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.
Priority
The instant application is a continuation of PCT/US2022/082059 filed on 12/20/2022 and claims domestic benefit to US provisional application no. 63/265,744 filed on 12/20/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/12/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
Claims 1-8 are pending and being examined on the merits herein.
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.
Claim 4 and 7 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 4 recites “The method of claim 1, wherein the two or more steps comprises the step of synthesizing benzyl (2S,4S,5R)-5-acetamido-2,4-dihydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]tetrahydropyran-2-carboxylate, … , the step of synthesizing (2R,4S,5R)-2-[[(2R,4S,5R)-5-(4-acetamido-2-oxo-pyrimidin-1-yl)-3,4-diacetoxy-tetrahydrofuran-2-yl]methoxy-hydroxy-phosphoryl]oxy-4-acetoxy-6-[(1S,2R)-1,2,3-triacetoxypropyl]-5-[[2-[(2,2,2-trifluoroacetyl)amino]acetyl]amino]tetrahydropyran-2-carboxylic acid or salt thereof.”.
Claim 7 recites “A method of synthesizing cytidine-5′-monophospho-N-glycyl-sialic acid (GSC) frorn N-Acetylneuraminic acid, the method comprising one or more of benzylation, … , triacetyl-cytidine coupling, acetyl and trifuoroacetamide deprotection reactions”.
The recited list of steps in claims 4 and 7 is a missing a conjunction such as “and” or “or”, making it unclear if all of the recited steps are required or only at least two or at least one of the recited steps are required for claims 4 and 7, respectively.
For purposes of examination, claims 4 and 7 are being interpreted such that only at least two or at least one of the recited list of steps are required for claims 4 and 7, respectively..
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Instant claim 1 recites a method of synthesizing cytidine-5′-monophospho-N-glycyl-sialic acid (GSC), the method comprising two or more steps wherein the first step of the two or more steps comprise benzylation of N-Acetylneuraminic acid.
Instant claim 2 recites the method of claim 1 wherein the first step comprises the steps of synthesizing benzyl (2S,4S,5R)-5-acetamido-2,4-dihydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]tetrahydropyran-2-carboxylate.
Instant claim 3 recites the method of claim 1, wherein the two or more steps comprises the step of synthesizing (2R,4S,5R)-2-[[(2R,4S,5R)-5-(4-acetamido-2-oxo-pyrimidin-1-yl)-3,4-diacetoxy-tetrahydrofuran-2-yl]methoxy-hydroxy-phosphoryl]oxy-4-acetoxy-6-[(1S,2R)-1,2,3-triacetoxypropyl]-5-[[2-[(2,2,2-trifluoroacetyl)amino]acetyl]amino]tetrahydropyran-2-carboxylic acid or a salt thereof.
Instant claim 4 recites the method of claim 1, wherein the two or more steps comprises the step of synthesizing benzyl (2S,4S,5R)-5-acetamido-2,4-dihydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]tetrahydropyran-2-carboxylate, … , the step of synthesizing (2R,4S,5R)-2-[[(2R,4S,5R)-5-(4-acetamido-2-oxo-pyrimidin-1-yl)-3,4-diacetoxy-tetrahydrofuran-2-yl]methoxy-hydroxy-phosphoryl]oxy-4-acetoxy-6-[(1S,2R)-1,2,3-triacetoxypropyl]-5-[[2-[(2,2,2-trifluoroacetyl)amino]acetyl]amino]tetrahydropyran-2-carboxylic acid or salt thereof.
Instant claim 5-6 recites a method of synthesizing cytidine-5′-monophospho-N-glycyl-sialic acid (GSC), the method comprising the recited list of steps or “any combination of the foregoing steps” and a starting N-acetylneuraminic acid material.
Claim 7 recites a method of synthesizing cytidine-5′-monophospho-N-glycyl-sialic acid (GSC) frorn N-Acetylneuraminic acid, the method comprising one or more of benzylation, … , triacetyl-cytidine coupling, acetyl and trifuoroacetamide deprotection reactions.
MPEP 2163 II.A.3.(a).ii. states that “[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention”, “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus … Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus”, and “The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." … The issue is whether a person skilled in the art would understand inventor to have invented, and been in possession of, the invention as broadly claimed. In LizardTech, claims to a generic method of making a seamless discrete wavelet transformation (DWT) were held invalid under 35 U.S.C. 112, first paragraph, because the specification taught only one particular method for making a seamless DWT and there was no evidence that the specification contemplated a more generic method. Id.; see also Tronzo v. Biomet, 156 F.3d at 1159, 47 USPQ2d at 1833 (Fed. Cir. 1998)(holding that the disclosure of a species in a parent application did not provide adequate written description support for claims to a genus in a child application where the specification taught against other species”.
In this case, instant claims 1-5 recite a method of synthesizing the instant GSC compound comprising two or more steps that comprises a first step of benzylation of a N-Acetylneuraminic acid (instant claims 1-2), further comprising a step of synthesizing the compound in instant claim 3, or any one or two or more of any combination of the recited list of steps in instant claims 4-7.
The disclosure, however, does not provide a representative number of species which would allow an ordinary skilled artisan to identify which additional steps alongside the benzylation of a N-Acetylneuraminic acid and/or synthesizing the instant claim 3 compound as well as which combination of one or two or more of the recited list of steps in instant claims 4-7 are needed to synthesize the GSC compound in instant claims 1-7.
Applicant demonstrates in Example 1 (pages 15-27) a 14-step process to synthesize the GSC compound.
The 14-step process involves the following steps (also see page 8):
Step 1: Benzylation of N-Acetylneuraminic acid (NeuAc); Step 2: Acetylation; Step 3: Thiophenol introduction; Step 4: Boc protection; Step 5: Deacetylation; Step 6: Acetylation; Step 7: Boc deprotection; Step 8: TFA-Gly introduction; Step 9: Thiophenol removal; Step 10: Phosphite introduction; Step 11: Oxydation; Step 12: Debenzylation; Step 13: Triacetyl-Cytidine coupling; and Step 14: Acetyl and trifuoroacetamide deprotection.
Applicant demonstrates that within each step, an intermediate compound is formed as seen in Table 1 (pages 8-11).
Applicant has only demonstrated in the disclosure the synthesis of the GSC using a specific 14 step intermediate process and has not demonstrated or provided further guidance that the GSC compound can be formed from any additional intermediate steps alongside the recited benzylation of N-Acetylneuraminic acid (instant claims 1-2) and/or triacetyl-Cytidine coupling (instant claim 3) as well as from any one or two or more of any combination of the recited list of steps in instant claims 4-7.
Furthermore, the state of the art also does not provide guidance to predictably determine which additional steps alongside the recited steps in instant claims 1-3 or what combinations of steps within the disclosed 14-step process as recited in instant claims 4-7 are required in order to synthesize the GSC compound because the prior art does not disclose or suggest an initial benzylation (acid protection) step or the synthesis of similar intermediate compounds to form the instant GSC compound or similar nucleotide-sugar based compounds, and further discloses that synthesis of sialic acid derivative compounds is challenging and requires specific synthetic steps to form them.
The prior art such as Amann (WO2018115309A1 in IDS filed 06/12/2024) and Felo (WO2007056191A2 in PTO-892) teach processes of synthesizing the instant GSC compound as shown in Fig. 2 of Amann and the Figure in paragraph 0188 page 55 in Felo. However, both Amann and Felo teach that the GSC compound is made starting from a mannosamine compound, and their synthesis steps involve an entirely different set of reagents / intermediate steps to synthesize the GSC compound and that do not involve a similar acid protecting benzylation step or synthesizing any of the intermediate compounds in the instant specification.
Furthermore, Kiefel (Chem. Rev., 2002 in PTO-892) discloses several synthetic steps of sialic acid derivatives including O-glycosylation of sialic acids such as compound 46 CMP-Neu5Ac (right column page 476). Kiefel discloses that formation of glycosides of sialic acids (sialosides) is one of the biggest challenges in sialic acid chemistry, and that the issue of selectively forming alpha-linked sialosides by chemical methods is far more complex than glycosidations on simple hexoses, due to the presence of the carboxylate group attached to the anomeric carbon in sialic acids and to the lack of functionality at C-3 (right column section A page 476). Kiefel further discloses that the lack of a C-3 substituent removes the ability to use neighboring group participation to direct the stereochemical outcome of the
glycoside forming step, while the electron-withdrawing carboxylate group at C-2 makes sialic acid
derivatives prone to 2,3-elimination during the glycosidation step. In addition, the anomeric carbon in
sialic acids is sterically hindered, resulting in further difficulties with attempts at forming sialosides. Therefore, Kiefel discloses that these factors have led to unusual anomeric activating groups for the formation of O-glycosidation of sialic acids (right column section A page 476).
Kiefel further demonstrates in Scheme 5-7 (page 477) enzymatic approaches in forming O-sialosides in which various enzymes are used to conjugate a CMP (cytidine monophosphate) to the Neu5AC sugar. Kiefel further demonstrates other glycosidation steps using various starting types of sialic acid derivatives and notes that the lack of nucleophilicity of the C-8 hydroxyl group in the Neu5Ac acceptor as well as issues of stereoselectivity of O-sialylations as some of the major difficulties in efficiently forming O-glycosylated sialic acids (first paragraph left column and first paragraph right column page 478).
The teachings of Kiefel show that O-glycosylation of sialic acids is difficult due to chemical constraints of the sialic acid structure and requires specific enzymatic/synthetic steps and intermediate compounds to form them. Furthermore, Kiefel teaches several enzymatic/synthetic steps that involve an entirely different set of reagents / intermediate steps and do not involve a similar acid protecting benzylation step or synthesizing similar intermediate compounds in the instant specification. Therefore, the teachings of Kiefel suggest that it would not be predictable to an ordinary skilled artisan to determine which additional steps alongside the benzylation of a N-Acetylneuraminic acid and/or synthesizing the instant claim 3 compound as well as which combination of the intermediate steps among the disclosed 14-step process are needed to form the recited GSC compound.
It is not evident by the disclosure or the prior art, that the Applicant was in possession of synthesizing the instant GSC compound using any other additional steps alongside benzylation of a N-Acetylneuraminic acid and/or synthesizing the instant claim 3 compound as well as from any one or two or more of any combination of the recited list of steps in instant claims 4-7. Furthermore, as described above, there is no disclosed and/or art recognized guidance for what additional steps or what combinations of the recited steps are needed in order to synthesize the instant GSC compound, and Applicant has only demonstrated the synthesis of the GSC compound using a specific 14 step process that involves the synthesis of several intermediate compounds.
Therefore, instant claims 1-7 do not meet the written description requirement under 35 USC 112(a)
Allowable Subject Matter
Claim 8 is allowable.
The closest prior art is Amann (WO2018115309A1 in IDS filed 06/12/2024).
As described above, Amann teaches a process of synthesizing the GSC compound as shown in Fig. 2.
However, Amann teaches that the GSC compound is made starting from D-mannosamine and uses an entirely different set of reagents / intermediate steps to synthesize the GSC compound.
It would not have been prima facie obvious before the effective filing date of the claimed invention to modify the teachings of Amann to arrive at the claimed invention.
One of ordinary skill in the art would not have a reasonable expectation of success because while several of the recited reaction steps such as benzylation, acetylation, and others may have been known routine reactions in the prior art, the prior art does not teach or suggest all of the recited materials or intermediate steps that are required in order to form the instant GSC compound and/or in any other similar nucleotide-sugar based compounds. Furthermore, as disclosed in Kiefel above, O-glycosylation of sialic acids is difficult due to chemical constraints of the sialic acid structure and requires specific enzymatic/synthetic steps and intermediate compounds to form them. Therefore, the ordinary skilled artisan would not have been able to arrive at the recited steps to form the instant GSC compound and would have relied on hindsight in order to determine which synthetic steps and intermediate compound formation is viable to form the instant GSC compound.
Conclusion
Claims 1-7 are rejected. Claim 8 is allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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