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 .
Claims 1-15 are pending and will be examined on the merits.
Rejections/Objections Withdrawn
The 35 USC §112(b) rejection of claims 14-15 have been withdrawn in view of claim amendments.
All 35 USC § 103 rejections of the last Office Action have been withdrawn.
New Rejections
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) 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Suzawa (Suzawa, et al., Bioorganic & Medicinal Chemistry (2000) 8:2175) in view of MedChemExpress (MedChem Express, et al., https://www.medchemexpress.com/duocarmycin-sa.html?srsltid=AfmBOoqW9almkVlAGjSKQBe8pq4QW2aO0WoiHvZi2ZufmN-ZfRf8pclf First published 08/22/20219; accessed 3/21/2026)
Suzawa teaches on the subject of the duocarmycin derivative DU-257, which is a enzymatically cleavable, PEG comprising duocarmycin derivative (Suzawa, Abstract). Suzawa teaches that duocarmycins are unique anti-tumor antibiotics but often times show marginal activities in solid tumors due to poor solubility in aqueous solution, side effects on normal tissues and rapid elimination from the body due to low molecular weight (Suzawa, p 2175, ¶ 1). Suzawa teaches that a duocarmycin immunoconjugate comprising a monoclonal antibody, a cleavable peptidic linker and a hydrophilic PEG moiety was made to address these issues (Suzawa, p 2175, ¶ 2 – 2176, ¶ 2). Suzawa teaches that the immunoconjugate of Suzawa is made by reacting NHS ester 14 of Suzawa (Suzawa, p 2177, Scheme 2):
(NHS)-O-CO- PEG-CO-Ala-Val-DU-257
… with antibody KM231, with PEG being the PEG moiety, Ala being alanine, Val being valine and DU-257 being the following compound (structure taken from Suzawa, p 2176, Scheme 1):
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Regarding instant claims 1-2, NHS ester 14 of Suzawa fully satisfies formula (1) of claim 1 except for a methyl group attached to the five-member ring instead of a hydrogen and also fully satisfies formula (3A) of claim 2 except for this same methyl group as well as a terminal NHS ester instead of a terminal azide. Regarding instant claim 3, NHS ester 14 of Suzawa comprises a Val-Ala dipeptide. Regarding instant claim 4, NHS ester 14 of Suzawa comprises a CO-PEG moiety (same as L6) and the -CH2-CH2-NH2 moiety present on DU-257 fully satisfies the L7 limitations of claim 4.
Suzawa does not teach NHS ester 14 of Suzawa comprising a terminal azide instead of an NHS ester and wherein the core duocarmycin moiety is duocarmycin SA.
MedChemExpress teaches that Duocarmycin SA (a derivative of the DU-257 of Suzawa) was a known antitumor antibiotic with an ic 50 of 10 pM and was commercially available before the effective filing date of the instant application.
It would be prima facie obvious to one of ordinary skill in the art to substitute the duocarmycin core moiety of Suzawa for the duocarmycin SA of MedChemExpress. One of ordinary skill in the art would be motivated to do this to create an art equivalent conjugate to DU-257. One of ordinary skill in the art would have a reasonable expectation of success substituting the duocarmycin SA of MedChemExpress in place of the duocarmycin moiety of Suzawa because MecChemExpress teaches that duocarmycin SA was also a known antitumor antibiotic known before the time of filing. Note that the resultant structure fills all limitations of (1).
It would be prima facie obvious to one of ordinary skill in the art to substitute the terminal NHS ester present in NHS ester 14 of Suzawa for a terminal azide. One of ordinary skill in the art would be motivated to do this in order to form an enzymatically cleavable, PEG-comprising duocarmycin-comprising moiety that may be conjugated to any alkyne-comprising molecule using azide-alkyne “click” chemistry, which is well-known in the art to be a highly efficient and biorthogonal reaction. The NHS ester crosslinker of Suzawa is an amine-reactive moiety that forms amide bonds with primary or secondary amine groups with the NHS moiety acting as a leaving group. Amine groups are very common in biomolecules such as proteins and this means that NHS ester-based conjugation could lead to nonhomogeneous and/or off-target conjugation. Azide groups react with alkyne groups to form triazole moieties and alkyne groups are not normally found in biomolecules and as such one of ordinary skill in the art would expect azide-based conjugation to produce more homogeneous conjugates with less off-target conjugation than NHS ester-based conjugation with a reasonable expectation of success.
Claim(s) 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Suzawa (Suzawa, et al., Bioorganic & Medicinal Chemistry (2000) 8:2175) and MedChemExpress (MedChem Express, et al., https://www.medchemexpress.com/duocarmycin-sa.html?srsltid=AfmBOoqW9almkVlAGjSKQBe8pq4QW2aO0WoiHvZi2ZufmN-ZfRf8pclf First published 08/22/20219; accessed 3/21/2026) as applied to claims 1-4 above and in further view of Tanaka (Tanaka et al., US 2022/0073641 A1; Published 3/10/2022; Priority to 12/28/2018 by way of JP2018-247363).
The teachings of Suzawa and MedChemExpress are discussed above. The combined teachings of Suzawa and MedChemExpress do not teach that the immunoconjugate of Suzawa and MedChemExpress compring the following bis biotin linker (linker in dashed red polygon):
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… wherein the bis biotin linker-comprising immunoconjugate is present in a therapeutic kit that comprises a mutant streptavidin of instant SEQ ID NO: 1 conjugated to an anti-CEA antibody.
Tanaka teaches on the subject of fusion proteins comprising antibodies recognizing cancer cells fused to mutant streptavidin having Tanaka’s SEQ ID NO: 1 (same as instant SEQ ID NO: 1) (Tanaka, Abstract). Tanaka teaches that the method of Tanaka is a drug delivery and retargeting method that combines the high binding ability between streptavidin and biotin in combination with an antibody wherein the streptavidin of Tanaka is a mutant streptavidin with reduced affinity for natural biotin but high affinity for the biotin dimer molecule of Tanaka (Tanaka, ¶ 0002). Tanaka teaches that the mutant streptavidin-antibody fusion protein of Tanaka is administered to a patient in need of cancer treatment and the action of the antibody will cause an accumulation of the mutant streptavidin within the patient’s cancer cells (Tanaka, ¶ 0045-0047). Tanaka teaches that the patient is then administered a conjugate comprising the biotin dimer (with high affinity for the mutant streptavidin) conjugated to a diagnostic or therapeutic compound, leading to accumulation of the diagnostic or therapeutic compound precisely within the patient’s cancer cells (Tanaka, ¶ 0047). Additionally, Tanaka teaches that the mutant streptavidin/antibody fusion protein and the biotin dimer comprising conjugate described above are present in a kit for treating or diagnosing cancer (Tanaka, ¶ 0046). Tanaka teaches the following compound, which is the biotin dimer compound of Tanaka conjugated to a phthalocyanine dye (Tanaka, ¶ 0089):
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Tanaka teaches that MKN45 cancer cells were treated with an anti-CEA antibody/mutant streptavidin fusion protein in conjunction with the compound above and then irradiated with a 690 nm LED at an energy flux of 100 J per square centimeter and dose-dependent photocytotoxicity was observed (Tanaka, ¶ 0106-0108; Fig. 8).
It would be prima facie obvious to one of ordinary skill in the art to modify the biotin dimer component present in the CEA-targeting kit of Tanaka to comprise the duocarmycin-SA immunoconjugate of Suzawa and MedChemExpress instead of the phthalocyanine dye of Tanaka. The net result of this combination would be a kit comprising: 1) an anti-CEA antibody linked to a mutant streptavidin of instant SEQ ID NO: 1 and 2) the duocarmycin-SA/biotin dimer conjugate of instant claim 13. One of ordinary skill in the art would be motivated to do this in order to target CEA expressing cancer cells with the duocarmycin-SA of Suzawa and MedChemExpress using the mutant streptavidin/biotin dimer targeting method of Tanaka. The phthalocyanine dye comprising biotin dimer conjugate of Tanaka is identical to the compound of instant claim 13 except for the presence of the phthalocyanine dye moiety as the therapeutic agent instead of the enzymatically cleavable, PEG comprising duocarmycin moiety taught by Suzawa substituted with the duocarmycin SA of MedChemExpress. The figure below shows the phthalocyanine-comprising biotin dimer of Tanaka (top) and the instant claimed duocarmycin-comprising biotin dimer of claim 13 (bottom):
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The dashed red line present in the top structure shows where the required point of attachment for the duocarmycin-val-ala-PEG moiety would be to differentiate the duocarmycin-comprising biotin dimer collectively taught by Suzawa and Tanaka from the phthalocyanine-comprising biotin dimer taught by Tanaka. Additionally, the terminal azide present in the duocarmycin-val-ala-PEG moiety discussed in the 35 USC 103 rejection above provides a biorthogonal means to covalently link the duocarmycin-comprising compound of Suzawa via azide-alkyne “click” chemistry, which is both well-known in the art and would inherently give rise to the triazole group present in the compound of claim 13. One of ordinary skill in the art would have a reasonable expectation of success modifying the biotin dimer component present in the CEA-targeting kit of Tanaka to comprise the duocarmycin immunoconjugate of Suzawa instead of the phthalocyanine dye of Tanaka because the mutant streptavidin/biotin dimer drug delivery technology of Tanaka is capable of selectively directing either a phthalocyanine dye moiety or a duocarmycin moiety to CEA-expressing cancer cells and the duocarmycin moiety of Suzawa is also capable of acting as an anti-tumor cytotoxin and does not require photoexcitation to elicit its cytotoxic effects.
Response to Arguments
Applicant's arguments filed 12/15/2025 have been fully considered but they are not persuasive.
Applicant grouped arguments related to both 35 USC § 103 rejections together and, as such, they will be addressed here together. Applicant first argues that the Suzuwara compound is different from the instant claimed compound. This issue has been addressed with the inclusion of the MedChemExpress reference.
Applicant disagrees that one of skill in the art would have reason to modify compound 14 of Suzawa to include the terminal azide as the last Office Action asserts. Applicant alleges hindsight. In response, the Nwe reference is presented (Nwe, et al., Canc. Biother. RadioPharm. 2009 24(3):289), which was published over a decade before the effective filing date about the growing popularity of biorthogonal “click” chemistry, specifically the azide-alkyne cycloaddition (Nwe, Abstract). Azide-alkyne cycloaddition was well-known and popular in the art long before the effective filing date of the instant application. Regarding the cleavable elements, the valine-alanine and valine-citrulline dipeptides are art equivalent, as they are recognized and cleaved by the same intratumoral cathepsins. Applicant also argues that Tanaka fails to teach a duocarmycin derivative as claimed that would compensate for the deficiencies of Suzawa, which have already been addressed.
Applicant then goes on to describe the invention’s basic functionality and manner of synthesis. Applicant then goes on to point out Example 5 and Figure 8, showing concentration-dependent inhibition vs CEACAM5 positive MKN45 cells, as well as Example 6, showing cytotoxicity against HeLa S3 cells, with the claimed invention outperforming the drug itself. In order to rebut a prima facie case of obviousness, results demonstrated must be unexpected (see MPEP § 716.02(a)). None of these results are unexpected. One of ordinary skill in the art would readily assume that a targeted therapeutic would kill cells expressing its target and that the targeted therapeutic would outperform its component drug. Applicant also argues that unexpected effects were observed when enzymatic cleavage of the val-cit was not observed when attached to streptavidin. This again is not unexpected. One of ordinary skill in the art would readily expect attachment to a large, bulky protein to hinder access of the val-cit moiety from the active site of the enzymes that cleave it, similar to how adsorption to albumin protects metabolites from enzymatic activity as they are transported through the blood.
Conclusion
Claims 1-15 are rejected.
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sydney Van Druff whose telephone number is (571)272-2085. The examiner can normally be reached 10 am - 6 pm.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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