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 .
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.
This office action is a response to applicant’s communication submitted January 16, 2024, wherein claim 17 was preliminarily amended, claim 44 was canceled, and claim 50 was cancelled.
Claims 1-43 and 44-50 are pending in this application.
Priority
This application is a 371 of PCT/JP2022/003512 filed 01/31/2022 and claims foreign priority to JP 2021-014624 filed 02/01/2021 and JP 2021-066316 filed 04/09/2021. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copies have been received. The Examiner notes that no English language translation was provided.
Claim Objections
Claims 1-4, 13, 17-19, 22-25, 31, 33-35, 40-43, and 45-50 are objected to because of the following informalities:
In claims 1-4, 13, 17-19, 22-25, 31, 33-35, 40-43, and 45-50 Each claim recites a roman numeric formula (i.e. IX) but also includes a numerical formula (i.e. Formula 29). A formula should be removed to avoid confusion.
Appropriate correction is required.
Claim Rejections - 35 USC § 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.
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 22-24 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.
Regarding claims 22-24: Claims 22-24 are independent claims, but refer back to claim 1 for definition of variables. Given that the claims are independent claims, the variables must be defined with in the claim in order to clarify the scope. Given that the scope of the claims is unclear, claims 22-24 are rendered indefinite.
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.
Claims 1-6, 8, 10-14, and 16-24 are rejected under 35 U.S.C. 103 as being unpatentable over Tsuda (WO 2020050406, IDS filed 10/24/2023) in view of Kataoka (WO 2019212063, cited on PTO-892). The English translation of Tsuda and Kataoka relied upon by the Examiner have been provided.
Regarding claims 1-4: Tsuda teaches the following synthesis:
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(English translation pg. 278, top of page).
The synthesis differs from that of the instantly claimed in that the starting material incorporates a phosphorous group via a different phosphorous reagent:
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. Tsuda does not teach wherein the following active phosphitylating agents are used:
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as recited by instant claims 1 and 3, which ultimately lead to different stereoisomers of the final product.
However, Kataoka teaches the a stereocontrolled oligonucleotide synthesis (abstract). Kataoka teaches the use of the following phosphitylating agents
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(English translation, pg. 12, last structure). Kataoka teaches the following synthesis
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(English translation, pg. 13, top of page).Kataoka teaches use of such a species results in the formation of the following dinucleotides,
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which can subsequently be removed in later steps following synthesis of the oligonucleotide
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(English translation, pg. 14, top scheme, pg. 21, top scheme). Kataoka teaches that by using L- or D-prolinol derivative can be used as one the raw materials in order to control the stereochemistry of the thiophosphate groups (English translation, pg. 22, top para.). Kataoka teaches that use of such a reagent can reduce synthetic steps, improve purification, or control to synthesize a desired steric structure (English translation, pg. 5, paras. 1-3).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the method such that either stereoisomer of the phosphitylating reagent of Kataoka is utilized. A person of ordinary skill in the art would have the motivation to do so with a reasonable expectation of success in order to control stereochemistry in the desired oligonucleotide and this reagent is known in the art to be capable of doing so.
Regarding claim 5: Kataoka teaches wherein the activator is BIT
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(i.e. benzimidazolium triflate, a salt of benzimidazole) (English translation, pg. 14, middle of page).
Regarding claim 6: Kataoka teaches wherein the acylating or alkoxycarbonylating agent is benzoic anhydride
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(English translation, pg. 14, middle of page).
Regarding claim 8: Tsuda teaches that following the cyclization reaction can be performed with a dehydrating condensing agent such as 2-chloro-5,5-dimethyl-1,3,2 5 -dioxaphosphinan-2-one (English translation, pg. 87, step A-5).
Regarding claim 10: Tsuda teaches that following a cyclization, an oxidation with iodine can be performed (English translation, pg. 87, step A-5).
Regarding claim 11: As shown above, Tsuda teaches wherein PG4 is benzoyl.
Regarding claim 12: As discussed above, Kataoka teaches wherein PG6 is benzoyl
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(English translation, pg. 14, middle of page).
Regarding claims 13-14: Tsuda teaches the preparation of the following intermediate using diphenyl phosphite
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(English translation, pg. 296, scheme, Step 1).
Regarding claim 16: Tsuda teaches the use of 3H-1,2-benzodithiol-3-one, N, N-dimethyl-N ′-(3-sulfanilidene-3H-1,2,4-dithiazole-5-) as sulfurization reagents following cyclization (English translation, pg. 85, steps A-3 and A-5).
Regarding claim 17: Tsuda teaches purification via silica gel column chromatography prior to conversion of the obtained compound to a sodium salt (English translation, pg. 112, step 11).
Regarding claims 18-21: Tsuda teaches the compounds are conjugated to antibodies using the following moiety
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(English translation, pg. 38, middle of page).Tsuda further teaches the compounds can be conjugated to anti-HER2 antibodies (English translation, pg. 291, example 114).
Regarding claims 22-24: As discussed above, Tsuda teaches
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(English translation pg. 278, top of page). Wherein it would have been obvious to substitute phosphitylating reagents, a person of ordinary skill necessarily arrives at the claimed compounds.
Claims 7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Tsuda (WO 2020050406, IDS filed 10/24/2023) and Kataoka (WO 2019212063, cited on PTO-892) as applied to claims 1-6, 8, 10-14, and 16-24 above in view of Cheruvallath (Organic Process Research & Development, 2000, cited on PTO-892). The English translation of Tsuda and Kataoka relied upon by the Examiner have been provided.
Regarding claims 7 and 9: As discussed above, the prior art render obvious the method of claim 1. Tsuda teaches the use of 3H-1,2-benzodithiol-3-one, N, N-dimethyl-N ′-(3-sulfanilidene-3H-1,2,4-dithiazole-5-) as sulfurization reagents (English translation, pg. 85, steps A-3 and A-5). As discussed above, Kataoka teaches wherein the sulfurization agent is PADS
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(English translation, pg. 14, top scheme, middle of page). They do not explicitly teach wherein the sulfurizing reagent is 3H-1,2-benzodithiol-3-one-1,1-dioxide.
However, Cheruvallath teaches 3H-1,2-benzodithiol-3-one-1,1-dioxide and PADS are both reagents capable of carrying out sulfurization of oligonucleotides (abstract). Wherein both are established reagents for carrying out such a reaction, it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)).
Claims 50 is rejected under 35 U.S.C. 103 as being unpatentable over Guo (Bioorg. Med. Chem. Lett., 1998, IDS filed 10/24/2023) in view of Watts (Organic & Biomolecular Chemistry, 2009, cited on PTO-892).
Regarding claim 50: Guo teaches the following synthesis of clofarabine:
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(pg. 123, figure 1). Compound 6 of Guo demonstrates the fluoro in opposite stereochemistry as the instantly claimed compound.
Guo does not teach the compound as instantly claimed wherein 2’F is the opposite stereochemistry.
However, Watts compares the stability of 2’F nucleic acid stability (abstract). Watts demonstrates that 2’F epimer positions are contemplated in the prior art (pg. 1904, figure 1).
Taken together it would have prima facie obvious to modify the synthesis such that the 2’F epimer of compound 5 is utilized in the production of a clofarabine analog. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order to prepare clofarabine with opposite stereochemistry at the 2’ position. As compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties (See MPEP 2144.09 (II)).
Allowable Subject Matter
Claims 33, 43, 45-49 are objected to due to minor informalities as described above, but would be allowable if corrected.
The following is a statement of reasons for the indication of allowable subject matter: As discussed above, the prior art render obvious the method of claim 1. Tsuda teaches
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(English translation pg. 278, top of page). Tsuda also teaches alternative synthesis for a thio moiety in the compound:
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(English translation, pg. 244, top of page).
While various protecting groups/intermediates are utilized there is no teaching that the claimed intermediates would be successful in the synthesis of the amino containing compounds. Additionally there is no teaching or suggestion to replace the acetyl species with a chlorine in the following species
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.. It would be improper hindsight to suggest a person of ordinary skill in the art would specifically modify these intermediates for the synthesis of the product as there is no teaching or suggestion it would be successful or beneficial to the synthesis. Thus, there is no teaching or suggestion to arrive at the compounds claims.
Claims 15, 25-32, and 34-42 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims and to correct for minor informalities.
The following is a statement of reasons for the indication of allowable subject matter: As discussed above, the prior art render obvious the method of claim 1.
Regarding claim 15: As discussed above, the prior art renders obvious the method of claims 13-14. Tsuda teaches the preparation of the following intermediate using diphenyl phosphite
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(English translation, pg. 296, scheme, Step 1). However, there is no teaching or suggestion to react with an acylating or alkoxycarbonylating agent as recited by instant claim 15. A person would lack the motivation to do so as the amino group is already protected with a Bz group prior to reaction with the diphenyl phosphite. It would be improper hindsight to suggest a person of ordinary skill would have had the motivation to do so with a reasonable expectation of success as there is no teaching or suggestion to do so.
Regarding claims 25-32 and 34-42: Tsuda teaches
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(English translation pg. 278, top of page). Tsuda also teaches alternative synthesis for a thio moiety in the compound:
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(English translation, pg. 244, top of page).
While various protecting groups/intermediates are utilized there is no teaching that the claimed intermediates would be successful in the synthesis of the amino containing compounds. Additionally there is no teaching or suggestion to replace the acetyl species with a chlorine in the following species
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. It would be improper hindsight to suggest a person of ordinary skill in the art would specifically modify these intermediates for the synthesis of the product as there is no teaching or suggestion it would be successful or beneficial to the synthesis. Thus, there is no teaching or suggestion to arrive at the compounds claimed.
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 AM - 5:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Y Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/S.L.G./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693