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 .
DETAILED ACTION
Claims 1-23 of Y. Shirakami et al., US 18/551,674 (Mar. 24, 2022) are pending. Claims 4 and 15 to the non-elected species and claims 17-23, to non-elected invention of Group (II), are withdrawn from consideration pursuant to 37 CFR 1.142(b). Claims 1-3, 5-14 and 16 are under examination on the merits and are rejected.
Election/Restrictions
Applicant elected Group (I), claims 1-16, with traverse in the Reply to Restriction Requirement filed on April 6, 2026. Claims 17-23, to non-elected invention of Group (II) are withdrawn from consideration pursuant to 37 CFR 1.142(b). The restriction/election requirement is made FINAL.
Pursuant to the election of species requirement Applicant elected, without traverse, the compound of Formula (4), Applicant elects, with traverse, N-Boc-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-O-(p-methoxybenzyl)-a-methyl-L-tyrosine ethyl ester, as described in the present application at Example 2 (compound 4).
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for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable.
In the elected species, claim 1 variables P1, P2, and P3 are as follows:
P1 is para-methoxybenzyl (PMB);
P2 is t-butyloxycarbonyl (BOC); and
P3 is ethyl
In the Reply, Applicant indicates that claims 1-3, 5-14, and 16 of elected Group I read on the elected species (i.e., claims 4 and 15 do not read on the elected species) The elected species was searched and determined to be unpatentable pursuant to § 103. The search/examination was not further extended. MPEP § 803.02 (III)(C)(2). The provisional election of species requirement is given effect and claims 4 and 15 of elected Group (I) are withdrawn from consideration as not reading on the elected species. MPEP § 803.02(III)(A).
Applicant’s Traversal
Applicant argues that the restriction requirement as between the claims of Groups (I) and (II) is improper because the nature of the claims is such that any burden encountered in searching the claims of Groups (I) and (II) together would, at most, be slight (and certainly not "serious").
This argument is not considered persuasive because the instant restriction was issued under the unity-of-invention rules governing restriction in international applications under 35 U.S.C. 371 (see MPEP § 802; MPEP § 1893.03(d); 37 CFR § 1.499), therefore MPEP 803 cited by Applicant does not apply in the instant case. Under the applicable PCT rules there is no requirement of a serious search burden. The instant Application is an international application entering the National Stage under 35 U.S.C. 371. Under the rules governing multiple inventions under 35 U.S.C. 371 (see MPEP § 1893.03(d)), an international application should relate to only one invention or, if there is more than one invention, the inclusion of those inventions in one international application is only permitted if all inventions are so linked as to form a single general inventive concept (Rule 13.1). International Preliminary Examination Under Chapter II Of The PCT, Chapter 10, Unity of Invention, (Oct. 3, 2011). As such, in the instant case, there is no requirement that the Examiner prove or show a serious search burden. Here, unity of invention is clearly lacking.
Rejections 35 U.S.C. 112(b)
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.
Pursuant to 35 U.S.C. 112, the claim must apprise one of ordinary skill in the art of its scope so as to provide clear warning to others as to what constitutes infringement. MPEP 2173.02(II); Solomon v. Kimberly-Clark Corp., 216 F.3d 1372, 1379, 55 USPQ2d 1279, 1283 (Fed. Cir. 2000). The meaning of every term used in a claim should be apparent from the prior art or from the specification and drawings at the time the application is filed. Claim language may not be ambiguous, vague, incoherent, opaque, or otherwise unclear in describing and defining the claimed invention. MPEP § 2173.05(a).
Unclear Claim Language
Claims 1-3, 5-14 and 16 are rejected pursuant to 35 U.S.C. 112, as indefinite because the scope/meaning of “Y is a boryl group (-B(OH)2)”, present in each of these claims is unclear. The plain meaning of “boryl group” is borader than the parenthetical term “(-B-(OH)2)”. The group -B-(OH)2 is a boronic acid. IUPAC, Compendium of Chemical Terminology, Gold Book, page 179 (2014). A boryl group is a functional group consisting of a boron atom bonded to two substituents. T. Yamamoto et al., 21 Organic Letters, 6235-6240 (2019). Here it is not clear whether the claims are directed to the broader term “boryl group” or the narrower term “(-B-(OH)2)”. The claim recitations of “Y is a boryl group (-B(OH)2)” in this context, improperly provide for preferences within the subject claims and thereby renders confusion over the intended claim scope. See, MPEP § 2173.05(d). This rejection can be overcome by amending the claims to recite “Y is a -B(OH)2 or its ester group”.
Claim Rejections - 35 USC § 102 (AIA )
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
§ 102(a)(1)/(2) Rejection over M. Torgov et al., US 2020/0283456 (2020) (“Torgov”)
Claim 13 is rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by M. Torgov et al., US 2020/0283456 (2020) (“Torgov”). In Example 5, Torgov teaches the following steps towards the synthesis of compound TLS00192, where claim correspondence is indicated:
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Torgov at page 11, [0151]-[0153] (referencing Fig. 3). Torgov clearly meets each and every limitation of claim 13.
13 . . . Step 4: a step of removing the protecting groups for the carboxy group, amino group and hydroxy group of a compound represented by Formula (4) to obtain the compound represented by Formula (5) or a salt thereof.
§ 102(a)(1) Rejection over S. Ghosh et al, 7 Arkivoc, 72-78 (2009) (“Ghosh”)
Claim 14 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by S. Ghosh et al, 7 Arkivoc, 72-78 (2009) (“Ghosh”). Toward a formal synthesis of piperazinomycin, Ghosh teaches the following synthesis of intermediate 6 (i.e. instantly claimed compound (4)), where correspondence to claim 14 is indicated:
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Ghosh at page 73, Scheme 1. Ghosh clearly meets each and every limitation of claim 14.
14 . . . Step 3: a step of reacting a compound represented by Formula (3) with a reagent for introducing boronic acid in the presence of a palladium catalyst and a base to obtain the compound represented by Formula (4).
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under AIA 35 U.S.C. 103(a) 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, 3, 5-12 and 16 are rejected under AIA 35 U.S.C. 103 as being unpatentable over S. Ghosh et al, 7 Arkivoc, 72-78 (2009) (“Ghosh”) in view of M. Torgov et al., US 2020/0283456 (2020) (“Torgov”).
Claim 2 is rejected under AIA 35 U.S.C. 103 as being unpatentable Ghosh in view of Torgov as above in further view of T.W. Greene, Greene’s Protective Groups in Organic Synthesis, 367-404, 533-546 (2007) (“Greene”).
S. Ghosh et al, 7 Arkivoc, 72-78 (2009) (“Ghosh”)
Toward a formal synthesis of piperazinomycin, Ghosh teaches the following synthesis of intermediate compound 7 (i.e. instantly claimed compound (4)), where correspondence to claim 1 is indicated:
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Ghosh at page 73, Schemes 1 and 2. Gosh teaches each of the following claim 1 steps.
Claim 1 . . . Step 1: a step of halogenating a compound represented by Formula (1) or a salt thereof to obtain a compound represented by Formula (2) or a salt thereof;
Step 2: a step of protecting the amino group and carboxy group of the compound represented by Formula (2) or a salt thereof and protecting the hydroxy group of the compound or salt with an ether-type protecting group to obtain a compound represented by Formula
(3); Step 3: a step of reacting the compound represented by Formula (3) with a reagent for introducing boronic acid in the presence of a palladium catalyst and a base to obtain a compound represented by Formula (4) . . .
Differences between Ghosh and Claim 1
Ghosh does not perform the claim 1 step of deprotecting compound 7 (i.e., claimed compound (4) and thus does not meet the claim 1, step 4 limitation of:
Claim 1 . . . Step 4: a step of removing the protecting groups for the carboxy group, amino group and hydroxy group of the compound represented by Formula (4) to obtain the compound represented by Formula (5) or a salt thereof.
M. Torgov et al., US 2020/0283456 (2020) (“Torgov”)
Torgov teaches compositions comprising natural amino acids which have been borylated via chemical synthesis for use as a delivery modality to treat human diseases such as cancer. Torgov at page 2, [0015]. Torgov teaches that TLS00192 is useful as an anticancer compound. Torgov at pages 12-13, Examples 9-11.
In Example 5, Torgov teaches the following step of deprotecting above Ghosh compound 7 (i.e., claimed compound (4)), to achieve the useful compound TLS00192, summarized as follows:
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Torgov at page 11, [0151]-[0153] (referencing Fig. 3).
For completeness, Torgov Example 5, synthesis of TLS00192 (instantly claimed compound 5) is summarized below, where structure correspondence to instant claim 1 is indicted.
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Torgov at page 11, [0147]-[0153] (Example 5, referencing Fig. 3).
T.W. Greene, Greene’s Protective Groups in Organic Synthesis, 367-404, 533-546 (2007) (“Greene”)
Claim 1 Protecting Group P1
Claim 1 requires protecting Group P1 of the phenol.
Green teaches that in developing a synthesis of any phenol-containing product, protection is often mandatory to prevent reaction with oxidizing agents and electrophiles or reaction of the nucleophilic phenoxide ion with even mild alkylating and acylating agents. Greene at page 369.
Greene teaches that benzyl is a suitable protecting group for a phenolic –OH groups as the benzyl ether. Greene at page 396. In general, benzyl ethers are prepared from a phenol by treating an alkaline solution of the phenol with a benzyl halide. Greene at page 396. Greene teaches that the benzyl protecting group can be removed by catalytic hydrogenation, for example, Pd-C/H2. Greene at page 398.
Similarly, Greene teaches that 4-methoxybenzyl (PMB) is a suitable protecting group for phenolic –OH groups. Greene at pages 402-403.
Claim 1 Protecting Group P3
Claim 1 requires protecting Group P3 of the carboxylic acid group. Greene teaches that carboxylic acids are protected for a number of reasons: (1) to mask the acidic proton so that it does not interfere with base-catalyzed reactions; (2) to mask the carbonyl group to prevent nucleophilic addition reactions; and (3) to improve the handling of the molecule in question (e.g., to make the compound less water soluble, to improve its NMR characteristics, or to make it more volatile so that it can be analyzed by gas chromatography).Greene at page 537.
Greene teaches that carboxylic acids can be protected as their corresponding alkyl esters. Greene at pages 538-543. Greene provides a number of synthetic strategies for carboxylic ester formation. Id. Green teaches that for simple esters, acid-catalyzed esterification with azeotropic removal of water is also very effective, but limited to simple systems for the most part. Greene at page 538.
Obviousness Rationale
Claim 1 and the elected species are obvious over Ghosh in view of Torgov for the following reasons. One of ordinary skill seeking to prepare TLS00192 (i.e., instantly claimed compound (5)), in view of the useful properties taught by Torgov, is motivated to prepared Ghosh compound 7 (i.e. instantly claimed compound (4)) according to the high-yield procedure of Ghosh, thereby meeting each and every limitation of claim 1, steps 1-3.
Claim 1 . . . Step 1: a step of halogenating a compound represented by Formula (1) or a salt thereof to obtain a compound represented by Formula (2) or a salt thereof;
Step 2: a step of protecting the amino group and carboxy group of the compound represented by Formula (2) or a salt thereof and protecting the hydroxy group of the compound or salt with an ether-type protecting group to obtain a compound represented by Formula
(3); Step 3: a step of reacting the compound represented by Formula (3) with a reagent for introducing boronic acid in the presence of a palladium catalyst and a base to obtain a compound represented by Formula (4) . . .
One of ordinary skill having obtained Ghosh compound 7 (i.e. instantly claimed compound (4)) is motivated to fully deprotect it, according to the method of Torgov, so as to arrive at TLS00192 (i.e., instantly claimed compound (5)), thereby meeting each and every limitation of claim 1, step 4:
Claim 1 . . . Step 4: a step of removing the protecting groups for the carboxy group, amino group and hydroxy group of the compound represented by Formula (4) to obtain the compound represented by Formula (5) or a salt thereof.
One of ordinary skill is so motivated because the simple combination of the two reference procedures provides a straightforward synthesis of TLS00192. Claim 1 is therefore obvious in view of the cited art combination.
Claim 2 is obvious for the following reasons. Claim 2 requires that “P1 is a benzyl group or a p-methoxybenzyl group”. Ghosh differs in teaching that corresponding claim variable P1 is a methyl group. As discussed for claim 16 below, one of ordinary skill is motivated to replace the methyl protecting group of Ghosh with either of benzyl or para-methoxy benzyl, thereby meeting the limitations of claim 2, because Greene teaches that these two groups are suitable equivalents for protection of phenols as the corresponding phenolic ethers and are easily cleaved, for example, by catalytic hydrogenation. Greene at page 398; Id. at pages 402-403.
The limitations of claim 3 are clearly met as because corresponding variable P3 in Ghosh is a methyl group.
The limitations of claim 5-8 are clearly met.
The limitations of claims 9-11 are obvious as follows. The limitations of claim 9 are already met because Ghosh employs PdCl2(dppf) in the conversion of compound 5 (claimed compound 3) to compound 6 (claimed compound 4), which corresponds to claim 1 step 3. Claims 10 and 11 are obvious because Torgov teaches the same as reaction but (per claim 10) DMSO is employed as the solvent and potassium acetate is employed as the base (per claim 11) as follows.
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Torgov at page 11, [0150]. Practice of Ghosh using DMSO as the solvent and potassium acetate as the base, as taught by Torgov, meets each and every limitation of claims 10 and 11.
The limitations of claim 12 are clearly met.
Compound claim 16 and the elected species are obvious for the following reasons. As discussed above, Ghosh teaches the following synthesis of intermediate compound 7:
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Ghosh at page 73, Schemes 1 and 2. Ghosh’s compound 7 differs from the compound of claim 16 in that corresponding clam variable P1a is methyl, versus claim 16’s P1a which is defined as either benzyl or p-methoxy benzyl. Claim 16 is obvious because one of ordinary skill is motivated to start out Ghosh’ above synthesis by protecting phenol compound 4 with either of either of benzyl or para-methoxybenzyl (instead of methyl as taught by Ghosh) because Greene teaches that either of benzyl or p-methoxy benzyl are suitable equivalents for protection of phenols as the corresponding phenolic ethers and are easily cleaved. Greene at page 398; Id. at pages 402-403. One ordinary skill practicing Ghosh as proposed above thereby arrives at the following compound:
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which meets the structural limitations of claim 16 compound (4a). Claim 16 is therefore obvious.
The above proposed compound differs from the elected species in that the corresponding P3 carboxylic-acid protecting group is methyl whereas variable P3 in the elected species is ethyl. However, this is an obvious variation. Compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. MPEP § 2144.09(II); In re Shetty, 195 USPQ 753, 756 (CCPA 1977). In this regard, Greene teaches that carboxylic acids can be protected as their corresponding alkyl esters. Greene at pages 538. One of ordinary skill is therefore aware that an ethyl group is a suitable replacement for the P3 methyl in the above-proposed compound. One of ordinary skill can therefore immediately envision or arrive at the elected species as an equally suitable product of Ghosh’s synthesis. For these reasons, the elected species is also obvious in view of the cited art.
Conclusion
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
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