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 .
DETAILED ACTION
Response to Amendment and Arguments
The Amendment filed on 3/26/2026 in response to the previous Non-Final Office Action (1/22/2026) is acknowledged and has been entered.
Claims 4, 8, and 11 have been cancelled.
Claims 1-3, 5-7, 9-10 and 12-20 are pending.
Claims 17-20 have been withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species.
Claims 1-3, 5-7, 9-10 and 12-16 are under consideration for a method of generating therapeutic T cell comprising obtaining patient-specific omics date from a cancer patient, and contacting recombinant APC having nucleic acid encoding tumor specific neoantigen.
Rejections withdrawn:
The rejection of claim(s) 1, 3, 5-7, 9-10, and 12-15 under 35 U.S.C. 102(a)(1) as being anticipated by or in the alternative under 35 U.S.C. 103 by Cancer Research Catalyst (AACR the Official Blog Nov 19, 2018) as evidenced by Forget et al (JI 37:448-460, 2014) and RD-Connect (1-2026) is withdrawn in view of the claim amendment and applicant’s argument.
The rejection of Claim(s) 1, 3, 5-7, 9-10, and 12-15 under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al (Cell Research, 27:11-37, 2017, published online Dec 2016) as evidenced by Cohen et al (J Clin Invest, 125: 3981-91, 2015, citation no 224 of Wang), Croft et al (NCBI Bookshelf: Madame Curie Bioscience Databse. Austin Landes Bioscensece 2000-2014) and RD-Connect (1-2026) is withdrawn in view of the clam amendment and applicant’s argument. The 103 rejection is maintained.
The arguments regarding with rejections are moot.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 3, 5-7, 9-10, and 12-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as being unpatentable over Wang et al (Cell Research, 27:11-37, 2017, published online Dec 2016) as evidenced by Cohen et al (J Clin Invest, 125: 3981-91, 2015, citation no 224 of Wang), Croft et al (NCBI Bookshelf: Madame Curie Bioscience Databse. Austin Landes BIoscensece 2000-2014) and RD-Connect (1-2026). The modification is slightly modified for clearity.
Applicant is noted that claim 12 should be included in all rejections having reference by Wang et al below since TIL cells are clonally distinct that recited in claim 12 and taught by Wang et al. Office regrets the error made in the last Office action.
In this rejection OX40L is considered to be expressed on recombinant APC cell.
Wang et al teach a method of generating neoantigen specific T- cells for cancer therapy. Wang et al first teach that tumor specific antigens with higher expression in the tumor cells/tissues compared to the normal cells that do not express such antigens are recognized by CD8+ T cells and discovered from tumor reactive T-cells (page 14, left col). Specifically, Wang et al teach method steps (page 24-25 and figure 5) comprising 1) obtaining TILs (Tumor infiltrated lymphocytes) from tumor mess or circulated blood samples from a patient,
2) isolating DNA/RNA and sequence to get genomic data (omics data), mutation analyzing, and
3) identifying epitope mutations (neoantigen),
4) pulsing or transfected to autologous APC to form recombinant APC,
5) co-culturing the recombinant APC with obtained TILs to produce neoantigen recognizing TIL, and then,
6) expanding and testing activity based on IFN-γ release by activated T cell that is evidenced by Cohen et al (page 26, left col line 24+ citation no [224]), who teach activated TIL or T cells secrets IFN-γ is as an activation marker (page 3983, right col, figures 3 and 5) or
alternatively isolating the neoantigen specific TILs based on the upgrading activation marker 4-1BB or OX-40. The TILs isolation and expansion based on expression of OX-40 expression on TILs are because recombinant APC cell expressing OX-40 ligand (OX-40L) which interacts with OX-40 on activated TILs to further expand the T cell populations, that is well known and evidenced by Croft et al (page 2) provided here, who teach the following
The majority of OX40L is found on professional antigen-presenting cells (APC) such as dendritic cells, B cells and macrophages and as with OX40 on T cells, OX40L is induced many hours to days after APC receive an activating stimulus.
The method steps “isolating DNA/RNA and sequence to get genomic data, mutation analyzing, and identifying epitope mutations (neoantigen)…” are considered by artisan in the field as obtaining omics data from both patient and normal tissue, which is also evidenced by definition of RD-Connect.
For 103 rejection:
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to generate therapeutic TILs with the steps of Wang et al and expand T cells by culturing the recombinant neoantigen presented APC with isolated activated TILs as evidenced by Cohen and Croft et al to arrive at current invention with expected result because the isolated TILs express OX40 and its ligand OX40L is expressed in the professional or recombinant neoantigen presented APC cells.
Response to applicant’s argument:
At page 9-10, regarding rejection under 35USC 102, applicant argues the following:
Wang teaches general neoantigen concepts and notes that some tumor antigens show
higher expression in tumor vs. normal tissue. See Col. 1, p. 14 ("1) tissue-specific tumor antigens with higher expression in cancer cells compared with normal cells...4) Overexpressed tumor antigens that are overexpressed in cancer cells compared with in normal cells"). However, Wang does not describe the claimed integrated workflow:
(1) obtaining and comparing tumor and matched-normal omics data to identify neoantigens, followed by
(2) generating recombinant APCs by transfecting them with nucleic acid constructs encoding those neoantigens plus T-cell enhancing proteins, then
(3) contacting with patient TILs to obtain functionally reactive cells based on activation markers.
Wang's discussion of "pulsing or transfected" APCs is generic and does not require the nucleic-acid encoding of patient-specific neoantigens identified via tumor/normal comparison and a T-cell-enhancing protein. See pg. 25, Fig. 5 description. The Office's assertion that "using tumor recognized T cells to discover the tumor antigens expressed in tumor cells/tissues as compared to the normal cells" supplies the comparison step is again hindsight. See Non-Final Office Action, p. 8. Wang does not integrate this into the specific method recited in amended claim 1.
In response, Wang’s reference has been further reviewed based on the claim amendment and applicant’s argument, which, as set forth in the rejection, teach details for preparation of therapeutic TIL cells including the specific steps of applicant argued above:
1) obtaining and comparing tumor and matched-normal omics data to identify neoantigens,
2) generating recombinant APCs by transfecting them with nucleic acid constructs encoding those neoantigens plus T-cell enhancing proteins, and
3) contacting with patient TILs to obtain functionally reactive cells based on activation of neoantigen.
Regarding the arguments of “pulsing or transfected” and “hindsight” above, although Wang and rejection above do not use the identical words, Wang clearly disclose nucleic acid has been isolated, identified and transfected into autologous APCs to form recombinant APC (figure 5). One skill in the art would understand the phrase “transfected into autologous APCs” (figure 5 legend) would mean introducing nucleic acid (DNA or RNA), but not peptide, into a cell. Thus, all elements set forth in the instant claims have been taught and suggested by Wang.
Since Wang’s reference was published earlier than the filing date of the present application and the method has been used in the field for years, the reference is a prior art publication that anticipates and is obvious over the present claimed invention. It is not hindsight as applicant argued.
On page 11, Regarding with the 103 rejection, applicant further argues:
Croft et al. merely describes the roles of OX40L expression on professional APCs (e.g., dendritic cells, B cells, and macrophages). There is no discussion of genetic engineering, transfection, recombinant nucleic acids, co-expression with neoantigens, or modifying APCs for therapeutic purposes. Specifically, it provides no reason to engineer a single nucleic acid that co- expresses a patient-specific neoantigen and OX40L inside the same transfected APC.
Although Cohen et al. addresses IFN-y as an activation marker, it is in a completely different context (research/validation setting rather than a personalized cancer therapy).
Lastly, RD-Connect (as discussed above) contains no disclosure of cancer neoantigen
identification or immunotherapy workflows and merely using it to evidence a generic definition of "omics data" does not supply the precise integrated workflow required by amended claim 1.
In response, the purpose of the Office providing Croft’s reference is to confirm OX-40 ligand (OX-40L) expressed by APC, which could act as costimulatory molecule for enhancing T cell stimulation and activity.
The purpose of the Office providing Cohen as evidence is to confirm that the T cell activation could be tested and confirmed by IFN-γ release, which is well known in the art and shown by Cohen here and many others.
RD-Connect reference does not need to disclose all the limitation because primary reference by Wang has done so. RD-Connect provided in the rejection is its definition of Omics data and what is included and referred to.
Applicant is reminded that the Office made the rejection under 35 U.S.C. 103(a) is based on the guideline of MPEP 2141 (rejection under 35 USC 103), particularly, MPEP 2141.02, which states
In determining the difference between the prior art and the claims, the question under 35 USC103 is not whether the difference themselves would have been obvious, but whether the claimed invention as a whole would have been obvious.
It is improper to argue and discuss the references cited under USC 103 rejected individually without clearly addressing the combined teachings. It must be remembered that the references are relied upon in combination and are not meant to be considered separately.
Thus, in this case, as stated in the rejection above, Wang et al provide the teaching on a method with steps recited in the claims, Croft, Cohen, and RD-Connect support the teachings, which provide evidence and further clarify Wang’s points. The invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent unexpected results as set forth in the rejection above.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
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.
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claims 1, 2, 3, 5-7, 9-10, 12-15 remain rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (Cell Research, 27:11-37, 2017, published online Dec 2016) as evidenced by Cohen et al (J Clin Invest, 125: 3981-91, 2015) and Croft et al (NCBI Bookshelf: Madame Curie Bioscience Databse. Austin Landes BIoscensece 2000-2014) and RD-Connect (1-2026), in view of Sanborn et al (US Patent 10,878,937 (June 2018, original application 15/618003).
Wang’s teachings on a method of generating therapeutic TILs cell for cancer immunotherapy are set forth above, but the none of the references teaches the specific formats of Omics data listed in claim 2.
Sanborn et al teach patient specific omics data, specifically software tool called BAMBAM data for comparison of tumor and germline sequence database for cancer, metastasis, etc. disorders (abstract, figures, page 19).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to use the BAMBAM omics data in the methods to generate therapeutic TIL cells recognizing specific neoantigen expressed tumor cells with recombinant APC cell with expected result. In order to benefit adoptive cellular therapy with specific TILs for treating the neoantigen expressed cancer, one of ordinary skill in the art before the effective filing date of was made would have been motivated with reasonable expectation of success to apply BAMBAM format the omics data of Sanborn to the teachings of CRC or Wang et al to generate tumor neoantigen specific TILs. Therefore, the references in combination teach every limitation of the claims and the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention was made, absent unexpected results.
Response to applicant’s argument:
At page 12, applicant states:
Sanborn's BAMBAM tool performs tumor/germline comparisons, Wang does not disclose or suggest using any such tool or format.
In response, the reference of Sanborn provided by Office is to make up the deficiency of Wang for claim 2 reciting Omics data including BAMBAM format, which is taught by Sanborn.
Wang merely teach Omics data collection but not specify what format of the data used. While Sanborn explain that BAMBAM is one kind of format of Omics data that often are used for patient specific Omics data to compare tumor and germline sequence database for cancer condition.
2. Claims 1, 3, 5-7, 9-10, 12-15, and 16 remain rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (Cell Research, 27:11-37, 2017, published online Dec 2016) as evidenced by Cohen et al (J Clin Invest, 125: 3981-91, 2015) and Croft et al (NCBI Bookshelf: Madame Curie Bioscience Databse. Austin Landes BIoscensece 2000-2014) and RD-Connect (1-2026, in view of Ott et al (J Immunotherapy of Cancer, 2017, 5:16, page 1-15).
Wang’s teachings on the method of generating therapeutic TILs cell for cancer treatment is set forth above, but the none of the references teaches administering TILs in combination with an immunostimulatory cytokine or checkpoint inhibitor set forth in claim 16.
Combinational therapies for cancer treatments are very popular and effective. Ott et al have summarized many combination therapies for cancer treatment comprising tumor targeting immunotherapy with checkpoint inhibitor to blockage PD-1/PD-L1 interaction (entire document). Ott et al specifically teach combination of adoptive T cell therapy including TILs therapy and immunotherapy PD-1/PD-L1 blockage for treating cancer (page 3, left col).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to combine other therapy in cancer treatment with expected result. In order to benefit adoptive cellular therapy with specific TILs for treating the neoantigen expressed cancer, one of ordinary skill in the art before the effective filing date of was made would have been motivated with reasonable expectation of success to add additional therapy, especially cytokine as adjuvant and PD-1/PD-L1 blockage to the teachings of CRC or Wang et al to reactivate more T cells to achieve best result of the neoantigen TIL therapy. Therefore, the references in combination teach every limitation of the claims and the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention was made, absent unexpected results.
Response to applicant’s argument:
At page 12, applicant argues:
Ott et al. discusses general combinations of adoptive cell therapy with checkpoint blockade but provides no teaching, suggestion, or reasoning to administer the specifically generated neoantigen-reactive T cells (produced via the recombinant-APC co-culture method of claim 1) together with both a checkpoint inhibitor and an immunostimulatory cytokine in a single regimen. The combination proposed by the Office is the very combination disclosed in the present application.
In response, Ott’s reference provided by Office is to make up the deficiency of Wang for claim 16 reciting combinational therapy comprising expanded T cell with an immunotherapy.
Wang merely teaches administering TILs but not in combination with checkpoint inhibitor as set forth in claim 16. While Ott teaches that TIL therapy could be combined with immunotherapy with PD1/PD-L1 blockage. Applicant is again reminded that this rejection is under US35 103, it is improper to argue and discuss the references cited under USC 103 rejected individually without clearly addressing the combined teachings. The references are relied upon in combination and are not meant to be considered separately (see response above for more).
For all the reasons above, applicant’s arguments are not persuasive and rejections are currently maintained.
Conclusion
No claim is allowed.
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 Lei Yao, whose telephone number is (571) 272-3112. The examiner can normally be reached on 8:00am-6:00pm Monday-Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LEI YAO/ Primary Examiner, Art Unit 1642
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