DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response and amendments received February 11, 2026 are acknowledged.
Claims 1-19 and 21 have been canceled.
Claims 20, 22, and 23 are pending in the instant application.
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.
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 20, 22, and 23 stand rejected under 35 U.S.C. 103 as being unpatentable over Kozak et al. in view of Henkel et al. and in view of Sebeika et al.
Kozak et al disclose a process for making an antibody-drug conjugate (ADC) comprising the steps of adding the reducing agent TCEP to an antibody solution, followed by addition of a maleimido drug derivative (MC-vc-PAB-MMAE, basically the auristatin MMAE joined to a linker comprising a maleimide group) to form an ADC wherein the linker-drug attaches covalently at interchain cysteines (see entire document, particularly the abstract and the experimental procedures section beginning in the left column of page 773). Such conditions generated antibodies having 4 attached drugs, and thus antibody species comprising 4 reduced SH groups were necessarily formed (see for example Figure 2). Such teachings differ from the instant claimed inventions in that the disclosed process steps did not include “an inhibitor of the reducing agent”.
Henkel et al. teach that thiols are highly reactive and thus useful for protein derivatization, but free thiols are typically not naturally found and instead must be generated by treatment with a reducing agent (see entire document, particularly the abstract and the left column of page 2260). They further disclose that TCEP is preferred over thiol-based reducing agents such as DTT as the thiol of the reducing agent would compete with the thiol of the cystine for coupling to maleimide (and thus generating unwanted side products) and since it was thought that TCEP did not interact with maleimide and thus did not need to be removed from the reaction prior to addition of the maleimide to the reduced cystine in the polypeptide (ibid). However, such early reports that TCEP did not react with maleimide were incorrect as Henkel et al. show that phosphines (of which TCEP is a member) do interact with maleimide to yield unwanted side products (see Schemes 1, 2, and Figures 2 and 4 in particular). Thus, they teach that excess phosphines should be removed or inactivated before maleimide is added to the reaction, and that addition of the TCEP inhibitor 4-azidobenzoic acid (ABA) in excess was sufficient to suppress formation of side products (see particularly page 2264 and Figure 4). Notably they used 10 equivalents to the amount of TCEP to inhibit the reducing agent (see the middle of page 2264). They further disclose that the addition of azidobenzoic acid is advantageous as it suppresses the formation of unwanted side products between TCEP and maleimide groups in the absence of prior purification to remove TCEP from the reaction (see most particularly the paragraph spanning the left and right columns of page 2264 as well as the last sentence of the paragraph spanning the left and right columns of page 2260).
Sebeika et al. disclose that ADC can be successfully created using continuous flow microreactors, and that the use of such apparatus provides the advantages of a high surface area to volume ratio to affords superior heating and mixing over convention setups thus yielding faster reactions with fewer byproducts (see entire document, particularly the top of the right column of page 151 and the Conclusion section on page 154).
Therefore, it would have been obvious to a person of ordinary skill at the time of the invention to add in the use of an inhibitor of TCEP as taught by Henkel et al. when making ADC using the maleimide conjugation protocol as disclosed by Kozak et al. Artisans would be motivated to do so as the presence of TCEP in a reaction to which maleimide is added yields unwanted side products that negatively impact yield as shown by Henkel et al, and the formation of such side products can be very strongly inhibited by adding 4-azidobenzene, and inhibitor of TCEP, to the reaction mixture after the reduction of the antibody by TCEP but before the addition of the drug attached to a maleimide linker as was also shown by Henkel et al. The ordinary artisan would have been further motivated to perform such reactions using a continuous flow microreactor in order to gain advantages including increased speed, grater control, and fewer side reactions as disclosed by Sebeika et al., and would have a reasonable expectation of success in doing so passed on the successful synthesis of an ADC construct in a microreactor as disclosed by Sebeika et al.
Applicant's arguments filed February 11, 2026 have been fully considered but they are not persuasive. Applicant argues on many grounds. Applicant begins by stating that the instant claims require that the linker and the inhibitor of TCEP are present simultaneously in a single mixture. Applicant then argues that the protocol as claimed isn’t fully disclosed in any one reference, that the increase in DAR as recited as an intended result of the method of claim 20 is unexpected, and that the cite art references do not describe how to build a microreactor.
These arguments have been considered and are not persuasive. Applicant is respectfully reminded that 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). As has been discussed in the rejection or record as well as throughout the history of prosecution in the instant case, the use of microreactors in making ADC, as well as their advantages including superior heating and mixing, faster reaction times, and fewer side products as compared to other methods was known in the prior art, such as that of Sebeika et al. as discussed in the rejection of record. Given such known advantages applicant’s apparent conclusion that artisans would not have been motivated to use microreactors when making ADC appears unreasonable. Further, with regard to applicant’s arguments that the cited prior art fails to teach how to make a microreactor (i.e. male a piece of laboratory equipment) applicant is reminded that no such information is disclosed in the instant specification. Indeed, the fact that Sebeika et al. appear to have bought their equipment (a Chemtrix Labtrix with a #3223 microreactor, see the right column of page 152) and the disclosure of paragraph [0052] in example 2 of the instant specification that a suitable microreactor can be found in WO 2017/179353, it more reasonably appears that suitable laboratory equipment was well known and commercially available prior to the filing of the instant invention. Additionally, if applicant is of the opinion that the specific of the laboratory equipment are equipment is “essential”, applicant is remined that 37 CFR 1.57, as well as MPEP 608.01, indicate that:
(d) "Essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. "Essential material" is material that is necessary to:
(1) Provide a written description of the claimed 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 set forth the best mode contemplated by the inventor of carrying out the invention as required by 35 U.S.C. 112(a);
(2) Describe the claimed invention in terms that particularly point out and distinctly claim the invention as required by 35 U.S.C. 112(b); or
(3) Describe the structure, material, or acts that correspond to a claimed means or step for performing a specified function as required by 35 U.S.C. 112(f).
(e) Other material ("Nonessential material") may be incorporated by reference to U.S. patents, U.S. patent application publications, foreign patents, foreign published applications, prior and concurrently filed commonly owned U.S. applications, or non-patent publications. An incorporation by reference by hyperlink or other form of browser executable code is not permitted.
Thus if applicant believes the particulars of the laboratory equipment are “essential subject matter” to reproduce the methods as presently claimed, applicant should clearly and unambiguously state this on the record, and it is worth pointing out that a WIPO publication is NOT a US patent or US pre-grant publication.
With regard to the alleged failure to disclose applicant’s intended result, applicant has claimed a process not the result of the process, and the cited art of Henkel et al. (use of TCEP inhibitors in ADC synthesis) and Sebeika et al. (use of microreactors in ADC synthesis) both indicate that their processes reduce side reactions and thus the formation of unwanted products. As taught by Kozak et al., their protocol yielded an average DAR of 3.5 over all antibodies tested, and given that reductions in unwanted side products would increase the yield of the desired product DAR, the addition of TCEP inhibitors and microreactors to the methods of Kozak et al. would necessarily increase DAR relative to its value in the absence of such modifications. It is noted that applicant has argued that the art is too unpredictable to expect success, and points to data in the instant specification concerning relatively larger peaks for ADC comprising a DAR of 4 that are obtained when using microreactors rather than batch processing. Such arguments are not persuasive as both the use of inhibitors of TCEP as well as the use of microreactors were known to be useful in ADC synthesis as shown by Henkel et al. and Sebeika et al. and given such prior art use it appears unreasonable to assert that such methodologies are unpredictable.
With regard to arguments concerning DAR, the claims recites a “DAR of 3 to 4” which is a range. Given that an antibody can only have an integer number of drugs conjugated thereto, the recitation of a range signifies that applicant intends the average when summing all recovered products (e.g. a DAR of 3.5 or 3.8) and that this value larger when preparing ADC with a microreactor than without.. Given the fact that both Henkel et al. (TCEP inhibitor) and Sebeika et al. (microreactor) teach that their improvements to ADC synthesis reduce side reactions (and thus necessarily decrease unwanted products) very reasonably indicates that DAR will increase since the side reactions that reduce yield are diminished. More explicit, using the indicated thiol chemistry the maximum yield is 4 conjugates per antibody, and thus any diminution from 4 is due to unwanted side reactions that make actual yield lower than theoretical yield. If side reactions (i.e. the outcomes that do not yield drug being attached to the antibody) are reduced logically the DAR must go up via simple logic that would be very apparent to chemists.
The rejection is maintained.
No claims are allowable.
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 Michael Szperka whose telephone number is (571)272-2934. The examiner can normally be reached Monday-Friday 8:30-5:00.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641