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 .
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 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.
Priority
The instant application, filed 02/16/2023, is a 371 filing of PCT/CN2021/106098, filed 07/13/2021, and claims foreign priority to CN202010917702.1, filed 09/03/2020.
Status of Application, Amendments, and/or Claims
Applicant’s response of 12/11/2025 is acknowledged. Claims 1, 6, and 8-13 are amended and claims 2-5 and 7 are cancelled. Claims 1, 6, and 8-13 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 09/16/2025,
The specification was objected to for missing the incorporation by reference paragraph required for the sequence listing. Applicant’s amendment to the specification to include the incorporation by reference paragraph has overcome the objection and the objection is withdrawn.
Claim 5 was objected to. The cancellation of the claim has rendered the objection moot and the rejection is withdrawn.
Claim 12 was rejected under 35 USC 112(b). Applicant’s amendment to claim 12 to remove the limitation “each time” has overcome the rejection and the rejection is withdrawn.
Claims 1-13 were rejected under 35 USC 101. Applicant’s amendment to the claims to change the claims from “Use” claims to method claims has overcome the rejections and the rejections are withdrawn.
Claims 2-5 and 7 were rejected under 35 USC 103 over Faltas, Zhang, and US’766. The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
The following grounds of rejections are modified as necessitated by applicant’s amendment to the claims.
Claim Interpretation – 112(f)
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Claim 13 recites the limitation “applying auxiliary medical means to the subject to effectively eliminate the solid tumor”. The limitation falls under 112(f) as follows:
112(f) prong (A): the claim recites “means”;
112(f) prong (B): the term “means” is modified the functional language of being an auxiliary medical means that is further applied to effectively eliminate the solid tumor;
112(f) prong (C): the term “means” is not modified by sufficient structure, material, or acts performing the claimed function.
Therefore, the limitation is interpreted under 112(f) as having the broadest reasonable interpretation in view of the description of the specification.
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.
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 1, 6, and 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over Faltas, B. (2012) Cornering metastases: therapeutic targeting of circulating tumor cells and stem cells Frontiers in Oncology 2(68); 1-7 in view of Zhang, B.L., et al (2019) Preclinical evaluation of chimeric antigen receptor-modified T cells specific to epithelial cell adhesion molecule for treating colorectal cancer Human Gene Therapy 30(4); 402-412 and US 2017/0281766 A1 (Wiltzius, J.) 5 Oct 2017.
Faltas teaches that the metastatic spread of cancer is the main cause of morbidity and mortality in cancer patients. The development of metastases from solid tumors is a complex multi-step process and is one of the most enigmatic aspects of cancer biology. Recently, studies using in vivo vital microscopy has shed more light on the physiology of the metastasis. These studies show a metastatic process that proceeds in a pre-determined cascade comprising the following steps: neoangiogenesis, trans-endothelial migration, entry into the blood stream (intravasation), transport through the vasculature followed by extravasation, and ultimately resulting in colonization and growth at distant sites (page 1, left column, paragraph 1; Page 2, Fig. 1).
Most currently developed anti-metastatic therapy strategies target the final step of the metastatic cascade such as extravasated dormant cancer cells in the metastatic niche, thus missing the opportunity to interrupt metastases development at earlier stages. Targeting earlier up-stream events is likely to be more effective in preventing metastases from developing with greater yield in reducing or even eliminating their devastating clinical impact. The hematogenous transport phase of cancer cells presents a particularly attractive opportunity for therapeutic targeting for multiple reasons: first, it occurs early enough to provide a rational up-stream target for strategies aiming to reduce or completely prevent the development of distant metastases. Secondly, hematogenous transport is the final common pathway of metastatic spread, even for tumors initially spreading through lymphatics which eventually interconnect with the circulatory system. Finally, the transport phase is relatively accessible to a variety of pharmacological and mechanical targeting interventions (page 2, left column, paragraph 1).
Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor and enter the blood stream. Several systems have been developed for the isolation and characterization of CTCs from blood samples including the FDA approved CellSearch® platform. Using these platforms, CTCs have been isolated from blood samples of patients with a variety of tumors including head and neck, breast, lung, colorectal, gastric, pancreatic, renal cell, urinary bladder, and prostate cancers. Recent studies show significant correlation between higher CTC counts and shorter overall survival in patients and these studies support a critical role for CTC in tumor progression and metastasis. As a result, it is now hypothesized that targeting CTCs during their hematogenous transport could lead to effective interruption of the metastatic cascade and ultimately, reduction of cancer morbidity and mortality (paragraph bridging columns, page 2). In vivo therapeutic targeting of CTCs and circulating tumor stem cells (CTSCs) to interrupt the transport phase of the metastatic cascade and subsequent development of metastasis was in itself a novel concept and a variety of targeting approaches were currently under development (page 3, right column, paragraph 2).
Faltas teaches that pharmacological targeting depends primarily on the identification of suitable molecular targets which are over-expressed and critically important for CTC survival and function (page 4, left column, paragraph 1). Epithelial cell adhesion molecule (EpCAM) is an interesting therapeutic target as it is frequently expressed on CSCs from breast, colon, pancreas, and prostate tumors. EpCAM is also expressed on CTCs but not on blood cells. This preferential expression is the basis of many diagnostic assays used to isolate CTCs from the blood stream. Clinical trials using anti-EpCAM monoclonal antibodies slowed progression and prolonged survival in patients with metastatic colorectal carcinoma (page 4, left column, paragraph 3).
Faltas, however, does not disclose that the CTC targeting therapeutic is an immune cell obtained by genetically modifying T cells with chimeric antigen receptors as claimed, that are injected into the peripheral blood of the subject.
Zhang teaches that recently, EpCAM was identified as a biomarker for circulating tumor cells (CTCs) and cancer stem cells (CSCs). CTCs are the potential precursors of tumor metastasis that actively invade or have been shed from primary tumor into the blood circulation. CTC capture using EpCAM-based gating is feasible for most cancer subtypes, especially for breast cancer (paragraph bridging columns, page 402). EpCAM is highly expressed in various types of cancer and is involved in promoting cell proliferation, survival, and metastasis. In addition, EpCAM has been identified as a biomarker for CTCs and CSCs. Therefore, EpCAM may be an even more interesting target for cancer immunotherapy. Using flow cytometry, the disclosed study validated EpCAM protein expression in several solid cell lines and found that EpCAM is widely expressed in a broad panel of human tumor cells (paragraph bridging pages 409-410).
Monoclonal antibodies (mAs) against EpCAM were in clinical trial for treating various cancers, but did not lead to a cure. Zhang proposes improving the therapeutic benefit by generating a CAR that targets EpCAM (page 410, left column, paragraph 2). Zhang constructed of a third-generation CAR recognizing EpCAM and transduced T cells by a lentiviral vector to redirect the T cells with specificity to EpCAM (EpCAM CAR-T). Zhang then evaluated whether the EpCAM CAR-T cells could inhibit the growth of solid tumors in vitro and in vivo and the safety of the EpCAM CAR-T cells was studied in xenograft mice. EpCAM CAR-T cells were shown to elicit lytic cytotoxicity to target cells in an EpCAM dependent manner, and adoptive transfer of EpCAM CAR-T cells significantly delayed tumor growth and formation against human colon cancers without serious adverse effects. This preclinical study of EpCAM CAR-T cells suggests that adoptive transfer of CAR T cells targeting EpCAM is safe and efficacious and is a promising therapeutic strategy for treating EpCAM+ solid tumors (page 403, left column, paragraph 3).
Zhang teaches an EpCAM specific CAR comprising a single chain variable fragment sequence (scFv) targeting EpCAM, a CD8α hinge, a CD8α transmembrane domain, CD28 and 4-1BB costimulatory domains, and the human CD3ζ intracellular signaling domain (page 405, Figure 1; page 403, right column, CAR construction).
Zhang further teaches studies in which the effect of EpCAM CAR-T cells was evaluated on tumor formation in xenograft mice models. In the study, H29 and SW480 cells were respectively co-inoculated subcutaneously with 2x107 EpCAM-specific CAR-modified T lymphocytes (page 404, mouse xenograft model). Compared to control T lymphocytes, the adoptive transfer of EpCAM-specific CAR-modified T lymphocytes significantly delayed tumor formation and growth in the xenograft models (page 408, right column).
Zhang teaches that the most critical contribution of the work disclosed is the demonstration of the applicability of EpCAM specific CAR-T cells to target not only prostate cancer, but also other solid tumors such as breast cancer, NSCLC, and colon cancer. The study demonstrated that human T cells expressing EpCAM-specific CAR lysed a panel of EpCAM+ cancer cells with high efficiency in vitro (page 411, left column, paragraph 2; Fig. 4). The study confirms the antitumor ability of CAR-T cells targeting EpCAM and provides a new target for CAR-T cell therapies in treating solid tumors (page 411, right column, paragraph 2).
US’380 teaches a chimeric antigen receptor (CAR) or a T cell receptor (TCR) as well as cells comprising the CAR or TCR and their use in T cell therapy (abstract). US’380 teaches that the CAR or TCR targets antigen including EpCAM (page 17, [0190]) and that the cells can be administered using various methods and delivery systems known to those skilled in the art including intravenous administration and subcutaneous administration using injection or infusion (page 6, [0087]). US’380 further teaches methods of treating cancer in a subject, reducing the size of a tumor, eliminating a tumor from a patient, preventing relapse of a tumor, preventing tumor metastasis, inducing remission in a patient, or any combination thereof. The cancer may a solid tumor (page 67, [0250]-[0252]).
US’380 further teaches that T cells are administered at a therapeutically effective amount and that therapeutically effective amounts of CAR or TCR modified T cells includes about 2x106 cells/kg, 3x106 cells/kg, 4x106 cells/kg, 5x106 cells/kg, 6x106 cells/kg, 7x106 cells/kg, 8x106 cells/kg, 9x106 cells/kg, 1x107 cells/kg, 2x107 cells/kg, 3x107 cells/kg, 4x107 cells/kg, 5x107 cells/kg, 6x107 cells/kg, 7x107 cells/kg, 8x107 cells/kg, 9x107 cells/kg (page 67, [0249]).
US’380 further teaches that a variety of additional therapeutic agents may be used in conjunction with the compositions (pages 67-69, [0256]-[0261]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of targeting CTCs to prevent development of solid tumor metastasis taught by Faltas to use the EpCAM specific CAR-T cells of Zhang as the targeting therapeutic and to inject the EpCAM CAR T cells into the peripheral blood of the subject, for instance through an intravenous route, as taught by US’380. An ordinarily skilled artisan would have been motivated to use the EpCAM specific CAR T cells of Zhang as the CTC targeting therapeutic as Zhang demonstrates that EpCAM CAR T cells are able to effectively target and lyse a panel of EpCAM+ cancer cells with high efficiency demonstrating powerful antitumor activity with a dramatic inhibition of tumor growth in subcutaneous xenograft models (page 411, left column, paragraph 2). An ordinarily skilled artisan would have a reasonable expectation of success as both Faltas and Zhang identify EpCAM as a therapeutic target that was known to be expressed on circulating tumor cells which were known precursors of tumor metastasis that actively invade, or are shed by the primary tumor, into the blood circulation. It would have further been obvious to inject the EpCAM CAR T cells directly into the peripheral blood of the subject as US’380 teaches intravenous injection as an alternative to the subcutaneous injection used by Zhang. Additionally, an ordinarily skilled artisan would have been motivated to inject the EpCAM CAR T cells into the peripheral blood as Faltas is teaching the targeting of CTCs that are circulating in blood stream of the subject. An ordinarily skilled artisan would have had a reasonable expectation of success as US’380 demonstrates known administration routes of CAR T cells, including CAR T cells that target EpCAM and administration for the treatment of solid tumors which overlaps with the teachings of Faltas and Zhang.
Regarding claims 10 and 11, while Zhang teaches co-inoculated subcutaneous administration of the tumor cells and the EpCAM-specific CAR-T cells, it would have been obvious to inoculate the tumor cells in models prior to injection of the CAR T cells and confirm CTC circulation based on the teachings of Faltas. Specifically, as discussed above, Faltas teaches that several systems have been developed for isolation and characterization of CTCs from blood samples and that using these platforms, CTCs have been isolated from blood samples of patients with a variety of tumors, and also teaches that a significant correlation between CTC counts and survival times in patients with metastasis (page 2, right column, paragraph 2). Additionally, Faltas teaches administration of anti-EpCAM antibodies in patients with metastatic colorectal carcinoma and teaches that the antibodies were able to slow progression and prolong survival (page 4, left column, paragraph 3).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the animal models in the method taught by the combination of Faltas, Zhang, and US’380 to first inoculate the tumor cells via subcutaneous transplantation then use the testing methods taught by Faltas to isolate and characterize CTCs in the peripheral blood prior to administration of the EpCAM CAR-T cells. It would have been obvious to make this modification in order to confirm and characterize CTCs in the peripheral blood while simulating metastatic tumor models as taught by Faltas. An ordinarily skilled artisan would have had a reasonable expectation of success as both Faltas and Zhang teach CTCs and the expression of EpCAM on CTCs in cancers which overlap including colorectal carcinomas.
Response to Arguments
Applicant’s arguments in the response filed 12/11/2025 have been fully considered, but are not persuasive.
With regards to the rejection under 35 USC 103, applicant argues that Faltas does not teach cell therapy. Applicant also argues that Faltas highlights the technical difficulties in targeting CTCs, noting their rarity and the need for ultra-efficient targeting citing Faltas, page 6. Applicant argues that, given that Faltas only adopts antibody drugs and device-based approaches, one of ordinary skill in the art would consider cell therapy as highly unpredictable for CTC targeting. Applicant argues that one of ordinary skill in the art would believe that it would be difficult to precisely recognize and bind rare CTCs in circulation and that off-target effects could cause unexpected toxicity.
These arguments, however, are not persuasive. While Faltas does not teach cell therapy, the rejections are not based on Faltas alone, but rather on a combination of the applied references and what the combination would have suggested to one of ordinary skill in the art prior to the effective filing date of the claimed invention. MPEP 2145 (IV) states “One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references… This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012).”
Faltas is not required to teach that the CTC targeting therapeutic is a cell therapy as this limitation is taught by Zhang. US’766 also demonstrates that EpCAM CAR T cells had been considered in the prior art. Furthermore, just because Faltas only teaches antibody drugs and device-based approaches, this alone does not suggest that cell therapy would have been considered to be unpredictable for CTC targeting. This is particularly the case as Zhang, like Faltas, teaches that EpCAM is an interesting target that is frequently expressed on CSC and can be used as an immunotherapy target for the treatment of solid cancers. Zhang also exemplifies a CAR that targets EpCAM and studied the inhibition of solid tumor growth in vitro and in vivo.
As cited by applicant in the response, Faltas p. 6 teaches that CTCs are rare in the general circulation relative to other blood elements and requires ultra-efficient targeting. Faltas goes on to teach that pharmacological agents designed to target CTCs/CTSCs need to achieve high selectivity while maintaining acceptable clinical toxicity. In this regard, Zhang teaches that the EpCAM CAR T cells tested were able to effectively target and lyse a panel of EpCAM+ cancer cells with high efficiency demonstrating powerful antitumor activity with a dramatic inhibition of tumor growth in subcutaneous xenograft models. Additional, Faltas teaches that EpCAM is expressed on CTCs but not on blood cells and that this preferential expression has been the basis of many diagnostic assays used to isolate CTCs from the bloodstream. Based on these teachings, one of ordinary skill in the art would reasonably expect that the EpCAM targeting CAR T cells of Zhang would be highly selective in targeting CTCs.
With regards to applicant’s arguments that one of ordinary skill in the art would believe that the off-target effects could cause unexpected toxicity, it is first noted that the claim doesn’t require any specific toxicity, or lack thereof, from the administration of the EpCAM CAR T cells. That said, Zhang studied safety of the EpCAM targeting CARs and teaches that the safety evaluation showed that the CAR T cells had no systemic toxicity in mice (abstract).
Applicant further argues that Zhang does not verify CAR T cell killing of CTCs in circulation, where target variation may occur and that; therefore, a person of ordinary skill in the art could not reasonably expect CAR T cell therapy to be effective against CTCs in a complex metastatic process.
While Zhang does not experimentally verify the killing of CTCs in circulation, conclusive proof of efficacy is not required to establish a prima facie case of obviousness. Rather, the requirement for obviousness is a reasonable expectation of success. MPEP 2143.02 (I) states that “conclusive proof of efficacy is not required to show a reasonable expectation of success. Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute"))”.
One of ordinary skill in the art would have had a reasonable expectation of success based on the combined teachings of the applied art for the reasons discussed in detail above. Specifically, both Faltas and Zhang teach the expression of EpCAM on CTCs in circulation and Faltas directly suggests targeting CTCs in circulation in the treatment of tumor metastasis. Zhang teaches that the CAR T cells disclosed are able to effectively target and lyse a panel of EpCAM+ cancer cells with high efficiency demonstrating powerful antitumor activity.
With regards to US’380, referenced by applicant in the response as “Wiltzius”, applicant argues that the reference only generally discloses intravenous administration of CAR-T cells intended to deliver them to solid tumor tissue and does not teach clearance of free CTCs in circulation.
While US’380 does not disclose targeting CTCs, US’380 is not required to teach this limitation as the limitation is taught by Faltas and also discussed by Zhang. As discussed above, the rejection is based on the combination of applied references and what the combination would have suggested to one of ordinary skill in the art. US’380 is applied in the rejections of the instant office action to demonstrate that intravenous administration of CAR T cells, including EpCAM targeting CAR T cells, for the treatment of solid tumors had been considered in the prior art. Additionally, the administration of EpCAM targeting CAR T cells into the peripheral blood via injection would naturally result in the targeting of cells expressing EpCAM, including CTCs which are in circulation.
Applicant further argues that the present invention is the first to propose using cell therapy by infusing cytotoxic cells into the peripheral blood to act on CTCs, achieving killing or clearance. This approach inhibits colonization of CTCs, blocks metastasis, and prolongs survival. Applicant cites instant example 3 as demonstrating that EpCAM targeted CAR T cells significantly reduce tumor cell survival in simulated blood samples, showing strong in vitro killing ability. Applicant also cites examples 4 and 5 as using mouse models of colorectal cancer hematogenous metastasis to demonstrate that EpCAM targeted CAR T cells persist longer in vivo, significantly killing circulating CTCs, and effectively inhibiting metastasis to lungs and liver without causing significant ALT/AST changes, indicating no obvious toxicity to the liver and good biosafety. Applicant argues that this synergistic effect exceeds routine expectations.
It is first noted that, as discussed above, the rejection of the instant claims depends on the combination of applied references and what the references would have suggested to one of ordinary skill in the art. Therefore, none of the applied references is individually required to teach each and every limitation of the claimed method or explicitly propose using cell therapy to act on CTCs. Furthermore, conclusive proof of efficacy is not required to establish obviousness; rather, the standard for obviousness is a reasonable expectation of success.
Example 2 of the instant specification details the production of the EpCAM targeting CAR T cells used in the examples discussed by applicant in the response and discloses that the CAR used comprised instant SEQ ID NO: 3 (starting on page 9, [0083]).
Example 3 studied the use of the CAR T cells in eliminating CTCs in in vitro simulations. The example comprised a healthy blood sample group, a blank control group, an untransduced T cell (UnT) group and a CAR T group. The CAR T group was divided into low dose and high-dose CAR T groups (1 and 2, respectively. The studied included the testing of human colorectal cancer cell suspensions (starting on page 11, [0096]). Results from the study are provided in Fig. 4, where it is shown that the EpCAM CAR T cells resulted in significantly reduced tumor cell survival rates.
Examples 4 and 5 studied CTC killing using the CAR-T cells in animal models of colorectal cancer tumor metastasis. The studies included a control group and an administration group which included a UnT group and a CAR T group. Example 4 discloses that the CAR T cells were administered at a dose of 3.57x106 CAR T cells per mouse model. The mice were weighted twice a week and results are shown in Fig. 7, which demonstrate that body weight was maintained indicating that the CAR T did not show obvious toxicity at the doses tested. The example concludes that the CAR T had a significant inhibitory effect on tumor metastasis at the dose tested compared to control and UnT groups (starting on page 12, [00106]). Example 5 discloses that the CAR T cells were administered at a dose of 8.93x106 CAR T cells per experimental mouse via tail vein injection. Again, mice in the CAR-T group maintained body weight indicating no obvious toxicity at the tested dose and have a significant anti-tumor effect.
While the examples of the instant disclosure do demonstrate that the CAR T cells significantly reduce tumor cell survival in vitro and in vivo with no obvious toxicity to the liver and good biosafety, such results would have been expected in view of the teachings of the prior art.
MPEP 716.02 states “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.”
As discussed in detail above, and in the rejection of the instant office action, Faltas teaches targeting circulating tumor cells, or CTCs, as a means to interrupt metastases development at earlier stages, ultimately reducing cancer morbidity and mortality. Faltas also teaches that EpCAM is an interesting therapeutic target that is expressed on CSCs from breast, colon, pancreatic, and prostate tumors and is also expressed on CTCs, but not on blood cells. Zhang corroborates the teachings of Faltas, teaching that EpCAM is a biomarker on CTCs and CSCs and that CTCs are potential precursors of tumor metastasis that actively invade or have been shed from the primary tumor into blood circulation. Zhang also identifies EpCAM as an interesting target for cancer immunotherapy and developed CAR T cells targeting EpCAM. In studies performed by Zhang, EpCAM CAR T cells significantly delayed tumor growth and formation against human colon cancers without serious adverse effects. Zhang teaches that the preliminary studies suggest that EpCAM targeting CAR T cells are safe and efficacious and a promising therapeutic strategy. Zhang also performed in vitro studies in xenograft mice models. Compared to control T lymphocytes, the adoptive transfer of the EpCAM specific CAR T cells significantly delayed tumor formation and growth.
Additionally, in the studies performed by applicant, targeting of CTCs using the EpCAM targeting CAR T cells is compared to controls, which were treated with PBS only, and untransduced T cells. The examples do not provide a comparison to the closest prior art in order to demonstrate unexpected results. For instance, in the case of the instant combination of applied references, the closest prior art could be considered to be the alternative treatment strategies disclosed by Faltas or the EpCAM targeting CAR T cells of Zhang.
MPEP 716.02 (b)(III) states “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.” MPEP 716.02 (e) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
Additionally, even if applicant did provide unexpected results over the prior art, the claims are not commensurate in scope with the examples of the instant disclosure.
MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
The independent claim of the instantly claimed invention encompasses any type of solid tumor using any CAR, at any concentration, so long as the CAR comprises an extracellular recognition domain that specifically recognizes EpCAM, a hinge, a transmembrane domain and an intracellular signaling domain. As discussed in detail above, the examples of the instant disclosure demonstrate the use of an EpCAM CAR of SEQ ID NO: 3 at specific concentrations in colorectal cancer models. Therefore, the examples do not demonstrate the results referenced over the entire scope of the instantly claimed invention.
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 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 AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693