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 .
Response to Remarks/Amendments
Applicant’s amendments filed June 18, 2025 have been entered. All rejections and objections not explicitly maintained herein are withdrawn. The rejections below constitute the full set of rejections being applied to the instant claims.
With respect to the rejections of claims 1, 7, 13, 15-16 and 19 under 35 USC 112(b) the rejection is withdrawn in view of the amendment to claim 1 to limit the claim to the narrower of the previous broad and narrow recitations of the claimed compound.
With respect to the rejection under 35 USC 103, Applicants traverse the rejection on several grounds, each of which has been considered but was not found to be persuasive for the reasons discussed herein.
Applicants contend that neither the primary reference, nor the combination of references cited by the examiner, teaches the required feature of the instant claims whereby the particularly claimed antibody is linked to the linker-drug portion of the compound by the dithiol linker. 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). Further, the examiner disagrees with the contention that the references do not teach any dithiol coupling connection method. Applicants appear to be arguing that the ‘034 publication (referred to as “Pan” in the arguments) are not enabled for the dithiol connected ADC compounds disclosed therein. However, there is no evidence that the preparation of dithiol connected conjugate compounds of formula (II)
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disclosed therein would not have been preparable by the prior art methods. Further, the art does teach a subgeneric formula demonstrating that antibodies linked through dithiol connections are covered by the scope of the disclosure therein:
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. The reference goes on to teach that in the preparation of antibody-drug conjugates with a dithiol linkage, the procedure described in CN103933575 was used (see p. 62, Table 3, ll. 10-15). Accordingly, the prior art both describes and is enabled for the preparation of antibody drug conjugates linked with two thiol groups.
Thus, Applicant’s argument that the prior art gives a teaching “completely deviated” from the present invention relating to antibodies conjugated through a dithiol linker, or that the rejection was formed by improper hindsight bias, is not persuasive. In particular, there is no teach- away aspect in the present art applied. Attention is directed to MPEP 2141.02 (VI) which deals with references that may “teach away” but also states that alternative embodiments should not be confused with “teaching away” citing a recent decision, In re Fulton (73 USPQ2d 1141). Note the following passage in Fulton at 1146: “The prior art's mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed in the ′198 application. Indeed, in the case cited by appellants, In re Gurley, we held that the invention claimed in the patent application was unpatentable based primarily on a prior art reference that disclosed two alternatives, one of which was the claimed alternative. Accordingly, mere disclosure of alternative designs does not teach away”.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
For at least the foregoing reasons, as well as those set forth in the original rejection, Applicants’ traversals are not persuasive and the rejection under 35 USC 103 is maintained.
Applicants contend that with respect to the rejection for nonstatutory double patenting over the claims of US 9,725,517, the rejection should be withdrawn for substantially the same reasons as those made with respect to the rejection under 35 USC 103 and responded to above. The rejection for double patenting is maintained herein for the same reasons as above.
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.
15. 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.
Claim(s) 1, 7, 13, 15-16, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/031034 (“the ‘034 publication”), in view of Pan, L.Q. et al, 2013, Advanced Materials, Volume 25, Number 34, pages 4718-4722 (“Pan”), and U.S Patent No. US 9,725,517 (“the ‘517 Patent”).
Applicant’s claims are drawn to antibody-drug conjugate (ADC) which is Zapadcine-1a or Zapadcine-3a, a pharmaceutical composition comprising the ADC, as well as methods for in vitro tumor cell inhibition and methods of cancer treatment comprising administering the claimed ADC.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
The ‘034 publication teaches ADC’s for targeted therapeutics, which allow for both selectivity and improved cytotoxic activity in cancer treatment (p. 1, ll. 12-14). The ADC’s disclosed therein have the following formula (II)
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(p. 19, ll.1-2), where A is defined as being a targeting moiety, which is later defined as being an antibody or antibody fragment (p. 25, ll. 5-7). Of particular relevance to the instantly claimed invention, the ‘034 publication teaches the linker-active agent portion of the conjugate as having the following structure
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(p. 16, l. 10), which yields an antibody-drug conjugate having the structure of formula II:
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(p. 29, l.5), which corresponds to the claimed Zapadcine-1a.
Relevant to the claimed Zapadcine-3a, the ‘034 publication teaches linker-active agent 75,
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(Table 1, p. 57), which is identical to those shown above, but for a minor change in the drug linked to the antibody (MMAE vs. MMAD). The ‘034 publication further teaches pharmaceutical compositions of the ADCs taught therein, further including a physiologically acceptable carrier and/or diluent allowing transport of the complexes to the target after administration (see p. 33-34). Further an in vitro assay wherein the ADC is administered to cancer cells is demonstrated in the example on p. 59, lines 15-25 on ovarian cancer cells. Finally, with respect to claims 16 and 19, the ‘034 publication further teaches a method for treating cancer (see claim 59), specifically teaching the treatment of squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, oral cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer including, for example, HER2-positive breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, multiple myeloma and B-cell lymphoma, brain cancer, headand neck cancers, and associated metastases (p. 31, ll. 7-18; Example III-1 on p.63 provides an in vivo treatment example of breast cancer).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The difference between the ‘034 publication and the instant claims is that the instantly claimed ADC’s are generically encompassed by those in the prior art since the “A” variable is never exemplified as being an mAB having the particular sequence requirements as in the instant claims.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2141.02)
Regarding the deficiencies in the teachings of the ‘034 publication compared to the instantly claimed invention, the teachings of Pan and the ‘517 patent are relevant.
Pan teaches in their summary section, page 4721, that, “In summary, we have presented a novel TRAIL-linker-MMAE (TRAIL-vc MMAE) conjugate that delivers MMAE to cytoplasm after targeting to death receptors (DR4 and DR5) on a tumor cell surface. We demonstrated that TRAIL conjugate is a conceptually viable therapeutic strategy with improved in vitro antitumor activity, cell circle arrest, uptake by tumor cells, receptor-mediated internalization and specific accumulation in tumor to treat TRAIL-resistant tumors. It is believed that the TRAIL conjugates, as well as antibody-drug conjugates (ADCs), will expand the application of toxic chemicals to serve as antitumor drugs. Further studies will focus on in vivo antitumor activity and toxicity of TRAIL-vc MMAE conjugates along with the conjugation of TRAIL with other toxic molecules”. The chemical structure of TRAIL-MMAE is shown in page 4719 (see scheme 1 below). Furthermore, Pan teaches in page 4719, left column, that, “Obviously, the conjugation of MMAE to TRAIL increased its uptake by tumor cells and binding affinity to DR5, which serves as an additional support for our strategy”.
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Regarding the in vitro method of claim 15, Pan teaches in page 4718, right column, 2nd paragraph, that, “In vitro antitumor activities of TRAIL and its conjugates were evaluated on a TRAIL resistant cell line (MCF-7). In page 4719, left column, Pan teaches that, “To examine the cell circle arrest induced by TRAIL-MMAE conjugates, MCF-7 cells were labeled with propidium iodide (PI) for 30 min before analysis by flow cytometry”, and right column, page 4719, Pan teaches that, “The effects were consistent with a rapid G2-M phase arrest induced by MMAE (see Figure 2 ), suggesting MMAE was released within 8 h and affected growth inhibition of MCF-7 cells”.
While Pan does not teach the particularly antibody, and the heavy/light chain variable region CDRs required by the instant claims, the ‘517 patent discloses the necessary information.
The ‘517 patent teaches in their background section, 2nd column, line 52, that, “Therefore, the technical purpose of present invention is to produce a novel humanized monoclonal antibody against human DR5 and the eukaryotic expression vector thereof, as well as the use of said humanized monoclonal antibody in the treatment of various cancers”. US’517 also teaches in their summary of the invention section, 7th column, line 55, that, the antibody is named as zaptuzumab. US’517 also teaches in their background section, 1st column, line 35, that, TRAIL receptor 2 (also named as TRAIL-R2 or death receptor 5 or DR5).
Regarding Claim 1, heavy chain variable region CDRs, SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 are identical to US’517 heavy chain variable domain SEQ ID NO:2. In this instant, the heavy chain CDRs encompassed in US’517 are identical to those disclosed in the instant application (Claim 1 heavy chain CDRs) for the monoclonal antibody as shown in the ABSS alignment below:
US’517, SEQ ID NO:2 aligned with instant application SEQ ID NO:1 fused to SEQ ID NO:2 fused to SEQ ID NO:3 (HCDR1,2,3).
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Regarding Claim 1, light chain variable region CDRs, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6 are identical to US’517 light chain variable domain SEQ ID NO: 1.(see ABSS alignment below)
US’517, SEQ ID NO:1 aligned with instant application SEQ ID NO:4 fused to SEQ ID NO:5 fused to SEQ ID NO:6 (LCDR1,2,3).
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Regarding Claim 7, heavy chain variable domain encompassed in US’517 is 100% identical to those disclosed in the instant application claim 7 for the antibody as shown in the ABSS alignment below:
US’517, SEQ ID NO:2 aligned with instant application SEQ ID NO:7
Q: 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTDFSMNWVRQAPGQGLEWMGW 50 |||||||||||||||||||||||||||||||||||||||||||||||||| S: 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTDFSMNWVRQAPGQGLEWMGW 50Q: 51 INTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARID 100 |||||||||||||||||||||||||||||||||||||||||||||||||| S: 51 INTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARID 100Q: 101 YWGQGTTVTVSS 112 |||||||||||| S: 101 YWGQGTTVTVSS 112
Regarding Claim 7, light chain variable domain encompassed in US’517 is 100% identical to those disclosed in the instant application claim 7 for the antibody as shown in the ABSS alignment below:
US’517, SEQ ID NO:1 aligned with instant application SEQ ID NO:8
Q: 1 DIVMTQSPLSLPVTPGEPASISCRSSQSLVHSNGNTYLHWYLQKPGQSPQ 50 |||||||||||||||||||||||||||||||||||||||||||||||||| S: 1 DIVMTQSPLSLPVTPGEPASISCRSSQSLVHSNGNTYLHWYLQKPGQSPQ 50Q: 51 LLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQSTHVP 100 |||||||||||||||||||||||||||||||||||||||||||||||||| S: 51 LLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQSTHVP 100Q: 101 HTFGQGTKLEIKR 113 ||||||||||||| S: 101 HTFGQGTKLEIKR 113
MPEP 2141 states, "The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit. The Court quoting In re Kahn, 441 F.3d 977, 988, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006), stated that "[R]ejections on obviousness cannot be sustained by mere conclusatory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.’" KSR, 550 U.S. at ___, 82 USPQ2d at 1396. Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) " Obvious to try " - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention." Further, MPEP 2144.06 states that it is obvious to substitute art-recognized equivalents which are known for the same purpose.
In the present case, the skilled artisan preparing the conjugate or conducting the method of the instantly claimed invention would merely be carrying out the explicit teaching or suggestion of the prior art as in rationale (B) or (G) above. In particular, the ‘034 publication teaches an identical linker-drug conjugate and attaching this structure to a moiety “A” defined as an antibody for targeting cancer cells. Pan discloses the particular benefits of targeting death receptors 4 and 5 (DR4 and DR5) with MMAE (the identical drug disclosed for the ADC’s in the ‘034 publication) via a TRAIL conjugate. Further, the ‘517 patent teaches that the monoclonal antibodies which bind to TRAILR2 as claimed are not novel and recognizes their utility for targeted cancer treatment. US’517 teaches in their example 4, 13th column, that, “The results show that the above humanized monoclonal antibodies have significant activity in killing various cancer cells”, and Pan teach TRAIL-linker-MMAE (TRAIL-vc MMAE) conjugate that delivers MMAE to cytoplasm after targeting to death receptors (DR4 and DR5) on a tumor cell surface. Thus, this combination of the said monoclonal antibody (zaptuzumab) conjugated to the drug (MMAE) or MMAD as disclosed in the ‘034 publication, could result in an improved method for treating tumor. Thus, it would have been obvious to use the already known mAB’s of the ‘517 patent as the “A” component of the ADC’s disclosed in the ‘034 publication with at least a reasonable expectation of success in developing MMAE and MMAD conjugates for targeting DR4 and DR5 in the treatment of cancer.
Absent a showing of surprising or unexpected results, the instantly claimed invention would have been prima facie obvious to the person of ordinary skill in the art.
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.
US 9,725,517 B2 (Zheng, D. et al) Issued 8 August 2017
Claim(s) 1, 7, 13, 15-16 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S Patent No. US 9,725,517 B2 in view of WO 2017/031034 (“the ‘034 publication”), and Pan, L.Q. et al, 2013, Advanced Materials, Volume 25, Number 34, pages 4718-4722 (“Pan”).
Regarding Claim(s) 1 and 7, the antibody of the instant claims is claimed in US’517. In this case, Claim 1 of US’517 teaches a monoclonal antibody that binds to extracellular domain of the human death receptor 5 (also known as TRAIL-R2) and comprises of SEQ ID NOs: 1 and 2. Claims 2-6 of US’517 are properties that the antibody has and does not affect the claimed method, claims 7, 12 of US’517 are drawn to nucleotide sequence encoding the antibody, claims 8, 13 are drawn to expression vector, claim 9 is drawn to preparing the monoclonal antibody, claims 10, 14 are drawn to composition, and claim 11 is drawn to method for treating cancer.
The instant claims are drawn to an antibody comprising SEQ ID NOs: 1-8, which are the same as those recited in US‘517. Both sets of claims differ in US’517 claims are drawn to method of using the monoclonal antibody for treating cancer, and the instant claims are drawn to the product (antibody-drug conjugate) and the method of using the antibody-drug conjugate for treating cancer, or an in vitro method for inhibiting tumor cells.
CDRs encompassed in US’517 claim 1 is identical to those disclosed in the instant application claim 1, for the monoclonal antibody, as shown in the ABSS alignment below: In this instant, the heavy chain CDRs encompassed in US’517 are identical to those disclosed in the instant application (Claim 1 heavy chain CDRs) for the monoclonal antibody.
US’517, SEQ ID NO:2 aligned with instant application SEQ ID NO:1 fused to SEQ ID NO:2 fused to SEQ ID NO:3 (HCDR1,2,3).
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Regarding Claim 1, light chain variable region CDRs, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6 are identical to US’517 light chain variable domain SEQ ID NO: 1.(see ABSS alignment below)
US’517, SEQ ID NO:1 aligned with instant application SEQ ID NO:4 fused to SEQ ID NO:5 fused to SEQ ID NO:6 (LCDR1,2,3).
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Regarding Claim 7, heavy chain variable domain encompassed in US’517 is 100% identical to those disclosed in the instant application claim 7 for the antibody as shown in the ABSS alignment below:
US’517, SEQ ID NO:2 aligned with instant application SEQ ID NO:7
Q: 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTDFSMNWVRQAPGQGLEWMGW 50 |||||||||||||||||||||||||||||||||||||||||||||||||| S: 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTDFSMNWVRQAPGQGLEWMGW 50Q: 51 INTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARID 100 |||||||||||||||||||||||||||||||||||||||||||||||||| S: 51 INTETGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARID 100Q: 101 YWGQGTTVTVSS 112 |||||||||||| S: 101 YWGQGTTVTVSS 112
Regarding Claim 7, light chain variable domain encompassed in US’517 is 100% identical to those disclosed in the instant application claim 7 for the antibody as shown in the ABSS alignment below:
US’517, SEQ ID NO:1 aligned with instant application SEQ ID NO:8
Q: 1 DIVMTQSPLSLPVTPGEPASISCRSSQSLVHSNGNTYLHWYLQKPGQSPQ 50 |||||||||||||||||||||||||||||||||||||||||||||||||| S: 1 DIVMTQSPLSLPVTPGEPASISCRSSQSLVHSNGNTYLHWYLQKPGQSPQ 50Q: 51 LLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQSTHVP 100 |||||||||||||||||||||||||||||||||||||||||||||||||| S: 51 LLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQSTHVP 100Q: 101 HTFGQGTKLEIKR 113 ||||||||||||| S: 101 HTFGQGTKLEIKR 113
Any differences between the instant claims and the claims of US’517, however, would have been obvious in view of the prior art.
Claims in patent US’517 does not teach an antibody-drug conjugate is selected from the group “Zapadcine-3a” or “Zapadcine 1a”, pharmaceutical composition (claim 13), the active ingredient is the antibody-drug conjugate (claim 14), inhibiting tumor cells (claim 15), and preventing and/or treating cancer (claim 16).
Regarding the differences between the ‘517 claims and the instantly claimed invention, Pan teaches in their summary section, page 4721, that, “In summary, we have presented a novel TRAIL-linker-MMAE (TRAIL-vc MMAE) conjugate that delivers MMAE to cytoplasm after targeting to death receptors (DR4 and DR5) on a tumor cell surface. We demonstrated that TRAIL conjugate is a conceptually viable therapeutic strategy with improved in vitro antitumor activity, cell circle arrest, uptake by tumor cells, receptor-mediated internalization and specific accumulation in tumor to treat TRAIL-resistant tumors. It is believed that the TRAIL conjugates, as well as antibody-drug conjugates (ADCs), will expand the application of toxic chemicals to serve as antitumor drugs. Further studies will focus on in vivo antitumor activity and toxicity of TRAIL-vc MMAE conjugates along with the conjugation of TRAIL with other toxic molecules”. The chemical structure of TRAIL-MMAE is shown in page 4719 (see scheme 1 below). Furthermore, Pan teaches in page 4719, left column, that, “Obviously, the conjugation of MMAE to TRAIL increased its uptake by tumor cells and binding affinity to DR5, which serves as an additional support for our strategy”.
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Regarding the in vitro method of claim 15, Pan teaches in page 4718, right column, 2nd paragraph, that, “In vitro antitumor activities of TRAIL and its conjugates were evaluated on a TRAIL resistant cell line (MCF-7). In page 4719, left column, Pan teaches that, “To examine the cell circle arrest induced by TRAIL-MMAE conjugates, MCF-7 cells were labeled with propidium iodide (PI) for 30 min before analysis by flow cytometry”, and right column, page 4719, Pan teaches that, “The effects were consistent with a rapid G2-M phase arrest induced by MMAE (see Figure 2 ), suggesting MMAE was released within 8 h and affected growth inhibition of MCF-7 cells”.
Further, regarding the claimed conjugates, the ‘034 publication teaches ADC’s for targeted therapeutics, which allow for both selectivity and improved cytotoxic activity in cancer treatment (p. 1, ll. 12-14). The ADC’s disclosed therein have the following formula (II)
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(p. 19, ll.1-2), where A is defined as being a targeting moiety, which is later defined as being an antibody or antibody fragment (p. 25, ll. 5-7). Of particular relevance to the instantly claimed invention, the ‘034 publication teaches the linker-active agent portion of the conjugate as having the following structure
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(p. 16, l. 10), which yields an antibody-drug conjugate having the structure of formula II:
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(p. 29, l.5), which corresponds to the claimed Zapadcine-1a.
Relevant to the claimed Zapadcine-3a, the ‘034 publication teaches linker-active agent 75,
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(Table 1, p. 57), which is identical to those shown above, but for a minor change in the drug linked to the antibody (MMAE vs. MMAD). The ‘034 publication further teaches pharmaceutical compositions of the ADCs taught therein, further including a physiologically acceptable carrier and/or diluent allowing transport of the complexes to the target after administration (see p. 33-34). Further an in vitro assay wherein the ADC is administered to cancer cells is demonstrated in the example on p. 59, lines 15-25 on ovarian cancer cells. Finally, with respect to claims 16 and 19, the ‘034 publication further teaches a method for treating cancer (see claim 59), specifically teaching the treatment of squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, oral cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer including, for example, HER2-positive breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, multiple myeloma and B-cell lymphoma, brain cancer, headand neck cancers, and associated metastases (p. 31, ll. 7-18; Example III-1 on p.63 provides an in vivo treatment example of breast cancer).
In particular, the ‘034 publication teaches an identical linker-drug conjugate and attaching this linker-drug structure to a moiety “A” defined as an antibody for targeting cancer cells. Pan discloses the particular benefits of targeting death receptors 4 and 5 (DR4 and DR5) with MMAE (the identical drug disclosed for the ADC’s in the ‘034 publication) via a TRAIL conjugate. Further, the ‘517 patent claims demonstrate that the monoclonal antibodies which bind to TRAILR2 as claimed are not novel and recognizes their utility for targeted cancer treatment. US’517 teaches in their example 4, 13th column, that, “The results show that the above humanized monoclonal antibodies have significant activity in killing various cancer cells”, and Pan teach TRAIL-linker-MMAE (TRAIL-vc MMAE) conjugate that delivers MMAE to cytoplasm after targeting to death receptors (DR4 and DR5) on a tumor cell surface. Thus, this combination of the said monoclonal antibody (zaptuzumab) conjugated to the drug (MMAE) or MMAD as disclosed in the ‘034 publication, could result in an improved method for treating tumor. Thus, it would have been obvious to use the mAB’s claimed in the ‘517 patent and modify the patented claims therein by linking the known mAB’s of the ‘517 patent as the “A” component of the ADC’s disclosed in the ‘034 publication with at least a reasonable expectation of success in developing MMAE and MMAD conjugates for targeting DR4 and DR5 in the treatment of cancer.
Conclusion
No claims are allowed.
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/ALICIA L OTTON/Primary Examiner, Art Unit 1699