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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-9 and 12-13) and species listed below in the reply filed on 11/28/2025 is acknowledged.
Elected Species:
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Z1 is ;
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PTX’ is paclitaxel;
W1 is ;
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W2 is ; and
The antibody is anti-TROP2 antibody hRS7.
Claim Status
Claims 5 and 10-13 have been amended as requested in the preliminary amendment filed on 12/28/2022. Following the amendment, claims 1-13 are pending in the instant application.
Claims 6 and 10-11 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as claims 10-11 are drawn to nonelected inventions and claim 6 is drawn to non-elected species (elected antibody hRS7 is humanized and monoclonal, i.e., monovalent and monospecific) in the Response filed 11/28/2025, there being no allowable generic or linking claim.
Claims 1-5, 7-9, and 12-13 are under examination in the instant office action.
Priority
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. However, it is noted that the claim to foreign priority has not been perfected, as no English translation of the foreign priority document has been provided.
Claims 1-5, 7-9 and 12-13 have an effective filing date of June 18, 2021 corresponding to PCT/CN2021/101061, because the claim to foreign priority has not been perfected.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/28/2022 and 09/19/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because Figures 1-9 are blurry and much of the figure contents are illegible. 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.
Specification
The abstract of the disclosure is objected to because the abstract currently recites "connexon"; this term is not a term recognized by the art and is not clearly defined by the specification and thus renders the abstract unclear. Additionally, the exemplary structure presented appears to be incorrect (see claim objection section below), and is blurry and very difficult to read. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
A substitute specification including the claims is 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 is 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. Additionally, the structures presented in the instant claims/specification appear to be incorrect (see claim objection section below).
A substitute specification must not contain new matter. The substitute specification must be submitted with markings showing all the changes relative to the immediate prior version of the specification of record. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. An accompanying clean version (without markings) and a statement that the substitute specification contains no new matter must also be supplied. Numbering the paragraphs of the specification of record is not considered a change that must be shown.
Claim Objections
Claims 1-3 and 12 are objected to because of the following informalities: the provided structures corresponding to the recited formulas are extremely blurry and are difficult to read; additionally, it is noted that the structures presented in the claims appear to be incorrect. The structures presented do not match the compound names presented in the instant specification; for example, Page 30 of the instant specification describes the synthesis and isolation of Compound 6 (i.e., Mal-PEG4-Val-Lys(m-PEG24)-PAB-PTX, also identified as VK-PTX). It is particularly noted that while Compound 6 is indicated to comprise Lys(m-PEG24), the corresponding structure, which matches the structures instantly claimed, comprise an (O-CH2-CH2-O)24 group which does not correspond to PEG24. It appears that the second bracket to designate the repeating unit is not in the proper location; i.e., m-PEG24 corresponds to (O-CH2-CH2)24-O-CH3.
Appropriate correction is required.
Claim Interpretation
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In view of the inconsistencies in the nomenclature and corresponding structures throughout the instant application, it is noted that the instantly claimed formulas I, Ia, III, and IV are being interpreted as comprising Lys(m-PEG24), wherein the structures match the nomenclature presented in the instant specification (see, for example, Page 30). For example, formula I of claim 1 is being interpreted as presented below:
Formulas Ia, III, and IV are also being interpreted as comprising the Lys(m-PEG24) group as presented above.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
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 for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites the limitation "the formula" in line 3. There is insufficient antecedent basis for this limitation in the claim; it is noted that claim 2 currently recites “[t]he compound of formula I according to claim 1, wherein the structure of the compound of formula I is as shown in formula Ia” and as such it is unclear as to if the recitation of “the formula” is referring to formula I of claim 1 or formula Ia presented in claim 2. This rejection can be obviated by amending the claim to recite the specific formula to which the claim is drawn; for example, line 3 of claim 2 may be amended to recite “in the formula Ia”.
Claim 13 is drawn to a method of preparing an antibody-drug conjugate comprising “using the compound of formula I of claim 1”. As such, the claim is drawn to a method/process, but fails to recite any active steps, rendering the claim indefinite. MPEP 2173.05(q) recites: “[a]ttempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. For example, a claim which read: ‘[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon’ was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986).”
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-5, 7-9 and 12-13 are 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; herein after referred to as "Velani").
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With regard to claims 1-5, 7-8, and 12-13, 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).
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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 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, III, and IV of instant claims 1-3 and 12, respectively; more specifically, the above-presented structure is an exact match to instant formula III of claim 3, which comprises the instantly elected species corresponding to Z1, W1, and W2, further wherein m1=4 and m2=24. 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 reads on instant claims 4-5, 7-8, and 13. However, while Wang teaches Mal-Peg4-Val-Lys(m-dPEG24)-PAB of the instantly claimed compound formulas of claims 1-3, 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.
Wang and Velani are considered analogous to the present invention as they are both in the same field of antibody drug conjugates comprising cytotoxic drug molecules. 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.
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.
Conclusion
Claims 1-13 are pending. Claims 6 and 10-11 are withdrawn. Claims 1-5, 7-9, and 12-13 are rejected. No claims are allowed.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642