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 .
Applicants’ amendments to the claims and arguments filed on May 11, 2026 have been received and entered. Claims 1, 6, 43-44 have been amended, while claims 3-5, 7-18, 20, 22-27, 32-33, 35-41 have been cancelled. Claim 45-51 are new claims.
Claims 1-2, 6, 19, 21, 28-31, 34, 42, 43-50 and 51 are pending in the instant application.
Election/Restrictions
Applicant’s election of 1-3, 6, 8, 10-12, 17-19, 21-22, 27-30 and 31 (group I) in the reply filed on January 1, 2025 was acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 34 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 1, 2025.
Priority
This application is a 371 of PCT/IL2020/050360 filed on 03/26/2020, which claims priority from US provisional application no 62/898,471 filed on 09/10/2019 and 62/823,711 filed on 03/26/2019.
Claims 1-2, 6, 19, 21, 28-31, 42, 43-50 and 51are under consideration.
Claim Objections
Claim 43 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Maintained-Claim Rejections - 35 USC § 112-in modified form
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 6, 19, 21, 28-31, 42, 45-50 and 51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims are directed to a nucleic acid molecule comprising a nucleotide sequence encoding an activating chimeric antigen receptor (aCAR), wherein said aCAR comprises a) SEQ ID NO: 60, 62, 64 or 66;b) a sequence with at least 85% sequence identity to SEQ ID NO: 60, 62 or 66 that when expressed in a T cells binds peptidoglycan (PGN) and activates said T cell upon said binding; or c) a sequence with at least 90% sequence identity to SEQ ID NO: 64 that when expressed in a T cells binds peptidoglycan (PGN) and activates said T cell upon said binding. Claims further limit the claims, wherein said aCAR comprises amino acids 1- 588 of SEQ ID NO: 64 linked to a sequence with at least 85% sequence identity to amino acids 589- 898 of SEQ ID NO: 64, aCAR comprises amino acids 1- 588 of SEQ ID NO: 66 linked to a sequence with at least 85% sequence identity to amino acids 589- 803 of SEQ ID NO: 66. aCAR comprises amino acids 1- 266 of SEQ ID NO: 60 linked to a sequence with at least 85% sequence identity to amino acids 267- 435 of SEQ ID NO: 60 or aCAR comprises amino acids 1- 270 of SEQ ID NO: 60 linked to a sequence with at least 85% sequence identity to amino acids 271- of SEQ ID NO: 62 and wherein said aCAR expressed in a T cell binds PGN and activates said T cell upon said binding. Claims further comprises a nucleotide sequence encoding a homodimeric IL-10 that is linked to any transmembrane intracellular stretch, optionally through a flexible hinge. Dependent claims limit the wherein said extracellular binding-domain is selected from extracellular domain of TLR2 and a single chain variable fragment (scFv) that specifically binds said peptidoglycan.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that ''applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1 117. The specification does not ''clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1116.
The claims encompass a large number of modified CAR structures comprising: (i) a sequence with at least 85% sequence identity to SEQ ID NO: 60, 62 or 66 that when expressed in a T cells binds peptidoglycan (PGN) and activates said T cell upon said binding; or c) a sequence with at least 90% sequence identity to SEQ ID NO: 64 that when expressed in a T cells binds peptidoglycan (PGN) and activates said T cell upon said binding.
The art teaches that extracellular domain of TLR2 is crucial for directly binding to PGN (peptidoglycan). The specific structure of this domain ensures that the CAR can recognize and bind to target antigens. It is emphasized that a small change in CAR sequence/domain arrangement can produce a very different functional outcome in terms of expression levels, activation phenotype. The art teaches CAR protein with highly similar sequences can behave very differently in terms of signaling function and T cell activation suggesting that even predictable primary sequence does not always ensures predictable cellular behavior (see abstract in Chen et al Cancer Immunol. Res. 2023, 11(2):150-163). Chen explicitly states “receptor protein conformation is, in turn, a function of the overall protein sequence, not just domains that directly engage in ligand binding or signaling. We thus contemplated the possibility that different CARs containing the same signaling domains could exhibit different signaling behavior due to differences in overall protein conformation. Specifically, we hypothesized that differences in the conformation of the intracellular portion of a CAR could alter the accessibility of the receptor’s docking residues to downstream signaling molecules, thus affecting the quality of the CAR’s signaling” (see page 155, col. 2, para. 3). This is further supported by Celichowski et al (Journal of Translational Medicine (2023) 21:197, 1-23) who states “ it is important to note that the activity of CAR proteins can differ depending on the overall construct design. The selection of signaling domains, such as immunoreceptor tyrosine-based activation motifs (ITAMs), incorporated into the CAR protein], as well as the affinity and engaging kinetics of the particular antigen-binding domain, can significantly affect the outcome of the therapy. Thus, predicting the effectiveness of CAR T cell therapy infusion can be difficult, as it could vary for each CAR construct. This publication clearly shows that one of ordinary skill in the art even knowing the building blocks of CAR would encounter significant unpredictability of the resulting functional outcome. Zhylko et al (Cancers 2020, 12, 2030, 1-29) states “despite the simplicity of the modular CAR structure, it is worth noting that even small changes in its sequence could affect the biologic functions of CAR-T cells, their efficacy and persistence” (see page 2, para. 4). In view of foregoing discussion, it is apparent that the CAR architecture is influenced by multiple components and complex and variable mechanisms are involved in the development, development, treatment, prevention of disease. The DNA sequences of an aCAR structures comprising: (i) any extracellular binding-domain of TLR2 binding PGN, other than the targeting anti-PGN and CAR comprising SEQ ID NO: 60, 62, 64 and 66, encompassed within the genus of extracellular domain specifically binding peptidoglycan have not been disclosed. The claims directed to the CAR comprising a sequence with at least 85% sequence identity to SEQ ID NO: 60 or 62, 64 or 66 read on variant of 60 or 62, 64 or 66. The art as discussed above shows that even small changes in its sequence could affect the biologic functions of CAR-T cells. Based upon the prior art there is expected to be sequence variation among the species of DNA encoding CAR sequences comprising the extracellular domain of TLR2 specifically binding PGN.. The specification has provided the description of a nucleic acid encoding CAR comprising SEQ ID NO: 60, 62, 64 and 66 binding to anti-PGN and. For instance, the art teaches that Anti-TLR2 mAb 2392 but Not mAb TL2.3 inhibits the binding of sTLR2 to iPGN (see page 24318, col. 1, para. 1), Iwaki et al JBC, 2002, 24315-24320). It is further disclosed that although the epitope for the monoclonal antibody has not been identified, the extracellular TLR2 region contiguous to the antibody epitope may be critical for ligand recognition (see page 24320, col. 1, para. 2). The specification however has not disclosed the sequences or a CAR structure of any extracellular binding-domain of TLR2 specifically binding any PGN, other than nucleic acid encoding CAR comprising SEQ ID NO: 60, 62, 64 and 66 that specifically binds to scFv is derived from the monoclonal antibody 3F6 and comprises a light chain variable domain (V,) of SEQ ID NO: 16 and encoded by a nucleic acid molecule as set forth in SEQ ID NO: 17, connected to a heavy chain variable domain of SEQ ID NO: 18 (encoded by e.g. a nucleic acid molecule as set forth in SEQ ID NO: 19) optionally through a first flexible linker, e.g. of the amino acid sequence GSTSGSGKPGSGEGSTKG (SEQ ID NO: 5), encoded by e.g. a nucleic acid molecule as set forth in SEQ ID NO: 6 or an a nucleic acid encoding extracellular binding domain of TLR2 as set forth in SEQ ID NO: 60, 62, 64 or 64 binding peptidoglycan (emphasis added).
There is no evidence on the record of a relationship between the structures of the CAR molecules that would provide any reliable information about the structure of DNA molecules within the claimed genus. There is no evidence on the record that embraced extracellular domain of TLR2 specifically binding PGN had known structural relationships to each other those specified above; the art indicated that there is variation between DNA sequences of such sequences. There is no single predictable nucleotide sequence for the claimed aCAR ORF and variant of protein sequence introduce additional complexity of the CAR modular structure with predictable functional outcome.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements or motifs which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics. Inc., 48 USPQ2d 1641, 1646 (1998).
In the instant case, the claimed embodiments of a nucleic acid encoding an extracellular domain of TLR2 specifically binding PGN, other than a nucleic acid encoding CAR comprising SEQ ID NO: 60, 62, 64 or 66 and the anti PNG scFv as set forth in exampled 10 encompassed within the genus lack a written description. The specification fails to describe what DNA molecules fall into this genus. The skilled artisan cannot envision the detailed chemical structure of the encompassed by the nucleic acid encoding a genus of aCAR specifically binding PGN, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In conclusion, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that applicant is in possession of the genus of modified CAR structures comprising: (i) any extracellular domain of TLR2 specifically binding PGN ii) any transmembrane domain;(iii) any intracellular domain including at least one signal transduction element that activates and/or co-stimulates a T cellas as embraced by the claims.
Response to arguments
Applicant disagree with the rejection arguing recitation of at least 85% sequence identity identity and the function. In Example 11B in the Written Description Training Materials it even makes it clear that the correlation would not guarantee that every alteration will produce a functioning protein as required, and that indeed some mutations that would be expected to function will not function ("Although all conservative amino acid substitutions in these domains will not necessarily result in a protein having activity Y, those of ordinary skill in the art would expect that many of these conservative substitutions would result in a protein having the required activity." Bottom page 41 to top of page 42). This level of unpredictability, that not every alteration will be functional and a skilled artisan will still have to check, is not considered undue experimentation and the claims are found to have proper written description even with this unpredictability. The instant claims are the same. While it is true that the nature of CAR functionality has a certain level of unpredictability, generally speaking it is known that scFvs from antibodies can be incorporated into a CAR with a reasonable expectation of success with minor tweaking if necessary. As such, instant claim 1 has proper written description. Applicant continue to argue Claims 46-47 are parallel to claims 6 and 45 in that they give the PGN binding domains exactly without a percent identity threshold. The alterations to keep 85% identity are therefore only with respect to the backbone of the CAR, which as discussed above is well known and with a very clear art-recognized structure function correlation. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that genus encompasses aCAR comprising any sequence with at least 85% sequence identity to SEQ ID NO: 60, 62 or 66 or at least 90% sequence identity to SEQ ID NO: 64 when expressed in a T cells bind peptidoglycan (PGN) and activates said T cell upon said binding. Thus, the 15% amino acid changes/variation or mutation could occur across the scFV, hinge, linker, transmembrane, and/or signaling domain that could affect folding of protein sequence, expression and signaling. Thus, genus may encompass a large number of structurally distinct aCARs. The guidance provided in the specification is limited to a description of a nucleic acid encoding CAR comprising SEQ ID NO: 60, 62, 64 and 66 binding to anti-PGN showing contemplated biological activity. The specification however has not disclosed the sequences or a CAR structure of any extracellular binding-domain of TLR2 or anti-PGN monoclonal antibody specifically binding any PGN, other than nucleic acid encoding CAR comprising SEQ ID NO: 60, 62, 64 and 66 that when expressed in a T cells bind peptidoglycan (PGN) and activates said T cell upon said binding. The specification is further provide a very limited guidance identifying which substitution, addition and/or deletion of amino acid would retain the contemplated biological activity as required by the claim. In the instant case, the issue is not percentage identity by itself as argued by the applicant, rather relevant issue pertains to whether specification provide adequate guidance to show possession of claimed genus showing contemplated biological activity. It is emphasized that a small change in CAR sequence/domain arrangement can produce a very different functional outcome in terms of expression levels, activation phenotype. The art teaches CAR protein with highly similar sequences can behave very differently in terms of signaling function and T cell activation suggesting that even predictable primary sequence does not always ensures predictable cellular behavior (see abstract in Chen et al Cancer Immunol. Res. 2023, 11(2):150-163). Chen explicitly states “receptor protein conformation is, in turn, a function of the overall protein sequence, not just domains that directly engage in ligand binding or signaling. We thus contemplated the possibility that different CARs containing the same signaling domains could exhibit different signaling behavior due to differences in overall protein conformation. Specifically, we hypothesized that differences in the conformation of the intracellular portion of a CAR could alter the accessibility of the receptor’s docking residues to downstream signaling molecules, thus affecting the quality of the CAR’s signaling” (see page 155, col. 2, para. 3). This is further supported by Celichowski et al (Journal of Translational Medicine (2023) 21:197, 1-23) who states “ it is important to note that the activity of CAR proteins can differ depending on the overall construct design. The selection of signaling domains, such as immunoreceptor tyrosine-based activation motifs (ITAMs), incorporated into the CAR protein], as well as the affinity and engaging kinetics of the particular antigen-binding domain, can significantly affect the outcome of the therapy. Thus, predicting the effectiveness of CAR T cell therapy infusion can be difficult, as it could vary for each CAR construct. Therefore, absent any specific guidance identifying critical domains and modification, one of skill in the art would conclude that this limited information is not deemed sufficient to reasonably convey to one skilled in the art that applicant is in possession of the genus of modified CAR structures
In response to applicant’s argument pertaining to alterations to keep 85% identity only with respect to the backbone of the CAR, it is emphasized that read on 3C11 CD8a/CD28 transmembrane- intracellular/FcRg (SEQ ID NO: 60), 3F6CD8a/CD28transmeme-intracellular/FcRg (SEQ ID NO: 62), aCAR TLR2-TIR(*)-zeta CARs (SEQ ID NO: 64) and aCAR TLR2-IgD zeta CARs (SEQ ID NO: 66). In the instant case, unlike Example 11B of the written description training materials, the specification fails to identifies any region and/or domain responsible for contemplated biological activity when expressed in a T cells bind peptidoglycan (PGN) and activates said T cell upon said binding. The specification further fails to disclose any amino acid substitutions outside of the disclosed species (SEQ IDN O: 60, 62, 64 and 66) that are likely to affect the contemplated biological activity. In this regard, Celichowski et al (Journal of Translational Medicine (2023) 21:197, 1-23) states “the selection of signaling domains, such as immunoreceptor tyrosine-based activation motifs (ITAMs), incorporated into the CAR protein], as well as the affinity and engaging kinetics of the particular antigen-binding domain, can significantly affect the outcome of the therapy. Thus, predicting the effectiveness of CAR T cell therapy infusion can be difficult, as it could vary for each CAR construct. This publication clearly shows that one of ordinary skill in the art even knowing the building blocks of CAR would encounter significant unpredictability of the resulting functional outcome. Zhylko et al (Cancers 2020, 12, 2030, 1-29) states “despite the simplicity of the modular CAR structure, it is worth noting that even small changes in its sequence could affect the biologic functions of CAR-T cells, their efficacy and persistence” (see page 2, para. 4). The post filing art further teaches mutations in CD28 and other signaling domains could substantially alter CAR function (see Leddon Frontiers in Immunology, 2020, 1-15). In view of foregoing discussion, it is apparent that the CAR architecture is influenced by multiple components and complex and variable mechanisms are involved in the development, development, treatment, prevention of disease. The DNA sequences of an aCAR structures comprising: (i) any extracellular binding-domain of TLR2, scFV antibody 3C11 or 3F6 binding PGN, other than the targeting anti-PGN and CAR comprising SEQ ID NO: 60, 62, 64 and 66, encompassed within the genus of aCAR comprising the extracellular domain ofTLR2 specifically binding peptidoglycan have not been disclosed. Based upon the prior art there is expected to be sequence variation among the species of DNA encoding CAR sequences comprising the extracellular domain of TLR2 specifically binding PGN. In view of foregoing, applicant’s disclosure and the knowledge within the art, those of ordinary skill in the art would conclude that the applicant was not in possession of the claimed genus of nucleic acids based on the disclosure of the single species of SEQ ID NO: 60, 62, 64 or 66.
New-Claim Rejections - 35 USC § 112- new matter-necessitated by amendments
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 48-51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the instant case, the recitation of limitations:
“wherein said aCAR comprises amino acids 1- 588 of SEQ ID NO: 64 linked to a sequence with at least 85% sequence identity to amino acids 589- 898 of SEQ ID NO: 64, wherein said aCAR expressed in a T cell binds PGN and activates said T cell upon said binding (claim 48).
wherein said aCAR comprises amino acids 1- 588 of SEQ ID NO: 66 linked to a sequence with at least 85% sequence identity to amino acids 589- 803 of SEQ ID NO: 66, wherein said aCAR expressed in a T cell binds PGN and activates said T cell upon said binding (claim 49).
wherein said aCAR comprises amino acids 1- 266 of SEQ ID NO: 60 linked to a sequence with at least 85% sequence identity to amino acids 267- 435 of SEQ ID NO: 60, wherein said aCAR expressed in a T cell binds PGN and activates said T cell upon said binding (claim 50) and
wherein said aCAR comprises amino acids 1- 270 of SEQ ID NO: 60 linked to a sequence with at least 85% sequence identity to amino acids 271- of SEQ ID NO: 62, wherein said aCAR expressed in a T cell binds PGN and activates said T upon said binding (claim 51)
are considered new matter. Upon further review of the instant specification, examiner could not find support for the above stated limitation. There is no explicit or implicit support for percentage identity to any specific combination of fragments in the CAR. Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of that CAR, as claimed above. In case if applicants have evidence to support otherwise, applicants are invited to indicate page and line number for the written support specifically for the limitations recited in claims 48-51 of the instant application. MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph-written description requirement”. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). This is a new matter rejection.
Withdrawn-Claim Rejections - 35 USC § 103-in modified form
Claims 1, 6, 8, 10-11, 17-18, 27-28, 41 are rejected under 35 U.S.C. 103 as being unpatentable over Iwaki et al (JBC, 2002, 277, 24315–24320) as evidenced by Hiroyuki et al (WO2011021524, dated 02/24/2011), Dawson et al (Frontiers in Immunology, 2017, 8(3), 1-8)/Sentman (WO2017058752, dated 04/06/20217) and Han et al (Molecular Therapy, 2017, 2466-2476). In view of Applicants’ amendment of base claim 1, introducing new limitation “a sequence with at least 90% sequence identity to SEQ ID NO: 64 that when expressed in a T cells binds peptidoglycan (PGN) and activates said T cell upon said binding”, that is not taught by the combination of prior art references, the previous rejection is rendered moot and hereby withdrawn. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claims 1 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Iwaki et al (JBC, 2002, 277, 24315-24320) as evidenced by Hiroyuki et al (WO2011021524, dated 02/24/2011), Dawson et al (Frontiers in Immunology, 2017, 8(3), 1-8)/Sentman (WO2017058752, dated 04/06/20217) and Han et al (Molecular Therapy, 2017, 2466-2476) as applied above for claim 1 and further in view of Goddard (US7696327, dated 04/13/2010). The rejection is withdrawn for the reasons discussed above.
Claim 2, 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Iwaki et al (JBC, 2002, 277, 24315–24320) as evidenced by Hiroyuki et al (WO2011021524, dated 02/24/2011), Dawson et al (Frontiers in Immunology, 2017, 8(3), 1-8)/Sentman (WO2017058752, dated 04/06/20217) and Han et al (Molecular Therapy, 2017, 2466-2476). as applied above and further in view of Walter et al (Curr Top Microbiol Immunol. 2014 ; 380: 191–212.) and Guo et al (Protein Expression and Purification 83 (2012) 152–156). The rejection is withdrawn for the reasons discussed above.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Iwaki et al (JBC, 2002, 277, 24315–24320) as evidenced by Hiroyuki et al (WO2011021524, dated 02/24/2011), Dawson et al (Frontiers in Immunology, 2017, 8(3), 1-8)/Sentman (WO2017058752, dated 04/06/20217), Han et al (Molecular Therapy, 2017, 2466-2476)., Walter (Curr Top Microbiol Immunol. 2014; 380: 191–212.), Guo et al (Protein Expression and Purification 83 (2012) 152–156), Tsien et al. (WO 2000/071565), Pule (WO 2015052538), Zimmerman et al. (WO 200189286) as applied above and further in view of Gross (WO/2003/106616, dated 12/24/2003). The rejection is withdrawn for the reasons discussed above.
New-Claim Rejections - 35 USC § 103-in modified form -necessitated by amendments
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 6, 8, 10-11, 17-18, 27-28, 41, 45, 48 are rejected under 35 U.S.C. 103 as being unpatentable over Iwaki et al (JBC, 2002, 277, 24315–24320) as evidenced by Goddard (US7696327, dated 04/13/2010), Dawson et al (Frontiers in Immunology, 2017, 8(3), 1-8)/ Sentman (WO2017058752, dated 04/06/20217) as evidenced by Rappl (PLoS One, 2012, 7, e30713, 1-10) and Choi (US 20180256744, 09/13/2018).
With respect to claims 1 and 6, Iwaki teaches an extracellular domain of TLR2 that directly binds PGN (a bacterial antigen) (see abstract, page 24318, col. 2, para. 2) (limitation of claim 6). The extracellular domain of TLR2 comprises the SEQ ID NO: 20 as evident from the teaching of Goddard who discloses SEQ ID NO: 12 that contains TLR2 that has 100% sequence identity to SEQ ID NO: 20 (see sequence search results, example ) (limitation of claim 6). Goddard cure the deficiency by disclosing a sequence of TLR2 as set forth in SEQ ID NO: 12 that has at least 90% sequence identity to residue 1-784 of SEQ ID NO: 64 or residue 1 to 589 of SEQ ID NO 66 (see sequence search results).
Query Match 86.9%; Score 4060; Length 784;
Best Local Similarity 99.9%;
Matches 783; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 1 MPHTLWMVWVLGVIISLSKEESSNQASLSCDRNGICKGSSGSLNSIPSGLTEAVKSLDLS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MPHTLWMVWVLGVIISLSKEESSNQASLSCDRNGICKGSSGSLNSIPSGLTEAVKSLDLS 60
Qy 61 NNRITYISNSDLQRCVNLQALVLTSNGINTIEEDSFSSLGSLEHLDLSYNYLSNLSSSWF 120 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NNRITYISNSDLQRCVNLQALVLTSNGINTIEEDSFSSLGSLEHLDLSYNYLSNLSSSWF 120
Qy 121 KPLSSLTFLNLLGNPYKTLGETSLFSHLTKLQILRVGNMDTFTKIQRKDFAGLTFLEELE 180 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KPLSSLTFLNLLGNPYKTLGETSLFSHLTKLQILRVGNMDTFTKIQRKDFAGLTFLEELE 180
Qy 181 IDASDLQSYEPKSLKSIQNVSHLILHMKQHILLLEIFVDVTSSVECLELRDTDLDTFHFS 240 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 IDASDLQSYEPKSLKSIQNVSHLILHMKQHILLLEIFVDVTSSVECLELRDTDLDTFHFS 240
Qy 241 ELSTGETNSLIKKFTFRNVKITDESLFQVMKLLNQISGLLELEFDDCTLNGVGNFRASDN 300 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ELSTGETNSLIKKFTFRNVKITDESLFQVMKLLNQISGLLELEFDDCTLNGVGNFRASDN 300
Qy 301 DRVIDPGKVETLTIRRLHIPRFYLFYDLSTLYSLTERVKRITVENSKVFLVPCLLSQHLK 360 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 DRVIDPGKVETLTIRRLHIPRFYLFYDLSTLYSLTERVKRITVENSKVFLVPCLLSQHLK 360
Qy 361 SLEYLDLSENLMVEEYLKNSACEDAWPSLQTLILRQNHLASLEKTGETLLTLKNLTNIDI 420 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 SLEYLDLSENLMVEEYLKNSACEDAWPSLQTLILRQNHLASLEKTGETLLTLKNLTNIDI 420
Qy 421 SKNSFHSMPETCQWPEKMKYLNLSSTRIHSVTGCIPKTLEILDVSNNNLNLFSLNLPQLK 480 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 SKNSFHSMPETCQWPEKMKYLNLSSTRIHSVTGCIPKTLEILDVSNNNLNLFSLNLPQLK 480
Qy 481 ELYISRNKLMTLPDASLLPMLLVLKISRNAITTFSKEQLDSFHTLKTLEAGGNNFICSCE 540 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 ELYISRNKLMTLPDASLLPMLLVLKISRNAITTFSKEQLDSFHTLKTLEAGGNNFICSCE 540
Qy 541 FLSFTQEQQALAKVLIDWPANYLCDSPSHVRGQQVQDVRLSVSECHRTALVSGMCCALFL 600 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 FLSFTQEQQALAKVLIDWPANYLCDSPSHVRGQQVQDVRLSVSECHRTALVSGMCCALFL 600
Qy 601 LILLTGVLCHRFHGLWYMKMMWAWLQAKRKPRKAPSRNICYDAFVSYSERDAYWVENLMV 660 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 LILLTGVLCHRFHGLWYMKMMWAWLQAKRKPRKAPSRNICYDAFVSYSERDAYWVENLMV 660
Qy 661 QELENFNPPFKLCLHKRDFIHGKWIIDNIIDSIEKSHKTVFVLSENFVKSEWCKYELDFS 720 |||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||
Db 661 QELENFNPPFKLCLHKRDFIPGKWIIDNIIDSIEKSHKTVFVLSENFVKSEWCKYELDFS 720
Qy 721 HFRLFDENNDAAILILLEPIEKKAIPQRFCKLRKIMNTKTYLEWPMDEAQREGFWVNLRA 780 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 HFRLFDENNDAAILILLEPIEKKAIPQRFCKLRKIMNTKTYLEWPMDEAQREGFWVNLRA 780
Qy 781 AIKS 784
||||
Db 781 AIKS 784
Iwaki differs from claimed invention by not disclosing the binding domain that targets a defined antigen at the CAR extracellular site also contains TIR-zeta
Before the effective filing date of instant application, Sentman teaches ligand binding domain (scFV, receptor ectodomain) are well known interchangeable module that confer extracellular specificity following fusing into receptor scaffold of CAR Sentman further teaches antigen or ligand expressed in disease colon that may be targeted by CAR (see table 1). It is relevant to note that claims encompass a large number of modified CAR structures, comprising an extracellular binding domain specifically binding to an antigen, a transmembrane region that anchors the antigen targeting domain to the cell surface, at least one signaling endodomain and an optional extracellular spacer/hinge domain between the antigen targeting domain or recognition domain and transmembrane region (see para. 26). ,Sentman teaches antigen targeting or antigen recognition by CAR molecules can involve the use of a single chain variable fragment (scFv) that has been assembled from a monoclonal antibody. Alternatively, targeting moieties can include receptors); ligands or a single domain antibody (see para. 27). The art teaches CAR- Ts having an extracellular domain targeting antigens of the gastrointestinal tract in colitis patients (limitation of claim 1, 6,). Sentman teaches an immune cell comprising nucleic acids encoding a chimeric antigen receptor and nucleic acid encoding at least one exogenous anti-inflammatory or immune suppressant cytokine. The chimeric antigen receptor includes an antigen targeting domain or recognition domain that binds an antigen or ligand at a site of inflammation or auto immunity and an immune signaling receptor containing an immunoreceptor tyrosine-based activation motif and a costimulatory endodomain. Dawson teaches an in vivo in vitro data demonstrating that a nucleic acid molecule encoding TNP-specific CAR Treg-mediated antigen-specificity suppresses effector T cells, thereby mediating resistance to colitis (see Table 1, page 3). It is note that Dawson specifically discloses the CARs comprises a hinge, a transmembrane region, a CD28 co-stimulatory domain and ITAMs either from the FcRγ or CD3ζ proteins (see table 1 and references therein). Regarding claim 28, Dawson discloses a retroviral vector encoding RNP-specific CAR (page 2, col. 2, para. 3). Dawson further discloses T-reg cells comprising said RNP-specific CAR that allows these ells the ability to protect from colitis in a dose dependent manner (see page col.2, last para). Dawson further discloses CAR Tregs specific for a different model antigen, prevented disease in a model of colitis better than CAR Tregs specific for an irrelevant antigen (see page 2, col. 2, para. 3). Rappl provided evidence of using CAR CD3-zeta-mediated activation that results in cytokine release and redirect cytotoxicity despite hypo-responsive TCR (abstract). Choi teaches the requisite CD3 zeta sequence as set forth in SEQ ID NO: 15 that has 100% sequence identity to residue 785 to 898 of SEQ ID NO: 64 or about 70% of 589-803 of SEQ ID NO: 66.
Qy 1 LERVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 418 LERVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGL 477
Qy 61 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 114
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 478 YNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 531
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify to use TLR2 extracellular domain that is known to bind PGNas chimeric antigen binding domain of Sentman /Dawson, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the CAR art would be motivated to do so because prior art recognized that functional binding domain of the CAR need not be limited to scFV against target antigen. It would have been further obvious to use CARs comprising TLR2 extracellular domain of Iwaki and Sentman with signal transduction element of CD3 zeta as suggested in prior art of Dawson and Rappl, with reasonable expectation of success. One of skill in the art would have been expected to have a reasonable expectation of success because (i) prior art recognized that any binding domain that targets a defined antigen could be incorporated into CAR extracellular site as evident from Sentman. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 44 are rejected under 35 U.S.C. 103 as being unpatentable over Iwaki et al (JBC, 2002, 277, 24315–24320) as evidenced by Goddard (US7696327, dated 04/13/2010), Dawson et al (Frontiers in Immunology, 2017, 8(3), 1-8)/ Sentman (WO2017058752, dated 04/06/20217) as evidenced by Rappl (PLoS One, 2012, 7, e30713, 1-10) and Choi (US 20180256744, 09/13/2018) as applied above and further in view of Xu et al (Nature 2000, 408(6808):111-5).
The teaching of Iwaki, Dawson, Sentman /Dawson, Rappl and Choi have been described above and relied in same manner here. The combination of reference discloses TLR-2-TIR(*)-Zeta CAR but differs from claimed invention by not disclosing T LR-2-TIR(*)-Zeta CAR, except for the replacement of a Pro into His codon at residue 681.
Xu teaches single-point mutation in the TLR2, Pro681His, disrupts signal transduction in response to stimulation by yeast and Gram-positive bacteria (see abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify to use TLR2 extracellular domain that is known to bind PGNas chimeric antigen binding domain of Sentman /Dawson and further incorporating mutation of residue in TLR2, Pro681His that would disrupt signal transduction in response to stimulation by Gram-positive bacteria as suggested in Xu, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the CAR art would be motivated to do so because prior art recognized that functional binding domain of the CAR need not be limited to scFV against target antigen. It would have been further obvious to use CARs comprising TLR2 extracellular domain of Iwaki and Sentman with signal transduction element of CD3 zeta as suggested in prior art of Dawson and Rappl, with reasonable expectation of success. One of skill in the art would have been expected to have a reasonable expectation of success because (i) prior art recognized that any binding domain that targets a defined antigen could be incorporated into CAR extracellular site as evident from Sentman. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claim 2, 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Iwaki et al (JBC, 2002, 277, 24315–24320) as evidenced by Goddard (US7696327, dated 04/13/2010), Dawson et al (Frontiers in Immunology, 2017, 8(3), 1-8)/ Sentman (WO2017058752, dated 04/06/20217) as evidenced by Rappl (PLoS One, 2012, 7, e30713, 1-10) and Choi (US 20180256744, 09/13/2018 and as applied above and further in view of Walter et al (Curr Top Microbiol Immunol. 2014 ; 380: 191–212.) and Guo et al (Protein Expression and Purification 83 (2012) 152–156).
The teaching of Iwaki, Dawson, Sentman /Dawson, Rappl and Choi have been described above and relied in same manner here. The combination of reference differs from claimed invention by not disclosing nucleic acid further comprises a nucleotide sequence encoding a homodimeric IL-10 that is linked to a transmembrane-intracellular stretch, optionally through a flexible hinge.
Walter et al. teaches a polypeptide, “IL-10 inhibits the expression of MHC and co-stimulatory molecules important for cell-mediated immunity. It is further disclosed that IL-10 exhibits immunostimulatory activities that include the ability to stimulate IFNγ production in CD8+ T cells activated with anti-CD3/anti-CD28, or other cytokine cocktails” (see introduction). Walter describes that the “two intra-chain disulfide bonds link the N-terminus, and helix C, to the DE loop in each subunit. Thus, the disulfide bonds stabilize the assembly of helices A-D, but do not cross-link the two domain-swapped chains of the dimer (see page 3). This meets the limitations wherein the polypeptide contains a membrane bound IL-10 domain containing two dimers fused to a heterologous transmembrane stretch comprising a transmembrane helix and an intracellular domain which can each be specified to interact with particular targets. Walter differs from claimed invention by not teaching creation of an IL-10 fusion protein.
Guo cure the deficiency by creating a “fusion protein containing human IL-10 and an IgG Fc fragment (hIL-10/Fc) (see abstract). The creation of the fusion protein shows that the “hIL-10/Fc has a prolonged circulating half-life of about 30 h. More importantly, the hIL-10/Fc fusion protein displayed highly specific biological activity, which was slightly higher than that of the recombinant human IL-10 (rhIL-10). Therefore, P. pastoris is useful in the large-scale production of hIL-10/Fc fusion protein for both research and therapeutic applications (see abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the aCAR-T to further include a nucleic acid encoding a IL-10 homodimeric polypeptide as disclosed in Walter et al., which critical for cell-mediated immunity, with the IL-10 fusion protein as suggested in Guo, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because of potential: (i) benefits of engineering a fusion protein for therapeutic purposes to extend the half-life of the membrane bound protein and (ii) enhance stability with the expectation of creating an IL-10 fusion protein that is durable and effective across a variety of research and therapeutic applications. One of skill in the art would have been expected to have a reasonable expectation of success because prior art successfully reported showing hIL-10/Fc fusion protein displaying highly specific biological activity. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Iwaki et al (JBC, 2002, 277, 24315–24320) as evidenced by Goddard (US7696327, dated 04/13/2010), Dawson et al (Frontiers in Immunology, 2017, 8(3), 1-8)/ Sentman (WO2017058752, dated 04/06/20217) as evidenced by Rappl (PLoS One, 2012, 7, e30713, 1-10) and Choi (US 20180256744, 09/13/2018 and Walter (Curr Top Microbiol Immunol. 2014; 380: 191–212.), Guo et al (Protein Expression and Purification 83 (2012) 152–156). as applied above and further in view of Tsien et al. (WO 2000/071565).
The teaching of Iwaki, Dawson, Sentman /Dawson, Rappl and Choi, Walter and Guo have been described above and relied in same manner here. The combination of reference differs from claimed invention by not disclosing said homodimeric IL-10 comprises a first and a second IL-10 monomer connected in a single-chain configuration such that the C- terminus of the first IL-10 monomer is linked to the N-terminus of the second IL-10 monomer via a first flexible linker.
Tsien et al. teaches a linker moiety, wherein the length of the linker moiety is chosen to optimize the kinetics and specificity of responsiveness of the r polypeptide. Tsein teaches that the linker moiety should be long enough and flexible enough to allow the sensor polypeptide to freely interact and respond to a particular parameter. The linker moiety is, preferably, a peptide moiety. The preferred linker moiety is a peptide between about one and 30 amino acid residues in length, preferably between about two and 15 amino acid residues One preferred linker moiety is a -Gly-Gly- linker. The linker moiety can include flexible spacer amino acid sequences, such as those known in single-chain antibody research (see page 34). This meets the limitations of instant claim 19 wherein the IL-10 dimers contain a heterologous transmembrane intracellular stretch, wherein the IL-10 polypeptide comprises a flexible hinge region, wherein the IL-10 polypeptide has two dimers with the C terminus linked to the N terminus via a flexible linker.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the aCAR-T to further include a IL-10 homodimeric polypeptide as disclose din Walter et al., which critical for cell-mediated immunity, with the IL-10 fusion protein as suggested in Guo with the flexible peptide linker taught by Tsien et al. which gives polypeptides flexibility and functionality, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to combine the IL-10 membrane protein with the teachings of the engineered IL-10 fusion protein to enhance stability and the linker taught by Tsien with the with the expectation of creating an IL-10 membrane bound fusion protein that is durable and effective across a variety of research and therapeutic applications. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Iwaki et al (JBC, 2002, 277, 24315–24320) as evidenced by Goddard (US7696327, dated 04/13/2010), Dawson et al (Frontiers in Immunology, 2017, 8(3), 1-8)/ Sentman (WO2017058752, dated 04/06/20217) as evidenced by Rappl (PLoS One, 2012, 7, e30713, 1-10) and Choi (US 20180256744, 09/13/2018 and Walter (Curr Top Microbiol Immunol. 2014; 380: 191–212.), Guo et al (Protein Expression and Purification 83 (2012) 152–156), Tsien et al. (WO 2000/071565), Pule (WO 2015052538), Zimmerman et al. (WO 200189286) as applied above and further in view of Gross (WO/2003/106616, dated 12/24/2003).
The teaching of Iwaki, Dawson, Sentman /Dawson, Rappl and Choi, Walter and Guo have been described above and relied in same manner here. The combination of references differs from claimed invention by not disclosing that (i) said homodimeric IL-10 is linked to the transmembrane-intracellular stretch via a flexible hinge, and said flexible hinge comprises a polypeptide selected from a hinge region of CD8a, and a second flexible linker comprising an amino acid spacer of up to 28 amino acids and (ii) the transmembrane-intracellular stretch is derived from the heavy chain of a human MHC class I molecule.
Pule teaches a chimeric antigen receptor that binds the B cell maturation antigen as a treatment for multiple myeloma, (see page 1, lines 6-8). Pule teaches comprises an amino acid sequence for a human CD8α hinge region or human IgG1 hinge region (see page 15, line 6-10). Pule differs from claimed invention by not disclosing the second flexible linker.
Zimmerman teaches construct peptide spacer #4, which is a 100% sequence identity match to instant SEQ ID NO: 13. Zimmerman also teaches that “preferred spacer peptides include, for example, GGG, and GGGGS, however, the spacer may be made larger or smaller and altered to include other molecules or amino acids, besides the amino acid glycine, such as in GGGGS (see page 17-18). The teaching of Pule and Zimmerman meet the limitations in instant claim 21 wherein the references teach the use of CD8α hinge or IgG1 hinge region, the extracellular stretch, and second flexible linker, as required by the claim 21. The combination of reference differs from claimed invention by not disclosing the transmembrane-intracellular stretch is derived from the heavy chain of a human MHC class I molecule
Gross et al. teaches sequence of an MHC class I heavy chain HLA-A2 molecule protein. Gross discloses a peptide is linked to the full or partial transmembrane and/or cytoplasmic domain of a molecule selected from the group consisting of: (i) a human MHC class I molecule selected from an HLA-A, HLA-B or HLA-C molecule; (ii) a costimulatory B7.1, B7.2 OR CD40 molecule; and (iii) a signal transduction element capable of activating T cell (see claim 2-3).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the aCAR-T to further include a IL-10 homodimeric polypeptide as disclose din Walter et al., which critical for cell-mediated immunity, with the IL-10 fusion protein as suggested in Guo with the flexible peptide linker taught by Tsien et al. which gives polypeptides flexibility and functionality with the targeted intracellular stretch for human MHC class I molecules, specifically HLA-2A, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One would be motivated to combine the polypeptide with the linker and the intracellular stretch with the expectation of creating a functional IL-10 membrane bound fusion protein capable of directing cell activity. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Response to arguments
To the extent that Applicants’ arguments are pertinent to the new rejection of claims, they are addressed as follows:
Applicant disagree with the rejection arguing Claim 1 now recites having at least 90% sequence identity to SEQ ID NO: 64. SEQ ID NO: 12 is shown in the Office Action to have only 86.9% identity to SEQ ID NO: 64. Applicant assert that since SEQ ID NO: 12 of Goddard is the full length TLR2 extracellular domain-transmembrane domain, there is no motivation to add further sequence to it that could boost the percent identity over 90%. The rest of SEQ ID NO: 64 is the CAR backbone. Applicants’ arguments have been fully considered, but are not found persuasive.
In response it is noted that applicant’s amendments to the claim necessitated new ground of rejection that provide explicit motivation to include signal transduction element of CD3 zeta with CARs as suggested in prior art of Dawson and Rappl in view of Choi as discussed above. The resulting aCAR would be greater than 90% identical to SEQ ID NO: 64 or 66.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants' arguments are not compelling and do not overcome the rejection of record.
Conclusion
No claims allowed.
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.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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