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 1-3, 6-8, and 12-13 have been cancelled; claims 4-5 and 11 have been amended; and claims 14-15 have been newly added, as requested in the amendment filed on 04/13/2026. Following the amendment, claims 4-5, 9-11, and 14-15 are pending in the instant application.
Claims 10-11 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 11/28/2025, there being no allowable generic or linking claim.
Claims 4-5, 9, and 14-15 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. Furthermore, 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 4-5, 9, and 14-15 have an effective filing date of June 28, 2020 corresponding to CN202010601915.3.
Specification - Objections Withdrawn
The abstract of the specification was objected to for the recitation of “connexon” and an exemplary structure that appeared to be incorrect and was difficult to read. Applicant has provided a replacement abstract that no longer recites “connexon” and comprises a corrected and more legible structure. As such, the objection to the abstract is withdrawn.
The specification was further objected to and a substitute specification was required pursuant to 37 CFR 1.125(a) because the legibility of the application papers renders it difficult to consider the application or to arrange the papers for printing or copying; more specifically, it was noted that almost all of the structures and tables presented in the specification and/or claims are either illegible or are very difficult to read. Applicant has provided a substitute specification wherein the structures and/or tables are legible. As such, the objection to the specification is withdrawn.
Claim Objections - Withdrawn
Claims 1-3 and 12 objected to because of the following informalities: the provided structures corresponding to the recited formulas ; additionally, it was noted that the structures presented in the claims appeared to be incorrect. Claims 1-3 and 12 have been cancelled, rendering their objection moot. As such, the objection to claims 1-3 and 12 is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 2 and 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. Claims 2 and 13 have been cancelled, rendering their rejection moot. As such, the rejection of claims 2 and 13 under U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Drawings - Objection Maintained
The drawings stand as objected to because the replacement f. Notably, Figures 1-9 still comprise text (i.e., figure labels) and/or structures that are either illegible or extremely pixelated and difficult to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 103 - Maintained
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 4-5 and 9 stand rejected, and new claims 14-15 are newly rejected, under 35 U.S.C. 103 as being unpatentable over CN 108066772 A (previously cited on PTO-892; machine translation of the description relied upon; herein after referred to as "Wang") in view of non-patent literature by Velani et. al. (Chapter 6.7 "The Taxanes" from the book "Cytotoxic Payloads for Antibody-Drug Conjugates", Royal Society of Chemistry, 2019, 123-125; previously cited on PTO-892; herein after referred to as "Velani").
It is specifically noted that the previously presented teachings of Wang and Velani as applied to render claims 4-5 and 9 obvious also render obvious new claims 14-15, as provided below. Thus, the crux of the claim rejections are the same, the new claims falling under the scope of the previous rejection, and therefore the rejection of the new claims does not constitute a new ground of rejection.
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With regard to claims 4-5, 9, and 14-15 as amended and/or newly presented, Wang teaches antibodies and drug conjugates targeting TACSTD2, wherein the antibody drug conjugates (ADCs) have the structure of Ab-(L-D)n wherein Ab is the antibody hRS7, D is a cytotoxic molecule, and L is a linker that connects the antibody and the drug (Description Pages 1-2, Original Document Pages 3-4). In an exemplary embodiment, L is Mal-PEG4-Val-Lys(PEG24-Me)-PABC and D is MMAE, wherein the antibody is hRS7 and the full structure is reproduced below (Description Page 5, Original Document Page 13).
Additionally, Wang discloses in Example 6 the synthesis of Mal-Peg4-Val-Lys(m-dPEG24)-PAB-MMAE (i.e., drug-linker) and its subsequent coupling to the hRS7 to yield ADC molecule hRS7-PEG4-VL(m-dPEG24)-PAB-MMAE (Description Pages 14-15, Original Document Pages 18-19). It is particularly noted that the structure of Mal-Peg4-Val-Lys(m-dPEG24)-PAB-MMAE that is subsequently coupled to the hRS7 antibody (i.e., humanized monoclonal anti-TROP2
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antibody) is of the structure provided below (Original Document Page 18).
It is noted that the above-presented structure reads on instant formulas I, Ia, and III, of instant claims 4 and 14-15, respectively; more specifically, the above-presented structure is an exact match to instant formula III of claim 15, which comprises the instantly elected species corresponding to Z1, W1, and W2, further wherein m1 = 4 and m2 = 23. Additionally, Wang discloses the coupling of Mal-Peg4-Val-Lys(m-dPEG24)-PAB-MMAE to the hRS7 antibody to yield the hRS7-PEG4-VL(m-dPEG24)-PAB-MMAE ADC, which further reads on instant claims 4-5, 9, and 14-15. However, while Wang teaches Mal-Peg4-Val-Lys(m-dPEG24)-PAB of the instantly claimed formulas of claims 4 and 14-15, and its subsequent coupling to an hRS7 antibody to produce an ADC, it is noted that the cytotoxic small molecule drugs disclosed by Wang (e.g., MMAE above) do not include taxoid compounds (i.e., PTX’, paclitaxel). This deficiency is remedied by Velani.
Velani teaches that paclitaxel is a highly cytotoxic mitotic inhibitor that binds and stabilizes the microtubules by interrupting normal mitotic spindle assembly and chromosome isolation during the G2/M stage of cell division, thus prompting apoptosis; however, one potential barrier to the clinical development of paclitaxel was its poor aqueous solubility (Page 123, The Taxanes, First Paragraph). Conjugating paclitaxel to antibodies to generate ADCs was also investigated, with some studies providing encouraging pre-clinical results (Id.). Two
analogues of paclitaxel, docetaxel (Taxotere) and carbazitaxel (Jevtana®), have been developed and are effective in the treatment of breast and prostate cancer and paclitaxel has also been approved by the FDA for the treatment of hormone-resistant metastatic prostate cancer; paclitaxel and docetaxel have had a significant effect on cancer chemotherapy due to their unique mechanism of action and their potency in multidrug-resistant (MDR) tumors (Page 124, First Paragraph). Paclitaxel-based antibody-prodrug conjugates (PTXMAbs) were designed to be capable of delivering therapeutically significant doses of paclitaxel to a tumor to avoid the solubility limitations of paclitaxel alone; another approach involved novel paclitaxel-based
ADCs incorporating discrete polyethylene glycol (dPEG) units as linkers. These conjugates had the potential for high drug-loading and good water solubility (Page 124, Second Paragraph). Thus, Velani suggest paclitaxel ADCs, and indicates that the use of dPEG linkers in such cases can overcome the issues of poor solubility and introduce the potential for high drug-loading.
Thus, it would have been obvious to one of ordinary skill in the art that the drug-linkers/antibody drug conjugates of Wang could be modified such that the disclosed cytotoxic drugs (e.g., MMAE) could be substituted with a taxoid compound (e.g., paclitaxel) as suggested by Velani because the combination of prior art elements according to known methods would be expected to obtain predictable results. One of ordinary skill in the art would have been motivated to modify the drug-linkers/hSR7 ADCs of Wang, and the coupling methods used to produce said ADCs, such that instead of MMAE, paclitaxel was the cytotoxic payload wherein the linker of Wang would be expected to overcome the solubility problems associated with paclitaxel and allow for high drug-loading due to its incorporation of PEG/dPEG units and wherein the resultant ADC would be expected to exhibit potent, anti-cancer effects as suggested by Velani, which would be specific for TROP2-expressing cancers.
More specifically with regard to claim 9, Wang further discloses pharmaceutical compositions that comprise an effective amount of an ADC of the invention and at least one pharmaceutically acceptable carrier, diluent, or excipient (Description Page 10). 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 filed 04/13/2026 (herein after referred to as "Remarks") have been fully considered but they are not persuasive.
On Pages 10-13 of Remarks, Applicant argues the following:
In tumor cell lines with different expression levels of Trop-2, the cytotoxicity of the PTX molecule alone was weaker than that of MMAE, but similar to that of SN38 (see Tables 1-2; Figures 4-6). However, after being prepared into ADCs, hRS7-VK-PTX was more effective than hRS7-VK-MMAE and hRS7-VK-SN38 in tumor cell lines with low expression of Trop-2, including COLO205, MDA-MB-231, SK-MES-1, Capan-1, NCIH2452 (see Tables 1 and 2). This effect reflects that the present application has produced an unexpectedly excellent technical effect in tumor cell inhibition over the ADCs disclosed in Wang.
Figure 1g of the instant application shows that the internalization rate of hRS7-VK-PTX of the instant application in Trop-2 expressing cells was significantly faster than that of hRS7-VK-MMAE, reflecting that the ADC of the present application has produced another unexpectedly excellent technical effect over the ADCs disclosed in Wang.
In Example 7, treatment with hRS7-VK-PTX (10 mg/kg) and hRS7-VK-MMAE (3 mg/kg) significantly inhibited the growth of xenografts heterogeneously expressing Trop-2, and the tumor growth inhibition index (TGI) were 99.5% and 91.7%, respectively (Figure le and Figure 10a). In addition, hRS7-VK-MMAE also had a killing effect on xenografts inoculated with NCIH1688 cells that did not express Trop-2, while hRS7-VK-PTX showed no such effect (Figure le and Figure 10a). The results indicate that hRS7-VK-PTX has a “bystander effect” and also show that the cell killing effect of hRS7-VK-PTX is significantly more Trop-2 specific than hRS7-VK-MMAE, providing reliable evidence for its safety in clinical applications. In addition, hRS7-VK-PTX (3 or 10 mg/kg) did not cause adverse reactions or weight loss in treated mice (Figure 9), in sharp contrast to the groups treated with hRS7-VK-MMAE (3 mg/kg), hRS7-VK-SN38 (3 or 10 mg/kg) or PTX alone. In Example 8, compared with the ADC with MMAE as the small molecule toxin moiety, the ADC of the present application did not show obvious signs of toxicity or weight loss. Thus, the linker-drug molecule or ADC as claimed in the instant application has unexpectedly significant technical effects in terms of safety compared with the ADC with MMAE as the small molecule toxin moiety in Wang.
There is no reason/motivation for one of ordinary skill in the art to combine Wang and Velani. The prior art does not provide any reason or motivation for combining Wang with Velani to bring the many unexpected technical effects (presented above) including but not limited to tumor suppression, internalization rate in Trop-2 expressing cells, bystander effect, and tolerability (adverse reactions, toxicity, and weight loss, etc.). Furthermore, numerous linkers have been disclosed in the prior art for ADC preparation, while Wang only involves one specific example among them. How to select a suitable type from these numerous disclosed linker options to achieve superior performance (such as even one of the aforementioned advantages demonstrated in this application) is unpredictable to a person skilled in the art.
With regard to the data/arguments presented by Applicant, it is noted that according to 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). It is specifically noted that Applicant has provided no statistical analysis of the data presented, and as such there is no clear support that the “significantly unexpected results” and “significantly superior technical effects” as argued are of both statistical and practical significance as currently argued. Furthermore, specifically regarding Example 7 wherein treatment with hRS7-VK-PTX (10 mg/kg) and hRS7-VK-MMAE (3 mg/kg) significantly inhibited the growth of xenografts heterogeneously expressing Trop-2, and the tumor growth inhibition index (TGI) were 99.5% and 91.7%, respectively (Figure le and Figure 10a), it is specifically noted that these data sets are not directly comparable; the comparison of results between hRS7-VK-PTX at a dose of 10 mg/kg and hRS7-VK-MMAE at 3 mg/kg are not comparable because of the difference in dosages. It is unclear as to if the difference in TGI is (i) solely the result of the argued improved/superior properties of hRS7-VK-PTX, (ii) solely the result of hRS7-VK-PTX being administered at a higher dose, or (iii) a combination of both. Thus, any arguments regarding superior and/or unexpected results are deemed not persuasive.
Regarding the arguments of no reason/motivation for one of ordinary skill in the art to combine Wang and Velani and the unpredictability thereof, it is noted that there is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). Furthermore, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). As recited in MPEP 2144.02, the rationale to support a rejection under 35 U.S.C. 103 may rely on logic and sound scientific principle. In re Soli, 317 F.2d 941, 137 USPQ 797 (CCPA 1963). As noted in the previous Office Action (01/12/2026), and as reiterated above, it would have been obvious to one of ordinary skill in the art that the drug-linkers/antibody drug conjugates of Wang could be modified such that the disclosed cytotoxic drugs (e.g., MMAE) could be substituted with a taxoid compound (e.g., paclitaxel) as suggested by Velani because the combination of prior art elements according to known methods would be expected to obtain predictable results. One of ordinary skill in the art would have been motivated to modify the drug-linkers/hSR7 ADCs of Wang, and the coupling methods used to produce said ADCs, such that instead of MMAE, paclitaxel was the cytotoxic payload wherein the linker of Wang would be expected to overcome the solubility problems associated with paclitaxel and allow for high drug-loading due to its incorporation of PEG/dPEG units and wherein the resultant ADC would be expected to exhibit potent, anti-cancer effects as suggested by Velani, which would be specific for TROP2-expressing cancers. Thus, the rational supporting the above claim rejection under 35 U.S.C. 103 over Wang in view of Velani relies on logic and scientific principle, wherein the teachings of the individual references support logic/rationale for the combination of references.
In view of the above, absent statistical analysis to support the arguments as presented, the arguments of “significantly unexpected results” and “significantly superior technical effects” are deemed not persuasive and as such the rejection of claims 4-5, 9, and 14-15 is deemed proper and is maintained.
Conclusion
Claims 4-5, 9-11, and 14-15 are pending. Claims 10-11 are withdrawn. Claims 4-5, 9, and 14-15 are rejected. 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 ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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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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