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 .
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.
Current Status of 17/619,794
This Office Action is responsive to the amended claims of 28 July 2025.
Claims 1-11 and 15-33 are currently pending.
Priority
Applicant’s claim for the benefit of the prior-filed patent applications PCT/NL2020/050386 (filed 17 June 2020) and EP 19180678.5 (filed 17 June 2019) under 35 U.S.C. 119(e), 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application for the following reasons: Figures 3-5 are labeled with some variation of “Figure 3” and “Figure 3 (Cont.)”. Title 37 CFR § 1.84(u)(1) states that partial views “must be identified by the same number followed by a capital letter”. Applicant may choose to relabel “Figure 3” and “Figure 3 (Cont.)” as “Fig. 3A” and “Fig. 3B”, along with relabeling the other figures listed above in an analogous manner.
Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Response to Amendments
The objections to the drawings, present in the previous office action, are hereby withdrawn due to the replacement drawing sheets, but new objections are made herein.
The objections to the claims, present in the previous office action, are hereby withdrawn due to Applicant’s amendments.
The 35 U.S.C. 112 rejections to the claims, present in the previous office action, are hereby withdrawn due to Applicant’s amendments.
The 35 U.S.C. 103 rejections to the claims, present in the previous office action, are maintained herein, but are altered as necessitated by Applicant’s amendments.
Response to Arguments
Applicant argues that the instant claims require a compound containing both an R1 group and an R87 group, and ROBILLARD does not teach such a compound. Applicant argues that the Examiner is using hindsight reasoning to pick a specific compound from ROBILLARD out of many options and to specifically modify that compound to produce a compound within the instant claims. Applicant argues that there would be no reason for one of ordinary skill in the art to apply PEGylation to additional molecules of ROBILLARD, as there are already PEGylated molecules therein that could be selected. Applicant then argues that if one was motivated to PEGylate molecules of ROBILLARD, “the Examiner cannot establish motivation to elect the particular configuration of the PEG out of the infinite ways to do so other than relying on hindsight”. Applicant then goes on to argue for the nonobviousness of the “surprising improvement in payload release afforded by the claimed compounds”, which include instant compounds 2.2, 2.4, 2.14, and 2.16.
The Examiner disagrees with Applicant’s arguments that the Examiner has used hindsight reasoning. The Examiner’s rejections below are based upon the state of the art and the understanding of one of ordinary skill in the art at the time of publication of ROBILLARD and BANERJEE.
ROBILLARD teaches the primary-amine-bearing compound shown below (claim 9). ROBILLARD also teaches PEGylation products of primary amine compounds very similar to the first compound below, such as the second compound shown below (claim 10). ROBILLARD teaches that the circulation time of the activator within the blood, and the PK/PD behavior of the compound, can be altered by attaching a polyethylene glycol group to the activator (Pg. 33, Ln. 12-23), which provides a clear motivation for PEGylating the compounds therein (Pg. 33). ROBILLARD additionally teaches other potential modifications of the compounds therein, such as the attachment of peptides and carbohydrates (Pg. 33, Ln. 21-23). ROBILLARD teaches that synthetic routes for all activators therein are “readily available to the skilled person, based on standard knowledge in the art” (Pg. 37, Ln. 21-25). ROBILLARD also specifically teaches methods for the attachment of molecules to primary amines of the activators therein, such as the two conjugation reactions shown on page 57.
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ROBILLARD teaches tetrazine compounds within chemical formula (7), and heteroaryl groups attached to the tetrazine core fall under the definition of R1 and R2 groups (claim 8 and Pgs. 26-27). It is important to note that ROBILLARD teaches those specific R1 and R2 groups to be any “aryl” group (claim 8 and Pgs. 26-27), and “aryl” groups are defined to be an aromatic or heteroaromatic group that is possibly substituted (Pg. 14, Ln. 1-3). Given this broad description, the artisan would be motivated to consider many possible R1 and R2 groups and modifications thereof. The PEGylated compound below is the basis for the Examiner’s rejections of the instant claims under 35 USC 103. To arrive at the PEGylated molecule below, the artisan needed only to apply PEGylation to the first molecule above, which was taught by ROBILLARD. That was well within the skill of one of ordinary skill in the art; it was well within the broad teachings of ROBILLARD; and it was obvious before the instant effective filing date.
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The Examiner has weighed the secondary considerations discussed by Applicant. The Examiner has determined that, due to the strong evidence of obviousness provided by ROBILLARD, the secondary considerations currently available to the Examiner are not able to overcome the evidence for obviousness of the instant claims.
Claim Interpretation
Regarding claims 23 and 28: There is no closed definition of a polymer within the instant specification. Page 42 of the specification describes a PEG polymer as having 2 to 4000 repeating units. Page 44 of the specification indicates that a PEG polymer may include multiple PEG units terminated by another moiety and includes copolymers. The Examiner is therefore interpreting a PEG polymer as a moiety with 2-4000 repeating polyethylene glycol units, along with any possible termination moieties and other dissimilar subunits under the definition of a copolymer, that could reasonably be referred to as a polymeric moiety.
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.
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 1-11 and 15-33 are rejected under 35 U.S.C. 103 as being unpatentable over:
ROBILLARD (WO 2012/156920 A1, International Publication Date 22 November 2012)
as evidenced by:
BANERJEE (Banerjee, S.S.; Aher, N.; Patil, R.; Khandare, J. “Poly(ethylene glycol)-Prodrug Conjugates: Concept, Design, and Applications” J Drug Deliv. 2012:2012:103973. doi: 10.1155/2012/103973. Epub 2012 May 7.).
Regarding claims 1-7, 17, 19-25, 27-29: ROBILLARD teaches targeted therapeutics made up of “triggers” and “activators”. ROBILLARD teaches that the invention therein includes the use of a tetrazine diene to act as an activator (Pg. 8, Ln. 1-3). ROBILLARD teaches the tetrazine diene molecule drawn below on page 110 within claim 9.
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ROBILLARD also teaches a specific tetrazine diene compound shown below with ethanol substituted amine groups, wherein the substituted amines are in the ortho position (claim 10, Pg. 113).
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ROBILLARD teaches the tetrazine diene molecule shown below on page 114 within claim 10.
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ROBILLARD teaches that the circulation time of the activator, within the blood, can be altered by attaching a polyethylene glycol group to the activator (Pg. 33, Ln. 19-21). ROBILLARD teaches methods for the attachment of molecules to primary amines of the activators therein, such as the two conjugation reactions shown on page 57.
BANERJEE provides evidence that conjugation of polyethylene glycol (PEG) to a molecule having a nucleophilic moiety was a well-known process before the instant effective filing date (abstract). Specifically, BANERJEE teaches the conjugation of PEG groups to primary amines or alcohols via the reactions in Figure 5 therein (Pg. 5).
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to test PEGylation of the activator (as taught by ROBILLARD) at all nucleophilic sites within the activators taught by ROBILLARD (as evidenced to be a well-known process by BANERJEE), for the purpose of tuning the circulation time of the activator within the blood (as taught by ROBILLARD). By applying the PEGylation shown in the molecule from Pg. 114 of ROBILLARD above to the molecule from Pg. 110 of ROBILLARD above, the molecule drawn below would be produced.
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One of ordinary skill in the art would have expected success in this conjugation, because primary amines in the ortho position of tetrazine compounds are shown to be functionalized with ethanol substituents by ROBILLARD.
Defining the variables of instant claim 1 as follows produces the compound rendered obvious above: Ya and Yb are both equal to Y1, Q1 of both Ya and Yb are both equal to R1, R1 of the uppermost aryl ring in the structure above is equal to NHC(O)X51, R1 of the lowermost aryl ring in the structure above is equal to N(X50)2, all Q2 moieties are equal to H, all Q3 moieties are equal to H, all Q4 moieties are equal to H, the X51 group is equal to -(SP)D-R87 (which is interpreted to be equivalent to -R87 when D is equal to 0 based upon Applicant’s claims), both X50 groups are equal to H, SP is a spacer moiety, D is equal to 0, and R87 is a PEG polymer having copolymer/termination units.
Regarding Claim 8: Defining the variables of instant claim 1 as follows produces the compound rendered obvious above: Ya and Yb are both equal to Y1, Q1 of both Ya and Yb are both equal to R1, both R1 groups are equal to N(X50)2, all Q2 moieties are equal to H, all Q3 moieties are equal to H, all Q4 moieties are equal to H, one of the X50 groups attached to the uppermost aryl ring in the structure above is equal to H and the other is equal to -(SP)D-R87, both X50 groups attached to the lowermost aryl ring in the structure above are equal to H, SP is the spacer moiety shown above between the nitrogen of the R1 group and the PEG moiety, D is equal to 1, and R87 is a PEG polymer terminated with ethyl amine.
Regarding Claims 9-11, 15, and 30-33: ROBILLARD teaches Scheme 1, which is copied below, on page 10 therein.
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Scheme 1 is further described in text on Pg. 10 of ROBILLARD. Scheme 1, as reproduced above, shows that the activator is also referred to as a diene. ROBILLARD teaches that the “trigger” portion of the prodrug is a dienophile, and is specifically trans-cyclooctene labeled TCO (Scheme 1 and Pg. 10). Scheme 1 of ROBILLARD above also teaches that contacting a diene (activator) compound therein with TCO, as part of a prodrug, releases the drug. This contact between these species constitutes their combination.
ROBILLARD teaches exemplary pathways for the releasee of a drug from a TCO trigger group on Pg. 17. ROBILLARD teaches TCO trigger groups wherein a releasable drug is present at the allylic position on Pg. 23 therein (shown below).
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ROBILLARD teaches that prodrugs or activators can each be administered with a pharmaceutically acceptable carrier (Pg. 48 at bottom). ROBILLARD also teaches that the invention therein is capable of specifically targeting cancer (Pg. 48 at top). Taken together, ROBILLARD teaches the administration of each of a diene (activator) and a TCO moiety with a releasable drug present at the allylic position for the treatment of cancer.
Regarding Claim 16 and 18: ROBILLARD teaches that administered chemical entities therein, such as prodrugs and activators, may be in the form of a salt (Pg. 49, Ln. 5-7). Because these chemical entities are referred to as prodrugs and as being administered (Pg. 48), one of ordinary skill in the art would assume that such a salt would be pharmaceutically acceptable.
Regarding Claim 26: ROBILLARD teaches the compound drawn below in the first row of compounds on page 110.
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Applying the PEGylation strategy rendered obvious, as explained above, to this molecule would result in the species drawn below. One of the R1 groups therein is equal to OH.
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Conclusion
No claims are currently allowable.
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 JOHN D MCANANY whose telephone number is (571)270-0850. The examiner can normally be reached 8:30 AM - 5:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, ANDREW D KOSAR can be reached at (571)272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JDMc/Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625