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 .
Receipt is acknowledged of Applicant’s Remarks and Arguments filed on 05/27/2025.
Claims 1, 2 and 4 are pending and presented for examination.
Response to Declaration under C.F.R. S 1.132
Applicants have submitted a Declaration of Sellmyer under 37 CFR 1.132, and assert that said declaration demonstrates the differences between the composition obtained when E.coli dihydrofoloate (eDHFR) is incorporated int a mammalian cell, and the composition of the instant application.
Applicant’s Declaration filed 05/27/2025 has been fully considered, but is not persuasive for overcoming the rejection. The Declaration states that the incorporation of E.coli dihydrofolate (eDHFR) into mammalian T-cells of June could trigger an immunogenic response; however, it is not clear if this the same E.coli dihydrofolate (eDHFR) and chimeric antigen receptor (CAR) of June, why it would trigger immunogenic response. As there is a similar structure in the contemplated composition and the composition of the prior art, there is a reasonable expectation that the composition will have similar properties of the instant application. Additionally, the Declaration does not state what are the components and amounts of “Applicant’s composition”, so it cannot be determined how Applicant’s composition differs from that of prior art combination. While the Declaration provides a visual comparison with “Applicants composition”, the Declaration does not provide any information regarding the components of Applicant’s composition”, or how it correlates with the composition of the claims. Furthermore, because applicants claim a composition, the disclosure in prior art may read on applicants claims for the composition, it is not necessary for the prior art reference to disclose the efficacy or toxicity of an adoptive cell therapy in vivo the composition. Furtthermore,any suggestion of non-obviousness by the opinion or any data is not commensurate in scope with the instant claim, with is drawn to any cell, having any CAR, and a broadly defined ligand binding domain.
Any previous rejections and/or objections not reiterated herein have been withdrawn in view of arguments filed on 05/27/2025. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over June et al. (US 8,911,993) in view of Fred A.M. Asselbergs et al. (Journal of Biotechnology, 43, 133-138, 1995) and Marek Sellmyer et al. (J. Nucl Med, 56, 2015) are maintained for reasons of record in the previous office action filed on 01/08/2025.
June discloses compositions and methods for treating cancer in a human. The method includes administering a genetically modified T cell to express a CAR wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain (abstract). In one embodiment, the antigen binding domain in the CAR is an antibody or an antigen-binding fragment thereof. In one embodiment, the cell comprising the CAR is selected from the group consisting of a T cell, a Natural Killer (NK) cell, a cytotoxic T lymphocyte (CTL), and a regulatory T cell (Col. 2 line 39-41). Additional disclosure includes that the genetically engineered T cells comprise at least one cell selected from the group consisting of a T cell that was administered to the human, a progeny of a T cell that was administered to the human, and a combination thereof.
June fails to disclose chimeric antigen receptor (CAR) comprising E.coli dihydrofolate reductase (eDHFR) ligand binding domain capable of binding to a radiolabeled tracer.
Asselbergs discloses the demonstration of the chromosomal dhfr of Escherichia coli as marker in mammalian cells and that it retains its sensitivity to methotrexate (MTX) and trimethoprim (TMP). Transfection of the dhfr expression plasmids was done using lipofectin and intracellular DHFR was visualized by labeling the living cells with FITC-labeled MTX. The cells were split to 2-5 X 105 ml-1 MEM-alpha with nucleosides and 4% dialyzed FCS containing 3 mM FlTC-methotrexate (page 134-135).
PNG
media_image1.png
273
572
media_image1.png
Greyscale
As E. coli cells carrying this plasmid were resistant to 10ug per ml TMP, the resulting plasmid, pBRdhfr expressed considerable amounts of DHFR apparently from the promoter of the pBR322 tetracycline gene. As evidence, Sellmyer shows that [11C]TMP is a radiotracer specific for Ec DHFR that yields over two-fold signal induction in xenografted tumor (abstract). In contrast, bacteria carrying the promoterless plasmid pTP8-51 were sensitive to TMP (page 135). Additional disclosure includes that when a dhfr-host cell is used, it is conceptionally even possible to use the two dhfr genes sequentially. In this scheme, dhfr-cells are first transfected with the folA dhfr gene and selected for dhfr expression in a medium rendering cell dependent on dhfr expression. Subsequently, the procedure is repeated with a mammalian dhfr gene, but selection is repeated in the presence of TMP, to which the mammalian DHFR is insensitive.
It would have obvious to one of ordinary skill in the art at the time the invention was made to incorporate E.coli dihydrofolate reductase (eDHFR) ligand binding domain into T cell to express a CAR composition of June. The person ordinary skill in the art would have been motivated to make those modifications because Asselbergs teaches that it is possible to use the folA dhfr gene as an efficient selection marker in mammalian cells and that, in contrast to the plasmid- or transposon-derived TMP and MTX-resistant bacterial DHFR proteins previously expressed in mammalian cells, the folA DHFR remains inhibitable in its new environment by these DHFR antagonists and reasonably would have expected success because TMP can also presumably be used to select for increased copy number of the transfected gene(s), which costs 100-fold less than MTX, the use of the folA dhfr gene as selective marker for mammalian cells might present in a number of situations advantages over the use of a mammalian dhfr gene.
Applicant arguments filed on 05/27/2025 have been fully considered but they are not persuasive. Applicant argues that office has failed to identify a reason to combine the chimeric antigen receptor (CAR) of June with the ligand binding domain of E.coli dihydrofolate reductase (eDHFR) of Asselbergs. This argument is not persuasive since the motivation to combine the references does not necessarily have to match with what applicant wants to accomplish. The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings. In the instant case, the June reference teaches compositions and methods including administering a genetically modified T cell to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and CD3 zeta signaling domain, wherein the antigen binding domain is selected to specifically recognize the target cell population or tissue (abstract). June discloses that the cell can be genetically modified to stably express an antibody binding domain on its surface, conferring novel antigen specificity that is MHC independent. In some instances, the T cell is genetically modified to stably express a CAR that combines an antigen recognition domain of a specific antibody with an intracellular domain of the CD3-zeta chain or Fc.gamma.RI protein into a single chimeric protein, while Asselbergs discloses the chromosomal dhfr of E.coli as a selection marker in mammalian cells which retains its sensitivity to MTX and TMP. Therefore, the combination of genetically modified T cell to express a CAR and the ligand binding domain of E.coli dihydrofolate reductase (eDHFR) of Asselbergs would obviously result in the composition as instantly claimed.
Applicant argues that there is no reasonable expectation of success for combining an eDHFR selection marker of Asselbergs with a CAR fusion protein in a cell for the assessment of the efficacy or toxicity of an adoptive cell therapy, detection of the quantity of engineered T cells in a subject and monitoring an immunotherapy treatment.’ This is not persuasive because the scope of the disclosures in the June and cited reference read on the claims of the present invention in that the claims of the present invention, when give the broadest interpretation, is a composition comprising a cell comprising a chimeric antigen receptor (CAR) and E.coli dihydrofolate reductase (eDHFR) ligand. Furthermore, because applicant claims a composition, the disclosure in June and cited reference may read on applicant's claims for the composition, it is not necessary for the prior art reference to disclose the use for the composition.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGADISHWAR RAO SAMALA whose telephone number is (571)272-9927. The examiner can normally be reached Monday-Friday 9am-6pm.
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) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Hartley G Michael can be reached at 571 272 0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.R.S/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618