AN IMPROVED PROCESS FOR THE PREPARATION OF TRABECTEDIN

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 . Priority This application is a 371 of PCT/IN2022/050769 08/30/2022 claiming priority to foreign application INDIA 202141039392 08/31/2021. Status of Claims Acknowledgement is made of the receipt and entry of the amendment to the claims filed on August 20, 2026. Claims 2-4 are canceled. Claims 1, 5, and 6 as amended are pending and under examination. Action Summary The objection to the abstract is withdrawn because the abstract has been amended to delete “novel.” The objection to claims 1-6 is withdrawn in view of the claim amendments. The 112(a) and the 112(b) rejections of claims 1, 5, and 6 are withdrawn in view of the claim amendments. The rejection of claims 1-6 under 35 U.S.C. 103 as being unpatentable over Muddasani et al. (WO2020/105068A1) and in further view of Cozzi et al. is withdrawn in view of the claim amendments. New Rejection necessitated by the claim amendments 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. Claims 1, 5, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Muddasani et al. (WO2020/105068A1) in view of He et al. (Angew. Chem. Int. Ed. 2019, 58, 3972-3975, cited in IDS of 04/15/2024). Muddasani teaches a process for preparing trabectedin comprising sequential reaction steps involving advanced ecteinascidin intermediates corresponding closely to the presently claimed compounds of Formulae V, IV, III, II, followed by conversion to trabectedin. Muddasani expressly describes conversation of Compound V to compound IV using zinc, conversion of Compound IV to Compound III using sodium glyoxylate or magnesium glyoxylate, reaction of Compound III with 3-hydroxy-4-methoxyphenethylamine to obtain Compound II, and subsequent conversion of Compound II to trabectedin. Step (a) reacting a compound of Formula V Formula IV PNG media_image1.png 212 572 media_image1.png Greyscale Formula IV Formula III Step (b): reacting PNG media_image2.png 216 614 media_image2.png Greyscale Step (c): reacting a compound of Formula III Formula II PNG media_image3.png 198 590 media_image3.png Greyscale . Steps (d): converting the compound of Formula II Trabectedin PNG media_image4.png 214 578 media_image4.png Greyscale . See pp. 6-12. Claim – step (a) With respect to step (a), Muddasani teaches reacting its Compound V with zinc to obtain Compound IV. More particularly, Example 6, “Preparation of Compound of Formula -IV,” teaches dissolving Compound V in THF/methanol and adding a freshly prepared buffer solution comprising H2PO4 and KH2PO4 in water, followed by addition of Zn-dust, stirring workup, and isolation of Compound IV. Muddasani further provides alternative preparation employing the same H3PO4/KH2PO4 aqueous buffer and Zn-dust. See Example 6, p. 16. Thus, Muddasani expressly teaches the presently recited reaction conditions comprising Zn in a buffer solution comprising H2PO4 and KH2PO4 in water for conversion of corresponding Compound V to Compound IV. Muddasani’s Compound V and resulting Compound IV differ from the presently claimed Formula V and Formula IV structures in that Muddasani depicts the phenolic oxygen of the upper aromatic ring as MOM-protected (MOMO), whereas the presently claimed Formula V and Formula VI structures depict the corresponding substituent as a free phenolic hydroxyl (HO). Claim 1 – step (b) Muddasani further teaches conversion of Compound IV to Compound III using glyoxylate chemistry. In particular, Example 7, “Preparation of compound of formula-III,” teaches dissolving Compound IV in acetonitrile, adding a freshly prepared buffer solution prepared by dissolving NaOAc in AcOH, followed by addition of magnesium glyoxylate, to produce Compound III. See Example 7, p. 17. Accordingly, Mudassani expressly teaches the presently recited magnesium glyoxylate in a buffer solution comprising sodium acetate (NAOac) in acetic acid (AcOH) for conversion of the corresponding Compound IV to Compound III. Again, Muddasani’s Compound IV and Compound III retain the MOM-protected phenolic oxygen, whereas the presently claimed corresponding structures contain the free phenolic hydroxyl. Claim 1 – step (c) Muddasani additionally teaches reacting Compound III with 3-hydroxyl-4-methoxyphenethylamine to produce Compound II. Specifically, Example 4 reacts Compound III with 3-hydroxy-4-methyxyphenyethylamine in anhydrous ethanol and obtains Compound II. See Example 4, p. 15. Thus, Muddasani teaches the recited amine coupling/cyclization and corresponding conversion of Compound III to Compound II, but again performs the reaction with an intermediate bearing the MOM-protected phenolic oxygen rather than the presently claimed free phenolic hydroxyl. Claim 1 – step (d) Muddasani further teaches conversion of Compound II to trabectedin. Example 5 describes treatment of Compound II followed by dissolution of the resulting residue in acetonitrile/water and addition of silver nitrate, ultimately providing trabecdin. See Example 5, pp. 15-16. Accordingly, Muddasami teaches the recited use of silver nitrate in the presence of acetonitrile in the conversion of the corresponding Compound II to trabectedin. Difference between Muddasani and claim 1 Muddasani therefore teaches the claimed sequence and substantially the specifically reaction conditions. However, Muddasani does not expressly teach carrying out the foregoing sequence using the presently claimed Formula V, IV, III, and II intermediates having the corresponding free phenolic hydroxyl group, because Muddasani carries out a MOM-protected phenolic oxygen through the corresponding advanced intermediates. He remedies this deficiency He teaches a scalable total synthesis ET-743 (trabectedin) involving advanced ecteinascidin intermediates and expressly demonstrates that advanced intermediates bearing the corresponding unprotected phenolic hydroxyl group may be subjected to subsequent synthetic transformation leading to ET-743. See Scheme 3, p. 3974. In particular, Scheme 3 depicts advanced ecteinascidin intermediates in which the phenolic substituent on the upper aromatic ring is OH rather than MOM-protected oxygen, and He carries out such advanced intermediates through further synthetic transformations ultimately leading to ET-743. PNG media_image5.png 692 628 media_image5.png Greyscale He also demonstrates that the protection state of phenolic functionality was a manipulatable feature during synthesis of the ET-743 scaffold. For example, He describes protection of phenol 5 with benzyl bromide and subsequently performs further transformations involving removal or alteration of protecting groups during assembly of the advanced scaffold. See Schemes 2-3, pp. 3973-3974. Motivation to combine It would have been prima facie obvious to one of ordinary skill I the art at the time the invention was filed to modify the process of Muddasani by employing the corresponding advanced intermediates having the phenolic hydroxyl group in its unprotected form, as taught by He, rather than retaining Muddasani’s MOM protecting group throughout the corresponding portion of the synthetic sequence. One of ordinary skill in the art would have been motivated to make such modification because He expressly demonstrates in the same field of ET-743/trabectedin synthesis that the corresponding free phenolic functionality is compatible with advanced ecteinascidin intermediates and that such free-phenol intermediates can undergo further synthetic manipulation in a sequence leading successfully to ET-743. Thus, He would have provided the skilled artisan with an art-recognized alternative protection state for this phenolic functionality during manipulation of the advanced ET-743 scaffold. The modification would additionally avoid the need to retain and subsequently remove the MOM protecting group employed by Mudassani, while permitting use of Muddasani’s expressly disclosed sequence for preparing trabectedin. The modification therefore is not based merely upon a conclusionary assertion that removal of a protecting group constituted “routine optimization.” Rather, Muddasani supplies the specific sequence and reaction conditions, while He provides evidence from the same ET-743 synthetic art that the corresponding advanced scaffold can exist and be synthetically manipulated with the phenolic hydroxyl group already protected. This constitutes an articulated reason for combining the teachings of the references. MPEP § 2143 recognizes, inter alia, application of known method and modification based upon a teaching or suggestion in the prior art as permissible obviousness rationale, provided the factual findings support the proposed modification. Reasonable expectation of success One of ordinary skill in the art would have had a reasonable expectation of success in employing the free-phenol counterparts in Muddasani’s synthetic sequence. Muddasani itself establishes that the claimed Zn/phosphate-buffer, magnesium-glyoxylate/acetate-buffer, amine-coupling, and silver-nitrate transformations are operative on closely corresponding advanced ecteinascidin intermediates. He, in turn, provides experimental evidence that advanced synthetic class bearing the corresponding free phenolic hydroxyl functionality can be carried through subsequent chemical transformation and ultimately to ET-743. Accordingly, the proposed modification does not depend solely upon speculation that an unsupported phenyl might survive advanced-stage synthesis. He supplies experimental evidence demonstrating the synthetic viability of advanced free phenol ecteinascidin intermediates. Absolute predictability is not required; the pertinent inquiry is whether the skilled artisan would have possessed a reasonable expectation of success in making the proposed modification. See MPEP § 2143.02. Therefore, it would have been obvious to modify Muddasani in view of He to perform corresponding free-phenolic Formula V, IV, III, and II intermediates, thereby arriving at the process of claim 1. With respect to claim 5, Muddasani additionally expressly teaches the use of zinc sulfate in the claimed glyoxylate reaction. Specifically, Example 7 of Muddasani teaches preparation of Compound III by dissolving Compound IV in acetonitrile, adding the NaOAc/AcOH buffer, adding magnesium glyoxylate, and further adding anhydrous zinc sulfate (ZnSO4) before carrying out the reaction to produce Compound III. See Example 7, p. 17. Thus, Muddasani itself expressly teaches the additional limitation of claim 5-zinc sulfate in addition to magnesium glyoxylate- in the same Compound IV → Compound III reaction relied upon for claim 1. Accordingly, claim 5 is unpatentable over Muddasani in view of He for substantially the same reasons set forth with respect to claim 1. With respect to claim 6, Muddasani expressly teaches that the organic solvent employed in Compound III → Compound II reaction may be ethanol, which falls within the claimed group consisting of methanol, ethanol, and isopropanol. In particular, Muddasani Example 4 reacts Compound II with 3-hydroxy-4-methoxyphenethylamine in anhydrous ethanol to produce Compound II. See Example 4, p. 15. Accordingly, Muddasani expressly satisfies the additional solvent limitation of claim 6. The difference concerning the MOM-protected versus free phenolic hydroxyl group is addressed by He as discussed above. Claim 6 is therefore unpatentable over Muddasani in view of He. Response to Arguments Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on August 20, 2026. Applicant’s arguments have been fully considered but are not persuasive of patentability of claims 1, 5, and 6 for the reasons discussed below. Applicant argues that Muddasani employs intermediates in which phenolic hydroxyl group is protected with a methoxymethyl (MOM) group and subsequently cleaves the MOM protecting group with TFA, whereas presently amended claim 1 requires Formula V, IV, III, and II intermediates having the corresponding free phenolic hydroxyl group unprotected. Applicant contends therefore that Muddasani provides no teaching or suggestion to conduct the process with the phenolic hydroxyl group unprotected and that one of ordinary skill in the art would not have been motivated to arrive at the presently claimed process. In response, the Examiner acknowledges that Muddasani’s corresponding Compound V, IV, III, and II intermediates contain a MOM protecting phenolic oxygen, whereas the structure presently recited in claim 1 contain the corresponding free phenolic hydroxyl group. Accordingly, the rejection based upon Muddasani alone is withdrawn and replaced by the rejection over Muddasani in view of He et al. However, Applicant’s argument does not establish the nonobviousness of the presently subject matter over the combined teachings of Muddasani and He. As discussed in the rejection above, Muddasani teaches substantially the same sequence of transformation leading to trabectedin and expressly teaches the reaction conditions newly incorporated onto claim 1. In particular, Example 6 teaches conversation of Compound V to Compound IV using Zn dust in a freshly prepared aqueous buffer comprising H3PO4 and KH2PO4. See Example 6, p. 16. Example 7 teaches conversion of Compound IV to Compound III using magnesium glyoxylate in a buffer comprising NaOAc and AcOH. See Example 7, p. 17. Muddasani further teaches reaction of Compound III with 3-hydroxy-4-methoxyphenethyl amine in ethanol and subsequent conversation of Compound II to trabectedin. See Examples 4-5, pp. 15-16 Thus, the distinction relied upon by Applicant is not the newly cited buffer, glyoxylate, solvent, or silver nitrate conditions, but the protection state of the phenolic hydroxyl group in the intermediates subjected to those transformations. He provides the teaching missing from Muddasani. He is directed to a scalable total synthesis of ET-743 (trabectedin) and demonstrates the preparation and further synthetic manipulation of advanced ecteinaascidin intermediates having the corresponding free phenolic hydroxyl functionality. In particular, Scheme 3 of He depicts advanced ET-743 intermediates bearing the phenolic hydroxyl group in unprotected form and subjects such intermediates to further transformation in the synthetic sequence ultimately producing ET-743. See p. 3974, Scheme 3. He therefore directly addresses Applicant’s contention that there is no teaching or suggestion that advanced intermediates bearing the unprotected phenolic hydroxyl group could be employed in a synthetic sequence leading to trabectedin. While Muddasani elects to retain MOM protection through its corresponding intermediates, He demonstrates that an unprotected phenolic hydroxy group is compatible with continued synthetic manipulation of an advanced ecteinascidin scaffold leading to ET-743. Accordingly, one of ordinary skill in the art, considering Muddasani together with He, would have had reason to employ the corresponding free-phenol form of advanced intermediates in Muddasani’s otherwise expressly taught process. Such modification would provide a known alternative protection state demonstrated in the same ET-743 synthetic art and would avoid the need to retain and subsequently remove the MOM protecting group. Applicant further argues that the presently claimed process is advantageous because it avoids the TFA treatment employed by Muddasani to remove the MOM protecting group, asserting that TFA is toxic and environmentally damaging and that avoiding its use, particularly the final stages of synthesis., is beneficial. In response, this argument is not persuasive of nonobviousness. Rather, to the extent Applicant identifies avoidance of the subsequent TFA-mediated MOM-deprotection operation as advantageous, that asserted advantage is consistent with the reason for the proposed modification. Once the skilled artisan employs the corresponding free phenolic hydroxyl functionality, as suggested by He, there would be no need to perform Muddasami’s later MOM-deprotection operation to generate the hydroxyl functionality. Thus, avoidance of the MOM deprotection step and its associated reagent follows directly from the proposed modification and does not, by itself, establish that the modification would have been obvious. Moreover, the rejection does not rely upon Muddasani alone for a suggestion to employ an unprotected phenolic hydroxyl group. Applicant’s contention that “there is no hint or suggestion in Muddasani” to conduct process using the free hydroxyl therefore does not address the rejection as presently formulation. The teaching relied upon for the free phenol alternative is supplied by He, while Muddasani supplies the closely corresponding trabectedin process and the claimed reaction conditions. Applicant further argues that the presently claimed process is advantageous because it avoids the MON-deprotection step employed by Muddasani and thereby eliminates the use of trifluoroacetic acid (TFA), which Applicant characterizes as toxic and environmentally damaging. This argument is not persuasive. Claim 1, even as amended, employs the open-ended transitional phrase “comprising the steps of” and therefore does not exclude additional process steps, including protection and subsequent deprotection reactions. Although claim 1 requires the specifically recited intermediates of Formulae V, IV, III, and II to contain a free phenolic hydroxyl group, the claim does not expressly exclude the use of MOM protecting groups at other stages of the process, nor does it require the absence of TFA. Accordingly, Applicant’s asserted advantage of avoiding MOM deprotection and TFA is not necessarily achieved throughout the full scope of the claimed process and, therefore, is not commensurate with the scope of claim 1. Moreover, as discussed above, He teaches advanced trabectedin intermediates bearing the corresponding unprotected phenolic hydroxyl group, thereby providing a reason to employ such intermediates in the process of Muddasani. Thus, Applicant’s argument does not overcome the rejection under 35 U.S.C. § 103. Applicant additionally asserts that there is no teaching in Muddasani that conducting the process with the phenolic hydroxyl group unprotected would provide the favorable purity and yield reported in Applicant’s specification at pages 6-8. In response, this argument is not persuasive. The presently rejected claims do not require any particular yield or purity. Therefore, the patentability determination is based upon the process actually recited in the claims rather than unclaimed yield or purity characteristics. Furthermore, He provides experimental evidence that advanced ecteinascidin intermediates containing the corresponding unprotected phenolic hydroxyl functionality are synthetically viable and may undergo additional transformation in a sequence leading to ET-743. This evidence supports a reasonable expectation of successfully employing an unprotected phenolic functionality in advanced-stage ET-743 chemistry. Obviousness does not require absolute predictability or a reasonable expectation of obtaining Applicant’s particular unclaimed yield or purity; rather, the relevant inquiry concerns a reasonable expectation of successfully carrying out the proposed modification. With respect to claim 5, Applicant argues that Cozzi and Zhou fail to cure the alone deficiency of Muddasani because those references are silent concerning use of the unprotected phenolic hydroxyl group. T In response, this argument is rendered moot by the newly formulated rejection. Cozzi and Zhou are no longer relied upon. He supplies the teaching concerning the unprotected phenolic hydroxyl functionality. Moreover, Muddasain itself expressly teaches the additional limitation of claim 5. Example 7 uses anhydrous zinc sulfate together with magnesium glyoxylate in the NaOAC/AcOH-buffered conversation of Compound IV to Compound III. See Example 7, p. 17. With respect to claim 6, Applicant argues that claim 6 is patentable by virtue of its dependency from claim 1 and its additional limitations. In response, this argument is not persuasive because the limitations inherited from claim 1 are rendered obvious by Muddasani in view of He for the reasons discussed above, while Muddasani expressly teaches ethanol as the organic solvent in the corresponding Compound III-to-Compound II reaction. See Example 4, p. 15. Ethanol is one of the solvents recited in claim 6. Conclusion Claims 1, 5, and 6 are not 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. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JEAN P CORNET/Primary Examiner, Art Unit 1628