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
Claims 14-26 are pending.
Claims 1-13 were cancelled.
Claims 18-21 are withdrawn of record as directed to a non-elected species and claims 23-26 are withdrawn of record as being directed to a non-elected method invention, the election having been made on 3/24/2022.
Claims 14-17 and 22 have been examined.
Priority
This application is a 371 of PCT/EP2019/058226 filed on 04/02/2019, which claims foreign priority of EPO EP18305390.9 filed on 04/03/2018.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/3/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Maintained Rejection
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.
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.
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.
1. Claims 14-17 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Legigan et al. (J. Med. Chem. 2012, 55, 4516−4520, previously cited 1/25/2022) in view of McConathy et al. (Primary Care Companion J Clin Psychiatry 2003;5:70–73, previously cited 5/15/2024), Miller et al. (Journal of Chromatography A, 849 (1999) 309–317, previously cited 7/3/2025), Zhang et al. (Drug Discov Today. 2005 Apr 15;10(8):571-7, previously cited 7/3/2025) and Li et al. (Encycl. Chem. Process 1 (2006): 449-458, previously cited 7/3/2025).
Claim 14 is drawn to a composition comprising a drug conjugate as follows.
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Legigan et al. show a doxorubicin conjugate shown as follows (p4517, scheme 1), reading on the compound formula (I) as claimed. Legigan et al. teach a composition comprising the conjugate functionalized by maleimide in a pharmaceutically acceptable phosphate salt solution for spontaneous conjugation to human serum albumin (p4517, col 2, biological Results).
Legigan et al. do not teach the conjugate being present as a single isomer with a purity of more than 90%.
McConathy et al. teach stereochemistry in drug action is a basic knowledge of the subject will be necessary for clinicians to make informed decisions regarding the use of single-enantiomer (reading on isomer) drugs. McConathy et al. suggest the advantages of using a single isomer formulation comprising greater selectivities for their biological targets, improved therapeutic indices, and/or better pharmacokinetics than a mixture of isomers (p70, col 1, para 1). McConathy et al. teach living systems are themselves chiral, each of the enantiomers/isomers of a chiral drug can behave very differently in vivo (p71, col 1, CHIRAL DRUGS IN BIOLOGICAL SYSTEMS, para 1), which motivates one of ordinary skill in the art to use a single isomer of a therapeutic agent.
Miller et al. is cited to show obtaining enantiomerically pure chemicals were known by methods comprising (1) asymmetric synthesis of the desired enantiomer and (2) resolution of a racemic mixture into individual enantiomers known in the art (p309, col 1, para 1). Miller et al. further suggest separation of a racemic mixture was performed on an intermediate to enhance enantioseparation of the final compound (p311, col 1, 3.1. Milligram scale separation). Zhang et al. and Li et al. are further cited to show various chiral drug separation techniques also well known in the art. Based upon Miller et al., Zhang et al. and Li et al., one of ordinary skill in the art would have knowledge, skill, and ability to perform asymmetric synthesis of the desired enantiomer and/or resolution of a racemic mixture into individual enantiomers (including separation of an intermediate from a racemic mixture). See MPEP 2121(I) “PRIOR ART IS PRESUMED TO BE OPERABLE/ENABLING”.
Because (a) McConathy et al. suggest the advantages of using a single isomer formulation comprising greater selectivities for their biological targets, improved therapeutic indices, and/or better pharmacokinetics than a mixture of isomers (p70, col 1, para 1), (b) Miller et al. is cited to show obtaining enantiomerically pure chemicals were known to by methods comprising (i) asymmetric synthesis of the desired enantiomer and (ii) resolution of a racemic mixture into individual enantiomers (p311, col 1, 3.1. Milligram scale separation), and (c) Zhang et al. and Li et al. teach various techniques for purification of enantiomers from racemates known in the art, one of ordinary skill in the art would have found it obvious to beneficially purify and use a single isomer of Legigan’s drug conjugate in a therapeutic composition as pure as possible (e.g., close to 100% purity of a single isomer), reading on a single isomer with a purity of more than 90%.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to beneficially purify Legigan’s mixed racemic drug conjugate isomers with (i) McConathy’s teaching of a single isomer formulation and (ii) techniques of making and/or purifying enantiomers taught by Miller et al., Zhang et al. and Li et al. because (a) McConathy et al. teach the benefits of using a single isomer formulation comprise greater selectivities for their biological targets, improved therapeutic indices, and/or better pharmacokinetics than a mixture of isomers (p70, col 1, para 1), (b) Miller et al. teach obtaining enantiomerically pure chemicals were known by methods comprising (1) asymmetric synthesis of the desired enantiomer and (2) resolution of a racemic mixture into individual enantiomers known in the art (p309, col 1, para 1), and (c) Zhang et al. and Li et al. teach various chiral drug separation techniques well known in the art. The combination would have reasonable expectation of success because McConathy et al. in view of Miller et al. in view of Zhang et al. and Li et al. teach methods of making and purifying a desired enantiomer known in the art.
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With respect to claims 15-16, Legigan et al. teach the conjugated drug is doxorubicin (p4517, Scheme 1).
With respect to claim 17, Legigan et al. show the self-immolative moiety is
With respect to claim 22, Legigan et al. teach a composition comprising an effective amount of the drug conjugate functionalized by maleimide in a pharmaceutically acceptable phosphate salt solution suitable for spontaneous reaction to human serum albumin (p4517, col 2, biological Results).
Applicant’s Arguments
Applicant disagrees Miller et al. in view of Zhang et al. and Li et al. teach how to make and purify enantiomers because of the following reasons:
First, Legigan’s chiral HPLC was poor for enatiomeric separation (Remarks, last para to p6, para 1).
Second, Miller’s intermediate is a benzylic alcohol of nitrophenol thus one skilled in the art would not have reasonable expectation of success (Remarks, p6, para 2).
Third, Koniev’s Declaration demonstrated only one set of separation conditions out of the 17 tested worked sufficiently well to obtain more than 90% enantiomeric excess (Remarks, p7, 2nd two para to p7, para 1-2).
Finally, the cited references also fail provide any evidence that the claimed enantiomer has unexpectedly more activity than the racemate SDVl00l and the other single isolated isomer SDVl00l-S (see the Koniev Declaration). The lack of guidance in the prior art and the real world failure demonstrates that one skilled in the art of medicinal chemistry as, of the priority date of the present application, would not have been able to obtain the claimed substantially pure final compound without undue experimentation (Remarks, p7, last para to p8, para 1-3).
Response to Arguments
Applicant's arguments filed 10/3/2025 have been fully considered but they are not persuasive for the reasons as follows.
Applicant’s first argument is not persuasive because Miller et al., Zhang et al. and Li et al. teach separation of a racemic mixture was performed on an intermediate (Miller et al. p311, col 1, 3.1. Milligram scale separation). Zhang et al. and Li et al. are further cited to show various chiral drug separation techniques also well known in the art. Even though Legigan’s chiral HPLC may be poor for enatiomeric separation, one of ordinary skill does not have to solely count on chiral HPLC to purify an enantiomer. It is noted 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).
Applicant’s second argument is not persuasive because Miller et al. clearly demonstrate chromatographic resolution of the enantiomers of a pharmaceutical intermediate from the milligram to the kilogram scale under suitable conditions (Title; Fig. 1-5). One of ordinary skill in the art would have found it obvious to select suitable solvents in the mobile phase to separate intermediates of Legigan’s compounds and use the purified intermediate enantiomer compound to synthesize Legigan’s compound followed by to further purification process taught by Zhang et al. and Li et al. to enhance the enantioseparation of final product at a purity of 90% or higher.
Applicant’s third argument is not persuasive because Koniev’s declaration is Koniev’s opinions not sufficient to demonstrate one of ordinary skill in the art using the combined known methods taught by Miller et al. in view of Zhang et al. and Li et al. has to fail so many tests as argued by Koniev’s declaration. In particular, one of ordinary skill can select suitable solvents for mobile phase for enatiomeric separation of intermediate compound to synthesize the final product as taught by Miller et al. in view of Zhang et al. and Li et al. See MPEP 2121(I) “PRIOR ART IS PRESUMED TO BE OPERABLE/ENABLING”.
Applicant’s last argument is not persuasive because McConathy et al. teach stereochemistry in drug action is a basic knowledge of the subject will be necessary for clinicians to make informed decisions regarding the use of single-enantiomer (reading on isomer) drugs. McConathy et al. suggest the advantages of using a single isomer formulation comprising greater selectivities for their biological targets, improved therapeutic indices, and/or better pharmacokinetics than a mixture of isomers (p70, col 1, para 1). Thus one of ordinary skill in the art would expect a single-enantiomer with higher purity would be more effective than a mixture of enantiomer. Thus, there is no unexpected property as argued by applicant. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). See MPEP 716.02(b).
Furthermore, the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See MPEP 2144. Miller et al. in view of Zhang et al. and Li et al. teach various known methods and techniques for enatiomeric separation of various compounds, providing sufficient teachings for one of ordinary skill to perform enatiomeric purification of a compound detailed in the office action above nor repeated here. A person of ordinary skill in the art (different from applicant) is well defined as a person of ordinary creativity able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at ___, 82 USPQ2d at 1396. See MPEP 2141.03 (I).
In summary, applicant relied on the assertion that one of ordinary skill in the art cannot perform enatiomeric separation to obtain an enantiomer with a purity greater than 90%. Miller et al. teach the use of purified intermediate during the stage of an enantiomer synthesis. Zhang et al. and Li et al. further teach various known methods and techniques for enatiomeric separation for a final protect. Thus, the combination of Miller et al. in view of Zhang et al. and Li et al. would be expected to obtain a purity of Legigan’s enantiomer with a purity greater than 90%.
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2. Claims 14-17 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Legigan et al. in view of McConathy et al. in view of Miller et al. in view of Zhang et al. and in view of Li et al. as applied to claims 14-17, 22 and further in view of Dubowchik et al. (Bioconjugate Chem. 2002, 13, 855-869, previously cited 4/18/2022).
Claim 17 is drawn to the G moiety selected from the compounds as follows.
Legigan et al. in view of McConathy et al. in view of Miller et al. in view of Zhang et al. and in view of Li et al. teach a composition comprising a drug conjugate having self-immolative doxorubicin as applied to claims 14-17 and 22 above.
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Legigan et al. in view of McConathy et al. do not teach the self-immolative moiety as the elected species of .
Similarly, Dubowchik et al. teach a doxorubicin (DOX) prodrug conjugate comprising a self-immolative spacer (Abstract). Dubowchik et al. show the beneficial use of a self-immolative p-aminobenzyloxycarbonyl (PABC) spacer in a DOX prodrug in response to a protease activation above (p856, Scheme 1), reading on the elected species of self-immolative moiety in claim 17.
One of ordinary skill in the art before the effective filing date of this instant invention would have found it obvious to combine Legigan et al. in view of McConathy et al. in view of Miller et al. in view of Zhang et al. and in view of Li et al. with Dubowchik’s self-immolative p-aminobenzyloxycarbonyl (PABC) spacer because (i) Legigan et al. in view of McConathy et al. teach a doxorubicin (DOX) drug comprising a self-immolative moiety and (ii) Dubowchik et al. show the use of an enzyme cleavable moiety comprising a self-immolative p-aminobenzyloxycarbonyl (PABC) spacer in a DOX prodrug conjugate in response to a protease activation (p856, Scheme 1). The combination would have reasonable expectation of success because both Legigan et al. and Dubowchik et al. teach a doxorubicin (DOX) drug conjugate.
Response to Arguments
Applicant's arguments filed 10/3/2025 have been fully considered but they are not persuasive. See response to argument above.
3. Claims 14-17 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Legigan et al. in view of McConathy et al. in view of Miller et al. in view of Zhang et al. in view of Li et al. and Dubowchik et al. as applied to claims 14-17, 22 and further in view of Papot et al. (US 2017/0095525 A1, previously cited 4/18/2022).
Claim 15 is drawn to a group of cytotoxic drugs for the conjugation.
Legigan et al. in view of McConathy et al. in view of Miller et al. in view of Zhang et al. and in view of Li et al. and Dubowchik et al. teach a drug conjugate comprising a self-immolative doxorubicin as applied to claims 14-17 and 22 above.
Legigan et al. in view of McConathy et al. in view of Miller et al. in view of Zhang et al. in view of Li et al. and Dubowchik et al. do not teach a conjugated drug as the elected species of dolastatin.
Similarly, Papot et al. teach a prodrug of dolastatin family compound (Abstract). Papot et al. suggest a prodrug conjugated anti-cancer compound can be dolastatin [0080] or doxorubicin [0070]. Because Papot et al. suggest a prodrug conjugated anti-cancer compound can be either dolastatin [0080] or doxorubicin [0070], one of ordinary skill in the art before the effective filing date of this invention would have found it obvious to use the self-immolative prodrug conjugate taught by Legigan et al. in view of McConathy et al. and Dubowchik et al. to deliver dolastatin or doxorubicin, reading on claim 15.
One of ordinary skill in the art before the effective filing date of this instant invention would have found it obvious to combine Legigan et al. in view of McConathy et al. in view of Miller et al. in view of Zhang et al. in view of Li et al. and Dubowchik et al. with Papot’s anti-cancer compound of dolastatin because (i) Legigan et al. in view of McConathy et al. in view of Miller et al. in view of Zhang et al. in view of Li et al. and Dubowchik et al. teach a prodrug comprising a self-immolative doxorubicin conjugate and (ii) Papot et al. suggest a prodrug conjugated anti-cancer compound can be dolastatin [0080] or doxorubicin [0070]. The combination would have reasonable expectation of success because both Legigan et al. and Papot et al. teach a prodrug conjugate of doxorubicin.
With respect to claim 22, Papot et al. teach a composition comprising an effective amount of a prodrug conjugate [0154, claim 11] and a pharmaceutically acceptable salt [0053-0054].
Response to Arguments
Applicant's arguments filed 10/3/2025 have been fully considered but they are not persuasive. See response to argument above.
Conclusion
No claim is allowed.
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.
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/J.L/Examiner, Art Unit 1658
23-December-2025
/LI N KOMATSU/Primary Examiner, Art Unit 1658