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 .
Claim Status
Claims 16-17 and 22 have been cancelled; claims 1-10, 12, 15, and 18-20 have been amended; and claims 23-24 have been newly added, as requested in the amendment filed on 03/02/2026. Following the amendment, claims 1-15, 18-21, and 23-24 are pending in the instant application.
Claims 10-13 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 09/11/2025, there being no allowable generic or linking claim.
Claims 1-9, 14-15, 18-21, and 23-24 are under examination in the instant office action.
Priority - Updated
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Additionally, it is noted that an English translation of the foreign priority document has been provided, and as such the claim to foreign priority has been perfected.
Claims 1-9, 14-15, 18-21, and 23-24 have an effective filing date of June 28, 2019 corresponding to CN201910577909.6.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/30/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Terminal Disclaimer
The terminal disclaimer filed on 03/02/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US Patent No. 12,178,880 and Application No. 18/796,365 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Specification - Objection Withdrawn
Applicant has amended the specification such that any trade names and marks used in commerce are properly represented and to include the generic terminology of SMCC. As such, the objection to the specification is withdrawn.
Claim Objections - Withdrawn
Claim 1 was objected to for a minor informality. Claim 1 has been amended to recite “and” in the listing of limitations. As such, the objection to claim 1 is withdrawn.
Claim 8 was objected to for a minor informality. Claim 8 has been amended such that the claim now ends with a period. As such, the objection to claim 8 is withdrawn.
Claim 9 was objected to for the recitation of duplicate embodiments. Claim 9 has been amended to remove the recitation of sequences of antibodies Trastuzumab, P2E5, and IMAB362. As such, the objection to claim 9 is withdrawn.
Claim 21 was objected to for a minor informality. Claim 21 has been amended such that “f” has been removed. As such, the objection to claim 21 is withdrawn.
Claim 22 was objected to for a minor informality. Claim 22 has been cancelled, rendering the objection moot. As such, the objection to claim 22 is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 2-7, 9, 15, and 20-22 were rejected under 35 USC § 112(b), second paragraph, as being indefinite. With regard to claims 2-6 and 20-21, it is noted that Applicant has amended the claims such that the only possible structure for L1 in independent claim 1 is that of formula III; as such dependent claims 2-6 and 20-21 are now deemed definite wherein the claims are not drawn to various alternatives of the independent claim and the claim language of dependent claims 2-6 and 20-21 has similarly been amended to remove ambiguity regarding listed alternatives. Claims 7, 9, and 20 have been amended to remove all limitations drawn to antibody sequences. Claim 22 has been cancelled, rendering its rejection moot. As such, the rejection of claims 2-7, 9, 15, and 20-22 under 35 USC § 112(b), second paragraph, as being indefinite is withdrawn.
Claims 1-9, 14-15, and 18-22 were rejected under 35 USC § 112(a), first paragraph, for failing to comply with the written description requirement. Applicant has amended independent claim 1 such that D, R1, L2, and L1 are more specifically defined, wherein D corresponds to a specific structure and the possible combinations of -L3-L2-L1- are limited to formula III for L1, five possible structures of L2, and two possible structures for L3; the species encompassed by this genus are considered to be adequately described by the 24 species of ADC disclosed at Pages 35-36 of the instant specification. It is also noted that claim 22 has been cancelled, rendering its rejection moot. As such, the rejection of claims 1-9, 14-15, and 18-22 under 35 USC § 112(a), first paragraph, for failing to comply with the written description requirement is withdrawn.
Claims 2, 4-5, rejected under 35 USC § 112(a), first paragraph, regarding scope of enablement. Claims 2, 4-5, and 19-20 have been amended to remove any “variant” language as pertains to the recited antibodies and has removed any reference to sequences thereof. As such, claims 2, 4-5, and 19-20 are now considered to be enabled and their rejection under 35 USC § 112(a), first paragraph, regarding scope of enablement is withdrawn.
Claims 19 and 22 were rejected under 35 USC § 112(d), fourth paragraph, as being of improper dependent form. Claim 19 has been amended such that claim 19 no longer recites duplicate limitations of claim 2 from which it depends, and claim 22 has been cancelled, rendering its rejection moot. As such, the rejection of claims 19 and 22 under 35 USC § 112(d), fourth paragraph, as being of improper dependent form is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claim 22 was rejected under 35 U.S.C. 103 as being unpatentable over CN 104755494A (previously cited on PTO-892; machine translation utilized; herein after referred to as "Masuda") in view of WO 2009/099741 Al (previously cited on PTO-892; herein after referred to as "Cohen"), non-patent literature by Jain et.al. (Pharm. Res., 2015, 32, 3526-3540; previously cited on PTO-892; herein after referred to as "Jain") and non-patent literature by Bryden et.al. (Org. Biomol. Chem., 2018, 16, 1882-1889; previously cited on PTO-892; herein after referred to as "Bryden") as evidenced by US 2009/0041770 Al (previously cited on PTO-892; herein after referred to as "Chamberlain").
Claim 22 has been cancelled, rendering its rejection moot. As such, the rejection of claim 22 under 35 U.S.C. 103 as being unpatentable over Masuda, Cohen, Jain, Bryden, and Chamberlain is withdrawn.
Double Patenting - Withdrawn
Claims 1-9, 14-15, and 18-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18 and 20-24 of copending Application No. 18/254,882 (herein after referred to as "reference application") in view of CN 104755494 A (machine translation utilized; herein after referred to as "Masuda") and WO 2009/099741 A1 (herein after referred to as "Cohen"), as evidenced by US 2009/0041770 A1 (herein after referred to as “Chamberlain”).
It is noted that Application No. 18/254,882 has since been issued as U.S. Patent No. 12,178,880. A terminal disclaimer has been filed and is accepted over U.S. Patent No. 12,178,880. As such, the provisional rejection of claims 1-9, 14-15, and 18-22 over Application No. 18/254,882 is withdrawn.
Claims 1-9, 14-15, and 18-22 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the copending Application Nos. listed below in view of CN 104755494 A (machine translation utilized; herein after referred to as "Masuda") and WO 2009/099741 A1 (herein after referred to as "Cohen"), as evidenced by US 2009/0041770 A1 (herein after referred to as “Chamberlain”).
Application No.
Brief Description of the Invention
Pertinent Claims
18255880
An Antibody-Drug Conjugate Generally Comprising a PABC Linker Component, a Topoisomerase Inhibitor, and an Anti-B7-H3 Antibody, Method of Preparation, and Pharmaceutical Composition Thereof
2-4, 6-9, 13-18
18256045
An Antibody-Drug Conjugate Generally Comprising a PABC Linker Component, a Topoisomerase Inhibitor, and an Anti-TROP2 Antibody, Method of Preparation, and Pharmaceutical Composition Thereof
2-4, 6-9, 13-18
18796365
An Antibody-Drug Conjugate Generally Comprising a PABC Linker Component, a Topoisomerase Inhibitor, and an Anti-B7-H3 Antibody, Method of Preparation, Method for Treating a Tumor, and Pharmaceutical Composition Thereof
1-16, 19-20
It is noted that previously copending reference applications 18/255,880 and 18/256,045 have since been abandoned. Furthermore, a terminal disclaimer has been filed and approved over copending application 18/796,365. As such, the provisional rejection of claims 1-9, 14-15, and 18-22 over the above-listed applications are withdrawn.
Claim 22 was provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the copending Application Nos. listed below in view of CN 104755494 A (machine translation utilized; herein after referred to as "Masuda") and WO 2009/099741 A1 (herein after referred to as "Cohen"), as evidenced by US 2009/0041770 A1 (herein after referred to as “Chamberlain”).
Application No.
Brief Description of the Invention
Pertinent Claims
18293078
An Antibody-Drug Conjugate Generally Comprising a PABC Linker Component, a Topoisomerase Inhibitor, and an Anti-DLL3 Antibody, Method for Treating a Disease, and Pharmaceutical Composition Thereof
10-13, 17-18, 22
18884153
An Antibody-Drug Conjugate Generally Comprising a PABC Linker Component, a Topoisomerase Inhibitor, and an Anti-TROP2 Antibody
1-11
Claim 22 has been cancelled, rendering its rejection moot. As such, the provisional rejection of claim 22 under nonstatutory double patenting over the above-listed copending applications is withdrawn.
Claim Objections - New as Necessitated by Amendment
Claim 20 is objected to because of the following informalities: as amended, the claim currently reads "[t]he antibody drug conjugate as defined in claim 19, wherein, or, in the R1...", but should read "[t]he antibody drug conjugate as defined in claim 19, wherein, in the R1...". Appropriate correction is required.
Claim Rejections - 35 USC § 112 - Maintained, Updated as Necessitated by Amendment
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 15 and 18 stand as rejected, and new claims 23-24 are newly 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 treating target antigen-expressing (e.g., HER2-, B7-H3-, or Claudin18.2-expressing) cancers with ADCs comprising target-antigen specific antibodies (e.g., anti-HER2, anti-B7-H3, or anti-Claudin18.2 antibodies, respectively), does not reasonably provide enablement for using ADCs comprising any antibody to treat any and all cancers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The Breadth of the Claims
With regard to claims 15, 18, and 23-24, the claims are drawn to methods of treating cancer in a subject in need thereof, comprising administering (i) the antibody drug conjugate as defined in claim 1 or (ii) the pharmaceutical composition as defined in claim 14. Under BRI, claims 15 and 18 are therefore drawn to treating any and all cancers using ADCs or pharmaceutical compositions wherein the antibodies utilized are specific to HER2 (trastuzumab), B7-H3 (P2E5), or Claudin 18.2 (IMAB362), wherein claims 23-24 further limit the types of cancer to be treated by tissue of origin (e.g., gastric, breast, urothelial, pancreatic, or non-small cell lung cancer). As such, claims 15, 18, and 23-24 are drawn to the treatment of cancers which may or may not express the antigen that is targeted by the antibodies of the ADCs or pharmaceutical compositions, the full scope of which is not enabled.
The State of the Prior Art/Level of Predictability in the Art
With regard to the treatment of any and all cancers, it is noted that cancer treatment is highly unpredictable. Even though the EGFR was identified in some cancers as a drug target, the in vitro (i.e., in a test tube) effectiveness of a drug in inhibiting the EGFR turned out to be a poor proxy for how effective that drug actually was in treating cancer in vivo (i.e., in the body). Numerous EGFR inhibitors that showed promising in vitro activity failed for a variety of reasons. These included poor pharmacokinetics due to poor absorption or rapid metabolism (or both), undesirable drug-drug interactions, drug toxicity due to drug binding onto healthy cells, drug toxicity due to binding onto other receptors, and metabolite toxicity. Some drug candidates were limited by one or more of these shortcomings, further underscoring the unpredictable nature of cancer treatment. OSI Pharmaceuticals , LLc, v. Apotex Inc, 939 F.3d 1375, 2019.
The state of the art at the time of filing was such that the functionality of an anti-tumor antibody was dependent on both its action on the intended target and whether or not the modulation of said target had an effect on any particular cancer cell. Baxevanis (Expert Opinion: Drug Discovery, Vol. 3, No. 4, Pg. 441-452, 2008; previously cited on PTO-892) teaches that, depending on the epitope against which an antibody is directed, antibody-antigen binding may neutralize circulating targets or cell surface receptors (Pg. 444, Column 1, Paragraph, first full). They teach that presently available monoclonal antibodies (mAbs) are directed against molecular targets that are expressed on tumor cells or play an important role in the tumor microenvironment (Pg. 444, Column 1, Paragraph, first full; Table 1). Table 1 lists currently available antibodies for use in clinical oncology and illustrates that each antibody has a specific target (Table 1, Column 2) and a specific set of cancers for which it has therapeutic utility (Table 1, Column 4). Taken together, the art does not recognize a single antibody that is an effective therapy against all tumors.
To further illustrate this point, Baxevanis goes on to explain the functionality of the more commonly used therapeutic antibodies. Trastuzumab targets the receptor HER-2 (HER-2/neu) which is overexpressed in some breast cancers and so is a viable treatment for said breast cancers (Pg. 444, Column 2, Lines 19-24). The basis of this variability in treatment response is due to the fact that the growth inhibitory effect of anti-HER-2 is dependent on the extent of HER-2 overexpression (pg. 443, Column 1, Paragraph, first partial). Because only a portion of breast cancer patients overexpress HER-2 and respond to trastuzumab, the selection of suitable patients is important (Pg. 445, Column 1, Lines 13-15).
Rituximab is an antibody against CD20 antigen, which is expressed on most B cells including B-cell lymphomas (Pg. 445, Column 1, Lines 36-38). Therefore, it is used to treat B-cell lymphomas (Pg. 444, Table 1). It has been used to treat patients with relapsed or refractory low-grade non-Hodgkin's lymphoma (a B-cell lymphoma) (Pg. 445, Column 1, Lines 41-50).
In contrast to trastuzumab and rituximab, some therapeutic antibodies show efficacy in treating multiple cancers. This stems from the fact that their target antigen is associated with multiple cancers. Cetuximab is an anti-EGFR antibody (Pg. 445, Column 1, Lines 19-20). EGFR is overexpressed in many epithelial cell tumors (Pg. 445, Column 1, Lines 20-21). The association of EGFR overexpression with multiple cell types gives cetuximab a broader therapeutic applicability than trastuzumab (Pg. 444, Table 1) as it is used to treat both renal and head and neck cancers.
As a final point, the art also recognizes that the function of the therapeutic antibody must correlate with an effect on its target conducive to tumor growth inhibition or tumor lysis, resulting in patient benefit. Anti-HER-2 antibodies, like Trastuzumab, disrupt HER-2 catalytic activity (Pg. 443, Column 1, Paragraph, first partial, Sentence, ultimate; Table 1, Column 3, (S) referring to decreased protein signaling (activity); and Pg. 444, Column 2, Lines 19-22). Cetuximab also inhibits its target’s activity as it prevents EGFR dimerization and subsequent activation via phosphorylation (Pg. 445, Column 1, Lines 23-25). Since both HER-2 and EGFR activity support growth of cancer cells in which they are overexpressed, their inhibition is therapeutic to patients. Rituximab causes tumor cell lysis by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) (Pg. 445, Column 1, Lines 38-39) and so its therapeutic benefit is provided by specifically inducing cancer cell death.
The teachings of Baxevanis discussed above underline the requirement of a link between an antibody’s target and specific cancers to make therapy of said cancer predictable to one of ordinary skill in the art.
The Amount of Direction Provided by the Inventor/Existence of Working Examples
Exemplary ADCs that were synthesized by Applicant are provided in Table 5 of the instant specification (Pages 62-64). Said exemplary ADCs were tested in vitro using HEK293 cells (high Claudin18.2 expression), SK-BR-3 cells (high HER2 expression), and NCI-N87 cells (high HER2 and B7-H3 expression); it is noted that lower IC50 values (indicating higher efficacy) were only observed for ADCs whose antibodies specifically targeted an antigen expressed by a specific cell line. For example, ADCs comprising trastuzumab demonstrated lower IC50 values only for SK-BR-3 cells and NCI-N87 cells whereas ADCs comprising IMAB362 demonstrated low IC50 values only for HEK293 cells. Applicant further discloses in vivo evaluation of ADCs comprising trastuzumab, wherein said ADCs were administered to Balb/c nude mice injected with either Capan-1 human pancreatic cancer cells (Embodiment 6, Pages 70-71) or NCI-N87 human gastric cancer cells (Embodiment 7, Pages 71-72); it is noted that both of the injected human cancer cell lines highly express HER2. Thus, the working examples provided by Applicant indicate a required connection between the antibody of the ADCs and their use in different cancers, wherein the cancer must express the antigen targeted by the antibody in order for the ADCs to be effective.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to use the ADCs and pharmaceutical compositions in the methods of instant claims 15, 18, and 23-24, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed ADCs and pharmaceutical compositions are functional/sufficient to treat cancer generally, commensurate in scope with the claimed invention.
Claim Rejections - 35 USC § 103 - Maintained, Updated as Necessitated by Amendment
Claims 1-9, 14-15, and 18-21 stand as rejected, and new claims 23-24 are newly rejected, under 35 U.S.C. 103 as being unpatentable over CN 104755494A (previously cited on PTO-892; machine translation utilized; herein after referred to as "Masuda") in view of WO 2009/099741 Al (previously cited on PTO-892; herein after referred to as "Cohen"), non-patent literature by Jain et.al. (Pharm. Res., 2015, 32, 3526-3540; previously cited on PTO-892; herein after referred to as "Jain") and non-patent literature by Bryden et.al. (Org. Biomol. Chem., 2018, 16, 1882-1889; previously cited on PTO-892; herein after referred to as "Bryden") as evidenced by US 2009/0041770 Al (previously cited on PTO-892; herein after referred to as "Chamberlain").
With regard to new claims 23-24, as presented in the previous Office Action, the antibody drug conjugate according to the structure of claim 1 and the pharmaceutical composition thereof of claim 14, respectively, are rendered obvious by Masuda, Cohen, Jain, and Bryden. It is further noted that Cohen teaches that an ADC of formula I may be used to treat various diseases or disorders in a patient, such as cancers characterized by the overexpression of a tumor-associated antigen (e.g., cancers overexpressing HER2) wherein the cancer may include colon, breast, gastric, pancreatic, and non-small cell lung cancer, for example, and the ADC is administered at an appropriate (i.e., therapeutically effective) dosage (Paragraphs 00383-00388). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Response to Arguments
Applicant’s arguments on Pages 35-49 of Remarks (03/02/2026) and the Affidavit under 37 CFR 1.132 filed 03/02/2026 are insufficient to overcome the rejection of claims 1-9, 14-15, 18-21, and 23-24 under 35 USC § 103 as set forth in the last Office Action. Applicant argues the following:
When different linker-drug conjugates as claimed are conjugated to transtuzumab, they all demonstrate better anti-tumor activity than ADC-8201 which comprises a linker-drug conjugate as disclosed by Masuda (see Table 7-8 of the instant specification). Table 9 of the instant specification further indicates compatibility of the instantly claimed drug-linker with different antibodies. Therefore, the technical problem to be solved by the present invention is to provide a novel linker better suited for Dxd, the linker-Dxd conjugates are applicable to conjugation with different antibodies, and the resulting antibody drug conjugates have better anti-tumor activity both in vivo and in vitro, and as such the instant invention is non-obvious over the cited references.
Cohen, Jain, and Bryden fail to disclose the instantly claimed linker, wherein the linker-drug attachment is via the terminal carbon atom of the linker (see Page 40 of Remarks). Applicant argues that Cohen fails to teach or suggest such an attachment, and as such the mode of connection between the linker and the cytotoxic drug in the instant application is different from that disclosed by Cohen, wherein it is further noted that Cohen does not disclose a cytotoxic drug that is Dxd. Jain and Bryden each also fail to disclose a cytotoxic drug that is Dxd and therefore do not five the teaching that the linker can be attached via the terminal carbon atom.
Cohen, Jain, and Bryden fail to teach that the combination between the instantly claimed linker and Dxd can improve anti-tumor activity of the antibody drug conjugates in vivo and in vitro. None of Cohen, Jain, and Bryden disclose that the payload can be a camptothecin, so there is no motivation to substitute the payload(s) of Cohen, Jain, and Bryden with Dxd, nor that the resulting ADC can effectively release Dxd, improving the anti-tumor activity of the ADC. Tables C-G (see Pages 44-48 of Remarks; see also the Affidavit filed 03/02/2026) collectively show that (i) the instantly claimed linker cannot work for other cytotoxic drugs, especially camptothecins wherein the instantly claimed linker only releases Dxd effectively, not SN-38; (ii) the instantly claimed ADC exhibits enhanced plasma stability compared to an ADC comprising SN-38; (iii) the instantly claimed ADC demonstrated higher anti-tumor activity compared to the ADC comprising SN-38. Thus, Applicant argues that the instantly claimed ADC exhibits more effective release of Dxd in different cells, and the linker as shown in formula III doesn't work for all payloads; Applicant argues it is impossible for those skilled in the art to predict which cytotoxic payload can be effectively combined with the linker to achieve superior anticancer activity.
Applicant’s arguments and the Affidavit have been fully considered, but are deemed insufficient.
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With regard to the arguments against the combination of the cited prior art references, it is noted that Applicant specifically argues that the combination of Cohen, Jain, and Bryden do not teach the instantly claimed linker, however it is noted that these arguments do not account for the teachings regarding the linker of Masuda, the primary art reference upon which the rejection is based. Masuda discloses anti-tumor drugs conjugated to antibodies capable of targeting tumor cells, wherein said drug is conjugated to an antibody via various embodiments of linker; one such linker is that corresponding to: -(succinimide-3-yl-N)-CH2-CH2-CH2-CH2-CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX). Notably, -(succinimide-3-yl-N)-CH2-CH2-CH2-CH2-CH2- corresponds to instantly elected -L3-L2- and -O-CH2-C(=O)-(NH-DX) corresponds to instantly elected D. The difference between Masuda and the instantly claimed linker corresponding to instant -L3-L2-L1- is the structure of L1. The closest structure of Masuda to instantly claimed L1 is the portion of the above-identified linker corresponding to -C(=O)-GGFG-NH-CH2-, wherein it is noted that the -CH2- group links to the instantly claimed drug (i.e., Dxd); Masuda effectively teaches an (L)p of -Gly-Gly-Phe-Gly (i.e., an enzymatically cleavable linker), and R1 of H, not an (L)p corresponding to -Val-Ala- and R1 corresponding to a C2 alkyl substituted by (C1 alkyl)-S(O)2- as instantly elected. Cohen is relied upon for its teaching of the structure highlighted in a rectangle below (i.e., an enzymatically cleavable linker with a self-immolative component):
wherein Y2 may be NR10 wherein R10 may be a C1-8 alkyl optionally substituted with -S(O)2CH3; R1 and R2 are independently an amino acid side chain which may be methyl (corresponding to alanine) or isopropyl (corresponding to valine); n is an integer from 1 to 7; and Y1 may be C(O)(C(R10)2)q wherein R10 may be hydrogen and q is an integer from 2 to 6 (Pages 41-42). Thus, Cohen suggests a linker wherein: Y2 may be N-CH2-CH2-S(O)2-CH3; R1 and R2 are independently methyl (corresponding to alanine) and isopropyl (corresponding to valine), respectively, wherein n=1 (i.e., a dipeptide component); and Y1 may be C(O)(CH2)5, which would yield the structure shown below.
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It was acknowledged that Masuda nor Cohen explicitly provided motivation for substituting the
-C(=O)-GGFG-NH- portion of Masuda with -C(=O)-Val-Ala-PAB-NH- taught by Cohen. Jain and Bryden were relied upon exclusively for such motivation. Jain supports the use of cleavable linker components (e.g., dipeptides) in combination with self-immolative (e.g., PABC) groups to facilitate drug release from ADCs and suggests that increasing hydrophilicity of linker components can reduce antibody aggregation to improve safety profiles. Bryden teaches that the Val-Ala dipeptide is also cathepsin B cleavable and may be more efficient at releasing drugs from ADCs wherein problems arising from the increased hydrophobicity of including the Val-Ala dipeptide can be overcome by adding hydrophilic. Thus, one of ordinary skill in the art would expect that the above-indicated modification of the linker component of Masuda for the linker component of Cohen would likely (i) promote stability and/or reactivity of the drug-linker by increasing hydrophilicity to yield a sufficient DAR, (ii) improve safety profiles by increasing overall linker hydrophilicity to reduce ADC aggregation, and (iii) yield ADCs more efficiently cleaved in the tumor microenvironment. As such, the instantly claimed ADC is obvious, and the results demonstrated by Applicant with regard to improved stability and enhanced drug release/activity are not unexpected.
More specifically with regard to the data argued above, as presented in the Affidavit, it is noted that Affidavit evidence must be statistically significant. MPEP 716.02b: The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). Additionally, evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e. First, the comparison of ADC-029 (encompassed by the instant claims) to ADC-030 is not considered a comparison of the instantly claimed ADC to the closest prior art (i.e., Masuda); ADC-030 comprises an entirely different drug than that of the instant claims and that described by Masuda and such structural differences may play a role in the differences observed between ADCs. With regard to the data comparing ADCs of the instant claims to ADC-8201 (comprising the linker of Masuda), no statistical analysis was performed to demonstrate the data is of statistical significance. Even when taking the data into account absent statistical analysis, it is specifically noted that Cohen suggests that the substitution of linker components with hydrophilic groups (e.g., CH2CH2S(O)2CH3) can improve linker/ADC properties, which is further supported by Jain who suggests that increasing hydrophilicity of linker components can reduce antibody aggregation to improve safety profiles and Bryden who teaches that Val-Ala-PABC based linkers (i) may be more efficient at releasing drugs from ADCs and (ii) problems arising from the increased hydrophobicity of including the Val-Ala dipeptide can be overcome by adding hydrophilic groups to increase DAR. Additionally, Jain supports the use of cleavable linker components (e.g., dipeptides) in combination with self-immolative (e.g., PABC) groups to facilitate drug release from ADCs. Thus, one of ordinary skill in the art would expect that the replacement of the linker component of Masuda for the linker component of Cohen would likely (i) promote stability and/or reactivity of the drug-linker by increasing hydrophilicity to yield a sufficient DAR, (ii) improve safety profiles by increasing overall linker hydrophilicity to reduce ADC aggregation, and (iii) yield ADCs more efficiently cleaved in the tumor microenvironment. As such, the instantly claimed drug-linkers having enhanced stability relative to Masuda, and no observable aggregation, is not unexpected. Furthermore, with regard to enhanced activity, it is specifically noted that the teachings of Bryden which suggest Val-Ala-PABC based linkers (i) may be more efficient at releasing drugs from ADCs and (ii) problems arising from the increased hydrophobicity of including the Val-Ala dipeptide can be overcome by adding hydrophilic groups to increase DAR suggest that the instantly claimed drug-linker (compared to Masuda) would be expected to exhibit enhanced release and thus enhanced anti-tumor effects. Furthermore, it is noted that the data presented is not considered fully commensurate in scope with the instant claims. The drug-linkers provided in Table A (see Page 38-39 of Remarks) are not considered to be sufficiently representative of the full scope of the instant claims. Applicant only presents data for seven drug-linkers, but it is noted that there are many more possible combinations of linker elements; there are five possible structures of L2 which comprise chemically distinct structures and there are various possible distinct structures provided for R1, wherein the structures within each of these structural elements have varied physiochemical properties. Thus, seven drug-linkers are not considered sufficient to establish that the argued trends/improvements are consistent across all claimed species, nor are the three cell lines used to test the antibodies considered to be sufficiently representative of any and all cancers (i.e., cancers that do not express antigen targeted by the antibodies).
Double Patenting - Maintained, Updated as Necessitated by Amendment
Claims 1-9, 14-15, and 18-21 stand as provisionally rejected, and new claims 23-24 are newly provisionally rejected, on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the copending Application Nos. listed below in view of CN 104755494 A (machine translation utilized; herein after referred to as "Masuda") and WO 2009/099741 A1 (herein after referred to as "Cohen"), as evidenced by US 2009/0041770 A1 (herein after referred to as “Chamberlain”).
Application No.
Brief Description of the Invention
Pertinent Claims
18293078
An Antibody-Drug Conjugate Generally Comprising a PABC Linker Component, a Topoisomerase Inhibitor, and an Anti-DLL3 Antibody, Method for Treating a Disease, and Pharmaceutical Composition Thereof
10-13, 17-18, 22
18884153
An Antibody-Drug Conjugate Generally Comprising a PABC Linker Component, a Topoisomerase Inhibitor, and an Anti-TROP2 Antibody
1-11
With regard to 18/293,078, Applicant argues that (i) the filing date of the instant application is earlier and (ii) the difference relative to the instant claims is that the copending application comprises an antibody that is an anti-DLL3 antibody defined by unique CDR sequences which have never been made public. With regard to 18/884,153, Applicant argues that (i) the filing date of the instant application is earlier and (ii) the difference relative to the instant claims is that the copending application comprises an antibody that is an anti-Trop2 antibody defined by unique light chain and heavy chain sequences absent in the antibodies of the instant invention.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
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182
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It was acknowledged in the previous Office Action that the copending applications both copending applications disclose full, general ADC structure as shown below:
wherein the above structure reads on the ADC structure of instant claim 1, which generally requires “an antibody”. It was also noted in the previous Office Action that the copending applications did not claim the instantly elected anti-HER2 antibody Trastuzumab, a pharmaceutical composition comprising the ADC, and/or methods of treating cancer. It is maintained that these deficiencies are remedied by the cited references, as provided by the teachings previously specified in the 103 section.
Notably, it would have been obvious to one of ordinary skill in the art to modify the ADC disclosed by the reference applications such that instead of an anti-DLL3 or an anti-Trop2 antibody, an anti-HER2 antibody such as Trastuzumab could be used in order to specifically target and treat cancers which overexpress the HER2 receptor, including colon, breast, gastric, pancreatic, and non-small cell lung cancer, for example, wherein for methods of treating cancer the ADC is administered at an appropriate (i.e., therapeutically effective) dosage (see Cohen Paragraphs 00199-00201 and 00383-00388). Applicant has provided no arguments as to why such a modification would not be obvious based on the cited prior art. Furthermore, regarding the earlier filing dates, the following is noted: if a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent (see MPEP 804(1)(b)(i)). The provisional nonstatutory double patenting rejections are not the only remaining rejections, and are therefore maintained.
Conclusion
Claims 1-15, 18-21, and 23-24 are pending. Claims 10-13 are withdrawn. Claims 1-9, 14-15, 18-21, and 23-24 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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