DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment of 3/27/26 has been entered in full. Claims 1, 3, 7, 11-12, 16-19 and 21 are amended. Claims 2, 4-6, 8-10 and 13-15 are canceled. Claims 1, 3, 7, 11-12, 16-19 and 21 are pending and under consideration.
Withdrawn Objections and/or Rejections
The following page numbers refer to the previous Office Action (11/28/25).
The objections to the specification at pages 1-2 are withdrawn in view of the amendments to the specification, except as noted below.
All rejections of canceled claims 2, 4-6, 8-10 and 13-15 are moot.
The rejection of claim 17 at page 8 under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn in view of the amendments to the claims.
The rejection of claims 18 and 19 at pages 3-7 under 35 U.S.C. 112(a) as failing to comply with the written description rejection is withdrawn in view of the amendments to the claims that limit the scope of claims 18 and 19 to a CAR comprising the sequence of SEQ ID NO: 13, 14 or 15.
The rejection of claims 1, 3, 7, 11-12, 19 and 21 at pages 9-12 under 35 U.S.C. 102(a)(1) as being anticipated by Feldman et al, U.S. Patent Application Publication 20150031624, published 1/29/15, is withdrawn in view of the amendments to the claims that limit the CAR to comprising an IgG4 hinge, which is not taught by Feldman.
The rejection of claims 16-18 under 35 U.S.C. 103(a) as being unpatentable over Feldman et al, U.S. Patent Application Publication 20150031624, published 1/29/15, as applied to claim 1, and further in view of Brown et al, U.S. Patent Application Publication 20160340649, published 11/24/16, is withdrawn in view of the claim amendments that limit the CAR to comprising an IgG4 hinge, which is not taught by Feldman or Brown.
Maintained Objections and/or Rejections
Specification
In the 11/28/25 Office action, the disclosure was objected to on several grounds. Applicants’ reply filed on 3/27/26 includes amendments to the specification that overcome the objections to the specification, except for the following:
“SEQ ID NO: 1 is also identified as being from “SS1” in the sequence listing and this should also be corrected” (page 2).
Applicants have removed the references to SEQ ID NO: 1 being erroneously referred to as “SS1” from the specification, but not from the sequence listing. As such, this ground of objection is maintained.
Claim Rejections - 35 USC § 112(a), written description
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, 3, 7, 11-12, 16 and 17 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection was set forth at pages 3-7 of the 11/28/25 Office Action.
In the reply at pages 10-11, Applicants indicate that the claims have been amended to limit the scope of the CAR to one comprising an scFv having defined light and heavy chain variable regions and that such subject matter was indicated, in the rejection of record, as meeting the written description requirement, and therefore the rejection should now be withdrawn.
This argument has been fully considered but is not found persuasive for the following reasons. The rejection of record indicated that a CAR comprising “an scFv comprising a light chain variable region having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region having the amino acid sequence of SEQ ID NO: 3” met the written description provision. Applicants have amended independent claim 1, but using different language, that recites “having an amino acid sequence of SEQ ID NO: 1” and “having an amino acid sequence of SEQ ID NO: 3”. Notably, the scope of such language is different from the scope of the language indicated as meeting the written description provision.
Specifically, proteins are frequently claimed using open language and "an" or "the" to refer to sequences identified by SEQ ID NOs, as in the following two examples: "A protein comprising the amino acid sequence of SEQ ID NO: 1" or "A protein comprising an amino acid sequence of SEQ ID NO: 1". These two phrases result in claims of very different scope, because while the former claims only proteins that comprise the full length of SEQ ID NO: 1, with or without additional amino acids at either or both ends, the latter encompasses proteins that comprise the full-length sequence of SEQ ID NO: 1 or any portion of SEQ ID NO: 1; i.e., fragments of SEQ ID NO: 1. The language used in claim 1 corresponds to the latter example; and thus the recitation of “a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 1” encompasses a light chain variable region comprising any fragment of SEQ ID NO: 1 of two amino acids or more, and the recitation of “a heavy chain variable region (VL) having an amino acid sequence of SEQ ID NO: 3” encompasses a heavy chain variable region comprising any fragment of SEQ ID NO: 3 of two amino acids or more
As such, the claims as amended remain genus claims because they encompass a genus of chimeric antigen receptors (CARs) having the required functionality, i.e., binding to MSLN. The rejection of this genus is maintained for the reasons set forth previously in the rejection of record. Note that this rejection could be overcome if the claims were amended to limit the “a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 1” and “a heavy chain variable region (VL) having the amino acid sequence of SEQ ID NO: 3”.
Note: Claims 18, 19 and 21 are not included in the because claim 18 limits the CAR such that “the CAR comprises SEQ ID NO: 13, 14 or 15”, which requires the entirety of one of the referenced amino acid sequences, each of which are fully described in the specification; see Table 1 on pages 22-23. Claims 19 and 21 are directed to polynucleotides (claim 19) or cell (claim 21) encoding the CAR of claim 18.
New rejections necessitated by Applicants’ amendment
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 16-19 and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 16, as amended, depends from canceled claim 13. As claim 16 depends from a canceled claim, the scope of claim 16 cannot be determined, and thus is indefinite. For purposes of advancing prosecution, claim 16 will be broadly interpreted as depending from independent claim 12.
The remaining claim(s) included in the rejection are dependent claims that depend from one of the claims rejected above, and encompass the same indefinite subject matter.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 at the time any inventions covered therein were effectively filed 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 at the time a later invention was effectively filed 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 1, 3, 16 and 17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Feldman et al, U.S. Patent Application Publication 20150031624, published 1/29/15 (cited on 12/21/23 IDS), as applied to claims 1 and 2 above, and further in view of Jensen et al, U.S. Patent Application Publication 2015/0306141, published 10/29/25 (cited previously) and further in view of Kaneko et al, 2009. Journal of Biological Chemistry. 284(6): 3739-3749 (cited previously).
Claim 1 as amended encompasses a chimeric antigen receptor (CAR) that binds to at least one epitope of mesothelin, and comprises “an scFv comprising a light chain variable region (VL) having an amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (VL) having an amino acid sequence of SEQ ID NO: 3”; an “IgG4 hinge having an amino acid sequence of SEQ ID NO: 6”; and a “CD28 transmembrane domain having an amino acid sequence of SEQ ID NO: 9”. An scFv comprising light and heavy chain variable regions having an amino acid sequence of SEQ ID NO: 1 and 3 comprises any two or more amino acids of SEQ ID NO: 1 and 3 (see above, in the section titled “Claim Rejections - 35 USC § 112(a), written description”), and as such encompasses the light and heavy chain variable regions of the antibody SS1. Likewise, an IgG4 hinge “having an amino acid sequence of SEQ ID NO: 6” and CD28 transmembrane domain “having an amino acid sequence of SEQ ID NO: 9” encompass, respectively, any fragment of SEQ ID NO: 6 and 9 of two or more amino acids.
The ‘624 publication is titled, “Anti-Mesothelin Chimeric Antigen Receptors”, and further teaches “The CARs of the invention having antigen specificity for mesothelin” (¶ 12) by including antibodies “that specifically recognize and binds to human mesothelin” (¶ 14). ‘624 further teaches that the CAR of the invention includes an scFv, e.g., at ¶ 14, which further may comprise a light and heavy chain variable region of SS1 (¶ 15). ‘624 further teaches that the CAR of the invention may include a CD28 transmembrane domain, including that of SEQ ID NO: 14, which comprises amino acids 2-27 of the 27 amino acids of SEQ ID NO: 9 (¶ 18). As such, ‘624 teaches all of the limitations of claim 1 as amended, except that ‘624 does not teach that the CAR comprises an IgG4 domain having an amino acid sequence of SEQ ID NO: 6.
‘141 teaches chimeric antigen receptors, including a spacer that “provides for enhanced T cell proliferation and/or cytokine production as compared to a reference chimeric receptor” (¶ 8). ‘141 teaches that the spacer is “between the ligand binding domain and the transmembrane domain of the chimeric receptor” and “provides for flexibility of the ligand binding domain” (¶ 93). ‘141 further teaches that “[i]f the epitope is located distal to the membrane, an intermediate or short spacer is selected (e.g. 119 amino acids or less or 12-15 amino acids or less)” (¶ 104). The spacers include “an intermediate sequence” that is “a IgG4 hinge sequence with a CH3 sequence having 119 amino acids or less (SEQ ID NO: 49)” (¶ 100), with SEQ ID NO: 49 comprising a sequence that is 100% identical to a combination of the IgG4 hinge domain of instant SEQ ID NO: 6 (6 amino acids) followed by the “Intermediate spacer” of instant SEQ ID NO: 7 (113 amino acids).
Kaneko teaches that the antibody SS1 binds to the same domain on mesothelin as the protein CA125 (also known as MUC16) and this is “a region of 64 amino acids at the N-terminal of cell surface mesothelin” (see Abstract).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to take the CAR that comprises a binding domain specific to mesothelin taught by ‘624 and modify it to include a spacer as taught by ‘141 and further to select an intermediate spacer in view of the teachings of Kaneko that the SS1 antibody binds to the N-terminus of mesothelin. The person of ordinary skill in the art would have been motivated to make such a change in order to employ the advantages of the spacer region taught by ‘141, including enhanced T cell proliferation and/or cytokine production, and would have chosen the “intermediate sequence” of ‘141 in view of the binding sequence of SS1 being distal to the membrane. The person of ordinary skill in the art would have had a reasonable expectation of success in conferring said advantages to the CAR of ‘624 because ‘141 teaches that the spacer is generally applicable to any CAR of interest.
Claim 3 as amended encompasses the CAR of claim 1, “wherein the signal peptide comprises a GM-CSFR signal peptide”. ‘624 further teaches that the antigen binding domain of the invention may comprise a leader sequence that is a GM-CSF receptor sequence (¶ 17). As such, it would have further been obvious to include such an embodiment as part of the CAR obvious over the teachings of ‘624 in view of ‘141 and Kaneko described above.
Claims 7, 11 and 12 are rejected under 35 U.S.C. 103(a) as being unpatentable over Feldman et al, U.S. Patent Application Publication 20150031624, published 1/29/15 (cited on 12/21/23 IDS), as applied to claims 1 and 2 above, and further in view of Jensen et al, U.S. Patent Application Publication 2015/0306141, published 10/29/25 (cited previously) and further in view of Kaneko et al, 2009. Journal of Biological Chemistry. 284(6): 3739-3749 (cited previously), and further in view of “Cloning of scFv fragments” (Antibody Design Laboratories, 2014. No author listed; 4 pages as printed from https://www.abdesignlabs.com/technical-resources/scfv-cloning/).
Claim 7 encompasses a CAR of claim 3 wherein the scFv comprises a (G4S)4 linker connecting the VL and the VH. ‘624 further teaches that the antigen-binding domain comprises a linker (¶ 16), which may connect the heavy and light chain variable domains (¶ 16). ‘624 further teaches that the linker may comprise SEQ ID NO: 7, which is a (G4S)3 sequence. ‘624 does not teach a linker that is a (G4S)4 linker.
The “Cloning of scFv fragments” webpage teaches the production of scFv molecules, and teaches the following regarding linkers:
“Linker length
Once the domain orientation has been chosen, a linker must be designed. It is now well-established that linkers too short will prevent the physical association of the two domains and lead to the formation of multimers (diabodies, tribodies, etc.) while linkers too long may favor proteolysis or weak domain association. Linkers of length between 15 a.a. and 20 a.a. are most often used. Some people have argued that the upper range, 18 a.a. to 20 a.a., is better to prevent the formation of dimeric forms” (page 1).
“Linker sequence
Many linker sequences if not most of them are multimers of the pentapeptide GGGGS (or G4S or Gly4Ser). Those include the very popular 15-mer (G4S)3 found in some of the first scFv fragments (Huston et al., 1988), the 18-mer GGSSRSSSSGGGGSGGGG (Andris-Widhopf et al., 2011) and the 20-mer (G4S)4 (Schaefer et al., 2010). Many other sequences have been proposed, including sequences with added functionalities, e.g. an epitope tag or an encoding sequence containing a Cre-Lox recombination site (Sblattero & Bradbury, 2000) or sequences improving scFv properties, often in the context of particular antibody sequences.”
It would have further been obvious to the person of ordinary skill in the art before the effective filing date that when producing the modified CAR that is obvious in view of the teachings of ‘624, ‘141 and Kaneko (as described above), to further modify the CAR to include a (G4S)4 linker as taught by the “Cloning of scFv fragments” in place of the (G4S)3 linker taught by ‘624. In view of the teachings of the “Cloning of scFv fragments” webpage, the person of ordinary skill in the art would have recognized that (G4S)4 linker, having a length of 20 amino acids, would have superior properties with respect to prevention of formation of dimeric forms, and thus would have been motivated to replace the (G4S)3 linker used by ‘624 with such a linker. The person of ordinary skill in the art would have had a reasonable expectation of success because the “Cloning” webpage is directed generally for application to any scFv of interest. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
Claim 11 encompasses the CAR of claim 7, “wherein the costimulatory domain comprises a 4-1BB costimulatory domain”. ‘624 further teaches that the CAR of the invention includes a 4-1BB co-stimulatory domain (¶ 19). As such, it would have further been obvious to include such an embodiment as part of the CAR obvious over the teachings of ‘624 in view of ‘141, Kaneko and the “Cloning” webpage described above.
Claim 12 encompasses the CAR of claim 2, “wherein the effector domain comprises a CD3ζ effector domain”. ‘624 further teaches that the CAR of the invention includes a CD3ζ (CD3 zeta) domain (¶ 19). As such, it would have further been obvious to include such an embodiment as part of the CAR obvious over the teachings of ‘624 in view of ‘141, Kaneko and the “Cloning” webpage described above.
Claims 16 and 17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Feldman et al, U.S. Patent Application Publication 20150031624, published 1/29/15 (cited on 12/21/23 IDS), as applied to claims 1 and 2 above, and further in view of Jensen et al, U.S. Patent Application Publication 2015/0306141, published 10/29/25 (cited previously) and further in view of Kaneko et al, 2009. Journal of Biological Chemistry. 284(6): 3739-3749 (cited previously), and further in view of “Cloning of scFv fragments” (Antibody Design Laboratories, 2014. No author listed; 4 pages as printed from https://www.abdesignlabs.com/technical-resources/scfv-cloning/), and further in view of Brown et al, U.S. Patent Application Publication 20160340649, published 11/24/16.
Claims 16 and 17 encompass the CAR of claim 13 (now canceled, but for purposes of advancing prosecution interpreted as claim 12), wherein the CAR further comprises a truncated form of CD19 (CD19t) comprising an amino acid sequence set forth in SEQ ID NO: 12 (claim 16) and further comprising a T2A sequence between the CD19t and the CD3ζ effector domain, wherein the T2A sequence comprises an amino acid sequence set forth in SEQ ID NO: 11 (claim 17).
The references of ‘624, ‘141, Kaneko and the “Cloning” webpage do not further teach that the CAR further comprises a truncated form of CD19 (CD19t) of SEQ ID NO: 12 or that the CD19t is CD3ζ effector domain by a T2A sequence of SEQ ID NO: 11.
‘649 teaches an improvement to a CAR that “[c]an be produced using a vector in which the CAR open reading frame is followed by a T2A ribosome skip sequence and a truncated CD19 (CD19t), which lacks the cytoplasmic signaling tail (truncated at amino acid 323). In this arrangement, co-expression of CD19t provides an inert, non-immunogenic surface marker that allows for accurate measurement of gene modified cells, and enables positive selection of gene-modified cells, as well as efficient cell tracking and/or imaging of the therapeutic T cells in vivo following adoptive transfer” (¶ 53). For CD19t, ‘649 further discloses the “323 amino acid CD19t sequence (SEQ ID NO: 9”) (¶ 94), which is 100% identical to the 323 amino acids of instant SEQ ID NO: 12, and for T2A, ‘649 further discloses the “24 amino acid T2A sequence (SEQ ID NO: 8)” (¶ 94), which is 100% identical to the 24 amino acids of instant SEQ ID NO: 11.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to take the CAR obvious over the teachings of ‘624, ‘141, Kaneko and the “Cloning” webpage that meets the limitations of claim 12 and further modify it to include a CD19t polypeptide marker as taught by ‘649, and separated by a T2A sequence as further taught by ‘649. The person of ordinary skill in the art would have been motivated to make such further changes to the modified CAR in order to employ the advantages taught by ‘649 with respect to expression in T cells, including employing the CD19t as “an inert, non-immunogenic surface marker that allows for accurate measurement of gene modified cells, and enables positive selection of gene-modified cells, as well as efficient cell tracking and/or imaging of the therapeutic T cells in vivo following adoptive transfer” (¶ 53 of ‘649). The person of ordinary skill in the art would have had a reasonable expectation of success because, in the absence of evidence to the contrary, the CD19t polypeptide marker would provide these advantages to the CAR specifically binding to mesothelin in the same manner as to the CAR taught by ‘649. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
Conclusion
No claims are 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 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated-interview-request-air-form.
/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
Prosecution Insights