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 .
Current Status of 18/725,704
This Office Action is responsive to the amended claims of 6/28/2024. Claims 1-11 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/CN2023086387, filed 04/06/2023, which claims priority to Chinese Patent Application No. CN202210366476.1, filed 04/08/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/28/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because the chromatograms of Figures 5-11 are grainy and illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: The figures in the following paragraphs are grainy and difficult to read: [0003], [0005], [0008], [0084], [0089], [0094], [0099], [00104], [00109], [00114], [00119], [00122], [00126], and [00131].
Appropriate correction is required.
Claim Objections
Claims 1 and 11 are objected to because of the following informalities: The figures of the indicated claims are grainy and difficult to read. Clear, legible figures should replace the current figures. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9 and 10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 recites the limitation "step D1" in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
Claim 10 recites the limitation "step D2 " in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
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.
Claims 1-4 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over CN 105968038 (herein referenced as ‘038, found in IDS filed 06/28/2024) in view of Doroski (WO 2013/0129753, found in IDS filed 06/282024) in view of Linas-Brunet (U.S. 6,323,180 B1) .
‘038 teaches a method of synthesizing a compound of Formula I comprising dissolving the compound of formula 2 in a first organic solvent and then contacting the compound of formula 2 with a hydrogen chloride solution to obtain the compound of formula 1
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(pgs. 1 and 2, Summary of Invention section). The compound of formula 1 is the same MMAE intermediate of formula (I) in the instant claims and the compound of formula 2 is the same as Compound 1-1. The method comprises deprotection of the amino protecting group using an HCl solution and then adding MTBE to the reaction mixture to form a precipitate of the crude product of formula 1. The crude product was added to THF and heptane was added slowly and afforded the product of formula 1 (pg. 4, General Method (1) and (2)). The reference does not expressly disclose the addition of ACN, MeOH, and/or EtOH and subsequent concentration under reduced pressure as claimed in B and C of the instant method of claim 1.
Doroski is directed to the synthesis and purification of peptide-based compounds and discloses the same type of post-deprotection workup of the instant method. Doroski discloses the synthesis of 178 from 177
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(Col 273). The method comprises deprotection of the Boc group of 177 in the presence of HCl in dioxane to afford a gum intermediate which was subsequently purified with a mixture of methanol and acetonitrile to afford 178 as a white solid (Col 276, lines 35-51). Although the compounds of Doroski are not identical to the instant compounds, the reference is analogous art as it relates to the synthesis of peptide-based compounds and teaches workup procedures following HCl deprotection of amino protecting groups.
Linas-Brunet teaches repeated co-evaporation of volatiles using methanol after HCl deprotection of amino protecting groups in peptide related intermediates (Col 60 line 54 – Col 61 line 7).
The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field and would have experience in the synthesis of peptides and peptide containing compounds. The artisan would be familiar with methodologies related to amino protection and deprotection and associated workup procedures.
The artisan would have been motivated to modify the procedure of ‘038 to incorporate additional steps known to be useful in the purification of peptide related intermediates post HCl deprotection. ‘038 establishes that deprotection of the protected MMAE precursor compound can be achieved using HCl and that the desired deprotected MMAE intermediate can be precipitated out of solution through the addition of MTBE. The artisan would have been motivated to incorporate the repeated solvent-addition steps and concentration procedures of Doroski and Linas-Brunet to facilitate solvent exchange and to remove volatile components from the reaction mixture. Because Linas-Brunet expressly teaches that the methanol co-evaporation procedure can be repeated after HCl deprotection of the amino-containing intermediate, the artisan would have reasonably expected that applying this repeated solvent addition and subsequent concentration under reduced pressure would have been amenable to the HCl-deprotection process of ‘038.
The artisan would have been further motivated to dissolve the concentrated crude intermediate in methanol and then add MTBE to precipitate out the hydrochloride solid. Linas-Brunet teaches that the combination of methanol and ether are used after the repeated methanol co-evaporations, while ‘038 teaches that MTBE precipitates the instantly claimed MMAE intermediate. ‘038 additionally teaches the general purification comprising dissolving the crude product in a solvent and then adding a nonpolar antisolvent to precipitate the pure product. The instantly claimed method applies the methanol/ether precipitation procedure of Linas-Brunet using MTBE, which is established by ‘038 as an effective precipitating solvent for the same MMAE intermediate.
The artisan would have reasonably expected that the combined process would succeed in producing the desired product because each step would perform the same function as taught in the prior art. HCl would remove the amino protecting group; repeated methanol addition and concentration would facilitate solvent exchange and remove additional volatile species from the crude deprotected residue; methanol would also provide a medium containing the deprotected amino hydrochloride; and MTBE would precipitate the intermediate compound for filtration and drying. The instantly claimed method therefore represents the application of know post-deprotection workup and isolation techniques to the known method of preparing the same MMAE intermediate disclosed by ‘038. Each step performs the same function in the instant claims as those previously described in the prior art and produce the predictable result of an isolated deprotected amino hydrochloride intermediate.
The Examiner has considered the reported results in the table of paragraph [00135] of the specification, which compares Examples 1-7 with Comparative Examples 1-4. Examples 1-7 provide some evidence that the exemplified combination of repeated concentration using acetonitrile, methanol, or absolute ethanol, followed by dissolution in methanol or absolute ethanol and precipitation with the non-polar solvents n-hexane or MTBE can provide favorable isolated yields and purities relative to certain alternative workup methods.
However, the comparative examples do not isolate the effects of each claimed variable. The examples differ in the reaction scales, deprotection conditions, solvents used, solvent amounts, the number of concentration steps, and the isolation procedures. The specification does not provide replicate experiments or statistical analysis to support the alleged differences in these methods.
The reported methods are not commensurate in scope with instant claims 1 and 11. For example, Comparative Example 4 uses two successive acetonitrile additions and reduced pressure concentration steps followed by further purification. This example appears to be encompassed by the method of claim 1, but provides a yield of only 67.1%. Comparative examples 2 and 4 both use reduced pressure concentration using acetonitrile and therefore appear to be encompassed by claim 11, yet only provide yields of 74.0% and 67.1%, respectively. Additionally, Comparative Examples 2 and 3 report purities of 99.54% and 99.57%, respectively. These purities are comparable to the purities of Examples 1-7. The data therefore do not establish that the improved yield or purity occurs throughout the claimed scope of the methods of claims 1 and 11.
Accordingly, the reported examples have been considered, but are insufficient to establish that the alleged improvements in yield and purity are unexpected. The evidence does not adequately demonstrate that the reported improvements are attributable to the claimed features which distinguish the methods of the prior art, nor does it establish that such improvements occur throughout the full scope of the methods of claims 1 and 11.
Conclusion
Claims 1-4 and 9-11 are rejected.
Claims 5-8 are objected to for being dependent upon a rejected base claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew 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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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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