DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 2, 5-15, 23-27, 33, 35, 36 and 38-40 are pending.
Claims 8, 11 and 38-40 have been withdrawn.
Claims 1, 2, 6, 7, 9, 10, 12-15, 23-27, 33, 35 and 36 are currently under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §119 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 09/523,095, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application.
Particularly, claims 1, 2, 6, 7, 9, 10, 12-15, 23-27, 33, 35 and 36 are not supported by the prior-filed application because the limitation “wherein the caTCR does not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50” is not supported in the prior-filed application US Patent Application NO. 16/608366). Thus, claim 6 is hereby assigned the priority date of March 1, 2024, the filing date of the present application.
Election/Restrictions
Applicant disagrees with the restriction requirement in that claim 1 requires that the antigen binding module of the caTCR binds a complex comprising a peptide and an MHC protein. Applicant argues that when the antigen binding module of the caTCR is multispecific as recited in claim 8, at least one moiety (e.g., an antibody moiety) within
the antigen binding module specifically binds to the peptide-MHC complex as recited in claim 1, regardless of what the other moiety binds to. Applicant argues that that there
would not be an increased search burden to search a multispecific caTCR in addition to a monospecific caTCR, because searching for an antigen binding module that specifically binds to the peptide-MHC complex will return prior art, if any, for both multispecific and monospecific situations discussed above.
In response it is noted that the term “multispecific antigen binding module’ may include multiple unrelated antibodies that bind different antigens. It is noted that the antigen binding module binds to a complex comprising a peptide and an MHC protein. Thus, the different antibodies may bind the peptide-MHC, the MHC or another antigen within the complex. There would be an increased search burden because prior art for one binding module may not be applicable to a binding module that binds another antigen within the target antigen complex. In addition, there may be non-prior art issues under 35 USC 112.
Furthermore, as disclosed in the restriction, if the elected species is found to be allowable, the search will be expanded by the Examiner to consider additional species and subgenuses within the generic formula.
Objections to Specification maintained
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: The limitations “proviso “the caTCR does not comprise the amino acid sequence of SEQ ID NO: 50” and “wherein the caTCR does not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50”.
35 USC § 112(a) rejection withdrawn
The rejection of claims 25 for failing to comply with the written description requirement is withdrawn in view of Applicant’s arguments.
Double Patenting rejections withdrawn
The rejections of claims 1, 2, 6, 7, 9, 10, 12-15, 23-27, 33, 35 and 36 on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 10,822,413 are withdrawn in view of Applicant’s amendments to claim 1.
The rejections of claims of 1, 2, 6, 7, 9, 10, 12-15, 23-27, 33, 35 and 36 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,965,021 are withdrawn in view of Applicant’s amendments to claim 1.
35 USC § 112(a) rejections maintained
The rejection of claim 2 for failing to comply with the written description requirement is maintained
There is no support in the specification for the negative proviso “the caTCR does not comprise the amino acid sequence of SEQ ID NO: 50” The specification only discloses that the amino acid sequence of a fragment of CD3-zeta consists of SEQ ID NO: 50 (page 200) not that the caTCR does not comprise the amino acid sequence of SEQ ID NO: 50.
In response to Applicant’s argument that prior to the filing date of the subject application, the intracellular sequence of CD3ζ was well known in the art, the issue is not whether the intracellular sequence of CD3ζ was well known in the art but whether the specification or the art discloses a caTCR that does not comprise the amino acid sequence of SEQ ID NO: 50. Neither the art nor the specification disclose a caTCR that does not comprise the amino acid sequence of SEQ ID NO: 50
Paragraphs11 of the specification recites “The intracellular signaling domain contains an immunoreceptor tyrosine-based activation motif (ITAM), such as those from CD3ζ or FcRy, and one or more costimulatory signaling domains, such as those from CD28, 4-lBB or OX40. Paragraph 169 recites “ Primary immune cell signaling sequences that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or ITAMs. Examples of ITAM-containing primary immune cell signaling sequences include those derived from TCRζ, FcRy, FcRβ, CD3γ, CD3δ, CD3ε, CD5, CD22, CD79a, CD79b, and CD66d. A " functional" primary immune cell signaling sequence is a sequence that is capable of
transducing an immune cell activation signal when operably coupled to an appropriate receptor”. There is nothing in the cited paragraphs that support the limitation “the caTCR does not comprise the amino acid sequence of SEQ ID NO: 50”. Paragraph 169 even appears to provide evidence against the support for the limitation “the caTCR does not comprise the amino acid sequence of SEQ ID NO: 50” given that it specifically recites “The CSRs described herein lack a functional primary immune cell signaling sequence, such as a functional signaling sequence comprising an ITAM. In some embodiments, the CSRs lack any primary immune cell signaling sequence”.
35 USC § 103 rejections maintained
The rejections of claims 1, 2, 7, 12-15, 23, 33, 35 and 36 under 35 U.S.C. 103 as being unpatentable over Kloss et al (US 2015/0342993, published 3 December 2015, IDS, cited previously) in view of Smith et al (WO 2014/039523, published 13 March 2014, IDS, cited previously), Loew et al (US 2018/0230193, published 16 August 2018, filed 5 August 2016, IDS, cited previously) and Wilkie et al (J Clin Immunol 32:1059-1070, 2012, IDS, cited previously) are maintained.
Kloss teaches a cytotoxic T cell comprising a CAR and a chimeric co-stimulating receptor (CCR) and methods for treating a cancer (paragraphs 5-8, 15; Fig 6). Kloss disclose that the intracellular signaling domain of the CCR is a CD97, CD11α -CD18, CD2, ICOS, CD27, CD154, CD5, OX40, 4-lBB or CD28 signaling domain (paragraph 13). The CCR binds to a different antigen than the CAT and stimulates the cell when both antigens are present on the tumor cell (Fig.6). Expression of the CSR protein may be inducible ([0095]). The receptor targets of the CAR (target antigen or first antigen) and the CCR (target ligand or second antigen) are disclosed and may be cancer-associated (such as CD19 or CD20).
Kloss does not specifically disclose a multi-chain CAR comprising a T cell receptor module (TCRM) having activation motifs comprising a first TCR domain (TCRD) comprising a first TCR transmembrane domain (TCR-TM) and a second TCRD comprising a second TCR-TM.
Smith discloses an immune cell comprising a multichain CAR, wherein the CAR comprises an antigen binding module, a first transmembrane domain and a second transmembrane domain, a module that facilitates recruitment of a TCR-associated signaling module, and an antibody-derived antigen-binding module (Abstract; page 1; Fig 3). Smith disclose CARs comprising TCR transmembrane domains consisting of γ and δ domains (page 19, paragraph 4).
One of ordinary skill in the art would have been motivated to apply Smith’s multi-chain CAR with a first and second transmembrane domain to Kloss’s cytotoxic T cell comprising a CAR module and a CCR because both Kloss and Smith disclose CARs that may be used to treat cancer. Furthermore, Wilkie disclose the advantages of T cells have two complementary antigen-binding receptors co-expressed in the same T-cell population, each directed to a distinct tumor target and engineered to provide
complementary signals (page 1060). It would have been prima facie obvious to substitute the chimeric antibody-TCR construct of Smith for the chimeric antibody-TCR construct of Kloss to have an immune cell comprising:
a) a chimeric antibody-T cell receptor (TCR) construct (caTCR) comprising:
i) an antigen binding module that specifically binds to a target antigen, wherein the target antigen is a complex comprising a peptide and a major histocompatibility complex (MHC) protein; and
ii) a TCR module (TCRM), wherein the TCRM comprises a first TCR domain (TCRD) comprising a first TCR transmembrane domain (TCR-TM) and a second TCRD comprising a second TCR-TM, wherein the TCRM facilitates recruitment of at least one TCR-associated signaling molecule; and
b) a chimeric signaling receptor (CSR) comprising:
i) a ligand-binding module that is capable of binding or interacting with a target ligand;
ii) a transmembrane module; and
iii) a co-stimulatory immune cell signaling module that is capable of providing a
co-stimulatory signal to the immune cell, wherein the ligand-binding module and the co-stimulatory immune cell signaling module of the CSR are not derived from the same molecule.
Neither Kloss nor Smith specifically disclose a CAR that does not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50.
Loew disclose a first and the second chimeric membrane proteins from a chimeric antigenic receptor lacking an ITAM signaling domain (paragraph 350, Examples 2-4, 6-8). Loew disclose that examples of ITAM containing primary intracellular signaling domains that are of particular use in the invention include those of CD3 zeta, CD3 gamma, CD3 delta and CD3 epsilon (paragraph 349). Loew disclose a primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain which has altered (e.g., increased or decreased) activity as compared to the native ITAM domain (paragraph 350). Loew disclose that a primary signaling domain comprises a modified ITAM-containing primary intracellular signaling domain (Id). Thus, Loew contemplates a CD3 zeta with a mutated ITAM region. Furthermore, given that Loew demonstrated that a T cell lacking endogenous ITAM domains was capable of TCR signaling it would have been obvious to make a signaling moiety comprising a truncated CD3 zeta proteins with deletions of the ITAM domains.
One of ordinary skill in the art would have been motivated to apply Loew’s chimeric antigen receptor lacking an ITAM signaling domain to Kloss and Smith’s T cell comprising a caTCR and CSR because Loew disclose that signaling domains lacking ITAM signaling domains were capable of cytolytic activity (paragraph 525). Thus, a T cell CAR does not require the ITAM module of a functional" primary immune cell signaling sequence to lyse target cells. It would have been prima facia obvious to substitute Loew’s intracellular chimeric antigen receptor domain lacking an ITAM signaling domain for Kloss and Smith’s intracellular domain of a caTCR because both the intracellular domains of Loew, Kloss and Smith were all capable of functioning to activate T cells. One of ordinary skill in the art would have had a reasonable expectation of success in substituting the intracellular domains because the intracellular domains were found to be functional and engineering constructs for use in CAR T cells was well known in the art.
Applicant argues that Kloss, Smith, Loew, and Wilkie, alone or in combination, do not teach or suggest a caTCR, let alone the presently claimed invention, where the caTCR does not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50. In addition, Applicant argues that one of ordinary skill in the art would not have been motivated to apply the constructs of Loew lacking a functional primary immune cell signaling domain to the CAR constructs of Kloss, Smith, and Wilkie, because CARs require a functional primary immune cell signaling domain. Applicant argues that even if one combines the constructs of Loew with the CAR constructs of Kloss, Smith, or Wilkie, one would still not arrive at the presently claimed invention
Applicant states that the caTCR within the presently claimed immune cell is drastically different from a CAR construct. CARs by definition comprise a functional primary immune cell signaling sequence (e.g., CD3ζ intracellular signaling sequence. Applicant argues that the caTCR within the presently claimed immune cell does not comprise ITAM sequence(s) and therefore the recited caTCR does not comprise a functional primary immune cell signaling sequence.
Applicant argues that in contrast to Loew' s TCARs whose activity rely on embedding into a TCR complex Kloss, Smith, and Wilkie's CARs require a functional primary immune cell signaling sequence (e.g., intracellular sequence of CD3ζ) to function. Applicant argues that the TCARs of Loew and the CARs of Kloss, Smith, and Wilkie are fundamentally different approaches to T cell therapy. As described at paragraph [0163] of Loew, "by making the targeting domain a part of the TCR complex, signaling induced by the TCAR utilizes the entire pathway of accessory proteins within the TCR complex and is not limited to the exclusive signaling provided by a traditional CAR from, for example, CD3zeta on the CAR chain." Applicant argues that in contrast to the Examiner's statement on p. 6, paragraph 5 of the Non-Final Office Action, one skilled in the art would not be motivated to "substitute Loew' s intracellular chimeric antigen receptor domain lacking an ITAM signaling domain for Kloss and Smith's intracellular domain of a [CAR]" to arrive at the claimed caTCR. Applicant further argues that one would not have reasonable expectation that such substitution would result in a functional chimeric receptor capable of activating T cells.
In addition, Applicant argues that all of the tested TCARs lacking ITAM sequences in Loew are based on a CD3ε/CDCTM-fusions. Applicant argues that in contrast, the caTCR within the presently claimed immune cell comprises a TCRM formed by two TCR transmembrane domains (TCRα/β or TCRγ/δ).
Applicant further argues that although the CARs of Kloss and Wilkie may function properly in combination with a chimeric receptor comprising a co-stimulatory signaling sequence (e.g., CCR, or HDF28) since the mechanism of CARs is drastically different from that of Loew' s TCARs, one of ordinary skill in the art would not have had a reasonable expectation that a TCAR would function properly in combination with a chimeric receptor comprising a co-stimulatory signaling sequence. Applicant argues that the purpose of employing a CAR together with a chimeric receptor comprising a co-stimulatory signaling sequence (e.g., CCR, or HDF28) is to position both a functional primary immune cell signaling sequence (e.g., CD3ζ intracellular signaling sequence;
of the as-filed specification, and paragraphs [0028] and [0034] of Kloss) and a co-stimulatory domain (e.g., 4-lBB, or CD28) close to the membrane to potentiate signaling. Applicant argues that it is not clear whether combining a TCR subunit-based construct lacking a functional primary immune cell signaling sequence, such as a TCAR of Loew, with a chimeric receptor that comprises a co-stimulatory signaling sequence (e.g., CCR, or HDF28) of Kloss or Wilkie, would result in both effective and safe signals. Applicant argues that one skilled in the art also would not be motivated to replace the CAR in Kloss or Wilkie with Loew' s TCAR, because Kloss' s CCR and Wilkie's HDF28 provide a co-stimulatory signal, and the tested TCARs in Loew already comprise a co-stimulatory domain. Applicant argues that one skilled in the art would not be motivated to combine the teachings of Kloss, Smith, and Wilkie with Loew to arrive at the presently claimed caTCRs with a reasonable expectation of success.
Applicant’s arguments have been considered but are not persuasive. In response to applicant's arguments against Kloss, Smith, Loew and Wilkie individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). All of the limitations of the present claims are present in the art and motivation to combine have been provided above.
Loew disclose a first and the second chimeric membrane proteins from a chimeric antigenic receptor lacking an ITAM signaling domain. Loew disclose that examples of ITAM containing primary intracellular signaling domains that are of particular use in the
invention include those of CD3 zeta, CD3 gamma, CD3 delta and CD3 epsilon (paragraph 349). Loew disclose a primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain which has altered (e.g., increased or decreased) activity as compared to the native ITAM domain (paragraph 350). Loew disclose that a primary signaling domain comprises a modified ITAM-containing primary intracellular signaling domain (Id). Thus, Loew contemplates a CD3 zeta with a mutated ITAM region. Furthermore, given that Loew demonstrated that a T cell lacking endogenous ITAM domains was capable of TCR signaling it would have been obvious to make a signaling moiety comprising a truncated CD3 zeta proteins with deletions of the ITAM domains. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success given that manipulating the TCR signaling domains was well known in the art as demonstrated in the design of CAR T cells. It was known that CARs combine both antigen-binding and T cell activating functions into a single receptor.
In response to Applicant’s argument that it is not clear whether combining a TCR subunit-based construct lacking a functional primary immune cell signaling sequence, such as a TCAR of Loew, with a chimeric receptor that comprises a co-stimulatory signaling sequence (e.g., CCR, or HDF28) of Kloss or Wilkie, would result in both effective and safe signals, Loew discloses that T cell activation resulted from a TCR that comprises a TCR-associated signaling molecule CD3 protein that does not include the ITAM domains. Thus, it would have been predictable that a CAR comprising a TCR-associated signaling molecule CD3 protein that does not include the ITAM domains would be have effective T cell activating functions.
The specification discloses that the term "TCR-associated signaling molecule" refers to a molecule having a cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM) that is part of the TCRCD3 complex. TCR-associated signaling molecules include CD3γε, CD3δε, and ζζ). (also known as CD3ζ or CD3ζζ). (paragraph 53). The specification also discloses that the CSRs described herein lack a functional primary immune cell signaling sequence, such as a functional signaling sequence comprising an ITAM. (paragraph 169). It is not clear in the specification is there a support for making a caTCR that comprises TCR-associated signaling molecules include CD3γε, CD3δε, and ζζ does not include the ITAM domains.
In response to Applicant’s argument that in contrast to Loew' s TCARs whose activity rely on embedding into a TCR complex Kloss, Smith, and Wilkie's CARs require a functional primary immune cell signaling sequence (e.g., intracellular sequence of CD3ζ) to function and that the TCARs of Loew and the CARs of Kloss, Smith, and Wilkie are fundamentally different approaches to T cell therapy, CD3ε, and CD3ζ are found in both CARs and endogenous TCR complexes and in both cases function as signaling molecules. Absent unexpected results, based on the cited art, it would have been obvious to have a caTCR comprising CD3ε or CD3ζ that do not include functional ITAMS.
In response to Applicant’s argument that one skilled in the art also would not be motivated to replace the CAR in Kloss or Wilkie with Loew' s TCAR, because Kloss' s CCR and Wilkie's HDF28 provide a co-stimulatory signal, and the tested TCARs in Loew already comprise a co-stimulatory domain, the Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One of the rationales was the simple substitution of one known element for another to obtain predictable results.
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To reject a claim based on simple substitution one known element for another to obtain predictable results, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
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(1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components;
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(2) a finding that the substituted components and their functions were known in the art;
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(3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and
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(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
Given that CD3 signaling proteins with and without ITAM signaling domains were known in the art, given that CD3 signaling proteins without ITAM signaling domains were known to function in T cell activation, it would have been obvious to substitute a CD3 signaling proteins without ITAM signaling domains for a CD3 signaling proteins with ITAM signaling domains. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making a TCR signaling module comprising CD3 signaling proteins without ITAM signaling domains.
In addition, Applicant argues that the present invention is at least based on the unexpected finding that T cells comprising the combination of i) a caTCR lacking ITAM sequence(s) (i.e. lacking a functional primary immune cell signaling sequence), and ii) a CSR comprising a costimulatory immune cell signaling module but no functional primary immune cell signaling sequence, demonstrates a comparable effect in tumor cell killing while retaining a much safer profile compared to T cells comprising a CAR. Applicant argues that these findings address the unmet need long-felt by use of various CAR-T therapies demonstrating strong evidence of inventiveness.
Applicant argues that Examples 2-6 of the present application show that sensitivity, responsiveness, cytotoxicity, proliferation, and persistence of T cells expressing both the recited caTCR and CSR are increased compared to T cells expressing only caTCRs, and killing of tumor cells is demonstrated both ex vivo and in vivo. Applicant argues that neither the caTCR nor the CSR comprises a functional primary immune cell signaling sequence, the in vivo cytotoxicity of T cells co-expressing caTCR+CSR is comparable to that of T cells expressing a CAR that contains a functional primary immune cell signaling sequence (Example 7, FIG. 18).
Applicant further argues that T cells co-expressing caTCR+CSR of the present invention demonstrated a great safety profile in vivo (Examples 6 and 7) and surprisingly even safer than T cells expressing a CAR. Applicant argues that in contrast, when a CAR is co-expressed with a CCR as exemplified in Kloss, specifically shown in FIG. IC and FIG. 4A, T cells co-expressing CAR +CCR induce a much higher cytokine level compared to T cells expressing a CAR alone. Applicant argues that this unexpected safety profile of T cells co-expressing caTCR+CSR vs. T cells co- expressing CAR +CCR of Kloss demonstrates strong evidence of inventiveness.
Applicant’s arguments have been considered but are not persuasive. As an initial note, the claims under examination are drawn to an immune cell comprising a caTCR and a CSR, not a method of using the immune cell.
The specification discloses anti-CD19 caTCR and an anti-CD19 CSR comprising a CD28 co-stimulatory cell signaling module as well as an anti-AFP caTCR and anti-GPC3 comprising a CD28 co-stimulatory cell signaling module. Given the species selection of “different target antigens” and “CD30 co-stimulatory receptors” there does not appear to be any selected combination of caTCR and CSR that are described in the specification as examples of unexpected results. Furthermore, the Examples do not disclose that the caTCR does not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50.
MPEP 716.02(d) states
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
Thus, the unexpected results described by Applicants are not commensurate in scope with the breadth of the claims as currently presented.
The specification discloses that anti-AFP caTCR and anti-GPC3 comprising a CD28 co-stimulatory cell signaling module increased amount of cytokines expressed in and released from CSR-caTCR double positive T cells indicates that the costimulation
of both caTCR-1 and CSR raises the cytotoxic potential of the T-cells (paragraph 505). The specification discloses that “As shown in FIG. 17, caTCR-1 CSR-I T cell-treated mice had significantly lower level of cytokine release than CAR-T treated mice”. The specification discloses that “As shown in FIG. 18, both anti-AFP CART cell treatment and anti-AFP caTCR-l/antiGPC3 CSR-1 T cell treatment resulted in tumor growth inhibition (paragraph 539). The specification disclose that all anti-AFP CAR-T treated and anti-AFP caTCR-l/anti-GPC3 CSR-1 T cell-treated mice demonstrated normal gait, posture, and activity/responsiveness for the duration of the study (Id). Tumor growth inhibition was comparable for both the anti-AFP CART cell treatment and anti-AFP caTCR-l/antiGPC3 CSR-1 T cell treatment. Thus, the results from Example 7 appears to demonstrate that the safety and efficacy of anti-AFP CAR-T cells and anti-AFP caTCR-l/anti-GPC3 CSR-1 T cells were comparable. This suggests that anti-AFP caTCR-l/anti-GPC3 CSR-1 T cells function as intended, not that the anti-AFP caTCR-l/anti-GPC3 CSR-1 T cells exhibited unexpected results.
Furthermore, given that the specification suggests that the caTCR of the present claims recruit accessory molecules in a TCR complex, such as CD3δε, CD3γε and CD3ζζ that are functional primary immune cell signaling sequences, it is not clear that evidence of a T cell response with the introduction of the claimed caTCR and CSR. The caTCR would have functional primary immune cell signaling sequences, albeit they would not be covalently linked to the caTCR. The art demonstrates the effectiveness of accessory signaling receptors introduced in combination with a functional CAR.
In response to Applicant’s argument that the present invention is at least based on the unexpected finding that T cells comprising the combination of i) a caTCR lacking ITAM sequence(s) (i.e. lacking a functional primary immune cell signaling sequence), and ii) a CSR comprising a costimulatory immune cell signaling module but no functional primary immune cell signaling sequence, demonstrates a comparable effect in tumor cell killing while retaining a much safer profile compared to T cells comprising a CAR, as discussed above, the Examples do not disclose that the caTCR does not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50. Furthermore, Loew discloses that T cell activation resulted from a TCR that comprises a TCR-associated signaling molecule, the CD3ε protein, that does not include the ITAM domains. Thus, it was known that T cell signaling did not require intact ITAMs from at least one of the TCR-associated signaling molecules.
The rejections of claims 1, 2, 7, 9, 10, 12-15, 23, 33, 35 and 36 under 35 U.S.C. 103 as being unpatentable over Kloss et al (US 2015/0342993, published 3 December 2015, IDS, cited previously) in view of Smith et al (WO 2014/039523, published 13 March 2014, IDS, cited previously), Loew et al (US 2018/0230193, published 16 August 2018, filed 5 August 2016, IDS, cited previously) and Wilkie et al (J Clin Immunol 32:1059-1070, 2012, IDS, cited previously) in further view of Brinkmann et al MABS, 9:182-212, February/March 2017, IDS, cited previously) and Harris (WO 94/09131, published 28 April 1994, IDS, cited previously) are maintained.
Kloss, Wilkie, Smith and Loew have been discussed supra.
Neither Kloss, Wilkie, Smith nor Loew specifically disclose a stabilization module comprising a first stabilization domain and a second stabilization domain, and wherein the stabilization module is selected from the group consisting of a CH1-CL module, a CH2-CH2 module, a CH3- CH3 module, and a CH4-CH4 module;
Harris discloses an antibody composition formed by a fusion of either a CH1 or VL antibody domain to one scFv antibody fragment and its corresponding partner to the second scFv (Figure 6).
Brinkman discloses CH1 and CL domains attached to antigen-binding antibody fragments (Figure 1). Brink further disclose that a TCR can be substituted for a Fab (page 187, 2nd column, 3rd paragraph).
One of ordinary skill in the art would have been motivated to apply Harris and Brinkmann’s CH1 – CL modules to Kloss and Smith’s T cell comprising a caTCR and CSR because Brinkman, Kloss and Smith all disclose CARs capable of treating cancer. Furthermore, both Harris (page 3, 2nd paragraph) and Brinkman (page 187, 5th paragraph) disclose that CH and CL domains were utilized to produce antigen-binding antibody constructs with higher stability (page 3, 2nd paragraph). It would have been prima facie obvious to combine Brink and Harris’s CH1 and CL modules with Kloss and Smith’s T cell comprising a caTCR and CSR to have a T cell comprising a caTCR with higher stability.
Applicant argues that the constructs described in Harris and Brinkmann are soluble multispecific antibodies or soluble Fab-like constructs. Applicant argues that nowhere do Brinkmann and Harris describe, teach, or suggest that the soluble constructs described therein can be used in the CARs of Kloss, Smith, or Wilkie, or the TCARs of Loew, for expression on effector cells. Applicant argues that one of ordinary skill in the art would have had a reasonable expectation that when the soluble constructs of Brinkmann and Harris are used in a chimeric receptor expressed on a cell surface, it will retain antibody binding affinity/specificity while allowing the obtained constructs to effectively transduce cellular signals.
Applicant’s arguments have been considered but are not persuasive. While the examples in Harris and Brinkman disclose soluble multispecific antibodies or soluble Fab-like constructs, a prior art reference is relevant for all its teachings, not only its examples. Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (holding that both preferred and unpreferred embodiments must be considered). In addition, Applicants point to narrow embodiments which are not the sum total of information conveyed by each. Art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. MPEP § 2123. In this case both Harris and Brinkman disclose Harris and Brinkmann’s CH1 – CL modules even if Harris and Brinkman do not provide a specific example of CH1 – CL modules for use in a CAR. A "specification need not contain a working example if the invention is otherwise disclosed in such a manner that one skilled in the art will be able to practice it without an undue amount of experimentation." In re Borkowski, 422 F.2d 904, 908 (CCPA 1970).
Given that making CAR constructs was well known in the art one of ordinary skill in the art would have had a reasonable expectation of success in making a CAR with CH1 – CL modules.
In response to Applicant’s argument that that Brinkmann and Harris are completely silent about caTCRs that do not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50, for the reasons set forth above, the rejections are maintained.
The rejections of claims 1, 2, 7, 9, 10, 12-15, 23, 26, 27, 33, 35 and 36 under 35 U.S.C. 103 as being unpatentable over Kloss et al (US 2015/0342993, published 3 December 2015, cited previously) in view of Smith et al (WO 2014/039523, published 13 March 2014, cited previously), Loew et al (US 2018/0230193, published 16 August 2018, filed 5 August 2016, cited previously), Wilkie et al (J Clin Immunol 32:1059-1070, 2012, IDS, cited previously), Brinkmann et al MABS, 9:182-212, February/March 2017, IDS, cited previously) and Harris (WO 94/09131, published 28 April 1994, cited previously) in further view of Taunton et al (US 2017/0306303, published 26 October 2017, filed 6 January 2017, IDS, cited previously) are maintained.
Neither Kloss, Smith, Loew, Wilkie, Brinkmann nor Harris disclose that the co-stimulatory immune cell signaling module is derived from the intracellular of CD30
Taunton disclose costimulatory signaling module comprising the intracellular portion of CD30, 4-1BB (CD137), CD28, ICOS, OX-40, BTLA, CD27, GITR, and HVEM (paragraph 199, 208, 432).
One of ordinary skill in the art would have been motivated to apply Tauton’s costimulatory signaling module comprising the intracellular portion of CD30 to Kloss, Smith, Wilkie and Brinkmann and Harris’s T cell comprising a caTCR and CSR because Tauton, Kloss, Smith, Wilkie and Brinkmann all disclose CARs capable of treating cancer. It would have been prima facie obvious to substitute Tauton’s costimulatory signaling module comprising the intracellular portion of CD30 for one of signaling domains listed in Kloss or Smith to have a T cell comprising a caTCR and CSR in which the costimulatory immune cell signaling molecule comprises the intracellular portion of CD30.
Applicant states that the Examiner's reasoning for combination of the cited references is unclear. Specifically, it is unclear which signaling domain listed in Kloss or Smith, e.g., the signaling domain of a CAR or CCR, would be substituted with Tauton' s costimulatory signaling module comprising the intracellular portion of CD30, to allegedly arrive at the presently claimed immune cell. Applicant argues that as discussed above, if the signaling domain of Kloss's CAR or Smith's CAR is substituted with Taunton' s costimulatory signaling module comprising the intracellular portion of CD30, the resulting immune cell would not function. Applicant argues that Taunton discloses heterodimeric receptors which comprise intracellular signaling domains, such as ZAP70 or CD3ζ See, paragraph [0007] of Taunton. The exemplified constructs of Taunton
as shown in FIGs. 12 and 13 each require a CD3ζ intracellular signaling domain.
In response to Applicant’s remarks stating that it is unclear which signaling domain listed in Kloss or Smith, e.g., the signaling domain of a CAR or CCR, would be substituted with Tauton' s costimulatory signaling module comprising the intracellular portion of CD30, Kloss discloses a CCR signaling domain comprising CD28 and CD137 (4-1BB). Taunton disclose costimulatory signaling modules comprising CD30, 4-1BB (CD137), CD28, ICOS, OX-40, BTLA, CD27, GITR, and HVEM (paragraph 199, 208, 432).
In response to Applicant’s argument that that Taunton is completely silent about caTCRs that do not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50, for the reasons set forth above, the rejections are maintained.
The rejections of claims 1, 2, 6, 7, 12-15, 23, 33, 35 and 36 under 35 U.S.C. 103 as being unpatentable over Kloss et al (US 2015/0342993, published 3 December 2015, cited previously) in view of Smith et al (WO 2014/039523, published 13 March 2014, cited previously), Loew et al (US 2018/0230193, published 16 August 2018, filed 5 August 2016, cited previously), Wilkie et al (J Clin Immunol 32:1059-1070, 2012, IDS, cited previously) in further view of de Berardinis et al (US 2019/0030071, published 31 January 2019, filed 3 November 2015, IDS, cited previously) are maintained.
Kloss, Smith, Loew and Wilkie have been disclosed supra.
Neither Kloss, Smith, Loew, nor Wilkie, disclose that at least one of the TCR-TMs is non-naturally occurring.
de Berardinis disclose mutations in the transmembrane regions of the TCR chains exogenously to optimize TCR pairings (paragraphs 1, 17-19, 25, 26, 61, 91).
One of ordinary skill in the art would have been motivated to apply de Berardinis’s non-naturally occurring TCR-TM to Kloss, Smith, Loew, Wilkie’s T cell comprising a caTCR and CSR because de Berardinis disclose that the correct pairing of the transferred exogenous TCR chains improves the functional activity and safety of the genetically modified T cells for the therapy of tumours (paragraph 1). It would have been prima facie obvious to combine Kloss, Smith, Loew and Wilkie T cell comprising a caTCR and CSR with de Berardinis’s non-naturally occurring TCR-TM to have a T cell comprising a caTCR and CSR in which at least one of the TCR-TMs is non-naturally occurring.
In response to Applicant’s argument that that de Berardinis is completely silent about caTCRs that do not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50, for the reasons set forth above, the rejections are maintained.
The rejections of claims 1, 2, 7, 12-15, 23, 24, 33, 35 and 36 under 35 U.S.C. 103 as being unpatentable over Kloss et al (US 2015/0342993, published 3 December 2015, IDS, cited previously) in view of Smith et al (WO 2014/039523, published 13 March 2014, IDS, cited previously), Loew et al (US 2018/0230193, published 16 August 2018, filed 5 August 2016, IDS, cited previously) and Wilkie et al (J Clin Immunol 32:1059-1070, 2012, IDS, cited previously) in further view of Son et al (Human Gene Ther 24:295-305, 2013, cited previously) and Kobold et al (JNCI 107:1-10, 2015, 2015, cited previously) are maintained.
Kloss, Wilkie, Smith and Loew have been discussed supra.
Neither Kloss, Wilkie, Smith nor Loew specifically disclose wherein the ligand-binding module of the CSR is derived from the extracellular domain of a receptor.
Son disclose a chimeric antigen receptor wherein the ligand-binding module of the CAR is a chimeric NKG2D (pages 296-301; Abstract).
Kobold disclose a chimeric antigen receptor wherein the ligand-binding module of the CAR comprising the extracellular domain of PD-1 (pages 2-; Abstract).
One of ordinary skill in the art would have been motivated to apply Son and Kobold’s chimeric antigen receptor comprising an extracellular domains of the receptors NKG2D and PD-1, respectively to Kloss, Wilkie, Smith and Loew’s immune cell comprising a chimeric antibody-T cell receptor (TCR) construct and a chimeric signaling receptor because Kloss, Wilkie, Smith Loew, Son and Kobold all disclose chimeric antigen receptors for treating cancer. It would have been obvious to substitute Son and Kobold’s chimeric antigen receptor comprising extracellular domains of the receptors NKG2D and PD-1, respectively for Kloss’s scFv to make a chimeric signaling receptor comprising an extracellular domains of the receptors, a transmembrane module; and a co-stimulatory immune cell signaling module. It would have been predictable to make a chimeric signaling receptor comprising extracellular domains of the receptors NKG2D and PD-1 because making constructs with antigen binding proteins for use in chimeric antigen receptors was well known in the art.
In response to Applicant’s argument that that Son and Kobold are completely silent about caTCRs that do not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50, for the reasons set forth above, the rejections are maintained.
The rejections of claims 1, 2, 7, 9, 10, 12-15, 23, 25, 27, 33, 35 and 36 under 35 U.S.C. 103 as being unpatentable over Kloss et al (US 2015/0342993, published 3 December 2015, cited previously) in view of Smith et al (WO 2014/039523, published 13 March 2014, cited previously), Loew et al (US 2018/0230193, published 16 August 2018, filed 5 August 2016, cited previously), Wilkie et al (J Clin Immunol 32:1059-1070, 2012, IDS, cited previously), Brinkmann et al MABS, 9:182-212, February/March 2017, IDS, cited previously) and Harris (WO 94/09131, published 28 April 1994, cited previously) in further view of Taunton et al (US 2017/0306303, published 26 October 2017, filed 6 January 2017, IDS, cited previously) and Crabtree et al (US 2006/0035325, published February 16, 2006, cited previously) are maintained.
Kloss, Wilkie, Smith Loew, Brinkmann, Harris, and Tauton have been discussed supra.
Neither Kloss, Wilkie, Smith Loew, Brinkmann, Harris, nor Tauton specifically disclose that the transmembrane module of the CSR comprises a transmembrane domain derived from CD30.
Crabtree disclose a construct comprising the transmembrane and cytoplasmic portion of CD30 in a signaling chimeric protein (paragraphs 213- 215).
One of ordinary skill in the art would have been motivated to apply Crabtree’s transmembrane and cytoplasmic domains derived from CD30 to Kloss, Wilkie, Smith Loew, Brinkmann, Harris, and Tauton’s immune cell comprising a chimeric antibody-T cell receptor (TCR) construct and a chimeric signaling receptor because Kloss, Wilkie, Smith Loew, Taunton and Crabtree all disclose signaling constructs that may be used for treating cancer. It would have been obvious to substitute Crabtree’s transmembrane and cytoplasmic domains derived from CD30 for the transmembrane and cytoplasmic domains of Kloss, Wilkie, Smith Loew, Taunton chimeric antigen receptors to make a chimeric signaling receptor comprising the transmembrane and cytoplasmic of CD30. It would have been predictable to make a chimeric signaling receptor comprising the transmembrane and cytoplasmic of CD30 because making constructs for use in chimeric antigen receptors was well known in the art.
In response to Applicant’s argument that Crabtree is completely silent about caTCRs that do not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50, for the reasons set forth above, the rejections are maintained.
NEW REJECTIONS: Based on the Amendments
Claim Rejections - 35 USC § 112
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.
Claims 1, 2, 6, 7, 9, 10, 12-15, 23-27, 33, 35 and 36 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
There is no support in the specification for the negative proviso “wherein the caTCR does not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50;”
Applicant argues that Prior to the filing date of the subject application, ITAMs, including those within intracellular signaling domains such as CD3ζ, and intracellular signaling sequence of CD3ζ were well known in the art. However, this does not give support for the claimed caTCR lacking the intracellular signaling sequence of CD3ζ which was not present in the application as filed.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1, 2, 6, 7, 9, 10, 12-15, 23-27, 33, 35 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (WO 2018/200583 , published November 1, 2018) in view of Loew et al (US 2018/0230193, published 16 August 2018, filed 5 August 2016, cited previously).
Liu discloses a an immune cell comprising a) a chimeric antibody-T cell receptor (TCR) construct (caTCR) comprising an antigen binding module that specifically binds to a target antigen, wherein the target antigen is a complex comprising a peptide and a major histocompatibility complex (MHC) protein; and a TCR module (TCRM), wherein the TCRM comprises a first TCR domain (TCRD) comprising a first TCR transmembrane domain (TCR-TM) and a second TCRD comprising a second TCR-TM, wherein the TCRM facilitates recruitment of at least one TCR-associated signaling molecule, a chimeric signaling receptor (CSR) comprising a ligand-binding module that is capable of binding or interacting with a target ligand, a transmembrane module, and
a co-stimulatory immune cell signaling module that is capable of providing a co-stimulatory signal to the immune cell, wherein the ligand-binding module and the co-stimulatory immune cell signaling module of the CSR are not derived from the same molecule, and wherein the CSR lacks a functional primary immune cell signaling domain, wherein the first TCR-TM is derived from one of the transmembrane domains of a TCR and the second TCR-TM is derived from the other transmembrane domain of the TCR, wherein the caTCR further comprises a stabilization module comprising a first stabilization domain and a second stabilization domain, wherein the transmembrane module of the CSR comprises a transmembrane domain derived from CD30, wherein the co-stimulatory receptor is selected from the group consisting of CD30 (paragraphs 15-25, 77, 84-96; Example2-5)
Liu does not specifically disclose that the caTCR does not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50.
Loew disclose a first and the second chimeric membrane proteins from a chimeric antigenic receptor lacking an ITAM signaling domain (paragraph 350, Examples 2-4, 6-8). Loew disclose that examples of ITAM containing primary intracellular signaling domains that are of particular use in the invention include those of CD3 zeta, CD3 gamma, CD3 delta and CD3 epsilon (paragraph 349). Loew disclose a primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain which has altered (e.g., increased or decreased) activity as compared to the native ITAM domain (paragraph 350). Loew disclose that a primary signaling domain comprises a modified ITAM-containing primary intracellular signaling domain (Id). Thus, Loew contemplates a CD3 zeta with a mutated ITAM region. Furthermore, given that Loew demonstrated that a T cell lacking endogenous ITAM domains was capable of TCR signaling it would have been obvious to make a signaling moiety comprising a truncated CD3 zeta proteins with deletions of the ITAM domains.
One of ordinary skill in the art would have been motivated to apply Loew’s chimeric antigen receptor lacking an ITAM signaling domain to Liu’s T cell comprising a caTCR and CSR because Loew disclose that signaling domains lacking ITAM signaling domains were capable of cytolytic activity (paragraph 525). Thus, a T cell CAR does not require the ITAM module of a functional" primary immune cell signaling sequence to lyse target cells. It would have been prima facia obvious to substitute Loew’s intracellular chimeric antigen receptor domain lacking an ITAM signaling domain for Liu’s intracellular domain of a caTCR because both the intracellular domains of Loew, Kloss and Smith were all capable of functioning to activate T cells. One of ordinary skill in the art would have had a reasonable expectation of success in substituting the intracellular domains because the intracellular domains were found to be functional and engineering constructs for use in CAR T cells was well known in the art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 6, 7, 9, 10, 12-15, 23-27, 33, 35 and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 10,822,413 in view of Loew et al (US 2018/0230193, published 16 August 2018, filed 5 August 2016, IDS, cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of U.S. Patent No. 10,822,413 are drawn to an immune cell comprising chimeric antibody-T cell receptor (TCR) comprising antigen binding module, a TCR module, a stabilization module and a chimeric signaling receptor comprising ligand-binding module, a transmembrane module and a co-stimulatory immune cell signaling module.
The claims of U.S. Patent No. 10,822,413 do not specifically recite that the caTCR does not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50.
However, Loew disclose a first and the second chimeric membrane proteins from a chimeric antigenic receptor lacking an ITAM signaling domain (paragraph 350, Examples 2-4, 6-8). Loew disclose that examples of ITAM containing primary intracellular signaling domains that are of particular use in the invention include those of CD3 zeta, CD3 gamma, CD3 delta and CD3 epsilon (paragraph 349). Loew disclose a primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain which has altered (e.g., increased or decreased) activity as compared to the native ITAM domain (paragraph 350). Loew disclose that a primary signaling domain comprises a modified ITAM-containing primary intracellular signaling domain (Id). Thus, Loew contemplates a CD3 zeta with a mutated ITAM region.
One of ordinary skill in the art would have been motivated to apply Loew’s chimeric antigen receptor lacking an ITAM signaling domain to the T cell comprising a caTCR and CSR of U.S. Patent No. 10,822,413 because Loew disclose that signaling domains lacking ITAM signaling domains were capable of cytolytic activity (paragraph 525). Thus, a T cell CAR does not require the ITAM module of a functional" primary immune cell signaling sequence to lyse target cells. It would have been prima facia obvious to substitute Loew’s intracellular chimeric antigen receptor domain lacking an ITAM signaling domain for the intracellular domain of a caTCR recited in U.S. Patent No. 10,822,413 because both the intracellular domains of Loew and U.S. Patent No. 10,822,413 were all capable of functioning to activate T cells.
Claims 1, 2, 6, 7, 9, 10, 12-15, 23-27, 33, 35 and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,965,021 in view of Loew et al (US 2018/0230193, published 16 August 2018, filed 5 August 2016, IDS, cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of U.S. Patent No. 11,965,021 are drawn to an immune cell comprising chimeric antibody-T cell receptor (TCR) comprising antigen binding module, a TCR module, a stabilization module and a chimeric signaling receptor comprising ligand-binding module, a transmembrane module and a co-stimulatory immune cell signaling module.
The claims of U.S. Patent No. 11,965,021 do not specifically recite that the caTCR does not comprise amino acids 18-38, 56-77, and 87-107 of SEQ ID NO: 50.
However, Loew disclose a first and the second chimeric membrane proteins from a chimeric antigenic receptor lacking an ITAM signaling domain (paragraph 350, Examples 2-4, 6-8). Loew disclose that examples of ITAM containing primary intracellular signaling domains that are of particular use in the invention include those of CD3 zeta, CD3 gamma, CD3 delta and CD3 epsilon (paragraph 349). Loew disclose a primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain which has altered (e.g., increased or decreased) activity as compared to the native ITAM domain (paragraph 350). Loew disclose that a primary signaling domain comprises a modified ITAM-containing primary intracellular signaling domain (Id). Thus, Loew contemplates a CD3 zeta with a mutated ITAM region.
One of ordinary skill in the art would have been motivated to apply Loew’s chimeric antigen receptor lacking an ITAM signaling domain to the T cell comprising a caTCR and CSR of U.S. Patent No. 11,965,021 because Loew disclose that signaling domains lacking ITAM signaling domains were capable of cytolytic activity (paragraph 525). Thus, a T cell CAR does not require the ITAM module of a functional" primary immune cell signaling sequence to lyse target cells. It would have been prima facia obvious to substitute Loew’s intracellular chimeric antigen receptor domain lacking an ITAM signaling domain for the intracellular domain of a caTCR of US Patent 11,965,021 because both the intracellular domains of Loew and U.S. Patent No. 11,965,021 were all capable of functioning to activate T cells.
Summary
Claims 1, 2, 6, 7, 9, 10, 12-15, 23-27, 33, 35 and 36 stand rejected
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 extension fee 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 date of this final action.
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/MARK HALVORSON/Primary Examiner, Art Unit 1646