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 .
Claim Status
The Applicant’s remarks filed September 17, 2025 have been entered. Claim 21 is canceled. Claims 1-19 are still withdrawn from further consideration as being drawn to a nonelected invention as discussed in the Election/Restrictions section of the non-final office action mailed July 07, 2025.
Thus, claim 20 previously presented is examined on the merits herein.
Withdrawn Objections and Rejections
With respect to the objections and/or rejections mailed in the non-final office action on July 07, 2025:
The objection to the drawings is withdrawn in view of Applicant’s replacement drawing of Fig. 6 filed on September 17, 2025.
Response to Arguments
The rejection of claim 20 under 35 U.S.C. 103 is maintained.
Applicant argues:
(A) Compounds of the present invention are prodrugs of actives containing hydroxyl groups not carboxyl groups, by conjugating molecules via existing hydroxyl groups or amine groups to an axial position of a platinum (Pt) center, see Applicant’s remarks, pg. 17 of 19, paragraph 4.
(B) For hydroxyl-group containing actives, the approach involves formation of a carbonate bridge between an axial OH group of the Pt center and a hydroxyl moiety of the bioactive agent. In other words, the bridge between the two hydroxyl groups is a carbonate, not a functionality containing a carbonate, yielding the structure as elected and discussed in said non-final office action mentioned above, see Applicant’s arguments, pg. 17 of 19, last full paragraph of the page.
(C) Such a carbonate bridge is not provided in the gemcitabine-biotin material of Callan, where the gemcitabine is directly associated to biotin, nor through a carbonate linkage, as the bridging moiety associating biotin and gemcitabine is a carboxy amine of the structure NH-(CH)2-O(C=O)- and not a carbonate (e.g. -O(C=O)O-), see Applicant’s remarks, pg. 17 of 19, last line of the page – pg. 18 of 19, lines 1-4.
(D) It would not be obvious to substitute the biotin conjugated on the gemcitabine of Callan with a Pt complex such as compound XXXIV of Gibson, since the substitution of the biotin would leave the carboxy amine bonded to the gemcitabine, in which case, substitution of the compound XXXIV would have an amine associating the Pt atom, leading to a completely different compound than that claimed, see Applicant’s remarks, pg. 18 of 19, second paragraph.
(E) It’s important to note that it’s impossible to conjugate a primary amine to the axial position of a Pt(IV) to obtain a compound from what the rejection recites and the compound having the structure of 1 as recited in Applicant’s remarks, see Applicant’s remarks, pg. 18 of 19, second paragraph and compound 1.
(F) One of ordinary skill in the art would have realized that the linker moiety is not what the Examiner indicated to be the case both in Callan and Gibson, namely -O-C(=O)-. Rather, in Gibson there is no linker moiety, as the actives containing hydroxyl groups are directly conjugated via the carbonate to the Pt center, and in Callan the linker is the carboxy amine mentioned above, see Applicant’s arguments, pg. 18 of 19, second paragraph from the bottom of the page.
(G) Associating gemcitabine directly or through the carboxy amine groups derived from Callan in the compound of Gibson is not enabled by Gibson. Conceptually the two cases are different. In the case of Callan, the carbonate is designed merely as a part of a stable linker between gemcitabine and biotin, while in our case, the conjugation of the carbonate to the Pt(IV) was designed specifically to decarboxylate, releasing the active following reduction of Pt(IV), see Applicant’s remarks, pg. 18 of 19, last paragraph of the page.
(H) Moufarij does not remedy the deficiencies of Callan and Gibson, see Applicant’s remarks, pg. 19 of 19, line 1.
With respect to Applicant’s arguments (A)-(H), the Examiner respectfully notes Callan teaches a chemotherapeutic agent is covalently bound to a linking group as discussed in the maintained 103 rejection below.
Callan exemplifies the chemotherapeutic agent that is covalently bound to a linking group is the gemcitabine-biotin conjugate discussed in the 103 rejection below.
The Examiner respectfully notes the biotin exemplified in said conjugate is separately modified to add a primary amine (e.g. -NH-(CH2)2- on the biotin structure as depicted in the synthesis of compound 2 in scheme 1 on pg. 44 of Callan; and to separately further add a carboxyl (e.g. -O-(C=O)-) on the biotin structure as depicted in the synthesis of compound 3 in scheme 1 on pg. 44 of Callan before said biotin is conjugated to the gemcitabine which results in the gemcitabine-biotin conjugate which is discussed in the 103 rejection below and wherein said gemcitabine-biotin conjugate is compound 4 of scheme 1 on pg. 44 of Callan.
The Examiner also respectfully notes when Callan teaches said “chemotherapeutic agent is covalently bound to a linking group”, the Examiner reasonably interpreted the limitation of “a linking group” to mean any linking group and thus was not limited to the linking group present on the biotin structure before conjugation with gemcitabine within scheme 1 on pg. 44 of Callan.
The Examiner respectfully notes Gibson teaches the compound known as compound XXXIV which contains a Pt(IV) that is directly connected to “L” at an axial position of the Pt(IV), wherein “L” is a therapeutically active anticancer moiety as taught by Gibson within the 103 rejection below.
The Examiner also respectfully notes Gibson teaches the therapeutically active moiety may be associated or bonded to the metal atom directly through a native atom or bond present on the therapeutically active moiety as exemplified within compound XXXIV of Gibson above; or through a linker moiety such as -O-C(=O)-, wherein at one end of the linker moiety is bonded to a therapeutically active moiety and at another is bonded to the compound directly to the metal atom as discussed in the 103 rejection below.
Therefore, Gibson does expressly teach the therapeutically active moiety of Gibson can be linked to a linker moiety, where Gibson exemplifies the -O-C(=O)- structure as said linker, where the linker at one end is directly connected to the therapeutically active moiety and at the other end is directly connected to the metal atom of the compound of Gibson, for example compound XXXIV of Gibson as discussed above.
Additionally, the Examiner further respectfully notes gemcitabine has a 5’-hydroxyl as depicted in scheme 1 of Callan before conjugation to the biotin structure known as compound 3 of Callan.
Furthermore, the Examiner respectfully notes compound 3 of Callan within scheme 1 teaches a carbonyl group -(C=O)- within the structure of -O-C(=O)- at a terminal end of the biotin reacts with the 5’-hydroxyl of the gemcitabine which results in a direct connection between the carbonyl (e.g. -C(=O)-) comprised within the biotin structure discussed above and the 5’-hydroxyl of the gemcitabine within scheme 1, wherein said connection results in said gemcitabine-biotin conjugate of Callan as exemplified within the 103 rejection below.
Therefore, the Examiner respectfully notes as a result of the reaction of compound 3 and gemcitabine to create the gemcitabine-biotin conjugate of Callan within scheme 1 as discussed above, a carbonate (e.g., -O-(C=O)-O-) structure is created at the 5’-hydroxyl position of the gemcitabine-biotin conjugate which links said gemcitabine to said biotin.
Thus, the Examiner respectfully notes when compound XXXIV of Gibson, where said compound XXXIV of Gibson contains the same -O-C(=O)- at a terminal end, is directly connected to the therapeutically active moiety as taught by Gibson above, specifically a DNA repair inhibitor, for example gemcitabine which is taught by Callan as evidenced by Moufarij in the 103 rejection below, the resulting structure would create a carbonate linker where at one end compound XXXIV of Gibson (e.g. the Pt(IV) of Applicant’s arguments) is directly connected to said -O-C(=O)- linker and at the other end of said -O-C(=O)- linker the 5’-hydroxyl end of gemcitabine is directly connected to said linker creating a carbonate linker (e.g., -O-(C=O)-O-) directly linking the gemcitabine of Callan with compound XXXIV of Gibson as discussed above.
Therefore, it would have been prima facie obvious to make the substitution of the biotin having the -O-C(=O)- linker before conjugation to the gemcitabine as taught in scheme 1 of Callan; for compound XXXIV of Gibson having a -O-C(=O)- linker directly connected to the Pt(IV) atom of compound XXXIV as taught by Gibson above in order to create a gemcitabine conjugate wherein the resulting structure comprises the gemcitabine of Callan linked to compound XXXIV of Gibson via the resulting carbonate linker resulting from the reaction of the gemcitabine and compound XXXIV following the exemplified reaction step of compound 3 and gemcitabine of Callan as discussed in scheme 1 on pg. 44 of Callan as discussed above.
One of ordinary skill in the art would have been motivated to create a chemotherapeutic agent that is covalently bound to a linking group, wherein the chemotherapeutic agent is exemplified as gemcitabine as taught by Callan in the 103 rejection below; by using compound XXXIV of Gibson which contains a -O-C(=O)- linker as discussed above.
One of ordinary skill in the art would have had a reasonable expectation of success to have made such a substitution because Callan exemplifies conjugating gemcitabine with a biotin molecule that contains a -O-C(=O)- linker at a terminal end and wherein said -O-C(=O)- linker is directly linked to the 5’-hydroxyl of gemcitabine resulting in the formation of a carbonate directly connected to the gemcitabine and the primary amine substituted biotin structure as taught by Callan in scheme 1 as discussed in further detail in the 103 rejection below.
Thus, Applicant’s arguments (A)-(H) have been fully considered but are not found persuasive.
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.
Claim 20 remains rejected under 35 U.S.C. 103 as being unpatentable over Callan et al. (Published 06 December 2018, WO-2018220376-A1, PTO-892 mailed 07/07/2025) in view of Gibson (Published 06 July 2017, WO-2017115372-A1, IDS filed 05/17/2022) and Moufarij et al. (Published April 2003, Molecular Pharmacology, Vol. 63, Issue 4, pp. 862-869, PTO-892 mailed 07/07/2025).
Regarding claim 20, Callan teaches a chemotherapeutic agent is covalently bound to a linking group, i.e. the chemotherapeutic agent is attached to the linking group via one or more covalent bonds, see pg. 8, paragraph 2.
Callan exemplifies said chemotherapeutic agent covalently bound to a linking group by the synthesis of a biotinylated gemcitabine in Scheme 1, wherein the resulting gemcitabine-biotin conjugate is depicted as having the following structure,
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300
683
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, see pg. 44, Scheme 1.
Callan teaches gemcitabine as a chemotherapeutic agent, specifically as a cytidine analog, see pg. 18, paragraph 2, lines 3-4.
The Examiner respectfully notes the biotin exemplified above is separately modified to add a primary amine (e.g. -NH-(CH2)2-) within the gemcitabine-biotin conjugate above as depicted in the synthesis of compound 2 in Scheme 1 on pg. 44 of Callan; and to separately further add a carboxyl (e.g. -O-(C=O)-) within the gemcitabine-biotin conjugate above as depicted in the synthesis of compound 3 in Scheme 1 on pg. 44 of Callan.
Moreover, Callan teaches within scheme 1 compound 3 discussed above is then reacted with the 5’-hydroxyl of gemcitabine to produce compound 4 which the Examiner respectfully notes is the gemcitabine-biotin conjugate above, wherein the gemcitabine is directly connected to a carbonate (e.g. -O(C=O)O-) at the 5’-hydroxyl position of gemcitabine where the hydroxyl was previously located, see pg. 44, scheme 1, compound 4.
Although, the gemcitabine conjugate depicted above differs from the elected species of claim 20 as discussed previously only due to the gemcitabine being conjugated with a biotin as depicted in the conjugate taught by Callan above (e.g. the biotin modified with both the primary amine and carboxyl before reacting with the 5’-hydroxyl of gemcitabine to produce compound 4 which is the gemcitabine-biotin conjugate discussed above). As the Examiner respectfully notes the elected species of claim 20 depicts the gemcitabine is conjugated with a platinum complex designated as Pt(L) via a carbonate linker, where said carbonate linker is directly bonded to both the Pt atom and at the 5’-hydroxyl position of the gemcitabine as required in claim 20.
However, in the same field of endeavor of anti-cancer conjugates, Gibson teaches the development of a family of complex (conjugate) molecules comprising an anticancer platinum drug associated with one or more therapeutically active anticancer drugs for the treatment of a variety of cancers, see pg. 2, summary of the invention, paragraph 1.
Gibson teaches the therapeutically active moieties or ligands may be associated or bonded to the metal atom or to any one atom in a compound of the invention, directly through a native atom or bond present on the therapeutically active moiety or ligand, or through a linker moiety such as -O-C(=O)-, wherein one end of the linker moiety is bonded to a therapeutically active moiety or ligand and another is bonded to the compound (directly to the metal atom or to any atom of the compound), see pg. 27, paragraph 7.
Gibson teaches a compound known as XXXIV which is depicted as having the following structure,
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353
592
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, wherein L is a therapeutically active anticancer moiety (e.g. a Pt complex designated as Pt(L), required in claim 20), see pg. 69, compound (XXXIV) and pg. 70 line 1.
Gibson teaches the therapeutically active moiety can be selected from amongst and including DNA repair inhibitors and cancer targeting moieties, see pg. 25, paragraphs 10-11.
Moreover, Moufarij teaches gemcitabine is a nucleoside analog with clinical activity against various solid tumors, including ovarian, NSCLC, head and neck cancer, and pancreatic cancers, see pg. 862, right column, paragraph 2. Moufarij teaches gemcitabine inhibits ribonucleotide reductase, hence depleting the deoxyribonucleotide pools required for DNA repair and replication (e.g. a DNA repair inhibitor), see pg. 863, left column, paragraph 1.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filling date to have substituted the biotin (e.g. compound 3 in scheme 1) of Callan conjugated to the gemcitabine as taught by Callan with compound XXXIV as taught by Gibson above as within the scope of the artisan; as one of ordinary skill in the art would have been motivated to use a linker moiety such as -O-C(=O)- as taught by both Callan and Gibson to link the gemcitabine taught by Callan as a therapeutically active moiety or ligand with compound XXXIV taught by Gibson above in order to act as a DNA repair inhibitor as Gibson teaches the therapeutically active moiety is linked to a -O-C(=O)- linker at one end and at the other end of said linker is directly bonded to the metal atom of the compound of Gibson, for example compound XXXIV of Gibson as discussed above.
One of ordinary skill in the art would have had a reasonable expectation of success to have made this substitution as Callan demonstrates the synthesis of a gemcitabine conjugate wherein the biotin moiety is linked to the gemcitabine via an -O-C(=O)- linker as shown above.
Thus, it would have been prima facie obvious to one of ordinary skill in art before the invention was filed to have substituted the biotin within the gemcitabine-biotin conjugate of Callan for compound XXXIV of Gibson as within the scope of the artisan as combining prior art elements according to known compositions to yield predictable results. One of ordinary skill in the art would have been motivated to make this substitution to use gemcitabine as an anticancer moiety, specifically as a DNA repair inhibitor, conjugated to the compound of XXXIV of Gibson via the -O-C(=O)- linker expressly taught by Gibson as discussed above. One of ordinary skill in the art would have had a reasonable expectation of success to have substituted the biotin within the gemcitabine-biotin conjugate of Callan for compound XXXIV of Gibson, as Callan teaches the synthesis of gemcitabine conjugates linked with a -O-C(=O)- linker at the 5’-hydroxyl of the gemcitabine of Callan, and Gibson teaches compound XXXIV can be linked to a DNA repair inhibitor with a -O-C(=O)- moiety as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
Conclusion
No claims are allowed in this action.
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 JARET J CREWS whose telephone number is (571)270-0962. The examiner can normally be reached Monday-Friday: 9:00am-5:30pm EST.
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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691