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
To summarize the current election, the applicant elected group I and the species where the monoclonal antibody conjugate has a taxane as the drug, trastuzumab as the antibody, a random configuration and a cleavable bond between the polymer backbone and the antibody (L2).
Claims 42-43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions an species, there being no allowable generic or linking claim. The applicant is reminded to update the claim status identifiers.
Specification
The disclosure is objected to because of the following informalities: The specification of record filed on January 28, 2022 shows the following text for example 2 on page 20
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The amendment states that the paragraph starting at line 21 is amended, but line 21 is not the beginning of a paragraph on this page. Thus the specification still recites an illegible line of characters, as shown, that is presumably a graphical representation of the reaction conducted in the example. Example 4 also still recites an illegible line of characters that are supposed to be a graphical representation of the reaction it conducted. These representations are also still illegible. Example 3 has text that describes a reaction that it conducts, but the included graphical representation omits any mention of PDS-CDTPA, a key component that is necessary to produce the final product that is shown. The amendment does not address any of these issues, but adds replacement text in the wrong places which yields a confusing mixture of text.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 30, 37, and 40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 30 recites the claimed conjugate to be obtained from as RAFT agent comprising “a C1-C402-(pyridine-2-yl disulphanyl) alcohol”. No such compound is mentioned in the disclosure. As a result, eh artisan of ordinary skill would not have deemed the applicant to be in possession of the invention as claimed
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 30, 37, and 40 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 30 recites “obtaining RAFT agent comprising disulphide by reacting a trithiocarbonate or dithioate molecule (RAFT agent), having carboxylic acid functional group thereon, with a C1-C402-(pyridine-2-yl disulphanyl) alcohol”. The “C1-C402-(pyridine-2-yl disulphanyl) alcohol” structural name is not standard terminology that defines the location of the alcohol substituent in the structure and appears to be a misquoting of “C1-C102-(pyridine-2-yl disulphanyl)” as recited in the instant specification at page 15 line 34. For the sake of compact prosecution, the compound 2-(pyridine-2-yl disulphanyl) ethanol that was instantly exemplified will be deemed as within the scope of the recitation. Clarification is still required.
The parenthetical recitation of “RAFT” in claim 30 is confusing as to whether it is stating that the trithiocarbonate or dithioate molecule is to be the RAFT agent or if the compound generated by reacting either of these compounds with C1-C402-(pyridine-2-yl disulphanyl) alcohol the RAFT agent. A later recitation of “reacting the RAFT agent” is then unclear as to which compound is being referenced as the RAFT agent.
Claims not explicitly elaborated upon are also indefinite because they depend from an indefinite claim and do not add clarity.
Claim Rejections - 35 USC § 103
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.
Claim 30, 37, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Sanyal et al. (previously cited) in view of Yang et al. (previously cited), Kulhari et al. (Scientific Reports 2016 6(1)(2317):1-13), and Vanparijs et al. (previously cited) as evidenced by Ponnusamy et al. (Journal of Polymer Science Part A: Polymer Chemistry 2013 51:1066-1078).
Sanyal et al. teach a cleavable polymer drug conjugate that is a copolymer composed of two monomers as shown below:
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In formula I of Sanyal et al., R1, R2, R3, x, y, n, D, and L are defined as in the instant formula, where L is equivalent to L1 of instant formula I (see page 3; instant claim 30). Terminal groups A and B are end groups that can optionally be null or a polymerization initiator or fragment (see page 3; instant claim 30). Z may be O or NH (see page 3; instant claim 30). Examples are detailed with methacrylate as a base monomer, thereby making Z exemplified as O (see examples 1-2; instant claim 30). Sanyal et al. teach the linking group, L, to be selected from a list of options that are the same as those instantly claimed and include GFLG as part of as an alternative to a C1-C10 hydrocarbon linker (see page 7 last full paragraph; instant claim 37). Amongst the initiators that are envisioned include trithiocarbonates which are RAFT agents (e.g., 2-(Dodecylthiocarbonothioylthio)propionic acid) (see page 11 and Ponnusamy et al. page 1072 first column last partial paragraph). Additionally, the polymer is taught to have a random configuration of its monomers (see page 5fifth full paragraph). They also teach the benefit of their structure bearing a polyethylene glycol moiety in its side chains as reducing accumulation of the conjugate in non-targeted organs when employed for cancer treatment (see page 1 first paragraph and page 4 first partial paragraph). Sanyal et al. teach a variety of envisioned compounds for the drug that include docetaxel which they also exemplify bound via the GLFG linker (see page 9 first paragraph and example 3; instant claims 30 and 40). An antibody bound at an end of the polymer is not detailed.
Yang et al. teach antibody-drug-polymer conjugates as a strategy to deliver drugs to a tumor target without systemic toxicity by targeting a desired drug to the tumor tissue via the antibody (see abstract and page 17 lines 10-14; instant claims 30 and 40). The conjugate structure binds one or more polymer backbone chains with a drug molecule bound to several of its monomers to a targeting antibody molecule (see page 1 lines 28-30). The polymer chains have a functional group at one end to facilitate attachment of multiple polymer chains to one antibody molecule and may be a copolymer arranged with an alternating, random, or block configuration (see page 9 lines 29-30 and page 19 lines 6-22). Yang et al. additionally teach that chemistry employed between the polymer and antibody may vary (see page 19 lines 6-22 and page 31 lines 17-20). Envisioned monomers include esters of acrylic acid and esters of methacrylic acid (see page 21 lines 6-13). The drug is envisioned as an anti-cancer compound, and more specifically as a taxane (page 22 lines 6-8, page 29 line 28-page 30 line 5, and example 8; instant claim 30). Yang et al. teach that the connection between the drug and polymer may be a peptide that is cleavable within a lysosome where the peptide GFLG is exemplified (see page 21 lines 3-6, page 31 lines 5-7, and example 8; instant claim 37). Further, the targeting antibody is envisioned as trastuzumab (see page 24 lines 27-33; instant claim 33). Yang et al. also teach 1 to 8 polymer chains per antibody-polymer-drug conjugate (see page 35 lines 21-22; instant claim 30).
Kulhari et al. teach the improved effectiveness of the combination of docetaxel with a trastuzumab conjugated polymer carrier over docetaxel alone or with just the polymer carrier at killing HER2 receptor overexpressing cancer cells as well as the increase in the pharmacokinetic profile it attained in vivo (see abstract, page 6 last partial paragraph-page 7 first partial paragraph, page 8 first full paragraph, and figures 8 and 9). They additionally teach treating the trastuzumab with Traut’s reagent to confer a thiol reactive group which is linked via amine groups along the antibody (see figure 1).
Vanparijs et al. teach chemistries employed to produce antibody-polymer conjugates, where the polymer has acrylate monomers and has a single reactive end (see abstract and Scheme 2). Here reaction with a thiol from the antibody can be facilitated via a terminal pyridyl disulfide which provides a disulfide bond between the antibody (protein) and polymer or via a terminal maleimide (see scheme 2). They employ a RAFT agent to provide the terminal pyridyl disulfide reactive group produced from the reaction of 2-(pyridine-2-yl disulphanyl) ethanol reacted with 2-(n-butyltrithiocarbonylthio)propionic acid (trithiocarbonate with a carboxylic acid functional group) (see scheme 2 third column).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare an antibody-drug-conjugate from a GFLG docetaxel-polymer conjugate of Sanyal et al. in light of Yang et al., who teach this approach for providing targeted delivery of such cancer treating compounds. This modification would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. Specifically, a polymer that is a random copolymer with the polyethylene glycol modified methacrylate and drug conjugated (meth)acrylate monomers as taught by Sanyal et al. would have been obvious. The selection of trastuzumab as the targeting antibody, in light of Kulhari et al., would have been obvious because they show its ability to improve docetaxel availability in vivo and specificity to HER2 overexpressing cancer cells. Kulhari et al. detail a Traut’s reagent induced thiol on the trastuzumab for binding to the polymer carrier, thus the selection of a route to the docetaxel bearing polymer of Sanyal et al. that has an initiator fragment capable of binding a thiol would have been obvious. Vanparijs et al. detail such initiator options that were known in the art, namely that provided via a RAFT agent composed of the reaction product of 2-(n-butyltrithiocarbonylthio)propionic acid and 2-(pyridine-2-yl disulphanyl) ethanol. This would have been obvious to select as a known and identified avenue to bind a thiol bearing antibody to a polymer, given that Sanyal et al. envision similar RAFT transfer agents as the source of their terminal initiator fragments. The number of polymer chains per antibody taught by Yang et al. overlaps with the range instantly claimed and are attainable due to the multiplicity of amine groups in an antibody that serve as linking points for the Traut’s reagent induced thiol groups, thereby rendering the claimed range obvious. “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed.Cir. 1990)” (see MPEP 2144.05). Claim 30 is recited as a product-by process. “’[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.’ In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)….The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)” (see MPEP 2113). Therefore when no structure is implied, the product-by-process recitation does not add any limitations that affect patentability. It is not evident that the recited pH of the reaction of Traut’s reagent treated antibody with the polymer having a disulphanyl bearing terminal group, as gleaned from applying the prior art teachings as discussed, yields a particular structure distinct from these teachings. Therefore claims 30, 37, and 40 are obvious over Sanyal et al. in view of Yang et al., Kulhari et al., and Vanparijs et al. as evidenced by Ponnusamy et al.
Declaration
The declaration under 37 CFR 1.132 filed November 24, 2025 is insufficient to overcome the rejection of claims 30, 32-33, 37, and 40 based upon Yang et al. in view of Sanyal et al., Gasparini et al., Ma et al., and Vanparijs et al. as set forth in the last Office action because: It includes statements which amount to an affirmation that the claimed subject matter functions as it was intended to function. This is not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716. The declarant provides two figures, the second of which has a legend that does not match its contained graph. Presumably the “APC” in the larger of the two legends corresponds to the “ADC” in the graph. Even with this presumed alignment, the outcome of the in vivo efficacy study yields the expected results, where the coupling of the trastuzumab and docetaxel to the polymer as a conjugate is most effective at anti-cancer cell activity followed by docetaxel bound to the polymer and then the unbound docetaxel in decreasing efficacy (see Kulhari et al. figure 8). Thus these data do not overcome the obviousness of the claimed conjugate.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Response to Arguments
Applicant's arguments filed November 24, 2025 have been fully considered. In light of the amendment, the objection to the abstract as well as claims 32 and 37 are hereby withdrawn. The rejection of claim 37 due to its particular clarity issues are hereby withdrawn as well due to the amendment. New grounds of rejections that modify the rejections under 35 USC 103 are detailed to address the new claim limitations. Arguments still relevant to the new grounds of rejection are addressed below.
Regarding the objection to the specification:
As noted above, the amendments were placed incorrectly and do not correct the illegible lines of characters that were highlighted in the rejection. They add confusion to the specification and should be deleted and made anew in the proper locations.
Regarding rejections under 35 USC 103:
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).
The applicant argues that Yang et al. do not teach two different connecting schemes for the antibody and drug in their conjugate compound. This argument appears inconsistent with the teachings of Yang et al. that detail a sulfur based connectivity for the antibody and a amide based connectivity for the drug (see figures 1A-1C). They also argue that Yang et al. only teach one linkage mechanism for antibody attachment, namely via a maleimide-thiol. Vanparijs et al. clearly shows that this route as well as via a disulfide were recognized alternatives for binding thiol bearing proteins to acrylate polymer terminal groups. The applicant also argues that Yang et al. do not provide the chemistry to incorporate docetaxel onto a polymer backbone, yet the cited combination of art that also relied upon Sanyal clearly exemplify that this chemistry was known utilized previously.
The applicant’s arguments against Sanyal et al. and Vanparijs et al. detail limitations they lack which are addressed by another cited reference. When considered in combination, as detailed, the claimed conjugate and composition are obvious in light of the prior art.
Conclusion
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARALYNNE E HELM whose telephone number is (571)270-3506. The examiner can normally be reached Mon-Fri 9-5.
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/CARALYNNE E HELM/Examiner, Art Unit 1615
/MELISSA S MERCIER/Primary Examiner, Art Unit 1615