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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/10/2025 has been entered.
Claims Status
The amendments and remarks filed 09/10/2025 are acknowledged.
Claims 1-22, 25-38, and 41-44 are canceled.
Claim 40 is amended.
Claims 45-51 are new.
Claims 23-24, 39-40, and 45-51 are pending and under examination.
Notice
Claims 1-22 lack a status identifier. See MPEP 714 which recites 37 CFR 1.121 section (c) stating “In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).” Since there are no claim limitations following “1. to 22”, the claims are being treated as canceled.
Withdrawn
The objections to the claims are withdrawn. Applicant has canceled the claims and corrected the claim numbering to overcome the objections.
The rejection of claim 42 under 35 U.S.C. 112(b) is withdrawn. Applicant has canceled the claim to overcome the rejection.
The rejections of claims 1-3, 5, 11-12, 16, 19-20, 22, 40, and 45 under 35 U.S.C. 112(a) written description are withdrawn. Applicant has canceled and/or amended the claims to overcome the rejections.
The rejections of claim 1-3, 5, 10-13, 16-17, 20, 41, and 44 under 35 U.S.C. 103 are withdrawn. Applicant has canceled the claims to overcome the rejections.
The double patenting rejections of claims 1-3, 5, 10-13, 16-17, 20, 41, and 44 over U.S. Patent No. 9,676,858 (‘858) are withdrawn. Applicant has canceled the claims to overcome the rejections.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing” and sequences appearing in claims 49 and 50 (i.e. 5 amino acid glycine4-serine linker and 15 amino acid glycine4-serine linker triplicate) are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure and amend the claims to recite sequence identifiers; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Claim Objections
Claims 23 and 45 are objected to because of the following informalities: The claims recite acronyms (i.e. EGFRvIII, CNS, Fab, (Fab’)2, IgG, mini-ab). The first time an acronym is used, it must be accompanied by the definition of the abbreviation. Appropriate correction is required.
Claims 45 and 51 are objected to because of the following informalities: The claims recite “bispecific single chain Fragment variable (bsscFv).” For consistency, the Examiner recommends amending the claims to recite “bispecific single chain fragment variable (bsscFv)” with “fragment” being all lowercase. Appropriate correction is required.
New Grounds of Rejection Necessitated by Amendment
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 49-51 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.
Claims 49 and 50 recite the limitation “wherein the scFv consists of the following segments from N- to C- terminus: (1) variable light chain of antibody clone 139, (2) 15 amino acid glycine4-serine linker triplicate, (3) variable heavy chain of antibody clone 139, (4) 5 amino acid glycine4-serine linker, (5) variable heavy chain of antibody clone 28F11, (6) 15 amino acid glycine4-serine linker triplicate, and (7) variable light chain of antibody clone 28F11.” The specification does not disclose antibody clone 139 or antibody clone 28F11 and further, the application does not provide a sequence listing. The antibodies do not appear to be known and readily available to the public nor obtainable by a repeatable method set forth in the specification. Therefore, since the sequences of antibody clone 139 and antibody clone 28F11 are unknown and cannot be determined, the scope of these claims are indefinite.
Claim 51, which depends from claim 50, is therefore rejected for the same reasons set forth above.
Claim Rejections - 35 USC § 112(a)
New Matter
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 49-51 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. This is a new matter rejection.
Claims 49 and 50 require that the scFv of consists of (1) variable light chain of antibody clone 139, (2) 15 amino acid glycine4-serine linker triplicate, (3) variable heavy chain of antibody clone 139, (4) 5 amino acid glycine4-serine linker, (5) variable heavy chain of antibody clone 28F11, (6) 15 amino acid glycine4-serine linker triplicate, and (7) variable light chain of antibody clone 28F11. The original disclosure does not provide support for antibody clone 139, antibody clone 28F11, 15 amino acid glycine4-serine linker triplicate, or 5 amino acid glycine4-serine linker triplicate, as required by the claims.
Claim 51, which depends from claim 50, is therefore rejected for the same reason.
Enablement
Claims 49-51 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 49 and 50 recite “wherein the scFv consists of the following segments from N- to C- terminus: (1) variable light chain of antibody clone 139,…(3) variable heavy chain of antibody clone 139,…(5) variable heavy chain of antibody clone 28F11,…and (7) variable light chain of antibody clone 28F11.” and as such this material is a required element needed to make and use the claimed invention. As a required element, the antibodies must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 U.S.C. 112, first paragraph, may be satisfied by a deposit of the pertinent cell line. See 37 CFR 1.801-1.809.
The specification does not disclose that wherein antibody clone 139 and antibody clone 28F11 have been deposited under the terms of the Budapest treaty and does not provide assurances that the recited materials will be irrevocably and without restriction or condition released to the public upon the issuance of a patent, or indicate that said material will be replaced if the material becomes unviable.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that antibody clone 139 and antibody clone 28F11 have been deposited under the Budapest Treaty and that antibody clone 139 and antibody clone 28F11will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent, whichever is longer. See 37 CFR 1.806 and MPEP 2410-2410.01. If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit was made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the antibody clone 139 and antibody clone 28F11 are the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant's possession at the time the application was filed.
Claim 51, which depends from claim 50, is therefore rejected for the same reason.
Rejections Maintained
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This rejection has been modified solely to address the amendments, specifically, the addition of new claims 45-48.
Claims 23-24, 39-40, and 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Bigner (US 20150132306; 07/05/2024 PTO-892) as evidenced by Bardal, 2011 (07/05/2024 PTO-892), and in view of O’Rourke, 2017 (07/05/2024 PTO-892).
Regarding claims 23-24, and 40, Bigner teaches a bispecific polypeptide comprising a first human single chain variable region (scFv), which binds to EGFRvIII, and is in series with a second human scFv, which binds to T cell activation ligand CD3 (a human EGFRvIII-CD3 bispecific scFv) [0006]. Bigner further teaches that the human EGFRvIII-CD3 bispecific scFv is a bispecific T cell engaging molecule that is selectively reactive with EGFRvIII and CD3 [0022] and teaches a method of treating an EGFRvIII-expressing tumor in a patient by administering the bispecific polypeptide, which induces a cytolytic T cell response [0008]. Bigner also teaches that any tumor that expresses EGFRvIII can be targeted and treated with the bispecific T cell engaging molecules, specifically brain tumors such as glioblastoma multiforme which express the EGFRvIII antigen [0025] and that the molecules may be delivered directly to the brain, for example by injection, or intravenously and then cross the blood-brain barrier [0058]. Additionally, Bigner teaches that the bispecific molecule redirects T-cells to tumor-specific antigens and can be used to carry other diagnostic or therapeutic compounds to cells expressing EGFRvIII on their surface [0056].
CD3 is well known to be a marker for T cells and all mature T cells express CD3 (as evidenced by Bardal). Thus, the human EGFRvIII-CD3 bispecific scFv would necessarily bind to T cells by binding to CD3.
However, Bigner does not specifically teach administering ex-vivo non-specifically activated T-cells to the human body.
O’Rourke teaches administering autologous T cells redirected to EGFRvIII by a chimeric antigen receptor (CAR) to human patients with glioblastoma (GBM; glioblastoma multiforme; a glioma) and found trafficking of the CART-EGFRvIII cells to regions of active GBM, and that intravenous infusion of the CAR T-cells resulted in on-target activity in the brain (CNS location) [see Abstract]. O’Rourke also teaches that the highest levels of CART-EGFRvIII cells in the tumor were detected within 14 days of infusion [page 6, left column, second paragraph] and there was a marked increase in the number and clonotypic diversity of tumor-infiltrating T cells after intravenous CART-EGFRvIII infusion [page 7, right column, first paragraph]. Thus, this indicates that the modified T cells migrate to the location of the tumor in the patient. O’Rourke further teaches that peripheral blood T cells from patients were stimulated (activated) and transduced with a lentiviral vector encoding the CAR, and that the CART-EGFRvIII cells were manufactured at a production facility (ex vivo) and cryopreserved until the patient was eligible and consented for treatment [page 12, left column, second paragraph].
Absent evidence to the contrary, the T-cells of O’Rourke were non-specifically activated because O’Rourke teaches activating the peripheral blood T cells in general, and does not specify a specific antigen used for activation.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the human EGFRvIII-CD3 bispecific scFv of Bigner with the CART-EGFRvIII cells of O’Rourke in order to increase the amount of an agent to reach a tumor expressing EGFRvIII (a CNS location in a human body), such as glioblastoma multiforme, in a human patient. One would have been motivated to combine the EGFRvIII-CD3 bispecific scFv and the CART-EGFRvIII in order to increase the amount of the agent to reach a location because O’Rourke teaches that high levels of CART-EGFRvIII cells go to the GBM tumor site (a specific location) in the human patients. Therefore, since the EGFRvIII-CD3 bispecific scFv of Bigner would bind to CD3 on the T-cells of O’Rourke, this would also result in the EGFRvIII-CD3 bispecific scFv reaching the tumor site at high levels. Additionally, both the EGFRvIII-CD3 bispecific scFv of Bigner and the CART-EGFRvIII of O’Rourke are taught to treat glioblastoma multiforme. This follows the logic of MPEP 2144.06 which states “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Therefore, it would have been obvious to combine the EGFRvIII-CD3 bispecific scFv and the CART-EGFRvIII for the same purpose of treating glioblastoma multiforme.
Claim 39 is included in this rejection because it further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the human EGFRvIII-CD3 bispecific scFv of Bigner and the CART-EGFRvIII cells of O’Rourke to a human patient, wherein the patient is immunocompetent. The art recognized definition of immunocompetent means to have a normal immune response. Since Bigner teaches that the human EGFRvIII-CD3 bispecific scFv is a bispecific T cell engaging molecule that is selectively reactive with EGFRvIII and CD3 [0022] and teaches a method of treating an EGFRvIII-expressing tumor in a patient by administering the bispecific polypeptide, which induces a cytolytic T cell response [0008], and since CD3 is well known to be a marker for T cells and all mature T cells express CD3 (as evidenced by Bardal), one would be motivated to administer the bispecific T cell engaging molecule of Bigner to an immunocompetent patient because the bispecific T cell engaging molecule is designed to bind to the patients’ own T cells to bring them to the tumor site in order to treat the tumor, and thus, one would want to make sure the T cells are functioning properly (i.e. immunocompetent).
Claim 45 is included in this rejection because O’Rourke teaches that the CART-EGFRvIII cells are made by modifying T-cells to express a humanized anti-EGFRvIII single-chain variable fragment (scFv; antibody fragment) fused to the hinge and transmembrane domain of CD8 and the human 4-1BB and CD3z intracellular signaling domains. [page 12, left column, second paragraph].
Claims 46-48 are included in this rejection because Bigner teaches that the bispecific T cell engaging molecules are particularly useful for intravenous administration and can be administered intravenously [0058] and O’Rourke teaches that the T-cells are administered by intravenous delivery [see Abstract].
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 23-24, 39-40, and 45-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, and 6 of U.S. Patent No. 9,676,858 (‘858) as evidenced by Bardal, 2011 (07/05/2024 PTO-892), and in view of O’Rourke, 2017 (07/05/2024 PTO-892).
This rejection has been modified solely to address the amendments, specifically, the addition of new claims 45-48.
Regarding claims 23-24, and 40, claim 1 of ‘858 teaches a bispecific polypeptide, comprising: a first single chain human variable region which binds to EGFRvIII, and comprises segments encoded by SEQ ID NO: 2 and 3; in series with a second single chain human variable region which binds to T cell activation ligand CD3 and comprises segments encoded by SEQ ID NO: 5 and 6; wherein the bispecific polypeptide comprises in N-terminal to C-terminal order segments encoded by SEQ ID NO: 2, 3, 4, 5, and 6, claim 5 of ‘858 teaches a method of treating a patient with an EGFRvIII expressing tumor, comprising: administering the bispecific polypeptide of claim 1 to the patient, whereby a cytolytic T cell response to the tumor is induced, and claim 6 teaches the bispecific polypeptide of claim 1 wherein each single chain variable region comprises a disulfide bond between the VH and the VL domain (i.e a scFv).
CD3 is well known to be a marker for T cells and all mature T cells express CD3 (as evidenced by Bardal). Thus, the human EGFRvIII-CD3 bispecific scFv would necessarily bind to T cells by binding to CD3.
However, ‘858 does not specifically teach administering ex-vivo non-specifically activated T-cells to the human body.
O’Rourke teaches administering autologous T cells redirected to EGFRvIII by a chimeric antigen receptor (CAR) to human patients with glioblastoma (GBM; glioblastoma multiforme; glioma) and found trafficking of the CART-EGFRvIII cells to regions of active GBM, and that intravenous infusion of the CAR T-cells resulted in on-target activity in the brain (CNS location) [see Abstract]. O’Rourke also teaches that the highest levels of CART-EGFRvIII cells in the tumor were detected within 14 days of infusion [page 6, left column, second paragraph] and there was a marked increase in the number and clonotypic diversity of tumor-infiltrating T cells after intravenous CART-EGFRvIII infusion [page 7, right column, first paragraph]. Thus, this indicates that the modified T cells migrate to the location of the tumor in the patient. O’Rourke further teaches that peripheral blood T cells from patients were stimulated (activated) and transduced with a lentiviral vector encoding the CAR, and that the CART-EGFRvIII cells were manufactured at a production facility (ex vivo) and cryopreserved until the patient was eligible and consented for treatment [page 12, left column, second paragraph].
Absent evidence to the contrary, the T-cells of O’Rourke were non-specifically activated because O’Rourke teaches activating the peripheral blood T cells in general, and does not specify a specific antigen used for activation.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the human EGFRvIII-CD3 bispecific scFv of ‘858 with the CART-EGFRvIII cells of O’Rourke in order to increase the amount of an agent to reach a tumor expressing EGFRvIII (a CNS location in a human body), such as glioblastoma multiforme, in a human patient. One would have been motivated to combine the EGFRvIII-CD3 bispecific scFv and the CART-EGFRvIII in order to increase the amount of the agent to reach a location because O’Rourke teaches that high levels of CART-EGFRvIII cells go to the GBM tumor site (a specific location) in the human patients. Therefore, since the EGFRvIII-CD3 bispecific scFv of ‘858 would bind to CD3 on the T-cells of O’Rourke, this would also result in the EGFRvIII-CD3 bispecific scFv reaching the tumor site at high levels. Additionally, both the EGFRvIII-CD3 bispecific scFv of ‘858 and the CART-EGFRvIII of O’Rourke are taught to treat an EGFRvIII expressing tumor (e.g. glioblastoma multiforme). This follows the logic of MPEP 2144.06 which states “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Therefore, it would have been obvious to combine the EGFRvIII-CD3 bispecific scFv and the CART-EGFRvIII for the same purpose of treating glioblastoma multiforme.
Claim 39 is included in this rejection because it further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the human EGFRvIII-CD3 bispecific scFv of ‘858 and the CART-EGFRvIII cells of O’Rourke to a human patient, wherein the patient is immunocompetent. The art recognized definition of immunocompetent means to have a normal immune response. Since ‘858 teaches that the human EGFRvIII-CD3 bispecific scFv is a bispecific T cell engaging molecule that is selectively reactive with EGFRvIII and CD3 [0022] and teaches a method of treating an EGFRvIII-expressing tumor in a patient by administering the bispecific polypeptide, which induces a cytolytic T cell response [0008], and since CD3 is well known to be a marker for T cells and all mature T cells express CD3 (as evidenced by Bardal), one would be motivated to administer the bispecific T cell engaging molecule of ‘858 to an immunocompetent patient because the bispecific T cell engaging molecule is designed to bind to the patients’ own T cells to bring them to the tumor site in order to treat the tumor, and thus, one would want to make sure the T cells are functioning properly (i.e. immunocompetent).
Claim 45 is included in this rejection because O’Rourke teaches that the CART-EGFRvIII cells are made by modifying T-cells to express a humanized anti-EGFRvIII single-chain variable fragment (scFv; antibody fragment) fused to the hinge and transmembrane domain of CD8 and the human 4-1BB and CD3z intracellular signaling domains. [page 12, left column, second paragraph].
Claims 46-48 are included in this rejection because ‘858 teaches that the bispecific T cell engaging molecules are particularly useful for intravenous administration and can be administered intravenously [column 10, lines 32-41] and O’Rourke teaches that the T-cells are administered by intravenous delivery [see Abstract]. See the decisions in Sun Pharmaceuticals v Eli Lily Fed Cir July 28, 2010; Geneva v GlaxoSmithKline 349, F.3d 1373; and Pfizer v Teva 518 F3d 1353 supporting the Office' s use of disclosed utilities of compositions when applying double patenting rejections to method claims.
Response to Declarant’s Arguments
The declaration under 37 CFR 1.132 filed 09/10/2025 is insufficient to overcome the rejections of claims 23-24 and 39-40 based on the teachings of Bigner, Bardal, and O’Rourke applied under 35 U.S.C. 103. Points 1-6 did not set forth any arguments. The Examiner acknowledges Declarant’s credentials and the rejections set forth in previous office action(s). It is noted that Declarant is an inventor of the pending application and is highly interested in the outcome of prosecution. In point 7, Declarant argues that the numerical values from Figures 3B and 3C cannot be numerically compared because they reflect experiments in which different bispecific antibodies were used and in which different tumor models were used, and that the results unexpectedly show an effect unique to the specific combination of ex vivo activated T cells and EGFRvIII-CD3 BiTE. This is not found persuasive because Figures 3B and 3C demonstrate results of EGFRvIII-CD3 bispecific antibody treatment and the effect of adoptive transfer of ex vivo activated T cells, both in combination and when the T cells were given alone. Claim 23 is not limited to any specific EGFRvIII-CD3 bispecific antibody or specific tumor, and therefore, the results demonstrated in these figures would apply to the broadly claimed EGFRvIII-CD3 bispecific antibody and ex vivo activated T cell treatment. Therefore, these results demonstrate an additive effect as one would expect the combination of the bscEGFRvIIIxCD3 and T cells to result in the improved survival as demonstrated. Points 8-10 do not set forth any arguments. The Examiner acknowledges the experimental procedures which resulted in the data demonstrated in Figures 3A and 3B. In Point 11, Declarant argues the data shown in Figure 3C, stating that the administration of ex vivo activated T cells did not increase survival when compared to vehicle (PBS) alone, and that the combination of BiTe + ex vivo activated T cells provided a significant increase in survival, far in excess of that which would be expected with simple summation of the parts as there was a minimal to no survival advantage with the BiTE alone compared to vehicle and no increase in survival with T cells alone compared with vehicle. This is not found persuasive because Figure 3B demonstrates an 80% survival rate at about 30 days with the bscEGFRvIIIxCD3 alone, Figure 3C demonstrates a 75% survival rate at about 10 days with the T cell alone, and an 80% survival rate at about 20 days with the bscEGFRvIIIxCD3 and T cell combined. Thus, these results demonstrate an additive effect as one would expect the combination of the bscEGFRvIIIxCD3 and T cells to result in the improved survival as demonstrated. Point 12 does not set forth any arguments. The Examiner acknowledges the experimental procedures which results in the data demonstrated in Figure 6. In point 13, Declarant argues the data shown in Figure 6, stating that when activated T cells were administered in addition to control bi-scFv (group 2) there was no increase in survival in comparison with control bi-scFv alone (group 1), and that administering activated T cells does not provide any survival
advantage when tumors are treated with antibodies which bind to tumor antigen but
not CD3, which supports the concept that the effect of ex vivo activated T cells plus the BiTE is not additive as the addition of ex vivo activated T cells produces no increase in survival compared to vehicle. This is not found persuasive because Figure 6 does not demonstrate results of the vehicle administered alone or the activated T cells when administered with only the vehicle. Therefore, the Examiner cannot make a determination of a trend that would lead to a conclusion of unexpected results. The burden is on Applicant to provide to the Examiner a trend proving the unexpected results. See MPEP 716.02(b). Point 14 and 15 do not set forth any argument. The Examiner acknowledges the data as presented in Figure 6. In point 16, Declarant, in summary, argues that the figures in the application show that in two different murine models with different CD3-EGFRvIII-binding bispecific antibodies [OKT3:MR11 and 28F11;139 bi-scFvs] the unique combination of EGFTvIII-CD3 BiTe and activated T cells provided an unexpected survival benefit against intracerebral tumor, pointing to Figures 2, 3B, 3C, and 6 for support. Declarant further argues that the alleged unique survival advantage with the specific combination of ex vivo activated T cells and CD3-
EGFRvIII binding bi-scFv relies on the ability of peripherally administered T cells and CD3-EGFRvIII binding bi-scFv relies on the ability of peripherally administered T cells to
traffic to the brain (Figures 7 and 8) which unexpectedly increases the biodistribution
of intravenously administered BiTE to tumors within the brain (Figures 9 and 10). The Examiner has addressed the arguments relating to Figures 3B, 3C, and 6 and maintains that these figures do not support a conclusion of unexpected results. Figure 2 further does not support unexpected results as the data does not demonstrate results of the T cells administered alone or the EGFRvIII-CD3 bi-scFv administered alone. Therefore, the Examiner cannot make a determination of a trend that would lead to a conclusion of unexpected results. The burden is on Applicant to provide to the Examiner a trend proving the unexpected results. See MPEP 716.02(b). Further, even if the data presented in these figures did support a conclusion of unexpected results, it would not be commensurate in scope with the claims. The Examiner cannot determine if the EGFRvIII-CD3 bi-scFv of the Figures comprises antibody clone 139 and antibody clone 28F11, as set forth in claims 49 and 50, and instant claim 23 generically claims any human EGFRvIII-CD3 bi-scFv. To conclude, Declarant presents many arguments about the alleged unexpected results, and while the declaration is given all due weight, Declarant is highly interested in the outcome of prosecution, and the data Declarant relies upon does not support a conclusion of unexpected results.
Response to Applicant’s Arguments
On pages 5-6 of the remarks, Applicant states that claim 49 and 50 have been [amended] to recite a human EGFRvlll-CD3 bispecific single chain variable fragment (scFv), wherein the scFv consists of the following segments from N- to C-terminus: (1) variable light chain of antibody clone 139, (2) 15 amino acid glycine4-serine linker triplicate, (3) variable heavy chain of antibody clone 139, (4) 5 amino acid glycine4-serine linker, (5) variable heavy chain of antibody clone 28F11, (6) 15 amino acid glycine4-serine linker triplicate, and (7) variable light chain of antibody clone 28F11, and further states that the description corresponds to the antibody which is used in the examples, pointing to paragraph 42 of the instant specification. Applicant also states that the cited publication [of paragraph 42] (i.e. Clinical Cancer Research) was expressly incorporated by reference in the subject patent specification, pointing to paragraph 41 of the instant specification, and that no new matter has been added. This is not found persuasive because the specification does not properly incorporate by reference the teachings of the cited publication. The antibody clone 139 and the antibody clone 28F11 are considered essential material because they are required elements needed to make and use the claimed invention. 37 C.F.R 1.57(d) states that "essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. See MPEP 608.01(p).
The rejections of claims 23-24, 39, and 40 under 35 U.S.C. 103 are maintained. On page 8 of the remarks, Applicant points to the Declaration under rule 132 of Dr. Gedeon for support of alleged unexpected results. The arguments set forth in the declaration are addressed above and will not be reiterated and are incorporated herein. Further, Applicant argues that one of skill in the art would not have had any reasonable expectation that the agents of Bigner and O’Rourke when combined would provide improved trafficking to the brain or improved therapeutic effect because one could not have known whether the effect of the CAR-T cells of O'Rourke was already maximal, because sufficient anti-EGFRvIII moieties were supplied to the tumor to bind all available target antigens. Applicant also argues that one of skill in the art could have imagined that the combination of the of the bispecific antibody of Bigner and the CAR-T cells of O'Rourke would have formed a bound entity that was too large to traverse the blood brain barrier, and that in such a scenario, the combination could have performed worse than either of the agents on its own. This is not found persuasive because Applicant is presenting chance scenarios rather than pointing to any specific deficiencies in the teachings of the art. Alleged improved or increased effects of the claimed combination is not equivalent to unexpected results and does not outweigh a conclusion of obviousness. Applicant is reminded that “arguments of counsel cannot take place of factually supported objective evidence” (see MPEP §2145).
On page 9 of the remarks, Applicant argues that additional references of Pruett, Piao, and Feng as applied in the rejections under 35 U.S.C. 103 do not remedy the deficiencies of Bigner and O’Rourke. This is not found persuasive because no such deficiency exists. See above. Further, the claims that these teachings were applied to are now cancelled and therefore, these arguments are moot.
On pages 9-10, Applicant argues the double patenting rejections over U.S. Patent No. 9,676,858 (‘858), stating that the one of skill in the art would not have expected the remarkable results in prolongation of overall survival that the claimed combination treatment produced, pointing to the alleged remarkable results as explained in Dr. Gedeon’s declaration. This is not found persuasive for the same reasons set forth in the response to Declarant’s arguments. The arguments set forth in the declaration are addressed above and will not be reiterated and are incorporated herein.
Conclusion
No claims are allowed.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675