end of line 8.
Claims 34 and 45 are objected to for referencing Tables 6 and 2 from the specification. MPEP 2173.05 (s) indicates where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant's convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993).
Claim 86 is objected to for the typo “amoutn” which should be corrected to --amount--.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
Claims 2, 7, 10, 12, 17, 25, 29, 31, 34, 37, 38, 52, 54, 56, 61, 64, 76, 78, 86, and 87 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.
Regarding claims 2, 7, 10, 12, 17, 25, 29, 31, 34, 37, 38, 52, 54, 64, 76, 78, and 86, the phrase "e.g." renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 56, 61, and 87, the phrase "optionally" renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112(a)
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.
WRITTEN DESCRIPTION
Claims 2, 7, 10, 12, 17, 25, 29, 31, 45, 52, 54, 56, 61, 63, 64, 68, 70, 71, 76, 78, and 86 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
The claimed invention is directed to a combination therapy comprising CAR therapy and a PD-1 inhibitor, where the different components of the CAR and PD-1 inhibitors are claimed based on percent identity of a parent structure.
Claims 2 and 7 are directed to methods comprising administration of a PD-1 inhibitor, wherein the PD-1 inhibitor is broadly directed to any molecule that inhibits PD-1. The PD-1 inhibitory molecules include antibodies, small molecules, polypeptides, and inhibitory nucleic acids all administered according to the claims at a dose of 200 to 450 mg.
Claim 34 claims PD-1 antibodies comprising a heavy chain variable region with CDRs set forth in SEQ ID NOs: 503, 504, 505 and light chain variable region with CDRs set forth in SEQ ID NOs: 500, 501, 502 or an amino acid sequence at least 85%, 90%, 95% or higher.
Claim 45(i) claims the anti-EGFRvIII binding domain of the CAR comprises one more or more a light chain CDR1, CDR2, CDR3 and one or more of a light chain CDR1, CDR2, CDR3 of any anti-EGFRvIII light chain binding domain amino acid sequence listed in Table 2 or SEQ ID NO: 11.
Claim 45(vi) claims the anti-EGFRvIII binding domain of the CAR comprises a light chain variable region and/or a heavy chain variable region up to 30 modifications or 95-99% identity of an amino acid sequence provided in Table 2 or SEQ ID NO: 11.
Claim 45(vii) claims the anti-EGFRvIII binding domain of the CAR comprises a sequence selected from a group consisting of SEQ ID NO:38, SEQ ID NO:44, SEQ ID NO:50, SEQ ID NO:56, SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, and SEQ ID NO:86, a sequence having at least 30, 20 or 10 modifications thereto, or a sequence with 95-99% identify thereof.
Claim 52 claims a transmembrane region comprising the amino acid sequence of SEQ ID NO: 15, (ii) an amino acid sequence comprises at least one, two or three modifications but not more than 20, 10 or 5 modifications of the amino acid sequence of SEQ ID NO: 15, or (iii) a sequence at least 95% identical, e.g., with 95-99% identity, to the amino acid sequence of SEQ ID NO:15.
Claim 54 claims a hinge region comprising SEQ ID NO:14, or a sequence at least 95% identical, e.g., with 95-99%, identity thereof.
Claim 56 claims the intracellular signaling domain of the CAR the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence having at least one, two, or three modifications but not more than 20, 10, or 5 modifications of the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 16 or the amino acid sequence of SEQ ID NO: 16 and/or the amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 99; or an amino acid sequence having at least one, two, or three modifications but not more than 20, 10, or 5 modifications of the amino acid sequence of SEQ ID NO: 16 and/or the amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 99; or an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 16 and/or the amino acid sequence of SEQ ID NO: 17 or SEQ ID NO:99.
Claim 61 claims the CAR comprises a leader sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:13.
Pertaining to the nature of the claimed molecules that inhibit PD-1, the specification discloses a single in vivo embodiment of the invention comprising “immune checkpoint blockade with PD-1” but does not define what agent was used. Table 6 of the specification discloses multiple anti-PD-1 antibodies known in the art.
The anti-PD-1 inhibitors, the EGFRvIII binding domain and various CAR components cited above have claimed functions which include binding specific epitopes and use in the treatment of cancer. The claims as written allow for extensive modifications to the parent molecules and do not provide guidance as to how the components can be modified and still retain their respective functions.
The specification discloses anti-PD-1 binding regions, EGFRvIII binding domains and the above CAR components with no mutations. The claims allow for mutations to the disclosed molecules, but in each case does not define the minimal structure required in order for the components to perform their claimed functions as part of a combination therapy to treat a subject having cancer.
State of the relevant art
Pertaining to the structure of the disclose anti-PD-1 antibody and anti-EGFR binding domain of the CAR:
It is well established in the art that the formation of an intact antigen-binding site in an antibody or chimeric antigen receptor usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
The prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, the unpredictability of single amino acid changes in an antibody is underscored by Winkler (J Immunol. 2000 Oct 15;165(8):4505-14) who teaches that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
Similarly, Herold et al. (Sci Rep. 2017 Sep 25;7(1):12276) performed single- and double-point mutations in exemplary antibodies and found that a single point mutation in the VH CDR region can completely abolish antigen binding (Page 8, Paragraph 1, Line 11).
The art thus underscores the importance of fully defined CDRs and evidence from the inventors that they were in possession of each claimed antibody embodiment.
Pertaining to the structural components of chimeric antigen receptors:
Fujiwara (Cells. 2020 May 9;9(5):1182) investigates the CAR structure-activity relationship by generating CAR embodiments with different hinge and transmembrane domains and analyzing the resulting effect on CAR expression levels and antigen-specific activity (see Abstract). Fujiwara determined that the hinge domain affected the transport efficiency of CAR proteins to the cell membrane (Fig. 5A) and the transmembrane domain regulated the membrane expression stability of the CARs (Fig. 5B).
The art thus teaches that the sequence and resulting structure of CAR components such as the hinge and transmembrane domain are essential for the appropriate functioning of CARs and must be fully defined in the application.
Claim Analysis
In light of the state of the relevant art and the lack of guidance provided in the specification, the claims have the following written description issues:
Claim 2, 7 and dependent claims disclose the use of a PD-1 inhibitor, but do not specify the class of molecule or provide support for the use of a PD-1 inhibitor other than antibody. PD-1 inhibitors disclosed in claim 31 include an antibody molecule, a small molecule, a polypeptide, e.g., a fusion protein, or an inhibitory nucleic acid, e.g., a siRNA or shRNA and the claims read on administration of each of these molecules at the same dose. Claims 2 and dependent claims disclose administration at 200 mg to 450 mg without providing support for administration of each class of molecules at that dose.
The anti-PD-1 antibodies of claim 34 are not completely defined because they claim mixing and matching of heavy and light chain variable regions from different antibodies and allow for mutations in the CDR regions of the antibodies.
The anti-EGFRvIII binding domains of claim 45 are incomplete because the claim is directed to “one or more” CDRs of a light chain or heavy chain binding domain and thus does not require 6 defined CDRs. The claim also allows for mutations in the CDRs regions.
The CAR transmembrane region of claim 52, the hinge of claim 54, the intracellular signaling domain of claim 56 and the leader sequence of claim 61 all claim mutations to the parent structure, but neither the specification or the claims identify which portions of the sequences can be mutated and still maintain functionality.
One of skill in the art would neither expect nor predict the appropriate functioning of the anti- anti-PD-1 antibody and EGFRvIII-specific CAR, as broadly as is claimed. As the disclosure does not define the minimum structure of each component that would impart functionality to each of these claimed elements, the disclosure does not allow those of skill in the art to recognize other members of the claimed genus.
Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of structures as broadly claimed.
Claims 10, 12, 17, 25, 29, 31, 63, 64, 68, 70, 71, 76, 78, and 86 are rejected for being dependent on claim 2 and not providing limitations that satisfy the written description requirement.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 2, 7, 10, 12, 17, 25, 29, 31, 34, 52, 54, 56, 61, 63, 64, 68, 70, 71, 76, and 78 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Oezlem (WO2018/023025A1, published 02/01/2018, effectively filed 07/28/2016).
The disclosure of Oezlem is directed to methods and compositions for treating disease associated with a specific antigen through a combination therapy comprising antigen-specific CAR-expressing cells and an inhibitor of PD-1 (Summary of the Invention, Pg. 2, Lines 15-25).
Regarding claims 2 and 29, pertaining to a method of treating a subject having cancer comprising administering to the subject (i) a CAR therapy comprising a population of immune effector cells expressing a chimeric antigen receptor (CAR) and (ii) a PD-1 inhibitor wherein the dose of PD-1 inhibitor is about 200 mg to about 450 mg, Oezlem discloses a CAR therapy comprising a population of immune effector cells expressing a CAR for use in combination with a PD-1 inhibitor, and wherein the dose of the PD-1 inhibitor is about 200 mg to about 450 mg (Pg. 444, claim 1).
Regarding claim 7, pertaining to a method of treating a subject having cancer comprising administering to the subject: (i) a CAR therapy comprising a population of immune effector cells expressing a chimeric antigen receptor (CAR) and (ii) a PD-1 inhibitor wherein the subject has or does not have CRS, Oezlem discloses the subject does not have, or is not identified as having CRS (Pg. 447, claim 13). Of note, the claim as currently written reads on administration to any subject due to the limitation that subject has or does not have CRS which is applicable to all possible subjects.
Regarding claims 10 and 17, Oezlem discloses the CAR therapy further comprises administering one or more subsequent doses of the PD-1 inhibitor (Pg. 446, claim 10)
Regarding claim 12, Oezlem discloses the method further comprises evaluating the presence or absence of CRS in the subject (Pg. 447, claim 12).
Regarding claim 25, Oezlem discloses the CAR therapy comprises an RNA CAR molecule and wherein the subsequent doses of a CAR therapy is administered to the subject after the initial dose of the CAR therapy (Pg. 450, claim 37).
Regarding claims 31 and 34, wherein the PD-1 inhibitor is an antibody molecule (claim 31) and is pembrolizumab (claim 34), Oezlem discloses the PD-1 inhibitor is pembrolizumab (Pg. 454, claim 55).
Regarding claim 52, Oezlem discloses the transmembrane domain comprises CD28 (Pg. 462, claim 74).
Regarding claim 54, Oezlem discloses the binding domain is connected to the transmembrane domain by a hinge region (Pg. 462, claim 76).
Regarding claim 56, Oezlem discloses the intracellular signaling domain comprises a costimulatory signaling domain (Pg. 462, claim 78).
Regarding claim 61, Oezlem discloses the CAR further comprises a leader sequence (Pg. 464. claim 83).
Regarding claim 63 and 64, Oezlem discloses the cell comprising a CAR comprises a nucleic acid encoding the CAR (Pg. 464, claim 85) and the nucleic acid encoding the CAR is a lentiviral vector (Pg. 464, claim 86).
Regarding claim 68, Oezlem discloses the cell is a T cell or an NK cell (Pg. 465, claim 90).
Regarding claim 70, Oezlem discloses the CAR therapy further comprises administering an additional anti-cancer agent (Pg. 465, claim 92).
Regarding claim 71, Oezlem discloses the subject receiving the combination therapy has a solid tumor, specifically glioblastoma (Pg. 386, Lines 21-28).
Regarding claim 76, Oezlem discloses the subject receiving the combination therapy is a mammal (Pg. 466, claim 98).
Regarding claim 78, Oezlem discloses the subject expresses PD-1, PD-L1, and/or PD-L2 (Pg. 466, claim 99). Of note, PD-1 and PD-L1 are expressed on various immune and non-immune cells under non-diseases conditions and the claim reads on administration of the treatment to any subject that is not modified genetically.
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 2, 7, 10, 12, 17, 25, 29, 31, 34, 45, 52, 54, 56, 61, 63, 64, 68, 70, 71, 76, and 78 are rejected under 35 U.S.C. 103 as being unpatentable over Oezlem (WO2018/023025A1) as applied to claims 2, 7, 10, 12, 17, 25, 29, 31, 34, 52, 54, 56, 61, 63, 64, 68, 70, 71, 76, and 78 above, and further in view of Brogdon (US2014/0322275A1, published 10/30/2014, IDS filed 03/07/2022).
Oezlem teaches a method of treating a subject having cancer comprising administering to the subject (i) a CAR therapy comprising a population of immune effector cells expressing a chimeric antigen receptor (CAR) and (ii) a PD-1 inhibitor. Oezlem teaches that in one embodiment, the CAR molecule comprises an antigen binding domain that is capable of binding EGFRvIII (Pg. 30, Lines 1-5), specifically a CAR set forth in US2014/0322275A1 (Pg. 39, Lines 19-22).
Oezlem incorporates Brogdon’s reference, but does not teach that the CAR anti-EGFRvIII binding domain comprises the light chain and heavy chain CDRs of SEQ ID NO:68 from Table 2, the species elected for examination.
This deficiency is taught by Brogdon.
The disclosure of Brogdon is directed to compositions and methods for treating diseases associated with expression of EGFRvIII comprising administration of CAR T cells that comprise an anti-EGFRvIII binding domain. Brogdon discloses the anti-EGFRvIII CAR of the instant invention, “CAR6” (see instant specification, Pg. 465).
Regarding claim 45, wherein the CAR comprises light chain CDRs and heavy chain CDRs set forth in SEQ ID NO:68 of Table 2 of the specification, Brodgon discloses CAR6 set forth in the identical SEQ ID NO:68. Brogdon teaches that CAR6 is highly specific for EGFRvIII with no crossreactivity with wildtype EGFR (Fig. 17, [0060], Lines 1-4). Brogdon shows that administration of CAR6-expressing cells reduced the tumor burden and increases survival in a preclinical glioma model (Fig. 18, [0423], Lines 1-18).
It would have been obvious to one having ordinary skill in the art to use CAR6 of SEQ ID NO:68 in the CAR + PD-1 inhibitor method of Oezlem. One would have been motivated to do so because Oezlem teaches an anti-EGFRvIII CAR selected from Brogdon’s disclosure, but does not claim the specific SEQ ID NO:68. Brogdon teaches that the CAR with the binding domain SEQ ID NO:68 has high affinity and specificity for EGFRvIII and has shown preclinical anti-tumor effects. There would be an expectation of success in using the CAR disclosed by Brogdon in the method of Oezlem because Brogdon provides evidence of the efficacy of the claimed anti-EGFRvIII CAR in vivo.
Claims 2, 7, 10, 12, 17, 25, 29, 31, 34, 52, 54, 56, 61, 63, 64, 68, 70, 71, 76, 78, 86, and 87 are rejected under 35 U.S.C. 103 as being unpatentable over Oezlem (WO2018/023025A1) as applied to claims 2, 7, 10, 12, 17, 25, 29, 31, 34, 52, 54, 56, 61, 63, 64, 68, 70, 71, 76, and 78 above, and further in view of O'Rourke (Sci Transl Med. 2017 Jul 19;9(399)).
Oezlem teaches a method of treating a subject having cancer comprising administering to the subject (i) a CAR therapy comprising a population of immune effector cells expressing a chimeric antigen receptor (CAR) and (ii) a PD-1 inhibitor. Oezlem teaches that in one embodiment, the CAR molecule comprises an antigen binding domain that is capable of binding EGFRvIII (Pg. 30, Lines 1-5).
Oezlem does not teach that the method is used to treat MGMT-unmethylated glioblastoma.
This deficiency is taught by O’Rourke.
The disclosure of O’Rourke is directed to the first human study of intravenous delivery of a single dose of autologous T cells specific for the EGFR mutation, EGFRvIII. The researchers describe the trafficking of anti-EGFRvIII CAR T cells to the regions of active glioblastoma and susequent increased and robust expression of inhibitory molecules (see Abstract). O’Rourke concludes that the data suggest the possibility of synergy between CAR T cells anti-PD-1/PD-L1 checkpoint blocking antibodies (Pg. 14, Full paragraph 1).
Regarding claims 86 and 87, pertaining to a method of treating MGMT-unmethylated glioblastoma comprising administering low dose radiation and a combination therapy comprising a CAR and PD-1 inhibitor, O’Rourke teaches administration of anti-EGFRvIII CAR T cells to patients with glioblastoma with unmethylated MGMT promoter previously received radiation (Pg. 5, Study Subjects).
It would have been obvious to one having ordinary skill in the art to use the combination therapy method as taught by Oezlem for treating patients with MGMT-unmethylated glioblastoma who previously received radiation as taught by O’Rourke. One would have been motivated to do so because O’Rourke teaches that the anti-EGFRvIII CAR T cells traffic to glioblastoma sites and their anti-cancer efficacy could be improved with the addition of agents that block the checkpoint inhibitors upregulated in the tumor environment. There would be an expectation of success because O’Rourke provides evidence of clinical use of anti-EGFRvIII CAR T cells and provides data that points to the use of PD-1 inhibitors to improve the CAR T therapy.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROL ANN CHASE whose telephone number is (571)270-0934. The examiner can normally be reached Monday-Friday 9:00am-6:00pm.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
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