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 arguments received 27 March 2026.
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.
Response to Amendments
The objections to the drawings, present in the previous office action, are hereby withdrawn due to the replacement drawing sheets.
The 35 U.S.C. 103 rejections to the claims, present in the previous office action, are maintained herein.
Response to Arguments
Applicant argues that the Examiner’s assertion, that it would have been obvious to one of ordinary skill in the art to envisage the PEGylation of all nucleophilic sites of all activators described within ROBILLARD, is not a directed toward any particular compound or class of compounds. Applicant then argues that the activator compounds of ROBILLARD are numerous and varied, which Applicant says is not a finite, manageable set of compounds.
The Examiner does not agree with this argument. The activator compounds described by ROBILLARD, specifically those bearing nucleophilic moieties, is a clear and finite class of compounds.
Applicant argues that the Examiner has “arbitrarily elected” a single compound from claim 9 of ROBILLARD without providing any rationale for the selection of that particular compound. Applicant argues that the particular compound of claim 9 chosen by the Examiner is not unique among the many compounds taught by ROBILLARD. Applicant argues that without a “principled basis” for the selection of that particular compound, the Examiner’s selection must involve impermissible hindsight reasoning.
This is an interesting argument, because Applicant has already argued that the Examiner required the artisan to apply PEGylation to an unmanageably large, possibly non-finite list of compounds. And now, Applicant is arguing that the Examiner required PEGylation to be applied to a single compound without proper support for the selection of the specific compound. The Examiner’s argument, as to why the artisan would envisage PEGylation at all nucleophilic activator compound sites described by ROBILLARD, is that ROBILLARD tells the reader that PEGylation can be applied to the activator compounds therein for the purpose of altering the circulation time of the compounds (Pg. 33, Ln. 19-21).
Applicant argues that ROBILLARD teaches PEGylation not as a general strategy, as argued by the Examiner, but only in specific examples. Applicant argues that if a skilled artisan desired a PEGylated activator, they would “simply use one of the PEGylated compounds already disclosed in ROBILLARD – they would have no motivation to go back to the non-PEGylated compounds of claim 9 and perform new PEGylation chemistry”. Applicant argues that the Examiner’s “theory” requires ignoring the already PEGylated examples of ROBILLARD “in favor of a synthetic program to create new ones”. Applicant again argues that the Examiner used hindsight reasoning.
The following is an excerpt from page 33 of ROBILLARD:
“The Activator according to the invention has a good bio-availability, implying that it is available inside the (human) body for executing its intended purpose: effectively reaching the Prodrug at the Primary Target. Accordingly, the Activator does not stick significantly to blood components or to tissue that is non-targeted. The Activator may be designed to bind to albumin proteins that are present in the blood (so as to increase the blood circulation time, as is known in the art), but it should at the same time be released effectively from the blood stream to be able to reach the Prodrug. Accordingly, blood binding and blood releasing should then be balanced adequately. The blood circulation time of the Activator can also be increased by increasing the molecular weight of the Activator, e.g. by attaching polyethylene glycol (PEG) groups to the Activator ('pegylation'). Alternatively, the PK/PD of the activator may be modulated by conjugating the activator to another moiety such as a polymer, protein, (short) peptide, carbohydrate.”
The Examiner presents the excerpt above as an entire paragraph to show that the Examiner has not taken a teaching of ROBILLARD out of context. ROBILLARD does teach, as a general teaching, that all of the activators therein can be PEGylated to tune their circulation time, as shown above. Applicant seems to be arguing that for the Examiner to find that a particular compound was obvious before the instant filing date, the artisan would need to have read ROBILLARD and decided to synthesize each and every obvious compound that was not explicitly taught. This type of intention to perform an actual synthesis is not needed for a finding of obviousness. One of ordinary skill in the art would have read the clear teaching of ROBILLARD, that the activators therein can be PEGylated to increase circulation time, and would have immediately envisaged PEGylated forms of the activator compounds therein, at least for the compounds explicitly shown in the claims of ROBILLARD with nucleophilic attachment sites. The artisan would have expected success with those PEGylated compounds, because ROBILLARD directly teaches the artisan to perform that chemical transformation.
Applicant argues that “the Examiner has created no expectation that simply PEGylating” the compounds of ROBILLARD would result in “the most favorable molecules”, and there would be no expectation that the molecules meeting the other requirements of the claims would be selected. This seems to be an argument from the Applicant that PEGylation is a general term and it isn’t clear why the Examiner arrived at the particular PEGylation pattern found in the rejections of the instant claims.
To arrive at the compound that is the basis for the Examiner’s rejections shown below, one of ordinary skill in the art would have needed to do the following: read the teaching of ROBILLARD that PEGylation of the activators therein can be used to tune their circulation time, see the types of PEGylation that are explicitly shown within claim 10 of ROBILLARD (of which there are 2 or 3), and mentally apply those exact types of PEGylation to the activator compounds bearing nucleophilic sites that are explicitly taught by ROBILLARD in claims 9 and 10. This would have been well within the ability of one of ordinary skill in the art. And to be clear, the Examiner is not combining a chemical transformation from one reference with another. The Examiner is simply applying a chemical transformation taught by one section of ROBILLARD to the explicitly claimed compounds of ROBILLARD.
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Applicant argues that the Examiner has improperly dismissed the secondary considerations provided. The Examiner has considered the secondary considerations provided by Applicant. In this particular case, the argument for obviousness based upon the teachings of ROBILLARD is strong. If Applicant would like to add claims that specify particular payload release characteristics, they can do so, with proper support.
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 envisage 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 ROBILLARD directly teaches the reader to apply PEGylation to the activator compounds therein. Also, 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.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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
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