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 .
Applicant’s arguments and amendments filed on 11/12/2025 have been entered.
Claim 21 has been amended.
Claim 22 has been cancelled.
In view of Applicants amendment to claim 21 regarding an antibody, the 103 rejection has been amended. The limitation that the immunomodulatory drug is an antibody is a new limitation and the teaching of Curran et al. have been removed and replaced with the teachings of Yuan et al.
Claims 21 and 23-55 are examined in the instant application.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 9/1/2022. It is noted, however, that applicant has not filed a certified copy of the 202211066571.6 application as required by 37 CFR 1.55.
Claim Rejections - 35 USC § 103 – Necessitated by Amendment
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.
Claim(s) 21 and 23-35 are rejected under 35 U.S.C. 103 as being unpatentable over Hollingshead et al. (U.S. Patent No. 5,698,413) in view of Cattaneo et al. (2020, Nat. Protoc., Vol. 15(1), pgs. 15-39) and Yuan et al. (US Pat. No. 11,365,255, issued 6/21/2022, published 10/10/2019).
Regarding claim 21, Hollingshead et al. teach “The present invention relates to a method of screening chemotherapeutic agents in vivo. The method comprises implanting into a laboratory animal a biocompatible, semipermeable encapsulation device containing a target cell-line, treating the laboratory animal with a test agent. then evaluating the target cells for reaction to the test agent” (Abstract).
Specifically, Hollingshead teach a method of treating cancer in a patient using an immunomodulator drug (i.e. methotrexate) against cancer comprising:
transferring into an animal an implant device (PVDF tube) comprising primary tumor cells derived from a patient and screening drugs for their efficacy in vivo (see Abstract, claim 1, Example 1, cols. 3-4 and 6 and col. 8 lines 16-36)
Hollingshead teaches that fresh patient derived tumor tissue can be used as the source for practicing their claimed method (col. 4 1st full parag. and claims 11 and 22).
Regarding claim 24, it is interpreted that the methotrexate is optimal for treating the patient’s cancer.
Regarding claim 25, while Hollingshead does not explicitly teach removing the implanted capsule and then administering the screened immunomodulatory drug, however it would be obvious to treat the patient following drug screening in view of Hollingshead teaching that their claimed method is for evaluating the efficacy of drugs against cancer and that their methods purpose is obtaining drugs that will treat a patients cancer (col. 9 line 6 bridge col. 10 line 9).
Regarding claim 30, Hollingshead teaches that additional capsules can be implanted (col. 3 lines 26-31).
Regarding claims 31 and 32, Hollingshead teaches that the multiple drugs can be combined (Tables 1-3).
Regarding claim 33, Hollingshead teaches that their PVDF tube had a permeability of 50,000 - 500,000 Daltons (claim 15).
Regarding claims 34 and 35, Hollingshead teaches obtaining fresh patient derived tumor tissue (col. 4 line 13 and claim 11) and it is interpreted that to obtain said fresh tissue this would be via a biopsy or resection.
Specifically, Hollingshead teaches:
“The present invention relates to a method of screening chemotherapeutic agents in vivo using target cells grown in biocompatible, selectively permeable macrocapsules.
More particularly, the present invention involves a method for providing a retrievable sample of syngeneic, allogenic or xenogeneic cells into laboratory animals using cells or cell lines grown in selectively permeable hollow fibers or dialysis tubing. Following in vivo culture, with or without chemotherapeutic treatment. the cells are retrieved for in vitro evaluation of cell viability, cell density, cell growth potential, virus burden or other parameters appropriate for the test system.” (col. 1 lines 5-17).
Hollingshead does not teach:
combining the patients’ CD3+ lymphocytes with the patient’s tumor cells to screen an immunomodulatory drug; and
an anti-PD1 antibody.
(i) Regarding combining a patients CD3+ lymphocytes with tumor cells, Cattaneo et al. teach a tumor organoid-T cell coculture system for assessing cancer drug efficacy.
Specifically, Cattaneo teaches (emphasis added):
“T cell-directed therapies, such as immune checkpoint inhibition and adoptive T cell transfer, have transformed the treatment landscape for solid tumors. Nonetheless, clinical efficacy is variable both between and within tumor types and the mechanisms that tumors use to escape elimination by the immune system are diverse1,2,3,4. Pre-clinical models that incorporate both endogenous T cells and tumor cells are scarce, especially for epithelial cancers. Moreover, the expansion of tumor infiltrating lymphocytes (TIL) has been more challenging for epithelial tumors compared to melanoma5.
We have recently developed a co-culture system of tumor organoids and peripheral blood lymphocytes6. Tumor-reactive T cells can be efficiently expanded from peripheral blood and evaluated for tumor reactivity and tumoricidal capacity. Here, we extend and detail the procedure for establishment of this co-culture system.” (pg. 2 parags. 1-2).
Regarding claims 26 and 27, Cattaneo teaches that the ratio of tumor cells to CD3+ lymphocytes was 5:1 (pg. 5 parag. 1).
Regarding claim 28, Cattaneo teaches the lymphocytes were CD3/CD8+ (pg. 4 parag. 2 and pg. 29 Anticipated Results).
Regarding claim 29, Cattaneo teaches that the ratio of CD8/3+ lymphocytes can be up to 20% (pgs. 29 and 30, Anticipated Results).
While Cattaneo teaches that immune checkpoint inhibition can be used as a means of treating cancer, Catteneo does not teach the immune checkpoint inhibitors anti-PD1 and anti-CTLA4.
Regarding an anti-PD1 antibody in claim 21, Yuan et al. teach that a method of treating cancer using an anti-PD1 antibody (allowed claim 10).
Yuan continues to teach that “The present invention further provides a method for treating and preventing the PD-1 mediated disease or disorder, a therapeutically effective amount of the PD-1 antibody or the antigen-binding fragment thereof according to the invention, or the pharmaceutical composition comprising the same; wherein the disease is preferably cancer, more preferably PD-LI-expressing cancer; the cancer is preferably breast cancer, lung cancer, stomach cancer, intestinal cancer, renal cancer, melanoma, non-small cell lung cancer, and most preferably non-small cell lung cancer, melanoma and renal cancer.” Col. 5 lines 25-37).
Thus at the time of filing the ordinary artisan would have found it prima facie obvious to combine the teachings of Hollingshead regarding a method of treating cancer in a patient using an immunomodulator drug against cancer with the teachings of Cattaneo regarding a co-culture of T cells an tumor cells for screening cancer drugs and with the teachings of Yuan regarding an anti-PD1 antibody to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make such a combination since the Cattaneo teaches the advantages of combining lymphocytes with tumor cells for the screening of anti-cancer drugs. Thus, the ordinary artisan would be motivated to combine patient lymphocytes with the patient’s tumor cells in the implant of Hollingshead since this will provide the ability to determine T cell infiltration and efficacy in response to anti-PD1 antibody.
There would have been a reasonable expectation of success that the implant of Hollingshead could comprise both patient lymphocytes and tumor cells for drug screening since Hollingshead teaches a variety of implants with different sizes to accommodate patient cells (see Table in col. 4). Further, Yuan teaches at the time of filing that an anti-PD1 antibody is effective for the treatment of cancer.
Thus the cited art provides the requisite teachings and motivations to make and use the invention as claimed.
Response to Arguments
While Applicant’ arguments have been fully considered they are not found persuasive. As set forth above, in view the amendments to claim 21, the teachings of Yuan provide motivation to use an anti-PD1 antibody for the treatment of cancer as embraced by the amended claims.
Claim(s) 36-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hollingshead et al. (U.S. Patent No. 5,698,413) in view of Cattaneo et al. (2020, Nat. Protoc., Vol. 15(1), pgs. 15-39) and Yuan et al. (US Pat. No. 11,365,255, issued 6/21/2022, published 10/10/2019). as applied to claims 21 and 23-35 above, and further in view of Wang et al. (2009, J. Gastroenterology, Vol. 24, pgs. 299-306) and Dagur et al. (2019, Trans. Med. Comm., Vol. 4:11, pgs. 1-7).
Hollingshead, Cattaneo and Yuan are relied upon above in teaching a method of treating cancer in a patient with an anti-PD1 antibody.
Hollingshead, Cattaneo and Yuan do not teach:
(i) isolating lymphocytes and tumor cells using MACS.
At the time of filing there were numerous techniques for enriching and isolating primary tumor cells from ex vivo tumor tissues via digestion and sorting using magnetic beads. For example, Wang et al. describe the use of magnetic activated cell sorting (MACS) to enrich gastric cancer cells from bone marrow of patients with gastric cancer (see Abstract).
(i) Regarding claim 36, Wang teaches that peripheral blood can be used to obtain sample cells (pg. 299 col. 2 parag. 2).
Additionally, Wang teaches separating the sample cells from mononuclear cells (see Abstract).
However, while Wang teaches the isolation of cancer cells from bone marrow, Wang does not teach isolating CD45+ lymphocytes from the patients peripheral blood. In this regard, it was routine and obvious to also isolate and sort CD45+ lymphocytes using FACS.
Specifically, Dagur et al. teach “Our methodology has been tested and optimized for the enrichment and purification of both Th17 and Tc17 cells using whole blood, fresh and frozen PBMCs, and skin biopsies of human specimens. The flow cytometry staining panel includes the following: (i) CD45 to identify leukocytes and to exclude circulatory endothelial cells and non leukocyte cells,” (pg. 2 col. 2 parag. 3 lines 1-7).
Regarding claims 37-39, Dagur teaches isolating and enriching CD45+ lymphocytes from peripheral blood using FACS (see Abstract and pg. 2 col. 1 parag. 4).
Regarding claim 40, Dagur teaches assessing viability using aqua fluorescent reactive dye (pg. 6 col. 1 parag. 1) and it is interpreted that cell viability for CD45+ cells is greater than 20% in view of the data in Figs. 1 and 3.
Thus at the time of filing the ordinary artisan would have found it prima facie obvious to combine the teachings of Hollingshead, Cattaneo and Yuan regarding a method of treating cancer in a patient using an immunomodulator drug against cancer with the teachings of Wang and Dagur regarding isolating CD45 lymphocytes and tumor cells with FACS or MACS to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make such a combination Wang and Dagur teach that lymphocytes and tumor cells can be efficiently obtained from fluids like blood and tissue like bone marrow using either MACS or FACS.
There would have been a reasonable expectation of success that the lymphocytes and tumor cells could be obtained with either FACS or MACS since Wang and Dagur teach successfully obtaining patient lymphocytes and tumor cells using FACS or MACS.
Thus the cited art provides the requisite teachings and motivations to make and use the invention as claimed.
Response to Arguments
While Applicant’ arguments and amendments have been fully considered they are not found persuasive. As set forth above, the 103 has been amended to address the amendments to claim 21 and the combination with the teachings with Yang, Wang and Dagur would be obvious as set forth above.
Conclusion
No claims are allowed.
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 DAVID A MONTANARI whose telephone number is (571)272-3108. The examiner can normally be reached M-Tr 8-6.
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DAVID A. MONTANARI
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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