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 .
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 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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/13/2025 has been entered.
Claims 121, 123-124, 126-127, and 129-132 are amended; claims 1-120, 122, 125, 128, and 133-147 are cancelled; and claims 148-187 are new.
Claims 121, 123-124, 126-127, 129-132, and 148-187 are currently pending and are examined on the merits herein.
Priority
The instant application, filed 27 August 2020, claims domestic benefit to US provisional application 62/892,114, filed 27 August 2019.
Nucleotide and/or Amino Acid Sequence Disclosures
In the specification filed 07/22/2024, page 155, lines 28-31 recites nucleic acid sequences, greater than 10 nucleic acids in length, without an appropriate SEQ ID NO.
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 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, 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.
Withdrawn Objections and Rejections
In the office action of 08/15/2025,
Claims 121, 123-124, 126-127, and 129-132 were rejected under 35 USC 103 and on the grounds of nonstatutory double patenting over App’288. The rejections are withdrawn in favor of the modified rejections below which take into account removal of limitations concerning checkpoint inhibitors and to add art concerning the orientation of the VH and VL regions in the scFv/CAR. Claims 125 and 138-147 were rejected under 35 USC 103 and on the grounds of nonstatutory double patenting over App’288. The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
The following rejections are modified or new based on applicant’s amendment to the 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.
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 application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 121, 124, 126, 148-149, 151-152, and 175 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/156711 A1 (Abate-Daga, D.) 30 August 2018, priority date 22 February 2017 in view of US 9,828,428 B2 (Ma, D., et al) 28 November 2017, Antibody design laboratories (2014) Cloning of scFv fragments; accessed from <https://www.abdesignlabs.com/technical-resources/scfv-cloning/> on 11/24/2025, US 7,169,894 B2 (Martin, M.T.) 30 January 2007, and Gould, N., et al (2014) Computational tools and algorithms for designing and customized synthetic genes Frontiers in Bioengineering and Biotechnology 2(41); 1-14 as evidenced by NCBI reference sequence NP_001139345.1.
It is noted that the instant specification discloses that the polynucleotide sequences of the instant claim, SEQ ID NOs: 57 and 61, encode the heavy and light chain variable regions of the Hu07 antibody, the amino acid sequences of which are instant SEQ ID NOs: 8 and 9, respectively (instant specification, pages 61-62 and 70-71).
Daga teaches chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer to target and kill IL13Ra2-expressing cancers. Also disclosed are immune effector cells, such as T cells or natural killer (NK) cells that are engineered to express the CARs. Also disclosed are methods of providing an anti-tumor immunity in a subject with an IL13Ra2-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs (abstract). Daga teaches that cancers that the disclosed compositions can be used to treat include glioblastoma (page 116, line 22).
Daga teaches that the CAR comprises an IL13Ra2 antigen binding domain, a transmembrane domain, an intracellular signaling domain as well as a co-stimulatory signaling region (page 134, claim 1). Daga teaches that, in some embodiments, the CAR is defined by the formula:
SP-IL13Ra2-HG-TM-CSR-ISD; wherein,
‘SP’ is a signal peptide,
‘IL13Ra2’ is an IL13Ra2 binding region,
‘HG’ is a hinge domain,
‘TM’ is a transmembrane domain,
‘CSR’ is one or more co-stimulatory signaling regions, and
‘ISD’ is an intracellular signaling region (page 5, lines 26-33).
Daga teaches isolated nucleic acid sequences encoding the disclosed CAR polypeptides, vectors comprising these isolated nucleic acids, and cells containing these vectors (page 3, lines 21-23). Daga teaches that nucleic acid sequences encoding the CARs, and regions thereof, can be obtained using recombinant methods known in the art, such as, for example, by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques. Alternatively, Daga teaches that the gene of interest can be produced synthetically rather than cloned (page 107, lines 4-9).
Daga further teaches that in some cases, the anti-IL13Ra2 variable heavy chain comprises the amino acid sequence of SEQ ID NO: 33 (page 101, lines 9-14) and the variable light chain comprises the amino acid sequence of SEQ ID NO: 41 (page 102, lines 25-29). The heavy chain variable domain of SEQ ID NO: 33 taught by Daga is identical to instant application SEQ ID NO: 8 and the light chain variable domain of SEQ ID NO: 41 taught by Daga is identical to instant application SEQ ID NO: 9, as shown in the ABSS alignments below:
Instant application SEQ ID NO: 8 aligned with Daga SEQ ID NO: 33 (HC variable region)
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Instant application SEQ ID NO: 9 aligned with Daga SEQ ID NO: 41 (LC variable region)
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Daga further teaches that the CAR comprises a hinge sequence that facilitates antibody flexibility and is positioned between the antigen recognition moiety and the transmembrane domain. The hinge sequence can be any suitable sequence, derived or obtained from, any suitable molecule. In some embodiments, the hinge sequence is derived from a CD8 alpha molecule (page 9, lines 15-21). Daga also teaches that the transmembrane domain is from CD8 alpha (page 9, line 27; Figure 1, second structure, figure page 1/5, pdf page 138). Daga teaches that the hinge and/or transmembrane domains are derived from CD8 and provides an example sequence for use in the CAR (page 104, lines 15-19) which is a portion of human CD8 alpha, as evidenced by NCBI reference sequence NP_001139345.1.
Daga teaches that the CAR comprises a costimulatory signaling domain and an intracellular signaling domain (page 134, claim 1; page 3, lines 16-18; Figure 1, second structure, figure page 1/5, pdf page 138). Daga teaches that the costimulatory domain comprises a costimulatory domain of 4-1BB (page 134, claim 6; Figure 1, second structure, figure page 1/5, pdf page 138). Daga teaches that the intracellular signaling domain is derived from CD3 zeta (CD3ζ), TCR zeta GenBank accno. BAG36664.1, and that the CD3ζ, also known as the T cell receptor T zeta chain or CD247, is a protein that is encoded by the human CD247 gene (page 8, lines 9-13; page 134, claim 9, Figure 1, second structure, figure page 1/5, pdf page 138), indicating the use of a human CD3ζ intracellular signaling domain.
Daga further teaches that expression of the nucleic acid sequences encoding the disclosed CARs is typically achieved by operably linking a nucleic acid encoding the CAR polypeptide to a promoter and incorporating the construct into an expression vector. The disclosed nucleic acids can be cloned into a number of types of vectors including viral vectors. Daga teaches that the vectors are lentiviral or retroviral vectors (page 107, lines 1-31). Daga further teaches that one suitable promoter is elongation growth factor 1-α (EF-1α) (page 108, lines 7-8). Daga further teaches lentiviral transduction for CAR expression from T cells (page 125, lines 1-8).
Daga differs from the instantly claimed invention in that Daga does not explicitly teach that the above heavy and light chain variable region are used in the same CAR or antibody structure. Additionally, Daga does not disclose polynucleotide sequences matching the instantly claimed polynucleotide sequences.
Ma teaches anti-IL-Ra2 antibodies and antibody drug conjugates and methods for preparing and using the same (abstract). Ma teaches the humanized antibody hu07, which binds to IL13Ra2, and comprises a light chain variable region amino acid sequence of SEQ ID NO: 41 and a heavy chain variable region amino acid sequence of SEQ ID NO: 48 (column 11, Table 3). Ma further demonstrates the expression of IL-13-Ra2 in a glioblastoma cell line (column 26, Table 14).
The amino acid sequences of SEQ ID NO: 41 and 48 taught by Ma, in the same antibody, are identical to those disclosed in Daga SEQ ID NOs: 33 and 41, respectively, indicating that the antigen binding domain recognizes and binds IL13Ra2 when the heavy and light chain variable regions disclosed by Daga are used together. Additionally, the demonstration of IL13Ra2 expression on glioblastoma further supports the teachings of Daga in which the compositions comprising IL13Ra2 targeting CAR cells are used to treat glioblastoma.
Antibody Design Laboratories teaches that scFv are obtained by connecting the VH and VL by a linker in a single polypeptide and provides a guide to some main aspects of their cloning (page 1, paragraph 1). Antibody design laboratories teaches that there is not a preferential orientation of one domain to the other and VH-L-VL and VL-L-VH constructs are likely equivalent (page 1, Domain orientation and tag location).
US’894 discusses processes through which polynucleotides are synthesized from a specific peptide or protein that they encode both through traditional techniques and via processes where sequence analysis of the peptide is not required (abstract; column 3, lines 5-17). US’894 teaches that reverse translation is the step of informational coupling of individual amino acids to their corresponding codons. Natural codons are trinucleotides and the three-nucleotide sequences of a codon specifies, or encodes, a specific amino acid (column 9, lines 29-33; Figure 1). There are 20 genetic code-encoded amino acids with 64 amino acid-encoding codons in the natural genetic code (column 18, lines 4-7; Figure 1). US’894 teaches that synthesis of an encoding polynucleotide, including RNA or DNA, that encodes a specific peptide or protein conventionally involves purifying a peptide or protein and sequencing it using an automated amino acid sequencing machine. Following sequencing, the identity and order of the amino acids are read and an oligonucleotide is synthesized using a second instrument, an oligonucleotide synthesizer. From the prepared oligo, the full-length polynucleotide can be cloned and the protein can be produced (column 3, lines 5-17).
Gould teaches that advances in DNA synthesis have enabled the construction of artificial genes and freedom in de novo design of synthetic constructs. To aid this goal, a large number of software tools of variable sophistication have been implemented enabling the design of synthetic genes for sequence optimization based on rationally designed properties. Gould teaches that years recent to the publication had seen the emergence of sequence design tools that aim to evolve sequences toward combinations of objectives. Gould provides a review of the approaches that different tools have adopted to redesign genes and optimize desired coding features and discusses their strengths and limitations (abstract). Gould provides a review of the most important objectives in synthetic gene design towards optimized expression as well as a review of 11 gene design tools that were available at the time of publication that incorporate the aforementioned objectives (page 1, right column, paragraph 3; page 4, table 1). The gene design tools disclosed can be used to translate and optimize DNA sequences without altering the chain of amino acids (page 4, left column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have used the heavy and light chain variable regions disclosed by Daga in the same antibody or CAR structure based on the teachings of Ma. It would have further have been obvious to use the VH and VL in either order in the binding domain as supported by Daga. It would have been obvious to an ordinarily skilled artisan to use the heavy and light chain variable regions together as Ma discloses a IL13Ra2 antibody that has the same variable domains together in a single antibody which recognizes and binds IL13Ra2. It would have been obvious to use the domains in either order as Antibody Design laboratories teaches that there is not a preferential orientation and that VH-linker-VL and VL-linker-VH orientations are likely equivalent. An ordinarily skilled artisan would have had a reasonable expectation of success as Antibody Design laboratories is teaching scFv constructs, which are the same type of binding domain taught by Daga for use in the disclosed CARs.
It would have further been obvious to have used reverse translation techniques known in the art, such as the methods of US’894 and/or the computational tools disclosed by Gould, to reverse translate the amino acid sequences disclosed by Daga and Ma into a nucleic acid sequence for encoding the CAR and/or CAR components. This conclusion of obviousness is further supported by KSR(E) obvious to try. In this case, Daga and Ma teach an IL13Ra2 binding CAR with amino acid sequences that are identical to those of the instantly disclosed invention. Daga also discloses the use of nucleic acids encoding the amino acid sequences and their use in vectors for the transformation of cells. US’894 teaches that there are 20 genetically encoded amino acids with 64 amino acid-encoding codons and both US’894 and Gould demonstrate that reverse translation was commonly practiced in the art of protein and gene synthesis. An ordinarily skilled artisan would have been able to pursue the known potential solutions with a reasonable expectation that the resulting nucleic acid would encode the amino acid sequence that it was reverse translated from, specifically those disclosed by Daga and Ma.
The combination of Daga, Ma, Antibody Design Laboratories, US’894, and Gould teach a CAR capable of binding IL13Rα2 that has an antigen binding domain with amino acid sequences that are identical to those encoded by the claimed nucleic acids. The references US’864 and Gould demonstrate that reverse translation from amino acid sequences to nucleic acid sequences was routinely practiced in the art rendering the claimed antigen binding domain obvious. The amino acid sequences disclosed by the combination of applied references and reverse translation would result in an encoded binding domain with sequences that were known to bind IL13Rα2 for use in CARs. As the references do not suggest any additional elements which would materially affect the basic characteristics of the claimed invention, the teachings of the combination of Daga, Ma, US’894, and Gould meet the instant claim limitations.
Claims 123, 127, 150, 153-155, 177, 180-182, and 186 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/156711 A1 (Abate-Daga, D.) 30 August 2018, priority date 22 February 2017 in view of US 9,828,428 B2 (Ma, D., et al) 28 November 2017, Antibody design laboratories (2014) Cloning of scFv fragments; accessed from <https://www.abdesignlabs.com/technical-resources/scfv-cloning/> on 11/24/2025, US 7,169,894 B2 (Martin, M.T.) 30 January 2007, and Gould, N., et al (2014) Computational tools and algorithms for designing and customized synthetic genes Frontiers in Bioengineering and Biotechnology 2(41); 1-14 as applied to claims 121, 149, and 175 above, and in further view of WO 2018/161017 A1 (Suri, V., et al) 07 September 2018, priority 03 March 2017.
It is noted that the instant specification discloses that the polynucleotides of SEQ ID NOs: 133 and 138 are Hu07 scFv (VL>VH) and Hu07 scFv (VH>VL), the amino acid translation of which are instant SEQ ID NOs: 10 and 11, respectively (instant specification pages 62, 84, and 85-86).
The instant specification further discloses that the polynucleotide sequences of SEQ ID NOs: 65 and 66, are Hu07 CAR (VH>VL) and Hu07 CAR (VL>VH) the amino acid translation of which are instant SEQ ID NOs: 23 and 55, respectively (instant specification pages 62-63, 70, and 71-72).
The combination of Daga, Ma, Antibody Design Laboratories, US’894, and Gould teach the modified cells of claims 121 and 149 and the polynucleotide of claim 175 as discussed above.
As discussed above, Daga and Ma teach the heavy and light chain variable regions of the Hu07 antibody (Daga, SEQ ID NO: 33 and 41) and Antibody Design Laboratories supports the use of a VH-linker-VL or VL-linker-VH orientation for the scFv.
Daga further teaches that the structure of the CAR is defined by SP-IL13Ra2-HG-TM-CSR-ISD where SP is a signal peptide; IL13Ra2 is an IL13Ra2-binding domain; HG is an optional hinge; TM is a transmembrane domain; CSR is a co-stimulatory signaling region; ISD is an intracellular signaling domain, and “-“ is a bivalent linker (page 134, claim 7). Daga teaches a structure for the CAR in which TM is a transmembrane region from CD8, the CSR is 4-1BB and the ISD is CD3ζ (Figure 1, second figure, Figure page 1/5, pdf page 138). Daga further teaches that a signal peptide is optionally included on the ectodomain so that the CAR can be glycosylated and anchored in the cell membrane of the immune effector cell (page 5, lines 18-21),
Daga discloses structures for the signal peptide, the linker between the VH and VL domains, the transmembrane domain, the costimulatory domain, and the intracellular signaling domain as follows:
Signal peptide, MVLLVTSLLLCELPHPAFLLIP (Daga SEQ ID NO: 15, page 105, lines 8-9).
Linker, GSTSGSGKPGSGEGSTKG (SEQ ID NO: 14, page 105, lines 5-7);
CD8 transmembrane domain and hinge (Daga SEQ ID NO: 9, page 104, lines 15-19).
4-1BB costimulatory domain (Daga SEQ ID NO: 12, page 104, lines 28-31).
CD3 ζ intracellular signaling domain (Daga SEQ ID NO: 13, page 104, line 32-page 105, line 4).
The combination of Daga, Ma, US’894 and Gould, however, do not disclose the linker GGGGSGGGGSGGGGS, which is the linker used in the instantly claimed scFvs. Additionally, while the combination of applied references teaches components of the CAR that are derived from the same genus of the claimed CAR, such as a signal peptide, linker, CD8 transmembrane domain, 4-1BB costimulatory domain, and CD3ζ intracellular domain, the species of amino acid sequences disclosed by the combination of the applied references are not identical in structure to those used in the CARs of the instant claims.
Suri teaches immunotherapeutic agents including chimeric antigen receptors comprising an extracellular targeting moiety, a transmembrane domain, an intracellular signaling domain; and optionally, one or more co-stimulatory domains (page 4, [0016]). Suri further teaches common amino acid sequences used in CARs.
Suri teaches that the extracellular domain may be selected from a Fab fragment or a single chain variable fragment (scFv) (page 4, [0018]). Suri teaches that single chain Fv, or scFv, refers to a fusion protein of VH and VL antibody domains, wherein these domains are linked together into a single polypeptide chain by a flexible linker (page 37, [00163]). Suri teaches linkers including GGGGSGGGGSGGGGS (page 95, row 2) which is further demonstrated in a CD19 scFv used to join the light and heavy chain variable regions (page 77, row 7, “CD19 scFv”). Suri also teaches the linker disclosed by Daga, GSTSGSGKPGSGEGSTKG (page 132, [00294], SEQ ID NO: 848) suggesting the linkers as alternatives for use in scFv production.
Suri further teaches that the signal peptide can be a CD8a leader with the following amino acid sequence (page 77, row 13):
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Suri teaches alternative portions of the CD8 transmembrane domain and hinge that can be used in the construction of CARs including the following sequence (page 77, row 9):
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The amino acid sequence of the CD8a hinge-TM taught by Suri is encoded by instant SEQ ID NOs: 45 and 46.
Suri further teaches alternatives of the 4-1BB costimulatory domain that can be used in the construction of CARs including the following sequence (page 77, row 12):
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The amino acid sequence of the 41BB costimulatory taught by Suri is encoded by instant SEQ ID NO: 47.
Suri also teaches alternatives of the CD3 zeta intracellular domain that can be used in the construction of CARs including the following sequence (page 61, row 1):
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The amino acid sequence of the CD3 zeta costimulatory taught by Suri is encoded by instant SEQ ID NO: 48.
Suri also teaches alternative hinge regions, transmembrane regions, including CD8 alpha, costimulatory regions, and intracellular signaling domains for use in the construction of CARs, which include sequences that are from the human sequences (pages 55-72).
Suri further teaches vectors that package polynucleotides for use in delivering the polynucleotides to a cell including RNA vectors and viral vectors (page 170, [00441]). Suri teaches that in general vectors contain promoter sequences and teaches the use of the preferred promoter elongation growth factor-1 alpha (EF-1 alpha) (pages 170-171, [00442]-[00443]). Suri further teaches that other elements provided in lentiviral particles may include a lentiviral reverse response element (RRE), a central polypurine tract (cPPT) sequence to improve transduction efficiency in non-dividing cells, or a Woodchuck Hepatitis virus posttranscriptional regulatory element (WPRE) which enhances the expression of the transgene and increases titer (page 173, 00453).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have substituted the linker of the scFv and/or the alternative amino acid sequences for the CAR components disclosed by Suri in place of the linker and sequences taught by Daga, Ma, US’894, and Gould. It would have been obvious to an ordinarily skilled artisan to make these substitutions as Suri teaches that the sequences were known alternatives for the construction of scFvs and CARs. An ordinarily skilled artisan would have had a reasonable expectation of success as the sequences are disclosed as alternatives and would be expected to have similar properties.
It would have further been obvious to an ordinarily skilled artisan to try scFv domains including HC-linker-LC and LC-linker-HC as both scFvs comprise the binding regions of an IL13Ra2 antibody. Furthermore, Daga teaches examples in which heavy and light chain order is interchanged and tested (see example 2, 131).
Using the anti-IL13Ra2 heavy and light chain variable regions taught by Daga and Ma (Daga, SEQ ID NOs: 33 and 41, respectively) with the linker taught by Suri, results in scFv domains that are identical to instant SEQ ID NOs: 10 and 11, as shown in the ABSS alignments below, which are the amino acid sequences encoded by the nucleic acids claimed in instant claim 123:
Daga, Ma, US’894, Gould, and Suri aligned with SEQ ID NO: 10:
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Daga, Ma, US’894, Gould, and Suri aligned with SEQ ID NO: 11:
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Substituting the alternative amino acid sequences taught by Suri in the CAR taught by Daga and Ma, results in CAR structures that are 98.4% identical to instantly claimed SEQ ID NOs: 23 and 55 (instant claim 128) as shown in the ABSS alignments below, which are which are the amino acid sequences encoded by the nucleic acids claimed in instant claim 127:
Daga, Ma, Antibody Design Laboratories, US’894, Gould, and Suri CAR aligned with instant SEQ ID NO: 23
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Daga, Ma, Antibody Design Laboratories, US’894, Gould, and Suri CAR aligned with instant SEQ ID NO: 55
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The sequences above are 98.4% identical to instant SEQ ID NOs: 23 and 55 with 4 indels in each sequence alignment indicating 4 additional amino acids. Specifically, the claimed CARs comprise a GS linker between the signaling domain and binding domain and a SG linker between the binding domain and the transmembrane domain. The addition of these amino acids, however, would have been obvious to an ordinarily skilled artisan in view of the teachings of the applied references. For example, Daga teaches that in a bivalent linker can be placed between each of the CAR components (page 134, claim 7). Suri further corroborates these teachings disclosing that “the CAR of the present invention may comprise one or more linkers between any domains of the CAR” (page 72, [00225]). Suri further teaches that the linker may be of the amino acid sequences SG (page 78, row 7; page 132, [00294]) or GS (page 95, row 3; page 132, [00294]).
While Daga, Ma, Antibody Design Laboratories, US’894, Gould, and Suri do not disclose the polynucleotide sequences of instant SEQ ID NOs: 138 or 133 or SEQ ID NOs: 65 and 66, these sequences encode amino acids that are obvious in view of the teachings of the combined prior art references, as discussed in detail above. As discussed in the rejection of claim 121, the reverse translation between amino acid sequences and the polynucleotides that encode them was routine in the art prior to the effective filing date of the claimed invention as taught by US’894 and Gould.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have used the amino acid sequences disclosed by the combination of Daga, Ma, Antibody Design Laboratories, US’894, Gould, and Suri to arrive at the instantly claimed nucleic acids using reverse translation that was known and routine in the art. This conclusion of obviousness is further supported by KSR (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. See MPEP 2143. In this case, the combination of Daga, Ma, Antibody Design Laboratories, US’894, Gould, and Suri teach an IL13Ra2 binding CAR with amino acid sequences that render obvious the amino acid sequences of the instantly claimed invention. Daga also discloses nucleic acids encoding the amino acid sequences and their use in vectors for the transformation of cells. US’894 teaches that there are 20 genetically encoded amino acids with 64 amino acid-encoding codons and both US’894 and Gould demonstrate that reverse translation was commonly practiced in the art of protein and gene synthesis. An ordinarily skilled artisan would have been able to pursue the known potential solutions with a reasonable expectation that the resulting nucleic acid would encode the amino acid sequence that it was reverse translated from, specifically those disclosed by the combination of the applied references.
Claims 129, 156-157, 159-162, 176, 179, 183-184, and 187 are rejected under 35 U.S.C. 103 as being unpatentable over Hedge, M., et al (2013) Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma Molecular Therapy 21(11) 2087-2101 in view of WO 2017/027291 A1 (Jensen, M.C.) 16 February 2017, US 9,828,428 B2 (Ma, D., et al) 28 November 2017, Antibody design laboratories (2014) Cloning of scFv fragments; accessed from <https://www.abdesignlabs.com/technical-resources/scfv-cloning/> on 11/24/2025, US 7,169,894 B2 (Martin, M.T.) 30 January 2007, and Gould, N., et al (2014) Computational tools and algorithms for designing and customized synthetic genes Frontiers in Bioengineering and Biotechnology 2(41); 1-14.
It is noted that the instantly claimed polynucleotides of SEQ ID NOs: 57 and 61 translate to the amino acids of instant SEQ ID NOs: 8 and 9, respectively; and the polynucleotides of instant SEQ ID NOs: 139 and 140 translate to the amino acids of instant SEQ ID NOs: 31 and 32, respectively. Instant SEQ ID NOs: 194 and 195 also translate to the amino acids of instant SEQ ID NO:s 31 and 32, respectively, and are alternative nucleic acid sequences for the 806 antibody.
Hedge teaches that preclinical and early clinical studies have demonstrated that chimeric antigen receptor (CAR)-redirect T cells are highly promising in cancer therapy (abstract). Hedge discloses that combination targeting of tumor-associated antigens could offset escape mechanisms in which the targeted antigen is no longer present on the tumor cells but the cells maintain expression of nontargeted tumor-associated antigens (abstract). Hedge studied single-cell coexpression patterns of HER2, IL-13Ra2, and EphA2 in primary glioblastoma samples using multicolor flow cytometry and immunofluorescence and then co-targeted HER2 and IL-13Ra2 in an attempt to maximally expand the therapeutic reach of the T cell product in the primary tumors studied (abstract).
Hedge generated bispecific T cell products from healthy donors and from GMB patients by pooling T cells individually expressing HER2 and IL-13Ra2 specific CARs and by making individual T cells that coexpress both CAR molecules. Hedge teaches that the HER2/IL-13Ra2 bispecific T cell product offset antigen escape producing enhanced effector activity in in vitro immune-assays and in orthotopic xenogeneic murine models. Hedge further teaches that T cells coexpressing HER2 and IL-13Ra2 CARs exhibited accentuated yet antigen-dependent downstream signaling and a particularly enhanced antitumor activity (abstract). Hedge further teaches that CAR T cell products were generated using T cell products from healthy donors and from GBM patients demonstrating allogenic and autologous modified cell production (abstract).
Hedge discloses that T cells coexpressing HER2.CD28ζ and IL-13Ra2.CD28ζ (biCAR T cells) were generated by tandem retroviral transductions, via a retroviral vector (page 2099, left column, paragraph 2; page 2098, right column, paragraph 3). Hedge discloses that the CARs comprise a binding domain, a CD28 transmembrane domain and a CD28.ζ signaling domain (page 2098, right column, paragraph 3), which indicates a CD28 costimulatory and CD3ζ intracellular signaling domain. Hedge further discloses that the T cells that were transfected were collected from peripheral blood mononuclear cells isolated by lymphoprep gradient centrifugation and then activated with OKT3 and CD28 monoclonal antibodies. OKT3 is an anti-CD3 antibody, indicating that the T cells that were transfected and activated were CD3+ lymphocytes. The OKT3/CD28 activated T cells were then transduced with retroviral vectors (page 2098, Retrovirus production and transduction).
Hedge teaches that it is demonstrated that biCAR T cells can be efficiently generated by sequential retroviral transduction without compromising T cell activation, proliferation potential, or antitumor activity. Generating a clinical grade biCAR T cell product by sequential retroviral transduction would nevertheless substantially increase cost and understandably be faced by multiple regulatory hurdles. To overcome this, one strategy is to use internal ribosomal entry site or 2A-containing retroviral bicistronic vectors, allowing for simultaneous expression of two (or more) CAR molecules from the same RNA transcript (page 2098, left column, paragraph 2).
Hedge further teaches that in preclinical models of GMB, CAR T cells have shown robust antitumor activity and are currently being investigated in phase I/II studies that target the glioma-restricted antigens IL-13Ra2, HER2, and EGFR (page 2087, right column, paragraph 1).
While Hedge exemplifies an immune cell comprising IL13Ra2 and HER2 CARs and not specifically IL13Ra2 and EGFR CARs, it would have been prima facie obvious to an ordinarily skilled artisan to have substituted a CAR targeting EGFR in place of the HER2 CAR in the immune cells and methods disclosed. It would have been obvious to an ordinarily skilled artisan to make this substitution as Hedge teaches that IL-13Ra2, HER2, and EGFR were glioma-restricted antigens that were being targeted in the treatment of GBM with CAR T cells. An ordinarily skilled artisan would have had a reasonable expectation of success in targeting EGFR in place of HER2 as Hedge teaches that EGFR targeting CARs had demonstrated robust antitumor activity in preclinical models and were currently being studied in phase I/II trials. Furthermore, Hedge teaches that targeting two tumor-associated antigens offers enhanced anti-tumor activity (abstract), offset antigen escape, and achieve better tumor control, conferring survival advantage (page 2097, left column, paragraph 2). Furthermore, it would have been obvious to include the first and second CARs in the same 2A- containing retroviral bicistronic vector which would allow for the simultaneous expression of two CARs from the same RNA transcript and to put the CARs in either order in the transcript. An ordinarily skilled artisan would have been motivated to use a 2A-containing retroviral bicistronic vector in order to overcome challenges with increased cost and regulatory hurdles. An ordinarily skilled artisan would have had a reasonable expectation of success as Hedge teaches 2A-containing bicistronic vectors as an alternative method of making T cells that encode 2 separate CARs.
Hedge, however, does not disclose that the binding domain of the first and second car comprises the recited amino acid sequences. Hedge also does not disclose that the CARs also comprise a hinge domain.
Jensen teaches methods of engineering bi-specific T cells that expresses a chimeric antigen receptor for promoting the in vivo expansion and activation of an effector cell and a second chimeric antigen receptor specific for a ligand on a tumor (abstract). Jansen teaches the use of a ribosome skip sequence which refers to a sequence that, during translation, forces the ribosome to skip and translate the region after the ribosome skip sequence without formation of a peptide bond. Jansen teaches that several viruses have ribosome skip sequences that allow sequential translation of several proteins on a single nucleic acid without having the proteins linked via a peptide bond. Jansen teaches that in some alternatives of the disclosed invention, the nucleic acids comprise a ribosome skip sequence between the sequence for the chimeric antigen receptor and the sequence of the marker protein, such that the proteins are co-expressed and not linked by a peptide bond. Jansen further teaches that in some alternatives the ribosome skip sequence is a P2A, T2A, E2A, or F2A sequence (pages 82-83, [0091]).
Jensen teaches that the nucleic acid is included in a vector and that the vector is a lentiviral vector, a retroviral vector, a plasmid or an mRNA (page 84, [0096]). Jensen also demonstrates dual transduced CD8+ T cells and teaches that the cells that are administered are provided by allogeneic transfer or autologous transfer (page 61, [0033]; page 116, [0174]).
Jensen further teaches a composition or product combination for human therapy where the composition or product comprises a pharmaceutical excipient and at least one population of genetically modified T-cells as well as excipients (page 109, [0160]).
Jensen teaches a CAR directed against EGFR comprising an amino acid sequence of the scFv set forth in SEQ ID NO: 19 (page 69, [0060]). The heavy and light chain variable regions of the scFv taught by Jensen are identical to instant SEQ ID NOs: 31 and 32 as shown in the ABSS alignments below:
Jensen, SEQ ID NO: 19 aligned with instant SEQ ID NO: 31
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Jensen, SEQ ID NO: 19 aligned with instant SEQ ID NO: 32
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Jensen further teaches the primary sequence of a CAR which includes an EF1p promoter (EF1p), a leader sequence, such as a sequence for targeting the protein to the cell surface; an antigen binding domain comprising an scFv with VL-linker-VH; a spacer domain comprising a hinge; a transmembrane domain, costimulatory domain (41BB), and CD3ζ (Fig. 2; pages 60-61, [0031]). Jensen also teaches that the spacer can be a CD8 alpha hinge (page 90, [0114]). Jensen teaches that scFv are commonly incorporated in CARs (page 2, [0005]).
Ma teaches anti-IL-Ra2 antibodies, antibody drug conjugates, and methods for preparing and using the same (abstract). Ma teaches that high levels of IL13Ra2 have been identified in a number of tumor cells, including pancreatic, breast, ovarian, and malignant gliomas. Ma teaches that in contrast, only a few types of normal tissues express IL-13-Ra2 and only at low levels (column 1, lines 38-41). Ma teaches the humanized antibody hu07 comprising a light chain variable region of SEQ ID NO: 48 and a heavy chain variable region of SEQ ID NO: 41 (column 11, Table 3, hu07). The variable regions taught by Ma are identical to instant application SEQ ID NOs: 8 and 9 as shown in the ABSS alignments below:
Ma heavy chain variable region of SEQ ID NO: 41 aligned with instant SEQ ID NO: 8:
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Ma light chain variable region of SEQ ID NO: 48 aligned with instant SEQ ID NO: 9:
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The teachings of Antibody Design Laboratories, US’894 and Gould are as discussed above.
As discussed in detail above, it would have been prima facie obvious to an ordinarily skilled artisan to arrive at a modified immune cell comprising a first and second CAR that bind to IL13Rα2 and EGFR based on the teachings of Hedge.
It would have further been prima facie obvious to have used the heavy and light chain variable domains of the anti-EGFR antibody disclosed by Jensen and the heavy and light chain variable domains of the anti-IL13Ra2 antibody disclosed by Ma as the binding domains in the CARs taught by Hedge and to further include a hinge in the CARs as disclosed by Jensen.
It would have been obvious to an ordinarily skilled artisan to use the EGFR antibody variable domains taught by Jensen and the IL13Ra2 antibody variable domains taught by Ma as Jensen and Ma teach that the variable regions, when used together in an antibody or fragment thereof, specifically target and bind to EGFR and IL13Ra2. An ordinarily skilled artisan would have had a reasonable expectation of success in using the heavy and light chain variable domains disclosed by Jensen and Ma as the binding domains in the CAR as the binding domains were demonstrated to specifically target and bind EGFR and IL13Ra2 which are the antigen targets of the CAR suggested by Hedge. It would have been obvious to further include a hinge region as Jensen teaches that the inclusion of a spacer, such as a hinge domain, is a common inclusion in CAR constructs in the art. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
It would have been further been obvious to use the VH and VL domains of the antibodies in either order as Antibody Design laboratories teaches that there is not a preferential orientation and that VH-linker-VL and VL-linker-VH orientations are likely equivalent. An ordinarily skilled artisan would have had a reasonable expectation of success as Antibody Design laboratories is teaching scFv constructs, which are the same type of binding that Jensen teaches is commonly used in CAR generation.
As discussed above, the applied references teach an IL13Ra2 binding domain comprising a heavy and light chain variable region matching instant SEQ ID NOs: 8 and 9 and an EGFR binding domain comprising a heavy and light chain variable region matching instant application SEQ ID NOs: 31 and 32. While the combination of applied references does not disclose the claimed nucleic acids that encode these amino acids, the reverse translation between amino acid sequences and the polynucleotides that encode them was routine in the art prior to the effective filing date of the claimed invention as taught by US’894 and Gould. It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have used the amino acid sequences disclosed by the combination of Hedge, Jensen, Ma, and Antibody Design Laboratories to arrive at the instantly claimed nucleic acids using reverse translation that was known and routine in the art at demonstrated by US’894 and Gould. An ordinarily skilled artisan would have been motivated to make this combination in order to produce polynucleotides that could be used to express the CARs disclosed by Hedge, Jensen, Ma, and Antibody Design Laboratories.
This conclusion of obviousness is further supported by KSR (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. See MPEP 2143. In this case, Hedge, Jensen, Ma, and Antibody Design Laboratories disclose amino acid sequences that are identical to those encoded by the nucleic acids of the instantly claimed invention. The applied references also disclose nucleic acids encoding the amino acid sequences and their use in vectors for the transformation of cells. US’894 teaches that there are 20 genetically encoded amino acids with 64 amino acid-encoding codons and both US’894 and Gould demonstrate that reverse translation was commonly practiced in the art of protein and gene synthesis. An ordinarily skilled artisan would have been able to pursue the known potential solutions with a reasonable expectation that the resulting nucleic acid would encode the amino acid sequence that it was reverse translated from, specifically those disclosed by the combination of the applied references.
Claims 130-131, 158, 163-174, 178, and 185 are rejected under 35 U.S.C. 103 as being unpatentable over Hedge, M., et al (2013) Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma Molecular Therapy 21(11) 2087-2101 in view of WO 2017/027291 A1 (Jensen, M.C.) 16 February 2017, US 9,828,428 B2 (Ma, D., et al) 28 November 2017, Antibody design laboratories (2014) Cloning of scFv fragments; accessed from <https://www.abdesignlabs.com/technical-resources/scfv-cloning/> on 11/24/2025, US 7,169,894 B2 (Martin, M.T.) 30 January 2007, and Gould, N., et al (2014) Computational tools and algorithms for designing and customized synthetic genes Frontiers in Bioengineering and Biotechnology 2(41); 1-14, as applied to claims 129, 176, 179, and 183-184 above, and in further view of WO 2018/161017 A1 (Suri, V., et al) 07 September 2018, priority 03 March 2017.
It is noted that the instant specification discloses that the polynucleotides of SEQ ID NOs: 133 and 138 are Hu07 scFv (VL>VH) and Hu07 scFv (VH>VL), the amino acid translation of which are instant SEQ ID NOs: 10 and 11, respectively (instant specification pages 62, 84, and 85-86). The instant specification also discloses that the polynucleotides of SEQ ID NOs: 33 and 141 are 806 scFv (VH>VL) and 806 scFv (VL>VH), the amino acid translation of which are instant SEQ ID NOs: 34 and 142 (instant specification pages 64-65).
The combination of Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, and Gould teach the modified cell of claim 129, the polynucleotide sequence of claim 176, and the vector of claim 184 as discussed above.
As discussed above, the combination of Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, and Gould teach heavy and light chain variable regions matching those encoded by the instantly claimed polynucleotides.
Jensen further teaches that the scFv of the EGFR CAR comprises an amino acid sequence of SEQ ID NO: 19 (page 208, claim 41). The scFv taught by Jensen matches the scFv of instant SEQ ID NO: 34 with the exception of the linker that is used between the heavy and light chain variable regions, specifically, Jensen teaches that the linker in the scFv is GSTSGSGKPGSGEGSTKG.
The combination of Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, and Gould do not disclose that the linker in the scFv is GGGGSGGGGSGGGGS. The combination of applied references also do not explicitly disclose that the hinge, TM, costimulatory and intracellular signaling domains are from human sequences or that the EF1 promoter is an EF1 alpha promoter.
The teachings of Suri are as discussed above.
Suri also teaches alternative hinge regions, transmembrane regions, including CD8 alpha, costimulatory regions, and intracellular signaling domains for use in the construction of CARs, which include sequences that are from the human sequences (pages 55-72).
Suri further teaches vectors that package polynucleotides for use in delivering the polynucleotides to a cell including RNA vectors and viral vectors (page 170, [00441]). Suri teaches that in general vectors contain promoter sequences and teaches the use of the preferred promoter elongation growth factor-1 alpha (EF-1 alpha) (pages 170-171, [00442]-[00443]). Suri further teaches that other elements provided in lentiviral particles may include a lentiviral reverse response element (RRE), a central polypurine tract (cPPT) sequence to improve transduction efficiency in non-dividing cells, or a Woodchuck Hepatitis virus posttranscriptional regulatory element (WPRE) which enhances the expression of the transgene and increases titer (page 173, 00453).
It would have prima facie been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have used the linker disclosed by Suri in place of the linker disclosed by Jensen in the construction of the scFvs regions of the first and second CARs taught by Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, and Gould. It would have further been obvious to modify the CARs taught by the combination of Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, and Gould by substituting the human derived hinge, transmembrane region (including CD8 alpha), costimulatory, and intracellular signaling domains disclosed by Suri and to further include an EF-1 alpha promoter.
It would have been obvious to use the linker disclosed by Suri in place of the linker of Jensen as Suri is teaches that the linker is a known alternative for the construction of scFvs. An ordinarily skilled artisan would have had a reasonable expectation of success as the linkers taught by Suri are known alternative linkers for the construction of scFvs in CAR production and, therefore, they would be expected to have analogous properties. Similarly, it would have been obvious to substitute the regions of the CARs with alternative regions, such as those disclosed by Suri, with the reasonable expectation that the regions would have analogous properties as they are taught to be alternative sequences for CAR manufacturing. An ordinarily skilled artisan would have been motivated to add an EF-1 alpha promoter in order to improve transduction efficiency and enhance expression of the transgene as taught by Suri.
Using the linker, GGGGSGGGGSGGGGS (page 95, row 2), taught by Suri in the scFv taught by Hedge, Jensen, Ma, US’894, and Gould results an scFv domain that is 99.7% identical to instant SEQ ID NO: 34, as shown in the ABSS alignment below:
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The mismatch in the scFv above is shown to be in the linker where a glycine residue is replaced by a serine residue. However, modifications to the linker comprising these two amino acid residues are well known and established in the art. For example, Jensen teaches that an artificially designed peptide linker may preferably be composed of polymer of flexible residues like glycine (G) and serine (S) so that adjacent protein domains are free to move relative to one another and goes on to describe numerous combinations of G and S in linkers that can be used to create scFv regions (page 132, [00294]). Based on the knowledge in the art regarding linkers, the substitution of the S for the G amino acid in the scFv would be considered to be an obvious simple substitution (see MPEP 2143, KSR (B)).
It is further noted that it would have been obvious to a skilled artisan that the heavy and light chain variable region order could be swapped in the CAR which would lead to the amino acid sequence of instant SEQ ID NO: 142, as is further supported by the teachings of Antibody Design Laboratories.
In regards to instant claim 130, as discussed previously in the rejection of claim 129, Ma teaches heavy and light chain variable regions matching those of the instantly disclosed CARs. While Ma does not teach these components combined in an scFv, the construction of scFvs was standard practice in the art of CAR construction. For example, Jensen teaches that CARs typically comprise a single chain variable fragment (scFv) that is derived from a monoclonal antibody (mAb (page 2, [0005]). Suri teaches that scFv refers to a fusion protein of VH and VL antibody domains wherein these domains are linked together into a single polypeptide chain by a flexible linker (page 37, [00163]). Based on these teachings, it would have been obvious to a skilled artisan to incorporate the linker GGGGSGGGGSGGGGS taught by Suri (page 95, row 2) in the construction of an scFv for use in the IL13Ra2 CAR taught by Hedge and Ma. Using this linker with the heavy and light chain variable regions taught by Ma results in scFvs that are identical to instant SEQ ID NOs: 10 and 11 as shown in the ABSS alignments below:
Instant SEQ ID NO: 10 aligned with structure taught by the applied references:
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Instant SEQ ID NO: 11 aligned with structure taught by the applied references:
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While the applied references do not teach the instantly claimed polynucleotides, the reverse translation between amino acid sequences and the nucleic acid sequences that encode them was routine in the art prior to the effective filing date of the claimed invention as taught by US’894 and Gould and discussed above. It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have used the amino acid sequences disclosed by Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, Gould, and Suri to arrive at the instantly claimed polynucleotides using reverse translation that was known and routine in the art. An ordinarily skilled artisan would have been motivated to make this combination in order to produce a nucleic acid that could be used to express the CARs disclosed by Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, Gould, and Suri.
This conclusion of obviousness is further supported by KSR (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. See MPEP 2143. In this case, Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, Gould, and Suri render obvious the amino acid sequences that are encoded by the nucleic acids of the instantly claimed invention. The applied references also disclose nucleic acids encoding the amino acid sequences and their use in vectors for the transformation of cells. US’894 teaches that there are 20 genetically encoded amino acids with 64 amino acid-encoding codons and both US’894 and Gould demonstrate that reverse translation was commonly practiced in the art of protein and gene synthesis. An ordinarily skilled artisan would have been able to pursue the known potential solutions with a reasonable expectation that the resulting nucleic acid would encode the amino acid sequence that it was reverse translated from, specifically those disclosed by the combination of the applied references.
Claim 132 is rejected under 35 U.S.C. 103 as being unpatentable over Hedge, M., et al (2013) Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma Molecular Therapy 21(11) 2087-2101 in view of WO 2017/027291 A1 (Jensen, M.C.) 16 February 2017, US 9,828,428 B2 (Ma, D., et al) 28 November 2017, Antibody design laboratories (2014) Cloning of scFv fragments; accessed from <https://www.abdesignlabs.com/
technical-resources/scfv-cloning/> on 11/24/2025, US 7,169,894 B2 (Martin, M.T.) 30 January 2007, and Gould, N., et al (2014) Computational tools and algorithms for designing and customized synthetic genes Frontiers in Bioengineering and Biotechnology 2(41); 1-14, as applied to claim 129 above, and in further view of WO 2018/156711 A1 (Abate-Daga, D.) 30 August 2018, priority date 22 February 2017 and WO 2018/161017 A1 (Suri, V., et al) 07 September 2018, priority 03 March 2017.
It is noted that the instant specification discloses that the polynucleotides of SEQ ID NOs: 65 and 66 are Hu07 CAR (VH>VL) and Hu07 CAR (VL>VH), the amino acid translations of which are instant SEQ ID NOs: 23 and 55, respectively (instant specification pages 62, 70, and 71-72). The instant specification also discloses that the polynucleotides of SEQ ID NOs: 35 and 196 are 806-BBZ-CARs, the amino acid translation of which are instant SEQ ID NOs: 36 and 197 (instant specification pages 65-66).
The combination of Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, and Gould teach the nucleic acid of claim 129 as discussed above.
The combination of applied references, however, does not disclose the sequence of the IL13Ra2 or EGFR binding CARs.
The teachings of Daga and Suri are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have used the CAR constructs disclosed by Daga and Suri for the construction of the CARs taught by Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, and Gould. It would have been obvious to use the sequences of Daga and Suri for the construction of the CARs as the references demonstrate that they were known and functional components for use in CAR production. An ordinarily skilled artisan would have had a reasonable expectation of success as Daga and Suri are also teaching the construction of CARs and, therefore, the components disclosed would be reasonably expected to result in functional CARs.
Combining the amino acids disclosed by Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, Gould, Daga, and Suri results in an IL13Ra2 CAR that is 98.4% identical to instant SEQ ID NO: 23 as shown in the ABSS alignment below:
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Combining the amino acids disclosed by Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, Gould, Daga, and Suri results in an EGFR CAR that is 98.3% identical to instant SEQ ID NO: 36 as shown in the ABSS alignment below:
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The sequences above are 98.4% and 98.3% identical to instant SEQ ID NOs: 23 and 36, respectively.
In the case of SEQ ID NO: 23, the CAR taught by the applied references matches instant SEQ ID NO: 23 with the exception of 4 indels. The addition of these amino acids, however, would have been obvious to an ordinarily skilled artisan. For example, Daga teaches that in between each of the CAR components a bivalent linker can be placed (page 134, 7.). Suri further corroborates these teachings disclosing that “the CAR of the present invention may comprise one or more linkers between any domains of the CAR.” (page 72, [00225]). Suri further teaches that the linker may be of the amino acid sequences SG (page 78, row 7) or GS (page 95, row 3).
In the case of SEQ ID NO: 36, the CAR taught by the applied references matches SEQ ID NO: 36 with the exception of the same 4 indels and also 1 mismatch located in the linker between the heavy and light chain variable regions of the scFv where a glycine residue is replaced by a serine residue. The four indels would have been an obvious addition for the reasons discussed above with regards to instant SEQ ID NO: 23. Additionally, linkers comprising G and S amino acid residues were well known and established in the prior art. For example, Jensen teaches that “an artificially designed peptide linker may preferably be composed of polymer of flexible residues like glycine (G) and serine (S) so that adjacent protein domains are free to move relative to one another” and goes on to describe numerous combinations of G and S in linkers that can be used to create scFv regions (page 132, [00294]). Based on the knowledge in the art regarding linkers, the substitution of the S for the G amino acid in the scFv taught by the applied references would be considered to be an obvious simple substitution (see MPEP 2143).
While the combination of applied references does not teach the instantly claimed polynucleotides, the reverse translation between amino acid sequences and the nucleic acid sequences that encode them was routine in the art prior to the effective filing date of the claimed invention as taught by US’894 and Gould and discussed above. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have used the amino acid sequences disclosed by Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, Gould, Daga, and Suri to arrive at the instantly claimed polynucleotides using reverse translation that was known and routine in the art. An ordinarily skilled artisan would have been motivated to make this combination in order to produce a nucleic acid that could be used to express the CARs disclosed by Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, Gould, Daga, and Suri.
This conclusion of obviousness is further supported by KSR (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. See MPEP 2143. In this case, Hedge, Jensen, Ma, Antibody Design Laboratories, US’894, Gould, Daga, and Suri render obvious the amino acid sequences that are encoded by the nucleic acids of the instantly claimed invention. The applied references also disclose nucleic acids encoding the amino acid sequences and their use in vectors for the transformation of cells. US’894 teaches that there are 20 genetically encoded amino acids with 64 amino acid-encoding codons and both US’894 and Gould demonstrate that reverse translation was commonly practiced in the art of protein and gene synthesis. An ordinarily skilled artisan would have been able to pursue the known potential solutions with a reasonable expectation that the resulting nucleic acid would encode the amino acid sequence that it was reverse translated from, specifically those disclosed by the combination of the applied references.
Response to Arguments
Applicant’s arguments in the response filed 11/13/2025 have been fully considered but were not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that, based on the teachings of Daga and Ma, the skilled person would have reasonably concluded that they should either use the VH/VL of SEQ ID NOs: 1 and 3 or the VH/VL of SEQ ID NOs: 2 and 4. Specifically, applicant argues that Ma describes humanized Hu07 and Hu08, but shows preference for Hu08 as biological studies use the Hu08 antibody and the claims are limited to Hu08. With regards to Daga, applicant argues that Daga uses SEQ ID NOs: 1 and 3 or 2 and 4. Applicant argues that, even four years after Ma, Daga suggests using a different VH and VL.
This argument, however, is not persuasive. Even if Daga and Ma teach alternative VH and VL domains for IL13Ra2 antibodies, the teaching of alternatives, even preferred alternatives, does not criticize, discredit, or otherwise discourage the use of the claimed sequences. Daga teaches the VH and VL amino acid sequences of the instant invention as domains that can be used in the disclosed anti-IL13Ra2 CARs and Ma demonstrates that, when combined, the VH and VL bind to IL13Ra2. Thus, one of ordinary skill in the art would have identified these sequences for use in the anti-IL13Ra2 CAR of Daga with a reasonable expectation of success. Applicant does not provide any comparison to suggest that the claimed VH and VL provide any unexpected result compared to any of the other IL13Ra2 binding domains disclosed by Daga and Ma.
Applicant further argues that, even if the references did suggest the use of SEQ ID NOs: 33 and 41 of Daga, none of the cited reference disclose, teach, or suggest the specific nucleic acids recited in the instant claims. Applicant argues that there are at least about 1058 possible nucleic acid sequences that would encode Hu07 VH and at least about 1058 possible nucleic acid sequences that would encode Hu07 VL. Applicant argues that this is an extremely large number and is surely not what was meant by “a finite number” in KSR. Applicant further argues that codon usage can play a major role in determining gene expression levels and protein structures. Applicant argues that codon usage influences translation, elongation, speed, and regulates translation efficiency and accuracy. Applicant argues that the selection of specific nucleic acid molecules for a therapeutic product is not straight forward, but rather an inventive process. With regards to claim 129, applicant argues that the above arguments apply with greater force as the claim requires the selection of four specific nucleic acids encoding the VH and VL of IL13Ra2 and the VH and VL of EGFR.
As discussed in detail in the rejection, anti-IL13Ra2 CARs were known in the prior art and the amino acid sequences suggested in the art for the CARs are identical to those that are encoded by the instantly claimed polynucleotide sequence. Additionally, the art had previously considered EGFR CARs and amino acid sequences identical to those claimed for binding EGFR were also known. While there is a vast number of potential polynucleotides that could be used to encode the amino acids, each would be reasonably expected to encode the amino acid sequence that they were generated from based on degeneracy of the genetic code. While applicant argues that the identification of specific nucleic acid molecules is an inventive process, applicant does not provide any details regarding what makes the claimed nucleic acid sequences unique or inventive over any of the other nucleic acid sequences that could be used to encode the known VH and VL or obvious CAR sequences. Applicant’s arguments essentially pertain to unexpected results; however, applicant does not provide any showing of unexpected properties by comparison to any other nucleic acid sequence that could be used to encode the known amino acid sequences.
With regard to the claimed nucleic acids, the examples of the instant disclosure state that second-generation CAR structures in pGEM vectors were provided and comprised a leader sequence, hinge and transmembrane sequence of human CD8α, and the sequence of stimulation domain of human 4-1BB and CD3ζ. The sequences of murine IL13Ra2 targeting scFvs (07/08) and the humanized versions were reverse translated into nucleic acid sequences with codon optimization and ligated into BamHI and BspEI sites between the leader and hinge domain. In the case of the EGFR CARs, a humanized EGFRvIII targeting scFv was put in place of the IL13Ra2 CAR in the constructs. The disclosure does not provide any other details regarding the reverse translation or the codon optimization that was used nor does the disclosure identify that the process was unique compared to the applied prior art which demonstrates that reverse translation was commonly practiced and routine in the art. In the response, applicant provides a list of ways that nucleic acid codons can impact expressed proteins, however, applicant does not provide any evidence to suggest that the claimed polynucleotide codons, or that the specifically claimed combination of codons, results in some unexpected property compared to all of the other polynucleotide sequences that could be used to encode the known anti-IL13Ra2 CARs.
Applicant further cites In re Bell and In re Deuel for support. It is not clear, however, that either of these cases pertain to the reverse translation of VH/VL, or CAR, amino acid sequences. In re Bell is concerned with IGF I and II nucleic acids and the portion of the case cited by applicant states that “given the nearly infinite number possibilities suggested by the prior art, and the failure of the cited art to suggest which of those possibilities is the human sequence, the claimed sequences would not have been obvious.” A citation that suggests that a specific property, being a human sequence, was claimed. This is further supported by the conclusions of In re Deuel, which, for instance, states “ For example, the amino acid sequence of a protein along with knowledge of the genetic code might put an inventor in possession of the genus of nucleic acids capable of encoding the protein, but the same information would not place the inventor in possession of the naturally-occurring DNA or mRNA encoding the protein. See In re Bell, 991 F.2d 781, 26 USPQ2d 1529 (Fed. Cir. 1993); In re Deuel, 51 F.3d 1552, 34 USPQ2d 1210 (Fed. Cir. 1995).” The instant claims, however, are not drawn to any specific property of the claimed nucleic acid sequences such that arrival at the claimed species would not be obvious.
MPEP 2163 II.A.3.a.ii further cites In re Bell as stating “Description of a representative number of species does not require the description to be of such specificity that it would provide individual support for each species that the genus embraces. For example, in the molecular biology arts, if an applicant disclosed an amino acid sequence, it would be unnecessary to provide an explicit disclosure of nucleic acid sequences that encoded the amino acid sequence. Since the genetic code is widely known, a disclosure of an amino acid sequence would provide sufficient information such that one would accept that an inventor was in possession of the full genus of nucleic acids encoding a given amino acid sequence, but not necessarily any particular species. Cf. In re Bell, 991 F.2d 781, 785, 26 USPQ2d 1529, 1532 (Fed. Cir. 1993) and In re Baird, 16 F.3d 380, 382, 29 USPQ2d 1550, 1552 (Fed. Cir. 1994).”
Based on this citation, also from In re Bell, the explicit disclosure of nucleic acid sequences that encode a disclosed amino acid sequence is not necessary because the genetic code is widely known. Therefore, the disclosure of an amino acid sequence, such as the VH/VL and CARs of the prior art cited in the rejection, provides sufficient information such that one would accept that an inventor was in possession of the full genus of nucleic acids encoding the given amino acid sequence. As such, the prior art can be thought to include a genus of nucleic acid sequences, all of which encode the disclosed amino acid sequence. While applicant claims a particular species, applicant does not present any evidence to suggest that this particular species has a unique property or advantage over any other species of the genus that is established by the prior art.
With regards to KSR(E) Obvious to try and In re Deuel, Example 3 of MPEP 2143 E states that “Relying on In re Deuel, 51 F.3d 1552, 34 USPQ2d 1210 (Fed. Cir. 1995), appellant argued that it was improper for the Office to use the polypeptide of the Valiante patent together with the methods described in Sambrook to reject a claim drawn to a specific nucleic acid molecule without providing a reference showing or suggesting a structurally similar nucleic acid molecule. Citing KSR, the Board stated that "when there is motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense." KSR, 550 U.S. at 402-03, 82 USPQ2d at 1390. The Board noted that the problem facing those in the art was to isolate a specific nucleic acid, and there were a limited number of methods available to do so. The Board concluded that the skilled artisan would have had reason to try these methods with the reasonable expectation that at least one would be successful. Thus, isolating the specific nucleic acid molecule claimed was "the product not of innovation but of ordinary skill and common sense."
With regards to the claimed scFv, applicant argues that the linker of Suri is used in a CD19 scFv and that there is no suggestion in the cited references to replace the linker of Daga with Suri. Applicant argues that Daga does not suggest replacing the linker or that the linker should be improved and that one of ordinary skill in the art would not consider using a linker used in an scFv that binds a different protein (CD19).
Explicit motivation in the prior art, however, is not required in order establish a prima facie case of obviousness. MPEP 2143 provides 7 exemplary rationales that may be used to support a conclusion of obviousness, KSR (A)-(G), only one of which requires that there be some teaching, suggestion, or motivation in the prior art. With regards to the linker, the rejection of the instant office action relies on KSR (B) simple substitution of one known element for another to obtain predictable results.
As discussed in the rejection, Suri teaches common elements of CAR production and teaches that single chain Fv, or scFv, refers to a fusion protein of VH and VL antibody domains, wherein these domains are linked together into a single polypeptide chain by a flexible linker (page 37, [00163]). Suri teaches linkers including GGGGSGGGGSGGGGS (page 95, row 2). While Suri demonstrates the linker in a CD19 scFv used to join the light and heavy chain variable regions (page 77, row 7, “CD19 scFv”), an ordinarily skilled artisan would recognize that the binding of the scFv is a result of the VH and VL regions that are used within the scFv, not particularly the linker that is used to bind the regions. As Suri teaches alternative linkers for use in CAR construction, one of ordinary skill in the art would have been able to substitute the linkers in the scFv with a reasonable expectation of success and analogous properties.
With regards to the VL-VH orientation, applicant argues that the cited art teaches away from the VL-VH orientation. Applicant cites Example 2 and Figure 4 of Daga as showing that when the VL was positioned upstream from the VH the scFv did not work. Applicant argues that, therefore, one of ordinary skill in the art would not have considered using the VL-VH orientation.
In the examples, Daga teaches the construction of three CARs expressed in human primary T cells that recognize IL13Ra2 expressing melanoma cells. Specifically, Hu08-H2L (SEQ ID NO: 5), Hu07-H2L (SEQ ID NO: 6), and Hu08-L2H (SEQ ID NO: 16). Daga teaches that, based on a bar graph showing IFNγ (pg/ml) levels in A375 cells contacted with the CARs, Hu08-L2H did not recognize A375 cells. While, in this instance the Hu08-L2H CAR did not recognize A375 cells, this does not necessarily teach away from using the VL-VH orientation in other scFvs/CARs that comprise different VH and VLs and even potentially different linkers. Additionally, while this example from Daga did not bind, Daga does not discourage or teach away from this orientation for other scFvs/CARs. In the rejections of the instant office action, the reference Antibody Design Laboratories has been added to demonstrate that, in the production of scFv, there is not a preferential orientation of one domain to the other and VH-L-VL and VL-L-VH constructs are likely to be equivalent. Therefore, despite the single example from Daga that demonstrates that the specific VL-L-VH construct did not bind, one of ordinary skill in the art would still have had a reasonable expectation of success in arriving at the claimed invention using the alternative VH and VL domain that is discussed in the rejection.
Additionally, it is noted that, if it was found that the orientation is not predictable, it is not clear that applicant demonstrates the claimed scFvs and CARs with both a VH-L-VL and a VL-L-VH orientation such as to demonstrate that the claimed constructs would be capable of performing the claimed functions in the absence of predictability. While the disclosure contemplates either orientation of the VH and VL domains, the examples appear to only demonstrate a single orientation of the murine scFvs 07/08 and the humanized versions thereof. There is no clear indication in the examples that both orientations of the claimed scFvs were tested.
With regards to the teachings of Hedge, applicant argues that Hedge does not suggest combining CARs that target IL13Ra2 and EGFR and that the reference is relied upon in the rejection as stating that IL13Ra2, HER2, and EGFR CAR T cells were currently being investigated in clinical trials. Applicant argues that Hedge only focuses on HER2, IL-13Ra2, and EphA2 and based on modeling suggests co-targeting of HER2 and IL13Ra2 for maximum reach. Applicant argues that, absent improper hindsight reconstruction, an ordinarily skilled artisan would not have considered co-targeting IL13Ra2 and EGFR.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Additionally, as discussed in detail above, explicit motivation in the prior art is not necessary in order to establish a prima facie case of obviousness. In this case, KSR(B) simple substitution of one known element for another is applied; a rationale that does not require explicit motivation or suggestion from the prior art. Furthermore, conclusive proof of efficacy is not required in order to establish obviousness. Rather, the standard of obviousness is a reasonable expectation of success. While Hedge does not study a dual CAR T cell with IL13Ra2 and EGFR, such a combination would have been obvious in view of the teachings of Hedge which specifically identify EGFR as a CAR target that was currently in clinical trials, making it obvious for use in a dual targeting CAR with IL13Ra2. Additionally, while Hedge does not disclose that EGFR was identified in their single cell expression analysis, this does not indicate that EGFR was not a valid antigen for targeting in the treatment of glioma. This is particularly the case as EGFR was being studied as a CAR target in clinical trials.
Applicant further argues that the rejection uses Suri to pick and choose different linkers to arrive at the instantly claimed CARs, specifically the GS and SG linkers that are within the claimed CAR constructs. Applicant argues that the term bivalent linkers appears nowhere else in Daga and that, even in terms of claim 7 of Daga, it is indicated that it is present between each of the domains of the CAR, which is not the case in the present claims. Applicant argues that the rejection turns to Suri to find a linker and picks one from a list at page 78 and 95, neither of which suggests picking the exact linker and where it should be placed in a CAR. Applicant cites KSR as stating that demonstrating that each element was, independently, known in the art does not demonstrate obviousness.
As discussed above, so long as the rejection takes into account only knowledge that was within the level of an ordinarily skilled artisan at the time that the claimed invention was made, and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper. As discussed in detail in the rejection, Daga teaches the inclusion of a bivalent linker between CAR components, even if it is only once in the disclosure. This inclusion is further supported by Suri which corroborates these teachings, disclosing that “the CAR of the present invention may comprise one or more linkers between any domains of the CAR” (page 72, [00225]), demonstrating that the inclusion of such linkers at one or more places between any domains in CARs was known in the art. Suri also teaches that an artificially designed peptide linker is preferably composed of a polymer of flexible residues, like glycine (G) and serine (S) so that the adjacent protein domains are free to move relative to one another. The examples of linkers provided by Suri include the amino acid sequences SG (page 78, row 7) or GS (page 95, row 3); examples which are also provided on page 132, [00294]. These teaching suggest that the inclusion of bivalent linkers between one or more domains in the CAR, including SG or GS, would have been obvious in view of the prior art and the knowledge in the art about CAR design and manufacturing. If applicant has any data demonstrating that the included linkers provided a result that would have been unexpected, such data could be presented and would be considered.
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.
Copending application 18/604,288
Claims 121, 123-124, 126-127, 129-132, and 148-187 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35, 37-57, 59-62, 64-75, 77-79 and 81 of copending Application No. 18/604,288 in view of US 7,169,894 B2 (Martin, M.T.) 30 January 2007. Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of App’288 are drawn to nucleic acids comprising a first polynucleotide sequence encoding a first CAR with an antigen binding domain that binds IL13Ra2, a transmembrane domain, and an intracellular signaling domain; a second polynucleotide sequence encoding a second CAR comprising an antigen binding domain that binds EGFR or an isoform thereof, a transmembrane domain, and an intracellular domain; and a third polynucleotide sequence encoding a dominant negative TGFB type II receptor (TGFBRII) (claims 1 and 32). The claims further recite that the first and/or second antigen binding domain is selected from the group consisting of a full-length antibody or antigen-binding fragment thereof, a Fab, a scFv, or a single-domain antibody (claim 2). App’288 further claims the amino acid sequences of the CDRs of the heavy and light chain variable regions of the first and second CAR (claims 3, 7, and 32) as well as amino acid sequences of the heavy and light chain variable regions of the first and second CAR (claims 4-5 and 8-9) and the amino acid sequence of the CARs (claims 6 and 10). App’288 further limits the sequences of the DN-TGFBRII receptor (claim 11). App’288 further limits the transmembrane domain to being CD8 alpha (claims 13-15) and the intracellular signaling domain to comprising a signaling domain and an intracellular signaling domain (claim 16) comprising 4-1BB (claims 17-18) and CD3 zeta (claims 19-20).
App’288 further claims a nucleic acid comprising a first polypeptide sequence encoding a CAR that binds IL13Ra2 and a second polynucleotide sequence encoding a DN-TGFBRII. The claims further limit the amino acid sequences of the antigen binding domain (claim 21). App’288 further claims the amino acid sequences of the heavy and light chain variable regions, the scFv, and the CAR (claims 22-24) as well as the amino acid sequence of the DN-TGFBRII receptor (claim 25).
App’288 further claims a nucleic acid comprising a first polypeptide sequence encoding a CAR that binds EGFR and a second polynucleotide sequence encoding a DN-TGFBRII (claim 26 and 31). App’288 further claims the amino acid sequences of the heavy and light chain variable regions of the EGFR CAR, the scFv, and the CAR (claims 27-29) as well as the amino acid sequence of the DN-TGFBRII receptor (claim 30).
App’288 further claims a nucleic acid comprising a first polynucleotide encoding a CAR capable of binding IL13Ra2 and a second polynucleotide encoding a second CAR capable of binding EGFR and a third polynucleotide sequence encoding a DN-TGFBRII where the first CAR comprises a heavy chain variable region encoded by a sequence that is at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% identical to SEQ ID NOs: 44 or 45; and a light chain variable region encoded by a sequence that is at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% identical to SEQ ID NOs: 48 or 58; and wherein the second CAR comprises a heavy chain variable region encoded by a sequence that is at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% identical to SEQ ID NO: 73; and a light chain variable region encoded by a sequence that is at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% identical to SEQ ID NOs: 74 (claim 33). App’288 further claims that the scFv of the first car is encoded by a sequence that is at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% identical to SEQ ID NOs: 64, 65, 66, or 69; and the scFv of the second CAR is at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% identical to SEQ ID NO: 70 (claim 34). App’288 further claims the entire sequence of the first and second CARs as having at least 80, 85, 90, 95, 96, 97, 98, 99, or 100% identity to SEQ ID NOs: 52, 53, 62, or 63 and SEQ ID NO: 34, respectively (claim 35). App’288 further claims that the sequences are separated by a linker and the order of the polynucleotides (claims 37-40).
App’288 claims a vector comprising the nucleic acids (claim 41) where the vector is an expression vector (claim 42) or selected from a DNA vector, an RNA vector, a plasmid, a lentiviral vector, an adenoviral vector, an adeno-associated viral vector, and a retroviral vector (claim 43). App’288 further claims that the vector comprises an EF-1a promoter, a WPRE, a RRE, a cPPT, and is self-activating (claims 44-48).
App’288 claims a modified immune cell or precursor cell thereof comprising the nucleic acids (claims 49-57, 59). App’288 further claims that the immune cell is a modified T cell (claim 60), is autologous (claim 61), and is obtained from a human subject (claim 62).
App’288 claims a pharmaceutical composition comprising the modified cell (claim 64, and methods of treating a disease in a subject comprising administering an effective amount of the modified cell (claims 64-65). App’288 further claims that the disease is cancer, and specifically glioma and specifically glioblastoma (claims 66-75, 77-79, and 81).
The nucleic acids of the CARs taught by App’288 comprise the heavy and light chain variable regions and the scFvs of the instantly claimed CARs. The entire polynucleotide sequences of the CARs are identical with the exception of the signal peptide that is at the beginning of the sequences. It is noted, however, that the signal peptide polynucleotides both encode the same amino acid sequence, specifically: MALPVTALLLPLALLLHAARPGS.
The teachings of US’894 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the CARs claimed by App’288 to try alternative nucleic acid codons for encoding the signaling peptide based on the degeneracy of the genetic code taught by US’894. US’894 teaches that the 20 amino acids are encoded by 68 codons demonstrating a finite number of codons that can be used to encode the same amino acid. An ordinarily skilled artisan would have been able to pursue these finite number of codons with the reasonable expectation that the resulting nucleic acid would encode the same peptide.
It is noted that, while the claims of App’288 include a DN-TGFBRII receptor with the CARs, the inclusion of this receptor still meets the instant claim limitations based on the use of “comprising” language in the instant claims. In the absence of a limiting definition for “comprising” in the instant specification, the claim is interpreted in view of the definition in MPEP 2111.03 I. which states “[t]he transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.” As such, even if the modified cell also comprised a DN-TGFBRII receptor, the modified cell would still meet the instant claim limitations.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments in the response filed 11/13/2025 have been fully considered regarding the provisional nonstatutory double patenting rejection, but were not persuasive.
Applicant argues that the instant application has a priority date that is about 4 years prior to the cited reference patent application. Applicant cites the PTAB decision in application 17/135,529 as explaining that a later filed later expiring unrelated patent application is not a proper OTDP reference patent to an earlier filed, earlier expiring patent application.
In the application cited by applicant, it appears that only remaining rejections were nonstatutory double patenting rejections. MPEP 804 states that “If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent”
As the provisional nonstatutory double patenting rejection is not the only remaining rejection in the application, the rejection is maintained.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693