DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09-10-2025 has been entered.
Status of the Claims
Claims 44-48, 50-54, 56-70, 72-77 are currently pending in the Application. As portion of the claims encompassing the SS1 antigen binding domain are allowable (as for example new claim 76), Examiner will move on to species of mesothelin “HN2” antigen binding domain represented by the SEQ ID NO: 188 for example. Examiner finds art for the claimed molecule therefore claim 74, which does not require either the SEQ ID NO: 186 or SEQ ID NO:188 or CDR regions thereof is withdrawn as directed to unexamined species. Therefore claims 50, 52-54, 56, 58-60, 62, 64-66, 72, 74 are currently withdrawn. Claims 44-48, 51, 57, 61, 63, 67-70, 75-77 are examined on the merits below.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 44, 47, 51, 57, 73, 75, 68-70 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson (US20180319862A1) and further in view of Feldman (US9359447). Instant claims 44, 47, 73 describes a chimeric co-stimulatory fusion protein comprising a particular mesothelin antigen binding domain as claimed and elected as the CDR 1-3, VH and CDR 1-3 VL of the SEQ ID NO: 186 or SEQ ID NO: 188 of the instant application, a transmembrane domain and an intracellular signalling domain comprising the SEQ ID NO: 25 and SEQ ID NO:32 as the complete intracellular domains of CD28 and CD40 respectively. Alternatively SEQ ID NO: 188 of the instant claims/application, embodiment (c) of the claim 44 and 51, 57, 75 is likewise examined as the “HN1” antigen binding domain of the disclosure of Feldman (SEQ ID NO: 12 scFv aligned below as 100% match).
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The disclosure of Thompson describes chimeric antigen receptor molecules which may have antigen binding domains directed to the mesothelin antigen (0021) as an antigen expressed by cancer cells (tumor). Thompson describes that mesothelin antigen ligand binding domain may be linked to a spacer which joins to a transmembrane domain (0022) and an intracellular signalling domain which is derived from the signalling domains of CD40 (0006) and additional signalling domain derived from CD28 for example (0012). The intracellular signalling domain may additionally comprise the signaling domain of CD3 zeta, or may not include any additional stimulatory signaling domain in addition to the CD40 and CD28 signaling domains (0011). Also see Thompson: claims 1-29 particularly claim 16, 17, 29; and [0471] and as applied to embodiment 107-117. Thus structurally the disclosure of Thompson discloses a chimeric receptor with [mesothelin antigen directed binding domain/CD28 extracellular domain/CD28 transmembrane domain/CD28 intracellular signaling domain/CD40 intracellular signaling domain]. Specifically no intracellular CD3zeta primary signalling domain is required. This is explicitly disclosed in as previously described and additionally referenced above. In regards to the intracellular signalling domains of CD40 and CD28 that are utilized (SEQ ID Nos: 32 and 25) as described above these are the identical intracellular signalling domains of the disclosure of Thompson as SEQ ID NO: 12 and 9. In regards to the antibody CDR sequences of the SS1 or HN1 mesothelin antigen binding domain the SEQ ID NO: 186 or alternatively SEQ ID NO: 188 of the disclosure of Feldman et al (USPAT9359447) utilizes a nearly identical (SS1) or identical (HN1) scFv molecule with identical CDR regions to that as are instantly claimed in 44 (a), (c) (see PE2E search) in the construction of a complete chimeric antigen receptor fusion protein. The SS1 (embodiment a) scFv thus comprises a single substitution prior to the occurrence of the VH variable CDR regions 1-3 and therefore satisfies the requirements of claim 44 (a) as antigen binding domain. With further regards to the particular sequence of the scFv mesothelin antigen binding domain claimed as Heavy and Light chain CDR 1-3 of the SEQ ID NO:186 as derived from the SS1 mesothelin antigen binding domain, the disclosure of Feldman describes (Col 3, 4-30) that mesothelin antigen binding domain as scFv molecules are utilized in chimeric antigen receptor molecules of the invention. An alignment of SEQ ID NO: 11 from the disclosure of Feldman with instant SEQ ID NO: 186 is provided attached to previous office action for Applicant as (2023-12-05_07-05-38) for simple illustrative and verification purposes. The aligned scFv molecules comprise 2 differences, one at the SEQ ID NO:186 residue 20, which is not in a CDR region of the scFv molecule as it precedes the VH chain CDR 1. The second residual difference is in the VH-VL GS linker region, and likewise not a CDR. Thus as applicant claims the CDR regions of the scFv molecule, not the entire sequence, with differences between the two sequences illustrated that are outside of the claimed sequences (CDR regions). It would be obvious to utilize the SS1 scFv of Feldman as an antigen binding moiety in the CAR of Thompson for purpose of utilizing a known previously disclosed functional component that has been successfully tested and incorporated into a CAR molecule. Thus considering the disclosure of Feldman and Thompson it would be obvious to construct a chimeric antigen receptor molecule with the claimed sequences and antigen binding domain for purposes of creating a functional chimeric receptor molecule which functions in a costimulatory manner utilizing known previously tested components.
With respect to the claim 47 which describes that the sequence ID NO:19 is additionally comprised in the amino acid sequence of the fusion protein. SEQ ID NO: 19 is essentially the extracellular and transmembrane domain of the native CD28 molecule. Thus claims 44+47 essentially a molecule that comprises a mesothelin binding domain (disclosed by Feldman), the entire native CD28 molecule and an additional CD40 intracellular signalling domain (disclosed by Thompson). Thus considering the disclosure of Feldman and Thompson it would be obvious to arrive at the claimed sequences, utilizing the CD28 native sequence of public database UNIPROT, P10747 as disclosed by Thompson and additionally the CD40 cytoplasmic signalling domain (P25942) for purposes of creating a CAR molecule with known previously disclosed sequences to create a functional costimulatory CAR molecule.
The claims 68-70 describe a cell which expresses a chimeric costimulatory receptor as described in claim 44. The applicant elects a TIL and that the cell additionally expresses a CAR molecule. The disclosure of Feldman and Thompson describe the structural components of the Costar molecule as indicated above. The disclosure of both Feldman (12, 35-50) and Thompson (0180) describe that T cells and particularly tumor infiltrating lymphocytes (TIL) are potential targets for chimeric receptors/systems of the invention and as primarily T cells are an expected target for chimeric receptor systems. What is implied by the structural components of the claimed receptor system of instant claim 70, amounts to what might essentially comprise a split receptor system in which a CAR , which may express an ITAM domain intracellular signalling domain to provide a “first signal” to a T cell on a first engineered signalling molecule (Thompson 0164,0372). The disclosure of Thompson further describes that in some embodiments a CAR may include activating domains providing a first signal (e.g. CD3 zeta) is included in one CAR while a required costimulatory signalling component is provided by a second CAR recognizing a different antigen (0137-0138). Such “split” chimeric antigen receptor systems thus allow further tuning of chimeric antigen receptor signalling systems in which binding of (2) separate antigens are required for recipient cell activation (a TIL T cell for example). Thus allowing effector cells to further differentiate between tumor cells which may express both target antigens and normal cells which may only express one or the other antigen. It would thus be obvious considering the disclosure of Thompson and Feldman to create such a CAR system (Costar-CAR system) to beneficially selectively target tumor cells.
Claims 45 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson and Feldman as applied to claim 44 above, and further in view of Burger et al (US7507412) and Tanaka (WO2016127257). The disclosures above do not describe a fusion protein with a signaling component (leader) sequence that is identical to the SEQ ID NO: 19. However the disclosure of Burger describes fusion proteins that are expressed and utilize the SEQ ID NO: 12 (identical to the instant SEQ ID NO: 1 OSM signal peptide as a preferred signal peptide sequence (col 7, 5-45). Likewise the disclosure of Tanaka discloses preferred signal peptide which are utilized in chimeric antigen receptor molecules as comprising an oncostatin M signal peptide (000111, Example 1). It would therefore be obvious to utilize a known leader sequence (“signal peptide”) when wanting to produce a fusion protein for purposes of successfully targeting and ultimately providing for appropriate amounts and targeting of a desired protein. One of ordinary skill in the art would utilize known sequences from previous described leader sequences in the art for the purposes of successfully producing such a fusion protein as the applicant has thus done.
Claim 48, 67 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson and Feldman as applied to claim 44 above, and further in view of Lee (Immunity 2015 August 18; 43(2): 227-239. Doi:10.1016). The above disclosures do not describe the exact sequence of SEQ ID NO: 18 (AAAGSGGSG), 9 amino acids as an appropriate linker to utilize between the antigen binding domain and downstream functional components (extracellular-transmembrane-cytoplasmic) in a Costar molecule for example. The disclosure of Lee is concerned with determination of the mechanical switch mechanism which is engaged upon TCR binding to cognate ligands. The disclosure of Lee describes flexible linker sequences utilized to separate functional components of fusion proteins involved in signalling of the TCR complex (p5). One such linker utilized is identical to the sequence of SEQ ID NO:8 (supplemental contents, figure 2B) and it would be obvious to utilize known functional linker/spacer sequences as described by Thompson (0084,0157) for the purpose of separating components of the antigen binding molecule from the downstream components and providing optimal distance between the engaged fusion receptor and the target cell antigen.
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 44-48, 51, 57, 67-70, 73, 75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 13, 16, 26 of copending Application No. 17361621 in view of Thompson, Feldman, Lee and Burger and Tanaka as applied above. The aforementioned claims of the pending reference application broadly describe a Costar molecule which is comprised of for example a tumour associated antigen binding domain, a first costimulatory binding receptor (complete receptor) linked to a second intracellular costimulatory signalling domain. The claim 4 describes that the costimulatory domain may be derived from the CD28 and/or CD40. Thus the reference claims broadly describe for example a [ScFv(cancer antigen)-CD28(complete molecule)-CD40(intracellular costimulatory signalling domain)]. The disclosure of Thompson/Feldman/ for example further account for the scFv cancer antigen binding domain as mesothelin directed, with the disclosure of Lee accounting for the instant claimed linker between the scFv and first costimulatory molecule, and the disclosure of Burger accounting for the use of the N-terminal OSM derived signal peptide. Thus it would be obvious to construct the instantly claimed Costar molecule solely through the consideration of the reference claims and substantially simple substitution of the “tumour associated antigen specific binding domain” with the MSLN directed antigen binding domains of or Feldman and Thompson as a known cancer antigen for the purposes of creating a MSLN directed Costar molecule as described in the reference application for the purposes of treating a cancer with a cell (claim 13, 16) transduced with an expression construct as claimed in the reference application (claim 23 for example).
Claims 44-48, 51, 57, 67-70, 73, 75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-14 of U.S. Patent No. 11945876 in view of Thompson, Feldman, Lee and Burger and Tanaka as applied above.
The reference claim 1 describes a costar molecule comprising a [CEA (cancer antigen)-ICOS(entire costimulatory molecule)-CD40(intracellular costimulatory domain)]. The disclosure of Thompson and Feldman describe the Mesothelin molecule as a cancer antigen that is in the same category that may be targeted by chimeric antigen receptors such and provides the specific antigen binding domains that are instantly claimed as referenced above (and PE2E sequence search). (Thompson 0021, CEA/mesothelin; 00148). The utilization of the entire CD28 molecule in place of the ICOS of the reference application is likewise made obvious by the disclosure of Thompson which describes CD28 as closely related costimulatory receptor similar to the ICOS and utilized in combination with CD40 as described above. The further details of the instant dependent claims (for example 45-48) such as the exact linker and signal peptide are accounted for by the additional references of Lee and Burger as detailed above.
Claims 44-48, 51, 57, 67-70, 73, 75 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1, 17-20, 23-26, 55-70 of copending Application No. 17843480 in view of Thompson, Feldman, Lee, Burger and Tanaka as applied above. The disclosure of the reference application (claim 1) describes a Costar molecule which comprises: [mov19scFv (directed to FOL1Ra cancer antigen)-CD28(entire molecule in embodiments)-CD40 intracellular signalling domain)]. The linker sequences and signal peptide of instant claims 45-48 are disclosed as reference claims 19 (SEQ ID NO:8-linker) and 58 (SEQ ID NO:1-signal peptide OSM). Thus the difference between the instant application claims and the reference application are the incorporation of a scFv directed to the mesothelin molecule (instant application) opposed to a Folate receptor 1a directed scFv in the reference application. Considering the disclosure of Feldman which disclose that the Mesothelin and Folate-ra molecules are cancer antigen targeted by costimulatory CAR molecules/CAR molecules (Feldman/ ) (0121/00150) it would be obvious to replace the scFv binding domain of the reference application with one which binds to the cancer antigen Mesothelin molecule as specific Mesothelin directed scFv as disclosed by Feldman for purposes of creating a similar Costar molecule directed to recognized cancer antigen mesothelin utilizing mesothelin binding domains previously disclosed as used in functional CAR molecules.
Claims 44-48, 51, 57, 67-70, 73, 75 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1-13 of U.S. Patent No. 12187778 in view of Thompson, Feldman, and Burger and Tanaka as applied above.
The claims of the reference patent (claim 1) describes a Costar molecule which comprises: [“196-14” scFV (directed to the MUC16/CA125 antigen)-CD28(entire molecule in embodiments)-CD40 intracellular signalling domain)]. The linker sequences and signal peptide of instant claims 45-48 are disclosed as reference claims 19 (SEQ ID NO:8-linker) and the disclosure of Burger (SEQ ID NO:1-signal peptide OSM). Thus the difference between the instant application claims and the reference application are the incorporation of a scFv directed to the mesothelin molecule (instant application) opposed to a Folate receptor 1a directed scFv in the reference application. Considering the disclosure of Feldman and which disclose that both the Mesothelin and CA125/MUC16 molecules are cancer antigen targeted by costimulatory CAR molecules/CAR molecules (Feldman/ ) (0121/00150) it would be obvious to replace the scFv binding domain of the reference application with one which binds to the cancer antigen Mesothelin molecule as specific Mesothelin directed scFv as disclosed by Feldman and (see PE2E sequence search) for purposes of creating a similar Costar molecule directed to recognized cancer antigen mesothelin utilizing mesothelin binding domains previously disclosed as used in functional CAR molecules.
In summary, the reference applications/patent in embodiments describe “Costar” molecules and nucleic acid encoding said molecules, expressed as proteins in cells which aside from the specific antigen binding domain comprise the same additional components/Sequence constructions as the instantly claimed molecule. Thus particularly the disclosure of Feldman and which describe the scFv SS1 and single amino acid substitution variant which binds the mesothelin molecule and as necessary Thomson, Lee and Burger and Tanaka which describes signalling components, linkers and signal peptides make obvious the instantly claimed material in view of the reference application claims as explained above for the instant claims.
Claim Objections
Claims 61, 63, 76 are 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.
Allowable Subject Matter
Claim 77 is allowed.
Response to Arguments- Claim Rejections - 35 USC § 103
Applicant extensively describes that the disclosure of Burger utilizes a signal peptide derived from Oncostatin M for the purposes of providing a secreted protein product. Thus Applicant extensively describes that there is no motivation therefore to provide a chimeric antigen receptor molecule which may comprise the Oncostatin M signal peptide as indicated in instant claim 44, 45,46. Applicant thereby describes that there is no reasonable expectation of success in using this signal peptide in a “CoStar” molecule. Initially it is noted that the signal peptide thus incorporated into the claims 45, 46, does not actually have to perform a function. Thereby it may of insert the CAR into a membrane or excrete the CAR into the extracellular space. Either option is possible based on the claim dependency. Thus the Oncostatin M peptide simply must perform as a “signal peptide” which the sequence of Burger therefore does. Possibly the Applicant would like the CAR secreted and/or inserted into the membrane. However , to satisfy Applicant’s concerns, and without extensively presenting the logistics of cellular protein trafficking which is beyond the scope of the office actions, the further disclosure of Tanaka provides CAR molecules which comprise antigen binding domain, transmembrane domain and intracellular signalling costimulatory/activation domains (abstract, Figure 1, for instance). Specifically the disclosure utilizes a human Oncostatin M protein signal peptide as the preferred signal peptide for production of membrane anchored (transmembrane domain) CD19 directed CAR molecules (000111, Example 2, 000152-000154). Surface expression of the CAR on T cells utilizing SP-Oncostatin protein signal sequences. The critical component for cellular membrane insertion appears to be the transmembrane domain, once the SP indicates delivery to the ER, Golgi apparatus.
Applicant further utilizes a similar argument with regards to the claimed “spacer/linker” element of claim 48 /67 (AAAGSGGSG, SEQ ID NO:18) for example disclosed by the reference of Lee as an intracellular membrane proximal spacer/linker is not reasonably expected to be utilized as an extracellular spacer domain with a reasonable expectation of success. Applicant appears to thereby describe that the invention is ultimately critically involved with this short linker sequence which is inserted in various constructs C terminal to the scFv binding moiety of the costimulatory receptor construct. Applicant’s arguments have been fully considered but are not found convincing. The Applicant has utilized the exact same biological sequence intended to perform the same function “linker” or “spacer” as in the cited reference. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) (discussed below and in MPEP § 2144) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. MPEP 2144.09 I. See also MPEP § 2144.08, subsection II.A.4.(c). In the instant case, Applicant claims the exact amino acid sequence (structure) that is utilized in the reference of Lee. The fact that the spacer is utilized extracellularly does not appear to the Examiner to impart any further characteristics and at worst the intracellular spacer configuration would be expected to be at least be reasonably “similar” functionally when compared to the same sequence expressed extracellularly , and as Applicant admits in the claim , the intended function is that of a linker/spacer.
Moving on, Applicant further claims unexpected results regarding the combination of CD28 and CD40 costimulatory domains when compared to other costimulatory signalling domains, particularly regarding the information presented in Figure 25. Applicant provides that none of the references , particularly that of Thompson illustrate functionality/reduction to practice of the disclosed chimeric molecules/systems which incorporate CD28/CD40 CAR molecules for example. Regarding reduction to practice of the disclosed invention while this is relevance to instant claims with respect to 112 and written description requirements it is not a requirement for the AIA FITF framework and section 103 findings of obviousness. The inventors of Thompson contemplate heterodimeric signalling chimeric receptor complexes and are thus well aware of the concept of split CAR systems in which primary signalling and co-stimulatory accessory domains are found on separate polypeptide chains (Thompson; 0176, 0391). Regarding the purported unexpected results with respect to figure 25 briefly as previously presented the constructs of the figure are targeting a CEA antigen (through mfe-23 antigen binding domain) and do not therefore comprise a particular mesothelin antigen binding domain of the instant claims (SS1 as the examined species). Thus the CTP190 and CTP192 are comparable in composition of the CAR to each other but are not what is instantly claimed. It is additionally noted that the CTP192 (4-1BB-CD40) data appears to include no error bars, making comparison between different conditions difficult. As MPEP 716.02(d) indicates “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support. Furthermore even if the disclosed figure indicates that CD28-CD40 provides superior proliferative results compared to for example 4-1BB-CD40 constructs, explanations for the differences exist. The 4-1BB and CD40 intracellular signalling domains are both known to recruit TRAF proteins to the receptor interface. CD28 on the other hand is unrelated to the TNSFR superfamily molecules and recruits a separate entourage of intracellular signalling accessory molecules to the receptor intracellular interface, ultimately activating separate and unique T cell activation cascades. Therefore one may in fact expect that the synergistic effect of the CD28-CD40-CD3zeta T cell activation cascade would be superior to that of a 4-1BB-CD40-CD3zeta T cell activation cascade in which marginally 4-1BB and CD40 activate the same downstream signals, and potentially compete for limited TRAF molecules at the receptor interface. Finally as previously indicated/presented the disclosure of Thompson clearly describes CD40/CD28 comprising CAR molecules. Thompson/Feldman makes obvious targeting the mesothelin antigen with a SS1 based chimeric receptor. Any superior performance of a CD28/CD40 chimeric receptor molecule/system may be attributed as a latent property of the molecule made obvious by the disclosure of Thompson for example. Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979)(MPEP 2145 II).
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/BRIAN HARTNETT/ Examiner, Art Unit 1644
/JANET L ANDRES/ Supervisory Patent Examiner, Art Unit 1671