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
The amendment filed February 18, 2026 in response to the Office Action of September 22, 2025 is acknowledged and has been entered.
Claims 1, 2, 4, 9, 12, 17, and 18 have been amended.
Claims 3, 6-8, and 19-25 have been cancelled.
Claims 1, 2, 4, 5, and 9-18 are pending.
Claims 4 and 5 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1, 2, and 9-18 are currently under consideration as drawn to the elected invention.
It is noted that the amended claims are now limited to the antibody EpAb2-6. In view of the claim amendments, the priority date for claims 1, 2 and 9-18 has been established as November 14, 2019.
Claim objections set forth in Office Action of September 22, 2025 are hereby withdrawn in view of amendments on claims 17 and 18.
The 112(b) rejection set forth in Office Action of September 22, 2025 is hereby withdrawn in view of amendments on claim 2.
The 112(a) Written Description rejection set forth in Office Action of September 22, 2025 is hereby withdrawn in view of amendments on the independent claim 9.
The 102 rejection set forth in Office Action of September 22, 2025 is hereby withdrawn in view of claim amendments.
Claim Objections
Claims 1 and 2, which are dependent on claim 9, are objected pursuant to 37 CFR 1.75(c), a claim dependent form must refer only to a claim or claims previously set forth.
MAINTAINED/MODIFIED REJECTION
Claim Rejections - 35 USC § 112
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, 2 and 9-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
a method for inhibiting or eliminating a cancer in a subject, comprising administering to the subject an effective amount of an antibody EpAb2-6 and an inhibitor or an antagonist targeting PD-L1 in an amount effective to inhibit expression or activation of PD-L1,
does not reasonably provide enablement for:
a method for treating, inhibiting or eliminating a cancer in a subject, comprising administering to the subject an effective amount of an antibody EpAb2-6 and an inhibitor or an antagonist targeting PD-L1 in an amount effective to inhibit expression or activation of PD-L1.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. This is a SCOPE OF ENABLEMENT rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention 5) the state of the art, 6) the relative skill of those in the art, 7) the predictability of the art and 8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Nature of invention and breadth of the claims:
The claims are drawn to a method of treating, inhibiting or eliminating a cancer in a subject, comprising administering to the subject an effective amount of an antibody EpAb2-6 and an inhibitor or an antagonist targeting PD-L1 in an amount effective to inhibit expression or activation of PD-L1.
Based on paragraph [0039] of the instant publication US 2022/0403044 A1: the term “treating” would encompass preventing occurrence of disease. Thus, the claims encompass methods of preventing a broad genus of cancers by administering a combination of EpAb2-6 and a broad genus of inhibitors or antagonists targeting PD-L1 to the subject.
Relative skill in the art:
The relative skill of those in the art is high with an MD or a PhD.
Level of unpredictability in the art and State of the prior art:
As evidenced by Brennan (Brennan et al., JNCI J Natl Cancer Inst (2022), 114 (3):djab204, Publication Year: 2022), it is still unclear about the proportion of the cancers which is preventable, both in practice and in theory; for example, what portion is attributable to the environment or lifestyle or genetic inheritance or bad luck. There are important causes that remain to be detected (page 354, col. 2, para. 1). Thus, one of ordinary skill in the art could not predict the claimed combination would be able to prevent a broad genus of cancers encompassed by the claims.
Direction or guidance and working examples:
The working example of the specification and prior art (see 102 and 103 rejection below) discloses that antibody EpAb2-6 (and humanized EpAb2-6) in combination with a PD-L1 antibody (atezolizumab) has anti-tumor activity (e.g. inhibiting or eliminating a cancer) (Figs. 6E, 6F and 6G). However, the working examples do not support the scope of the claims: preventing all cancers of claim 9 or those of claims 13-17.
The quantity of experimentation needed:
The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the MPEP 2164.01 (a): "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genetech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Given the numerous combinations and cancers encompassed by claim 9, the lack of specific guidance and the insufficient working examples, undue experimentation would be required of one of skilled in the art to produce the invention commensurate with the scope of the method as claimed.
Response to Arguments
For the 112(a) Scope of Enablement rejections applicant argues:
Applicant has amended the specification to provide a more focused definition of "treating." This amendment is intended to directly address the Examiner's concerns regarding the scope of enablement.
Applicants’ arguments have been considered, but have not been found persuasive. The amended claim 9 recites “a method for treating, inhibiting, or eliminating cancer”. Based on paragraph [0039] of the instant publication US 2022/0403044 A1: the term “treating” would encompass preventing occurrence of disease. Thus, the claims encompass methods of preventing a broad genus of cancers by administering a combination of EpAb2-6 and a broad genus of inhibitors or antagonists targeting PD-L1 to the subject. As set forth above, the specification and prior art does not reasonably provide enablement for preventing the broadly claimed cancers. Thus, the rejection is maintained for the reasons of record.
Claim Rejections - 35 USC § 103
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.
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, 2, and 9-17 are rejected under 35 U.S.C. 103 as being unpatentable over Wu (Wu et al., US 2015/0017230 A1, Publication Date: 01/15/2015, cited in IDS of 05/13/2022, of record) in view of Campbell (Campbell et al., WO 2017/220989 A1, Publication Date: 12/28/2017, cited in IDS of 05/13/2022, of record), as evidenced by the instant publication US 2022/0403044 A1.
Wu teaches a method of treating cancer comprising administering to a subject in need thereof a composition that comprises anti-EpCAM antibody ([0025]), wherein the cancer can be colorectal cancer (claim 18).
Wu teaches that administration of EpAb2-6 can inhibit tumor growth in oral cancer xenografts. Targeting EpCAM by EpAb2-6 inhibits tumor sphere formation and tumor growth, while it prolongs the lifespan of tumor-bearing mice ([0118]).
Wu teaches EpCAM antibody EpAb2-6 and amino acid sequence of EpAb2-6 (Fig. 17).
Wu teaches that EpAb2-6 binds EGF-I (aa 27-59) of human EpCAM and EGF-II (aa66-135) of human EpCAM ([0121]). Thus, EpAb2-6 would target both EGF-1 and EGF-II. In addition, as evidenced paragraph [0054] of the instant publication US 2022/0403044 A1, EpAb2-6 is an EpCAM-neutralizing antibody targeting EGF-like domain I.
Wu teaches that EGF-like domain I corresponding to amino acids of 27-59 of human EpCAM (Fig. 8A on the same page of Fig. 5).
Wu teaches treating cancer with an inhibitor or antagonist targeting to EGF-like domain I of EpCAM, such as EpAb2-6 as set forth above, however, Wu does not teach that the method further comprises administering an inhibitor or an antagonist targeting to PD-L1 in an amount to inhibit expression or activation of PD-L1.
Campbell teaches that 1) PD-L1 is expressed in a number of tumors, including breast cancer, colon cancer, colorectal cancer (page 3, para. 2); 2) PD-1/PD-L1 negatively regulate T-cell responses; 3) upregulation of PD-l1 may allow cancer to evade the host immune system; 4) the expression of PD-L1 is associated with reduced survival and an unfavorable prognosis; 5) therapeutic antibody may enhance anti-tumor immune responses in cancer patients by blocking PD-1/PD-L1 pathway (page 3, para. 3);
Campbell teaches a method of treating a human PD-L1 mediated disease or condition such as cancers by administering a therapeutic effective amount of an anti-PD-L1 antibody (page, 106, Concept 43).
Campbell teaches that a therapeutically effective amount of an antibody may comprise an antigen-binding site that specifically binds PD-L1 (page 107, lines 23-24), or inhibition of a hPD-L1 biological activity of a cell (page 24, lines 16-17). This would read on an amount effective to inhibit activation of PD-L1.
Campbell teaches the method further comprising administering to the human a further therapy, for example a bispecific molecule comprising IL-15 and targeting to EpCAM (page 108, Concept 46).
Campbell teaches an immunocytokine comprising an immunoglobulin and an IL-2 cytokine, wherein the immunoglobulin specifically binds PD-L1, for example an antigen-binding site comprising the CDRs of atezolizumab (pages 127-128, Aspect 1a).
Campbell teaches the immunocytokine can be administered to a human for treating a hPD-L1 mediated disease or condition, such as colorectal cancer (page 163, Aspect 52; and page 165, Aspect 55).
Campbell teaches that anti-PD-L1 antibody can be administered with other therapies, including other antibodies (page 207, para. 4; page 28, para. 2).
Campbell teaches the method further comprising administering to the human a further therapy, for example a bispecific molecule comprising IL-15 and targeted toward EpCAM (page 165, Aspect 56).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine teachings of Wu and Campbell and to use the EpCAM inhibitor of Wu e.g. EpAb2-6 as the EpCAM targeting moiety in the combination therapy (e.g. atezolizumab + EpAb2-6) taught by Campbell, because Wu teaches that EpAb2-6 has high affinity to cancer cells ([0120] of Wu), has been tested in both in vitro and in vivo, and shows good anti-tumor activity ([0118] of Wu), can be used to treat colorectal cancer (claim 18 of Wu), and Campbell teaches that anti PD-L1 antibody such as atezolizumab can be combined with other immunotherapy for cancer treatment and atezolizumab (the elected species) is the most advanced PD-L1 antibody in clinical trials, and anti-PD-L1 antibody shows therapeutic effects in various cancers (the bridging paragraph of pages 3-4) and can be used to treat colorectal cancer. Based on the references, one of ordinary skilled in the art would have expected that the combination would have enhanced anti-tumor activity to cancers (e.g. colorectal cancer) by combining two mode-of -actions. The motivation would have been to develop a treatment with greater efficacy and to develop a novel therapeutic antibody combination for EpCAM and PD-L1 expressing cancers.
Regarding claim 12, Campbell teaches the antibody or fragment according to concept 46, wherein the further therapeutic agent is administered sequentially or simultaneously with the anti-hPD-L1 antibody or fragment (page 109, Concept 47).
Regarding claims 14, Campbell teaches the antibody can bind to cells expressing PD-L1 including tumor cells by means of ADCC (page 205, para. 3). Campbell teaches surface expression of PD-L1 may significantly enhance the clinical success of treatment with drugs targeting the PD-1/PD-L1 pathway. As set forth above, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine teachings from Wu and Campbell to reach the method of instant claim 9, and to modify/apply the method to cancers expressing PD-L1, because one of ordinary skill in the art would have expected that the method taught by Wu and Campbell would be more effective to patients with PD-L1 expressing or overexpressing cancers. One of ordinary skill in the art would have expected that PD-L1 expressing cancer would respond to a therapy targeting to PD-L1.
Regarding claim 16, Campbell teaches the diseases can be treated include neoplastic disease and the metastasis associated with such neoplastic disease, such as colon cancer, colorectal cancer, small cell lung cancer (page 207, para. 3).
Regarding claim 17, Wu teaches a method of detecting and/or diagnosing cancer cells expressing EpCAM (claim 15) and a method of treating cancer expressing EpCAM (claim 14). Wu teaches that normal control cells does not expressing EpCAM (Fig. 1C and [0115]), thus, cancer expressing EpCAM would read on EpCAM over-expressing cancer. In addition, one of ordinary skill in the art would have expected that EpCAM overexpressing cancer would respond to a therapy targeting to EpCAM.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Wu (Wu et al., US 2015/0017230 A1, Publication Date: 01/15/2015, cited in IDS of 05/13/2022, of record) in view of Campbell (Campbell et al., WO 2017/220989 A1, Publication Date: 12/28/2017, cited in IDS of 05/13/2022, of record) as applied to claims 1, 2, and 9-17 above, and further in view of Sun (Sun et al., Cellular Oncology, (2018) 41: 651-662, Publication Date: 08/16/2018, of record) and Wangpaichitr (Wangpaichitr et al., Cell Dev. Biology, 2017, 6:2, Publication Date: 04/28/2017, of record).
Wu and Campbell teach method of claim 9 as set forth above. Wu further teaches that overexpression of EpCAM is associated with drug resistant ([0130] of Wu). However, Wu and Campbell do not explicitly teach wherein the subject who has been treated with at least one anti-cancer therapy or anti-cancer agent.
Sun teaches that 1) tumor cells (OE-19) develop resistance to adriamycin, cisplatin and 5-fluorouracil (ACF) treatment; 2) OE-19 cells resistant to the drug treatment have increased EpCAM expression; 3) downregulation of EpCAM increased the ACF efficacy to kill OE-19 cells; 4) increased EpCAM expression is associated with an aggressive growth pattern of OE-19 cell spheres in vivo (the whole document, Abstract in particular).
Wangpaichitr teaches acquired cisplatin resistance results in accumulation of cellular ROS. Increased ROS levels involved in metabolic reprogramming by switching cisplatin resistant cells from glycolysis toward oxidative metabolism and triggers epithelial-mesenchymal transition (EMT). Furthermore, induction of EMT may lead to increase in PD-L1 expression tumor cells (Fig. 1).
Wangpaichitr teaches that treatment with cisplatin and 5-Fu contribute to acquired PD-L1 expression in many solid tumors. Knocking down PD-L1 was able to overcome cisplatin resistance (page 3, Drug resistance and PD-L1 expression).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use the combination of therapy of claim 9 for treating a cancer in a subject as set forth above, and to apply the combination (e.g. EpAb2-6 and atezolizumab) taught by Wu and Campbell to a subject who has been treated with at least one anti-cancer-therapy e.g. cisplatin, because Sun and Wangpaichitr teach 1) cisplatin can induce drug-resistant in various cancer cells; 2) cisplatin-resistant is associated with increased expression of EpCAM and PD-L1; 3) down-regulation of EpCAM or PD-L1 can overcome cisplatin resistant. Thus, based on the references, one of ordinary skilled in the art would have expected that targeting both EpCAM and PD-L1 would be able to overcome cisplatin-resistance and would be effective for patients have been treated with cisplatin and have developed resistance to cisplatin. The motivation would have been to develop a novel treatment for this special patient population.
Response to Arguments
For the 103 rejections applicant argues:
The Examiner's position is that Campbell teaches the use of a further therapeutic agent in the pharmaceutical composition (pages 108-109, Concept 46). However, except for mentioning EpCAM is a long laundry list of potential targets for so-called further therapeutic agents, Campbell is completely silent about an actual combination targeting EpCAM.
It is noted that Campbell fails to specifically identify EpCAM as a preferred target, nor does it provide any experimental data demonstrating the efficacy of the specific combination of "PD-LI + EpCAM." In fact, Campbell lacks any guidance or 'roadmap' explaining how to select a promising target from its extensive list of candidates.
Without the guidance provided by the present disclosure, a person having ordinary skill in the art, when faced with the numerous options disclosed in Campbell, would not have a reasonable expectation of success in selecting EpCAM specifically for this combination. Consequently, Applicant submits that Campbell is non-enabling with respect to the claimed
subject matter.
Furthermore, Campbell focuses on the creation of bi-specific molecules or CAR-T therapies, which involve complex molecular engineering, whereas the present application claims a combination therapy based on a distinct mechanism. The teaching of Campbell was heavily focused on cytokines, particular! y IL-2 and IL-15' s role, and the CAR-T cells aspect of the therapeutic effects. Without further guidance from the cited references, the complexity and unpredictability of cancer treatment bar a skilled artisan from foreseeing the outcome of the therapy combining Wu and Campbell's teaching.
Applicants’ arguments have been considered, but have not been found persuasive. First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As set forth above, Wu explicitly teaches a method of treating cancer comprising administering to a subject in need thereof a composition that comprises anti-EpCAM antibody ([0025]), wherein the cancer can be colorectal cancer (claim 18). Wu further teaches that administration of EpAb2-6 can inhibit tumor growth in oral cancer xenografts. Targeting EpCAM by EpAb2-6 inhibits tumor sphere formation and tumor growth, while it prolongs the lifespan of tumor-bearing mice ([0118]). Based on teachings of Wu, one of ordinary skill in the art would have recognized that EpAb2-6 would be a good therapeutic antibody for treating colorectal cancer. Campbell’s teachings are not limited to the points recited by applicant. As set forth in above, Campbell teaches PD-L1 is expressed in a number of tumors, including colorectal cancer (page 3, para. 2); therapeutic antibody may enhance anti-tumor immune responses in cancer patients by blocking PD-1/PD-L1 pathway (page 3, para. 3). Campbell teaches that PD-L1 antibody (such as atezolizumab) can be used for treating cancers, such as colorectal cancer (page 163, Aspect 52; and page 165, Aspect 55), and can be combined with antibody targeting EpCAM. Based on the references, one of ordinary skilled in the art would have expected that the combination would have enhanced anti-tumor activity to cancers (e.g. colorectal cancer) by combining two mode-of -actions. The motivation would have been to develop a treatment with greater efficacy and to develop a novel therapeutic antibody combination for EpCAM and PD-L1 expressing cancers.
Regarding enablement and unpredictability argument, Wu and Campbell combined teach specific antibody: EpAb2-6, specific PD-L1 antibody: atezolizumab and specific cancer: colorectal cancer. One of ordinary skilled in the art would have known to combine two well-known components in the art for treating specific. As set forth above, one of ordinary skill in the art would have a reasonable expectation the combination would be effective, because either component alone can be used to treat colorectal cancer and bringing two anti-tumor agents together would enhance the anti-tumor activity. In addition, in the field of biological technology, no invention has absolute certainty of success before experimental tests. Thus, only a reasonable expectation of success (not absolute) would have motivated an artisan to make the claimed fusion protein. Given the teachings from references, an ordinary skilled in the art would have would have had a reasonable expectation of success in producing the claimed invention.
Applicant further argues unexpected results:
The present disclosure surprisingly found that EGF-like domain I within the extracellular domain of EpCAM (EpEX) binds EGFR, activating both AKT and MAPK signaling to inhibit FOXO3a function and stabilize PD-LI protein. A treatment with EpAb2-6 inhibits AKT and FOXO3a phosphorylation, increases FOXO3a nuclear translocation, and upregulates HtrA2 expression to promote apoptosis while decreasing PD-LI protein levels to enhance the cytotoxic activity of CD8+ T cells. As shown in the working examples, the combination of an anti-EpCAM antibody and an anti-PD-LI antibody exhibited an unexpected effect in tumor elimination and extension of survival of a subject in metastasis, suggesting a new combination therapy for cancer immunotherapy in subjects (paras., 0005, 0151, and 0152 of the instant specification). The inhibitory effect roots in a synergistic effect that permits a lower dosage of EpAb2-6 and a PD-LI inhibitor or antagonist, which achieves additional benefits of reduced potential side effects or toxicity (para. 0066 of the instant specification).
Furthermore, the significant therapeutic effects were evident in, for example, Example 6 of the present disclosure. See para. 0156-0160 and especially 0159. Using a PBMC-cell line- derived xenograft (CDX) model, mice were intravenously injected with PBMC cells and treated with Atezolizumab (anti-PD-LI antibody) and EpAb2-6 twice weekly for one month. Treatment with Atezolizumab or EpAb2-6 alone inhibited tumor growth in PBMC-H441 mice, and combination therapy produced a much better tumor inhibitory effect (Figures 6F and 6G). At the end of treatment, tumor tissues were collected, and CD8+ T cells were analyzed by flow cytometry. The CD8+ T cell population increased in mice receiving combination therapy (Figure 6H). Collectively, these data indicate the synergistic effect of EpAb2-6 and an anti-PD-LI therapy that was not suggested by the cited references.
Applicants’ arguments have been considered, but have not been found persuasive. First, Wu teaches the same antibody: EpAb2-6 as the one used in the instant examples. Thus, EpAb2-6 would have the properties of activating both AKT and MAPK signaling to inhibit FOXO3a function and stabilize PD-LI protein. In addition, as set forth above, based on the teachings of Wu and Campbell, one of ordinary skilled in the art would be able to reach the claimed invention without knowing the specific mechanism.
Regarding the synergistic effect of a specific EpAb2-6 + Atezolizumab combination to lung cancer model (PBMC-H441 xenograft), the evidence of nonobviousness must be commensurate in scope with the claims to rebut the prima facie case of obviousness. See MPEP 716.02 (d). In this case, the claims are not limited to the specific combination and specific cancers. Thus, the example is not commensurate in scope with the claimed invention and is not probative on the non-obviousness of the claimed invention.
Thus, in view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 9,187,558
Claims 1, 2, and 9-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,187,558 B2 (hereinafter Pat. 558, of record), as evidenced by the instant publication US 2022/0403044 A1, in view of Wu (Wu et al., US 2015/0017230 A1, Publication Date: 01/15/2015, cited in IDS of 05/13/2022, of record) and Campbell (Campbell et al., WO 2017/220989 A1, Publication Date: 12/28/2017, cited in IDS of 05/13/2022, of record).
The claims of Pat. 558 teach an isolated monoclonal antibody or an antigen-binding fragment thereof that has a specific binding affinity to an epitope within the sequence of KPEGALQNNDGLYDPDCDE (SEQ ID NO: 63) located within the EGF-like domain II of epithelial cell adhesion molecule (EpCAM, SEQ ID NO: 1) (claim 1 of Pat. 558).
The claims of Pat. 558 teach The antibody or binding fragment of claim 1, comprising:
(a) a heavy chain variable region, comprising: (i) complementarity determining region 1 (CDR1) comprising SEQ ID NO: 4; (ii) complementarity determining region 2 (CDR2) comprising SEQ ID NO: 5; and (iii) complementarity determining region 3 (CDR3) comprising SEQ ID NO: 6; and
(b) a light chain variable region, comprising: (i) CDR1comprising SEQ ID NO: 7; (ii) CDR2comprising SEQ ID NO: 8; and (iii) CDR3comprising SEQ ID NO: 9 (claim 3). As evidenced by Fig. 17, the CDRs recited by claim 3 are the CDRs of antibody EpAb2-6. As set forth above, EpAb2-6 reads on the inhibitor or antagonist of instant claims 1, 2, and 6-8.
The claims of Pat. 558 teach the antibody or antigen-binding fragment comprising the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 24, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 25 (claims 6, 11 and 15). As evidenced by Fig. 7, SEQ ID NO: 24 and SEQ ID NO: 25 are VH and VL domain of humanized EpAb2-6 (hEpAb2-6).
Although the claims 1-12, 17 and 19 of Pat. 558 are directed to a composition, claims 14-17 and 20 are drawn to methods of treating cancers using the compositions of claims 1-12, 17 and 10.
The claims of Pat. 558 teach a method of inhibiting growth of cancer cells and/or tumor-initiating cells, comprising: administering to a subject in need thereof a composition that comprises: (a) the antibody or antigen-binding fragment of claim 10; and (b) a pharmaceutically acceptable carrier, wherein said cancer cells and/or tumor-initiating cells express EpCAM (claim 13 of Pat. 558).
The claims of Pat. 558 teach that the cancer can be colorectal cancer (claim 17).
As evidenced by paragraph [0054] of the instant publication US 2022/0403044 A1, EpAb2-6 is an EpCAM-neutralizing antibody targeting EGF-like domain I. Thus, EpAb2-6 would read antibody of claim 1 and 2.
Taken together, the claims of Pat. 558 teach antibody EpAb2-6 and humanized hEpAb2-6 and a method of using the antibodies to treat EpCAM expressing cancers.
The claims of Pat. 558 teach treating cancer with an inhibitor or antagonist targeting to EGF-like domain I of EpCAM, such as EpAb2-6 as set forth above, however, the claims of Pat. 558 do not teach the method further comprises administering an inhibitor or an antagonist targeting to PD-L1 in an amount to inhibit expression or activation of PD-L1.
Wu and Campbell teach as set forth above. In particular, Wu teaches that EpAb2-6 has high affinity to cancer cells, has been tested in both in vitro and in vivo, and shows good anti-tumor activity, can be used to treat colorectal cancer. Campbell teaches a method of treating a human PD-L1 mediated disease or condition such as colorectal cancer by administering a therapeutic effective amount of an anti-PD-L1 antibody (e.g. atezolizumab) and the method further comprising administering to the human a further immunotherapy therapy.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine teachings of the claims of Pat. 558, Wu and Campbell and to use EpCAM inhibitor taught by the claims of Pat. 558 and Wu e.g. EpAb2-6 as the EpCAM targeting moiety in the combination therapy with atezolizumab taught by Campbell, because EpAb2-6 has high affinity to cancer cells ([0120] of Wu), has been tested in both in vitro and in vivo, and shows good anti-tumor activity ([0118] of Wu), and can be used to treat colorectal cancer; Campbell teaches that anti PD-L1 antibody such as atezolizumab can be combined with other immunotherapy for cancer treatment and atezolizumab (the elected species) is the most advanced PD-L1 antibody in clinical trials, and anti-PD-L1 antibody shows therapeutic effects in various cancers (the bridging paragraph of pages 3-4) and can be used to treat colorectal cancer. Based on the references, one of ordinary skilled in the art would have expected that the combination would have enhanced anti-tumor activity to cancers (e.g. colorectal cancer). The motivation would have been to develop a treatment with greater efficacy and to develop a novel therapeutic antibody combination for EpCAM and PD-L1 expressing cancers.
Regarding claim 12, Campbell teaches the antibody or fragment according to concept 46, wherein the further therapeutic agent is administered sequentially or simultaneously with the anti-hPD-L1 antibody or fragment (page 109, Concept 47).
Regarding claims 14, Campbell teaches the antibody can bind to cells expressing PD-L1 including tumor cells by means of ADCC (page 205, para. 3). Campbell teaches surface expression of PD-L1 may significantly enhance the clinical success of treatment with drugs targeting the PD-1/PD-L1 pathway. As set forth above, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine teachings from the claims of Pat. 558, Wu and Campbell to reach the method of instant claim 9, and to modify/apply the method to cancers expressing PD-L1, because one of ordinary skill in the art would have expected that the method taught by Wu and Campbell would be more effective to patients with PD-L1 expressing or overexpressing cancers. One of ordinary skill in the art would have expected that PD-L1 expressing cancer would respond to a therapy targeting to PD-L1.
Regarding claim 16, Campbell teaches the diseases can be treated include neoplastic disease and the metastasis associated with such neoplastic disease, such as colon cancer, colorectal cancer, small cell lung cancer (page 207, para. 3).
Regarding claim 17, Wu teaches a method of detecting and/or diagnosing cancer cells expressing EpCAM (claim 15) and a method of treating cancer expressing EpCAM (claim 14). Wu teaches that normal control cells does not expressing EpCAM (Fig. 1C and [0115]), thus, cancer expressing EpCAM would read on EpCAM over-expressing cancer. In addition, one of ordinary skill in the art would have expected that EpCAM overexpressing cancer would respond to a therapy targeting to EpCAM.
Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,187,558 B2 (hereinafter Pat. 558, of record) as evidenced by the instant publication US 2022/0403044 A1, in view of Wu (Wu et al., US 2015/0017230 A1, Publication Date: 01/15/2015, cited in IDS of 05/13/2022, of record) and Campbell (Campbell et al., WO 2017/220989 A1, Publication Date: 12/28/2017, cited in IDS of 05/13/2022, of record) as applied to claims 1, 2, and 9-17 above, and further in view of Sun (Sun et al., Cellular Oncology, (2018) 41: 651-662, Publication Date: 08/16/2018, of record) and Wangpaichitr (Wangpaichitr et al., Cell Dev. Biology, 2017, 6:2, Publication Date: 04/28/2017, of record).
The claims of Pat. 558, Wu and Campbell teach method of claim 9 as set forth above. Wu further teaches that overexpression is associated with drug resistant ([0130] of Wu). However, the claims of Pat. 558, Wu and Campbell do not explicit teach wherein the subject who has been treated with at least one anti-cancer therapy or anti-cancer agent.
Sun teaches that 1) tumor cells (OE-19) develop resistance to adriamycin, cisplatin and 5-fluorouracil (ACF) treatment; 2) OE-19 cells resistant to the drug treatment have increased EpCAM expression; 3) downregulation of EpCAM increased the ACF efficacy to kill OE-19 cells; 4) increased EpCAM expression is associated with an aggressive growth pattern of OE-19 cell spheres in vivo (the whole document, Abstract in particular).
Wangpaichitr teaches acquired cisplatin resistance results in accumulation of cellular ROS. Increased ROS levels involved in metabolic reprogramming by switching cisplatin resistant cells from glycolysis toward oxidative metabolism and triggers epithelial-mesenchymal transition (EMT). Furthermore, induction of EMT may lead to increase in PD-L1 expression tumor cells (Fig. 1).
Wangpaichitr teaches that treatment with cisplatin and 5-Fu contribute to acquired PD-L1 expression in many solid tumors. Knocking down PD-L1 was able to overcome cisplatin resistance (page 3, Drug resistance and PD-L1 expression).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use a combination of therapy of claim 9 for treating a cancer in a subject as set forth above, and to apply the combination (e.g. EpAb2-6 and atezolizumab) taught by the claims of Pat. 558, Wu and Campbell to a subject who has been treated with at least one anti-cancer-therapy e.g. cisplatin, because Sun and Wangpaichitr teach 1) cisplatin can induce drug-resistant in various cancer cells; 2) cisplatin-resistant is associated with increased expression of EpCAM and PD-L1; 3) down-regulation of EpCAM or PD-L1 can overcome cisplatin resistant. Thus, based on the references, one of ordinary skilled in the art would have expected that targeting both EpCAM and PD-L1 would be able to overcome cisplatin-resistance and would be effective for patients have been treated with cisplatin and have developed resistance to cisplatin. The motivation would have been to develop a novel treatment for this special patient population.
Application No. 18/572,564
Claims 1, 2, and 9-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of co-pending Application No. 18/572,564 (hereinafter Appl. 564, US 2025/0129146 A1, of record) in view of Wu (Wu et al., US 2015/0017230 A1, Publication Date: 01/15/2015, cited in IDS of 05/13/2022, of record) and Campbell (Campbell et al., WO 2017/220989 A1, Publication Date: 12/28/2017, cited in IDS of 05/13/2022, of record).
The claims of Appl. 564 teach a method for treating cancer, comprising
administering to a subject in need thereof (i) an effective amount of a first inhibitory agent that inhibits the activation of epithelial cell adhesion molecule (EpCAM) signaling; and (ii) an effective amount of a second inhibitory agent that inhibits the activation of Wnt signaling (claim 1 of Appl. 564).
The claims of Appl. 564 teach the method of claim 1, wherein the first inhibitory agent is an antibody directed to EpEX or an antigen-binding fragment thereof (claim 5), wherein the antibody specifically binds to epidermal growth factor (EGF)-like domains I and II (claim 6 of Appl. 564); wherein the antibody has a specific binding affinity to an epitope within the sequence of CVCENYKLAVN (aa 27 to 37) (SEQ ID NO: 20) located in the EGF-like domain I, and KPEGALQNNDGLYDPDCD (aa 83 to 100) (SEQ ID NO: 19) located in the EGF-like domain II (claim 7 of Appl. 564).
The claims of Appl. 564 teach wherein the antibody or antigen-binding fragment comprises (a) a heavy chain variable region (VH) which comprises a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 4, and a heavy chain complementary determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 6; and (b) a light chain variable region (VL) which comprises a light chain complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 9, a light chain complementary determining region (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 11, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 13 (claim 8 of Appl. 564).
As evidenced by paragraph [0080] and Table 1 of the specification of Appl. 564 (US 2025/0129146 A1), antibody EpAb2-6 comprises the recited CDRs. In addition, paragraph [0074] of the specification teaches EpAb2-6 is a neutralizing antibody.
The claims of Appl. 564 teach the cancer can be a colon cancer (claim 14 of Appl. 564).
Although the claims of Appl. 564 recites a secondary inhibitory agent that inhibits the activation of Wnt signaling, the instant claims 1, 2, and 6-8 do not excluding additional agents in the method.
The claims of Appl. 564 teach treating cancer with an inhibitor or antagonist targeting to EGF-like domain I of EpCAM, such as EpAb2-6 or variant of EpAb2-6 as set forth above, however, the claims of Appl. 564 do not teach the method further comprises administering an inhibitor or an antagonist targeting to PD-L1 in an amount to inhibit expression or activation of PD-L1.
Wu teaches as set forth above. In particular, Wu teachesEpAb2-6 has higher binding affinity to EpCAM, and EpAb2-6 inhibits tumor growth in oral cancer xenografts by administering EpAb2-6. Targeting EpCAM by EpAb2-6 inhibits tumor sphere formation and tumor growth, while it prolongs the lifespan of tumor-bearing mice ([0118]).
Campbell teaches as set forth above. In particular, Campbell teaches a method of treating or preventing a human PD-L1 mediated disease or condition such as cancers by administering a therapeutic effective amount of an anti-PD-L1 antibody and the method further comprising administering to the human a further therapy, for example a bispecific molecule comprising IL-15 and targeted toward EpCAM.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine teachings of the claims of Appl. 564, Wu and Campbell and to use EpCAM inhibitor taught by the claims of Appl. 564 and Wu e.g. EpAb2-6 as the EpCAM targeting moiety in the combination therapy with atezolizumab taught by Campbell, because EpAb2-6 has high affinity to cancer cells ([0120] of Wu), has been tested in both in vitro and in vivo, and shows good anti-tumor activity ([0118] of Wu), and can be used to treat colorectal cancer; Campbell teaches that anti PD-L1 antibody such as atezolizumab can be combined with other immunotherapy for cancer treatment and atezolizumab (the elected species) is the most advanced PD-L1 antibody in clinical trials, and anti-PD-L1 antibody shows therapeutic effects in various cancers (the bridging paragraph of pages 3-4) and can be used to treat colorectal cancer. Based on the references, one of ordinary skilled in the art would have expected that the combination would have enhanced anti-tumor activity to cancers (e.g. colorectal cancer). The motivation would have been to develop a treatment with greater efficacy and to develop a novel therapeutic antibody combination for EpCAM and PD-L1 expressing cancers.
Regarding claim 12, Campbell teaches the antibody or fragment according to concept 46, wherein the further therapeutic agent is administered sequentially or simultaneously with the anti-hPD-L1 antibody or fragment (page 109, Concept 47).
Regarding claims 14, Campbell teaches the antibody can bind to cells expressing PD-L1 including tumor cells by means of ADCC (page 205, para. 3). Campbell teaches surface expression of PD-L1 may significantly enhance the clinical success of treatment with drugs targeting the PD-1/PD-L1 pathway. As set forth above, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine teachings from the claims of Appl. 564, Wu and Campbell to reach the method of instant claim 9, and to modify/apply the method to cancers expressing PD-L1, because one of ordinary skill in the art would have expected that the method taught by Wu and Campbell would be more effective to patients with PD-L1 expressing or overexpressing cancers.
Regarding claim 16, Campbell teaches the diseases can be treated include neoplastic disease and the metastasis associated with such neoplastic disease, such as colon cancer, colorectal cancer, small cell lung cancer (page 207, para. 3).
Regarding claim 17, Wu teaches a method of detecting and/or diagnosing cancer cells expressing EpCAM (claim 15) and a method of treating cancer expressing EpCAM (claim 14). Wu teaches that normal control cells does not expressing EpCAM (Fig. 1C and [0115]), thus, cancer expressing EpCAM would read on EpCAM over-expressing cancer. In addition, one of ordinary skill in the art would have expected that EpCAM overexpressing cancer would respond to a therapy targeting to EpCAM.
This is a provisional nonstatutory double patenting rejection.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of co-pending Application No. 18/572,564 (hereinafter Appl. 564, US 2025/0129146 A1, of record) in view of Wu (Wu et al., US 2015/0017230 A1, Publication Date: 01/15/2015, cited in IDS of 05/13/2022, of record) and Campbell (Campbell et al., WO 2017/220989 A1, Publication Date: 12/28/2017, cited in IDS of 05/13/2022, of record), as applied to claims 1, 2, and 6-17 above, and further in view of Sun (Sun et al., Cellular Oncology, (2018) 41: 651-662, Publication Date: 08/16/2018, of record) and Wangpaichitr (Wangpaichitr et al., Cell Dev. Biology, 2017, 6:2, Publication Date: 04/28/2017, of record).
The claims of Appl. 564, Wu and Campbell teach method of claim 9 as set forth above. Wu further teaches that overexpression is associated with drug resistant ([0130] of Wu). However, the claims of Appl. 564, Wu and Campbell do not explicit teach wherein the subject who has been treated with at least one anti-cancer therapy or anti-cancer agent.
Sun teaches that 1) tumor cells (OE-19) develop resistance to adriamycin, cisplatin and 5-fluorouracil (ACF) treatment; 2) OE-19 cells resistant to the drug treatment have increased EpCAM expression; 3) downregulation of EpCAM increased the ACF efficacy to kill OE-19 cells; 4) increased EpCAM expression is associated with an aggressive growth pattern of OE-19 cell spheres in vivo (the whole document, Abstract in particular).
Wangpaichitr teaches acquired cisplatin resistance results in accumulation of cellular ROS. Increased ROS levels involved in metabolic reprogramming by switching cisplatin resistant cells from glycolysis toward oxidative metabolism and triggers epithelial-mesenchymal transition (EMT). Furthermore, induction of EMT may lead to increase in PD-L1 expression tumor cells (Fig. 1).
Wangpaichitr teaches that treatment with cisplatin and 5-Fu contribute to acquired PD-L1 expression in many solid tumors. Knocking down PD-L1 was able to overcome cisplatin resistance (page 3, Drug resistance and PD-L1 expression).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use a combination of therapy of claim 9 for treating a cancer in a subject as set forth above, and to apply the combination (e.g. EpAb2-6 and atezolizumab) taught by the claims of Appl. 564, Wu and Campbell to a subject who has been treated with at least one anti-cancer-therapy e.g. cisplatin, because Sun and Wangpaichitr teach 1) cisplatin can induce drug-resistant in various cancer cells; 2) cisplatin-resistant is associated with increased expression of EpCAM and PD-L1; 3) down-regulation of EpCAM or PD-L1 can overcome cisplatin resistant. Thus, based on the references, one of ordinary skilled in the art would have expected that targeting both EpCAM and PD-L1 would be able to overcome cisplatin-resistance and would be effective for patients have been treated with cisplatin and have developed resistance to cisplatin. The motivation would have been to develop a novel treatment for this special patient population.
This is a provisional nonstatutory double patenting rejection.
Application No. 18/573,623
Claims 1, 2, and 9-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of co-pending Application No. 18/573,623 (hereinafter Appl. 623, of record) in view of Wu (Wu et al., US 2015/0017230 A1, Publication Date: 01/15/2015, cited in IDS of 05/13/2022, of record) and Campbell (Campbell et al., WO 2017/220989 A1, Publication Date: 12/28/2017, cited in IDS of 05/13/2022, of record).
The claims of Appl. 623 teach a method for treating cancer, comprising administering to a subject in need thereof (i) an effective amount of a first inhibitory agent that inhibits the activation of epithelial cell adhesion molecule (EpCAM) signaling; and (ii) an effective amount of a second inhibitory agent that inhibits the activation of HGFR signaling (claim 1).
The claims of Appl. 623 teach wherein the first inhibitory agent is an antibody directed to an extracellular domain of EpCAM (EpEX) or an antigen-binding fragment thereof (claim 3), wherein the antibody binds to EGF-like domains I and II (claim 4), wherein the antibody has a specific binding affinity to an epitope within the sequence of CVCENYKLAVN (aa 27 to 37) (SEQ ID NO: 20) located in the EGF-like domain I, and KPEGALQNNDGLYDPDCD (aa 83 to 100) (SEQ ID NO: 19) located in the EGF-like domain II (claim 6). Thus, the claims of Appl. 564 teach antibodies reading on instant claims 1, 2, and 6.
The claims of Appl. 623 teach wherein the antibody or antigen-binding fragment comprises (a) a heavy chain variable region (VH) which comprises a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 4, and a heavy chain complementary determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 6; and(b) a light chain variable region (VL) which comprises a light chain complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 9, a light chain complementary determining region (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 11, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 13 (claim 7).
As evidenced by paragraph [0064] and Table 1 of the specification of 12/22/2023, antibody EpAb2-6 comprises the recited CDRs.
The claims of Appl. 623 teach the cancer can be a colon cancer (claim 13).
The claims of Appl. 623 teach treating cancer with an inhibitor or antagonist targeting to EGF-like domain I of EpCAM, such as EpAb2-6 or variant of EpAb2-6 as set forth above, however, the claims of Appl. 623 do not teach the method further comprises administering an inhibitor or an antagonist targeting to PD-L1 in an amount to inhibit expression or activation of PD-L1.
Wu teaches as set forth above. In particular, Wu teaches EpAb2-6 has high binding affinity to EpCAM, and EpAb2-6 inhibits tumor growth in oral cancer xenografts by administering EpAb2-6. Targeting EpCAM by EpAb2-6 inhibits tumor sphere formation and tumor growth, while prolongs the lifespan of tumor-bearing mice ([0118]).
Campbell teaches as set forth above. In particular, Campbell teaches a method of treating or preventing a human PD-L1 mediated disease or condition such as cancers by administering a therapeutic effective amount of an anti-PD-L1 antibody and the method further comprising administering to the human a further therapy, for example a bispecific molecule comprising IL-15 and targeted toward EpCAM.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine teachings of the claims of Appl. 623, Wu and Campbell and to use EpCAM inhibitor taught by the claims of Appl. 623 and Wu e.g. EpAb2-6 as the EpCAM targeting moiety in the combination therapy with atezolizumab taught by Campbell, because EpAb2-6 has high affinity to cancer cells ([0120] of Wu), has been tested in both in vitro and in vivo, and shows good anti-tumor activity ([0118] of Wu), and can be used to treat colorectal cancer; Campbell teaches that anti PD-L1 antibody such as atezolizumab cab be combined with other immunotherapy for cancer treatment and atezolizumab (the elected species) is the most advanced PD-L1 antibody in clinical trials, and anti-PD-L1 antibody shows therapeutic effects in various cancers (the bridging paragraph of pages 3-4) and can be used to treat colorectal cancer. Based on the references, one of ordinary skilled in the art would have expected that the combination would have enhanced anti-tumor activity to cancers (e.g. colorectal cancer). The motivation would have been to develop a treatment with greater efficacy and to develop a novel therapeutic antibody combination for EpCAM and PD-L1 expressing cancers.
Regarding claim 12, Campbell teaches the antibody or fragment according to concept 46, wherein the further therapeutic agent is administered sequentially or simultaneously with the anti-hPD-L1 antibody or fragment (page 109, Concept 47).
Regarding claims 14, Campbell teaches the antibody can bind to cells expressing PD-L1 including tumor cells by means of ADCC (page 205, para. 3). Campbell teaches surface expression of PD-L1 may significantly enhance the clinical success of treatment with drugs targeting the PD-1/PD-L1 pathway. As set forth above, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine teachings from the claims of Appl. 623, Wu and Campbell to reach the method of instant claim 1, and to modify/apply the method to cancers expressing PD-L1, because one of ordinary skill in the art would have expected that the method taught by Wu and Campbell would be more effective to patients with PD-L1 expressing or overexpressing cancers.
Regarding claim 16, Campbell teaches the diseases can be treated include neoplastic disease and the metastasis associated with such neoplastic disease, such as colon cancer, colorectal cancer, small cell lung cancer (page 207, para. 3).
Regarding claim 17, Wu teaches a method of detecting and/or diagnosing cancer cells expressing EpCAM (claim 15) and a method of treating cancer expressing EpCAM (claim 14). Wu teaches that normal control cells does not expressing EpCAM (Fig. 1C and [0115]), thus, cancer expressing EpCAM would read on EpCAM over-expressing cancer. In addition, one of ordinary skill in the art would have expected that EpCAM overexpressing cancer would respond to a therapy targeting to EpCAM.
This is a provisional nonstatutory double patenting rejection.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of co-pending Application No. 18/573,623 (hereinafter Appl. 623, of record) in view of Wu (Wu et al., US 2015/0017230 A1, Publication Date: 01/15/2015, cited in IDS of 05/13/2022, of record) and Campbell (Campbell et al., WO 2017/220989 A1, Publication Date: 12/28/2017, cited in IDS of 05/13/2022, of record), as applied to claims 1, 2, and 6-17 above, and further in view of Sun (Sun et al., Cellular Oncology, (2018) 41: 651-662, Publication Date: 08/16/2018, of record) and Wangpaichitr (Wangpaichitr et al., Cell Dev. Biology, 2017, 6:2, Publication Date: 04/28/2017, of record).
The claims of Appl. 623, Wu and Campbell teach method of claim 9 as set forth above. Wu further teaches that overexpression is associated with drug resistant ([0130] of Wu). However, the claims of Appl. 623, Wu and Campbell do not explicit teach wherein the subject who has been treated with at least one anti-cancer therapy or anti-cancer agent.
Sun teaches that 1) tumor cells (OE-19) develop resistance to adriamycin, cisplatin and 5-fluorouracil (ACF) treatment; 2) OE-19 cells resistant to the drug treatment have increased EpCAM expression; 3) downregulation of EpCAM increased the ACF efficacy to kill OE-19 cells; 4) increased EpCAM expression is associated with an aggressive growth pattern of OE-19 cell spheres in vivo (the whole document, Abstract in particular).
Wangpaichitr teaches acquired cisplatin resistance results in accumulation of cellular ROS. Increased ROS levels involved in metabolic reprogramming by switching cisplatin resistant cells from glycolysis toward oxidative metabolism and triggers epithelial-mesenchymal transition (EMT). Furthermore, induction of EMT may lead to increase in PD-L1 expression tumor cells (Fig. 1).
Wangpaichitr teaches that treatment with cisplatin and 5-Fu contribute to acquired PD-L1 expression in many solid tumors. Knocking down PD-L1 was able to overcome cisplatin resistance (page 3, Drug resistance and PD-L1 expression).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use a combination of therapy of claim 9 for treating a cancer in a subject as set forth above, and to apply the combination (e.g. EpAb2-6 and atezolizumab) taught by the claims of Appl. 623, Wu and Campbell to a subject who has been treated with at least one anti-cancer-therapy e.g. cisplatin, because Sun and Wangpaichitr teach 1) cisplatin can induce drug-resistant in various cancer cells; 2) cisplatin-resistant is associated with increased expression of EpCAM and PD-L1; 3) down-regulation of EpCAM or PD-L1 can overcome cisplatin resistant. Thus, based on the references, one of ordinary skilled in the art would have expected that targeting both EpCAM and PD-L1 would be able to overcome cisplatin-resistance and would be effective for patients have been treated with cisplatin and have developed resistance to cisplatin. The motivation would have been to develop a novel treatment for this special patient population.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
For the Double Patenting rejections applicant argues:
The Applicant disagrees with the nonstatutory double patenting rejections and
respectfully requests that the rejection be held in abeyance until the claims in the involved applications are otherwise found to be allowable.
Applicants’ arguments have been considered, but have not been found persuasive because the claims of the instant application are still obvious in view of the patented or co-pending claims and a terminal disclaimer has not been filed. Thus, the rejection is maintained for the reasons of record.
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 CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (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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/CHENG LU/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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