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 .
DETAILED ACTION
1. Applicant’s amendment and response filed 3/10/26 is acknowledged and have been entered.
2. Applicant is reminded of Applicant's election without traverse of Group I and species of:
---an ITAM2 variant consisting of the amino acid sequence set forth in SEQ ID NO: 29, an ITAM3 variant consisting of the amino acid sequence set forth in SEQ ID NO: 33, a native ITAM1 consisting of the amino acid sequence set forth in SEQ ID NO: 23, a dominant negative form of PD-1 DN comprising amino acids 21-165 of SEQ ID NO: 48, a first TM domain comprising a CD8 polypeptide, a second TM domain comprising a CD8 polypeptide and a costimulatory domain comprising a CD28 polypeptide, and a T cell---
in Applicant’s response filed 6/9/25.
Claims 1-22, 26-34, 37-39, 43 and 45 read on the elected species. Applicant’s present amendment to the claims filed 3/10/26 which obviates the prior art rejections of record has necessitated the inclusion of dependent claim 35 in examination
Claims 1-22, 26-35, 37-39, 43 and 45 are presently being examined.
Claims 1, 37 and 43 are independent claims.
3. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
4. Claims 1-22, 26-35, 37-39, 43 and 45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
This is a new ground of rejection necessitated by Applicant’s amendment filed 3/10/26.
Claim interpretation: The recitation of the open transitional phrase “comprising” in instant base claim 1 opens the claim to encompass additional non-recited components. “CD3z” is equivalent to “CD3z” in this office action. There is no limiting or other definition for “a polypeptide composition”.
“To be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech, Inc. v. Novo Nordisk, A/S, 108F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997) (quoting In re Wright, 999F2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)). In In re Wands 8 USPQ2d 1400 (CAFC 1988), a number of factors are set forth which a court may consider in determining whether a disclosure would require undue experimentation. These factors were set forth as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. All the factors need not be reviewed when determining whether a disclosure is enabling. Amgen, Inc. v. Chugai Pharm. Co., Ltd., 927F2.d 1200, 1213, 18 USPQ2d 1016, 1027 (Fed. Cir. 1991) (noting that the Wands factors “are illustrative, not mandatory. What is relevant depends upon the facts.”).
Presently amended instant base claim 1 recites a polypeptide composition comprising a CAR that comprises the ABD (antigen binding domain comprising the CDRs of an anti-mesothelin antibody), a first TM domain (transmembrane domain), an intracellular signaling domain comprising a modified CD3z polypeptide comprising an ITAM2 and ITAM3 variant, each of which comprises two loss-of-function (LOS) mutations, a self cleaving peptide, and a PD-1 DN comprising at least a portion of an ECD of PD-1 comprising a ligand binding region, and a first transmembrane domain, wherein the self cleaving peptide is positioned between the CAR/TM/CD3z and the PD-1 DN/TM. The components i, ii, and iii of claim 1 are essentially recited as a single polypeptide sequence having an interposed self cleaving peptide between the CAR/TM/CD3z and the PD-1 DN/TM. Thus, the polypeptide composition recited in instant base claim 1 is being interpreted as it comprises a single polypeptide comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM.
The specification does not disclose how to make and/or use the instant invention:
(1) the polypeptide composition comprising a single polypeptide comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM that is not disposed on a cell (instant base claim 1 and its dependent claims 2-22 and 26-29) and, (2) a cell/composition thereof/kit thereof comprising the [single] polypeptide composition of claim 1 (claims 30-35, 37-39, 43 and 45).
The specification has not enabled the breadth of the claimed invention because:
the claims encompass (1) a polypeptide composition that is one continuous fusion polypeptide of the recited components comprising two TM regions and that is not disposed on a cell, wherein it is unpredictable that such a composition can be made due to the hydrophobic nature of the TM domains and resulting unpredictability in correct folding of the polypeptide composition; it is equally unpredictable even if it could be made as an isolated and properly folded polypeptide that the protein(s) can be used both due to the hydrophobic nature of the composition and because the composition is not present anchored on a cell by at least a first TM domain of the CAR and the first TM domain of the PD-1 DN, and (2) a cell/composition/kit thereof that comprises a single polypeptide comprising all of the recited components in their recited order and having two TM regions for separate insertions into the cell membrane. In addition, depending upon the particular first and second polypeptides, the addition of amino acid residues from the self cleaving peptide to the carboxy-terminus of the CAR/TM/CD3z polypeptide and to the amino-terminus of the second PD-1 DN/TM polypeptide renders another level of unpredictability to making and using the claimed polypeptide composition.
As is discussed further below, regarding the Wands factors, there is no guidance or working examples for making a [single fusion] polypeptide that comprises a CAR/TM/CD3z intracellular region, a self cleaving peptide positioned next, followed by a PD-1 DN/TM portion as is recited in the instant claims. There is no evidence of record that such a fusion polypeptide can be made and/or used, and the state of the art indicates that this is unpredictable, as the nature of the invention is a single large (approximately over 500 amino acid residues in length) fusion polypeptide that comprises two transmembrane regions (TMs). It is unpredictable according to the state of the art that a polypeptide having a TM (or more than one TM) can be made due to the hydrophobic (sticky) nature of the TM amino acid residues, it is unpredictable according to the state of the art that such a polypeptide can be made non-recombinantly and properly folded, and it is unpredictable therefore that it can be used at all or that it can be used for its disclosed purpose even if it is made. (If recombinant methods were to be used via a nucleic acid sequence encoding the polypeptide, the self cleaving peptide would effectively produce two separate polypeptides, one comprising the CAR/TM/CD3z plus residues of the self cleaving peptide at the carboxy-terminus and one comprising the PD-1 DN/TM plus residues of the self cleaving peptide at the amino terminus; the peptide as is recited in the instant claims, i.e., one having a self cleaving peptide positioned between the CAR and the PD-1 DN as is presently recited in the instant claims, would not be produced.) This is also the case for a cell that comprises the recited [single polypeptide] fusion polypeptide having a CAR portion followed by a self cleaving peptide, followed by a PD-1DN, including wherein the polypeptide has two separate TMs (one associated with the CAR portion and one associated with the PD-1 DN portion) for cell membrane insertion. There are no enabled embodiments presently recited in the instant claims.
There is evidence of record for a specific species of nucleic acid construct disclosed in the specification that uses the P2A self cleaving peptide and the specific encoding CAR/TM/CD3z and PD-1 DN/TM sequences and wherein the two polypeptides are made in a cell from a single bicistronic nucleic acid construct; that is, for a cell comprising the CAR/TM plus residues from the self cleaving peptide at the carboxy-terminus disposed on the cell through its TM domain and also comprising the PD-1 DN/TM plus residues from the self cleaving peptide at the amino terminus also disposed on the same cell through its TM domain. This nucleic acid sequence is expressed, properly folded, and functional, and thus this embodiment is enabled (see for example, Figure 2 at the last nucleic acid construct and Example 2). However, as is stated above, this is not what the instant claims recite.
Claims 30-35, 37-39, 43 and 45 are included in this rejection because the cell recited by these said claims comprises a [single] polypeptide comprising a CAR having a TM and intracellular signaling domain positioned to [fused to] a self cleaving peptide and a PD-1 DN/TM in that order. However, a polypeptide comprising all three components must be produced and folded from a recombinantly encoded nucleic acid construct, wherein during translation as a result of the self cleaving peptide, a ribosomal skipping occurs which results in a missing peptide bond, effectively separating the CAR and the PD-1 DN/TM as two separate proteins, including wherein portions of the self cleaving peptide may be appended onto the carboxy-terminus of the CAR and onto the amino terminus of the PD-1 DN/TM (see for example, evidentiary reference Page, L (BiteSizeBio, 2026, 4 pages). Claims 1-22 and 26-29 do not recite a cell comprising a nucleic acid construct encoding the polypeptide composition, but the polypeptide composition itself. Claims 30-35, 43 and 45 do not recite a cell comprising a nucleic acid encoding two separate proteins anchored into the cell membrane by virtue of an encoding nucleic acid portion of a self cleaving peptide positioned between the encoding portions of the two said proteins, but rather recite a cell comprising a single fusion polypeptide that comprises a self cleaving peptide between the CAR portion and the PD-1 DN portion.
The specification further discloses that the purpose of the [P2A] self cleaving peptide, is to efficiently mediate bicistronic transgene expression (i.e., both the CAR and the PD-1 DN are expressed from a nucleic acid encoding them as separate polypeptides) (e.g., specification at page 113, lines 7-9 or page 128 at lines 21-22).
The specification does not disclose any working examples of a [an isolated] fusion protein comprising in order, a CAR/TM/CD3z, a self cleaving peptide, and a PD-1 DN/TM. The specification discloses an example of a nucleic acid molecule (not a polypeptide) encoding fusion proteins comprising the CAR as well as the PD-1 DN (PD1-DNR) with an interposed encoding sequence for a self cleaving peptide (see for example Figure 2 at the last construct and Example 2).
The specification discloses that the dominant negative form of PD-1 (PD-1 DN) can enhance the therapeutic efficacy of an immunoresponsive cell comprising a CAR ( page 26 at lines 17-18), native PD-1 being a negative immune regulator of activated T cells upon engagement with its corresponding ligands PD-L1 and PD-L2 expressed on endogenous macrophages and dendritic cells (para graph spanning pages 26-27). The specification discloses PD-1 DN with loss of function mutations in the modified CD3z polypeptide of the CAR at a tyrosine amino acid residue in ITAM2 and ITAM 3 (e.g., page 4 at lines 25-32).
The specification discloses that the use for the claimed polypeptide composition comprising the recited CAR comprising an extracellular antigen-binding domain specific for the tumor antigen mesothelin and the PD-1 DN and for immunoresponsive cells comprising them is for example, treating cancers (page 2 at lines 10-14).
Evidentiary reference Hu et al (Protein Science, 2007, 16: 2153-2165, of record) teaches that transmembrane domains have a highly hydrophobic amino acid composition and because of the near absence of water in the transmembrane environment, the whole balance of molecular interactions that stabilizes protein structure is altered (paragraph spanning pages 2153-2154, first paragraph of the Discussion section). Hu et al teach that proteins and their domains are significantly influenced by their environment, and the expression, purification, and sample preparation for these constructs can be challenging (first paragraph on page 2153). See entire reference.
Evidentiary reference Page, L (BiteSizeBio, 2026, 4 pages) teaches that amino acid residues of a self-cleaving peptide (P2A) will be attached to the first and second polypeptides that are produced from encoding nucleic acid molecules comprising encoding sequence for a first polypeptide and a second polypeptide having an intervening self-cleaving peptide encoding region. Page teaches that these amino acid residues can affect the functionality or targeting of the proteins (see entire reference).
There is insufficient guidance in the specification as to how to make and/or use the instant invention. Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).\.
Applicant’s arguments in the amendment and response filed 3/10/26 on page 11 have been fully considered, but are not persuasive.
However, an isolated chimeric antigen receptor that is not disposed in/on a cell still remains an issue in the instant claims. Applicant does not address this point.
Applicant’s said amendment adding a self cleaving peptide positioned between the CAR and the PD-1 DN, making it a single polypeptide fusion raises new issues, as is enunciated in the instant rejection.
Applicant is requested to consider amending the claims to recite a cell comprising a nucleic acid construct/molecule encoding in this order the CAR/TMCD3z, the self cleaving peptide, and PD-1 DN/TM as a single nucleic acid construct for bicistronic expression of the CAR and the PD-1 DN (i.e., a cell comprising encoding nucleic acid sequence for expression and membrane anchoring of two separate polypeptides through their TM regions by virtue of the encoded the self cleaving polypeptide that induces ribosomal skipping during translation for bicistronic expression of the two proteins).
5. Applicant’s amendment filed 3/10/26 has overcome the prior rejection of record of claims 1-34, 36-39 and 43 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
6. Applicant’s amendment filed 3/10/26 has overcome the prior rejection of record of claim 31 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicant has amended claim 31 to recite that both the CAR and the PD-1 DN are recombinantly expressed.
7. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28 30-34, 36-39 and 43 under 35 U.S.C. 103 as being obvious over Cherkassky et al. (J. Clin. Invest., 2016, 126: 3130-3144) in view of Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by US 8,357,783, NLM-NCBI Accession No. NP_005009.2 (2025, 5 pages), NLM Accession No. NP_00113945.1 (2025, 4 pages), NLM Accession No. NM_000734.4 (2025), and Emboss Needle _001 (2025, 2 pages).
Applicant has presently amended the claims to recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM, a limitation the art references do not teach. Although the primary art reference Cherkassky et al. teaches the P2A self-cleaving peptide is part of a nucleic acid construct encoding the CAR, the self-cleaving P2A peptide separates the carboxy-terminus of the CAR/TM/CD3z signaling domain from a labeled reporter domain (see for example, Figure 1B), rather than a PD-1 DN. The PD-1 DN taught by the primary art reference was co-expressed in the cell as a separate construct from the CAR.
In addition, Applicant’s arguments regarding unexpected results specifically pertaining to the disclosure that that there were no signs of on-target, off-tumor toxicity ---citing paragraph [0612] in the pgPUB of the instant application (i.e., US 20220125905 A1) of administration of a signal dose of regionally delivered mycM28z1XXPD1DNR CAR-T cells (i.e., which comprises the last construct in shown in Figure 2 of the instant application, that is an anti-mesothelin scFv from m912 (fully human antibody fragment) with a CD28 TM domain, a CD28 cytoplasmic domain, a CD3z1xx intracellular signaling domain, P2A self-cleaving peptide allowing for bicistronic expression of the PD-1 DNR --- are persuasive.
Although the said CAR comprises a fully human antibody fragment and the distribution of mesothelin (the antibody specificity) on normal tissues is low and restricted to several tissues only while overexpressed on a variety of tumor cell types, and while mesothelin also present as a soluble cleavage product of cell-expressed mesothelin may act as a sink for the CAR, there is still a chance for off-target reactivity and toxicity.*
*(See for example US 10,633,441, of record. ‘441 discloses “The enhanced localization and activation of mesothelin-targeted CAR T cells in the vicinity of normal tissues that express low levels of mesothelin may increase the hypothetical risk of “on-target off -tumor” toxicities such as pleuritis and pericarditis. However, mesothelin expression is markedly higher in tumor tissues compared to normal tissues, as previously reported….Since CAR T cell activation is stronger in the presence of higher antigen density, CAR T cells are expected to more strongly respond to tumor than to the normal tissue….It is also noteworthy that histopathological studies in mice treated with mesothelin-targeted CAR T cells did not reveal inflammatory changes in the pleura or pericardium. Furthermore, clinical studies targeting mesothelin with immunotoxins have not shown toxicity to normal tissues in over 100 patients…The reported toxicity observed in a patent treated with mesothelin-targeted CAR T cells (an anaphylactic shock) was due to an antibody response to the CAR, which comprises a murine scFv…M28z CAR [the same CAR as the art CAR] is comprised of human sequences only….Nonetheless, it was believed that additional strategies are necessary to limit or prevent reactivity against normal tissue” (column 108 at lines 13-34)).
However, for completeness of the record, Applicant’s argument regarding alleged unexpected results specifically pertaining to tumor eradication are not persuasive for the following reasons.
Applicant argues that the claimed subject matter has demonstrated unexpected results including tumor eradication with no on-target, off-tumor toxicity (in mice), including tumor eradication (with a single low dose of 3 x 104 CAR T cells delivered regionally) observed up to the termination of the study and median survival was not reached during the course of the study. However with regard to tumor eradication, the primary art reference Cherkassky et al. teach just for the second generation CAR-T cell having the co-transfected human PD-1 DNR and native CD3z (without the ITAM2 and ITAM3 CD3z variant polypeptide) (“MBBz”) when administered intrapleurally (i.e., regionally) at a similar dose (slightly higher at 4 x 104), induced tumor eradication within 20 days of treatment with the vast majority of mice (7 of 8) remaining tumor free for more than 100 days (median survival was not reached by day 100) (paragraph spanning columns 1-2 on page 3133 and continuing on to page 3134). Thus, Applicant’s said argument is not persuasive, as the teaching of the primary art reference alone rebut Applicant’s allegation of unexpected results with regard to tumor eradication.
8. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28 30-34, 36-39 and 43 under 35 U.S.C. 103 as being obvious over WO 2018044866 A1 (pub date 3/8/2018, IDS reference) in view of Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by US 8,357,783, Emboss Needle _001 (2025, 2 pages), NLM-NCBI Accession No. NP_005009.2 (2025, 5 pages), and NLM Accession No. NP_00113945.1 (2025, 4 pages) for the same reasons as set forth above at item #8 above.
9. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28 30-34, 36-39 and 43 under 35 U.S.C. 103 as being obvious over US 10,633,441 in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144), and Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by NLM-NCBI Accession No. NP_005009.2 (2025, 5 pages), NLM Accession No. NP_00113945.1 (2025, 4 pages), NLM Accession No. NM_000734.4 (2025), and Emboss Needle _001 (2025, 2 pages).
The presently amended claims recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM, a limitation the art references do not teach. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
10. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28 30-34, 36-39 and 43 under 35 U.S.C. 103 as being obvious over US 10,538,588 in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144), and Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by NLM-NCBI Accession No. NP_005009.2 (2025, 5 pages), NLM Accession No. NP_00113945.1 (2025, 4 pages), NLM Accession No. NM_000734.4 (2025), and Emboss Needle _001 (2025, 2 pages).
The presently amended claims recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM, a limitation the art references do not teach. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
11. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28 30-34, 36-39 and 43 under 35 U.S.C. 103 as being obvious over US 11,702,472 in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144), and Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by NLM-NCBI Accession No. NP_005009.2 (2025, 5 pages), NLM Accession No. NP_00113945.1 (2025, 4 pages), NLM Accession No. NM_000734.4 (2025), and Emboss Needle _001 (2025, 2 pages).
The presently amended claims recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM, a limitation the art references do not teach. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
12. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28 30-34, 36-39 and 43 under 35 U.S.C. 103 as being obvious over WO2017040945 A1 (IDS reference) in view of Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by US 8,357,783, Emboss Needle _001 (2025, 2 pages), NLM-NCBI Accession No. NP_005009.2 (2025, 5 pages), and NLM Accession No. NP_00113945.1 (2025, 4 pages).
The presently amended claims recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM, a limitation the art references do not teach. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
13. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28, 30-34, 36-39 and 43 under 35 U.S.C. 103 as being obvious over U.S. Patent No. 11,932,690 in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144), as evidenced by US 8,357,783, GenBank No. NP_005009.2, NLM-NCBI Accession No. NP_005009.2 (2025, 5 pages), NCBI reference no. NP_001139345.1, and NLM Accession No. NP_00113945.1 (2025, 4 pages).
The presently amended claims recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM, a limitation the art references do not teach. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
14. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-7, 9-22, 26-34, 36-39 and 43 under 35 U.S.C. 103 as being obvious over US 2024/0166743 A1 (pgPub of 18/436,160) in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144) and Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by Accession No. NP_005009.2 (2025, 5 pages), NLM Accession No. NP_00113945.1 (2025, 4 pages), NLM Accession No. NM_000734.4 (2025), and Emboss Needle _001 (2025, 2 pages).
The presently amended claims recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM, a limitation the art references do not teach. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
15. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28, 30-34, 36-39 and 43 under 35 U.S.C. 103 as being obvious over WO 2017100428 A1 (IDS reference) in view of Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by US 8,357,783, Emboss Needle _001 (2025, 2 pages), NLM-NCBI Accession No. NP_005009.2 (2025, 5 pages), and NLM Accession No. NP_00113945.1 (2025, 4 pages).
The presently amended claims recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM, a limitation the art references do not teach. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
16. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28, 30-34, 36-39 and 43 as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36, 40 and 41 of U.S. Patent No. 10,633,441 in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144) and Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by NLM-NCBI Accession No. NP_005009.2 (2025, 5 pages), NLM Accession No. NP_00113945.1 (2025, 4 pages), NLM Accession No. NM_000734.4 (2025), and Emboss Needle _001 (2025, 2 pages).
Neither do art references teach, nor the claims of ‘441 recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM as is indicated in the presently amended claims. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
17. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28, 30-34, 36-39 and 43 as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 10,538,588 in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144) and Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by Accession No. NP_005009.2 (2025, 5 pages), NLM Accession No. NP_00113945.1 (2025, 4 pages), NLM Accession No. NM_000734.4 (2025), and Emboss Needle _001 (2025, 2 pages).
Neither do art references teach, nor the claims of ‘588 recite ta polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM as is indicated in the presently amended claims. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
18. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-7, 9-22, 26-28, 30-34, 36-39 and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 11,702,472 in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144) and Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by Accession No. NP_005009.2 (2025, 5 pages), NLM Accession No. NP_00113945.1 (2025, 4 pages), NLM Accession No. NM_000734.4 (2025), and Emboss Needle _001 (2025, 2 pages).
Neither do art references teach, nor the claims of ‘472 recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM as is indicated in the presently amended claims. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
19. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-7, 9-22, 26-28, 30-34, 36-39 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 62-74 and 98-117 of copending Application No. 18/318,588 in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144) and Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by Accession No. NP_005009.2 (2025, 5 pages), NLM Accession No. NP_00113945.1 (2025, 4 pages), NLM Accession No. NM_000734.4 (2025), and Emboss Needle _001 (2025, 2 pages).
Neither do art references teach, nor the claims of ‘588 recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM as is indicated in the presently amended claims. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
20. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-22, 26-28, 30-34, 36-39 and 43 as rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of U.S. Patent No. 11,932,690 in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144) and Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by US 8,357,783, GenBank No. NP_005009.2, NLM-NCBI Accession No. NP_005009.2 (2025, 5 pages), NCBI reference no. NP_001139345.1, and NLM Accession No. NP_00113945.1 (2025, 4 pages).
Neither do art references teach, nor the claims of ‘690 recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM as is indicated in the presently amended claims. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
21. Applicant’s amendment and response filed 3/10/26 has overcome the prior rejection of record of claims 1-7, 9-22, 26-34, 36-39 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 93-132 of copending Application No. 18/436,160 in view of Cherkassky et al (J. Clin. Invest., 2016, 126: 3130-3144) and Feucht et al (Nat. Med. 1/2019, 25(1): 82-88, IDS reference), as evidenced by Accession No. NP_005009.2 (2025, 5 pages), NLM Accession No. NP_00113945.1 (2025, 4 pages), NLM Accession No. NM_000734.4 (2025), and Emboss Needle _001 (2025, 2 pages).
Neither do art references teach, nor the claims of ‘160 recite a polypeptide composition comprising a [single] polypeptide (or a cell comprising the polypeptide composition) comprising in this order, the CAR/TM/CD3z, a self cleaving peptide, and the PD-1 DN/TM as is indicated in the presently amended claims. In addition, Applicant’s arguments pertaining to unexpected results as to no on-target off-tumor toxicity is persuasive, as is enunciated above.
22. Claims 1 and 30 are objected to because of the following informalities:
a) “PD-1DN” should be recited as ‘PD-1 DN’ at the last line of claim 1.
b) “a” polypeptide composition should be recited as ‘the’ polypeptide composition in claim 30.
23. No claim is allowed.
24. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
25. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights