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 .
Withdrawal of Rejections
The response and amendments filed on 11/24/2025 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality corrections and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous rejections under 35 U.S.C. 112(b) for indefiniteness have been withdrawn necessitated by Applicant’s amendments. The previous rejection under 35 U.S.C. 112(a) for lack of written description has been withdrawn necessitated by Applicant’s arguments.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant invention.
New Grounds of Rejection Necessitated by Amendments
Claim Rejections - 35 USC § 103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 7, 13, 17, 22, 25-26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Fiebig (US 2017/0037440; Date of Publication: February 9, 2017 - previously cited) in view of Lau (Highly efficient chemoenzymatic synthesis of β1-4-linked galactosidases with promiscuous bacterial β1-4-galactosyltransferases; 2010 – cited in the IDS filed on 05/20/2022 – previously cited) and Hanashima (Divergent Synthesis of Sialylated Glycan Chains: Combined Use of Polymer Support, Resin Capture-Release, and Chemoenzymatic Strategies; 2005 – previously cited).
Fiebig’s general disclosure relates to “in vitro methods for producing Neisseria meningitidis capsular polysaccharides which have a defined length. The present invention also relates to compositions comprising at least one capsule polymerase, at least one donor carbohydrate and at least one acceptor carbohydrate, wherein the ratio of donor carbohydrate to acceptor carbohydrate is a ratio from 10:1 to 400:1. Moreover, the present invention provides truncated versions of the capsule polymerases of Neisseria meningitidis serogroups A and X” (see, e.g., Fiebig, abstract). Moreover, Fiebig discloses a sugar acceptor moiety [[Wingdings font/0xE0]6)-α-D-Gal-(1-4)- α-Neu5Ac-(2[Wingdings font/0xE0]]n (see, e.g., Fiebig, [0405]), wherein UDP-Gal is used as the galactose donor (see, e.g., Fiebig, [0323]) and CMP-Neu5Ac is used as the sialic acid donor (see, e.g., Fiebig, [0336], [0419], Figure 17).
Regarding claim 1 pertaining to the preparation of a bacterial capsular saccharide product, Fiebig teaches methods for producing capsular polysaccharides (see, e.g., Fiebig, abstract, [0021]), wherein the composition comprises “at least one capsule polymerase, at least one donor carbohydrate and at least one acceptor carbohydrate” (see, e.g., Fiebig, abstract). Fiebig teaches that the reaction is regulated to allow for the production of capsular polysaccharides (see, e.g., Fiebig, [0021]). Moreover, Fiebig teaches Neisseria meningitidis SiaDW (NmSiaDw) (see, e.g., Fiebig, [0012], [0409]). Fiebig teaches UDP-Gal as the galactose donor (see, e.g., Fiebig, [0323]) and CMP-Neu5Ac as the sialic acid donor (see, e.g., Fiebig, [0336], [0419], Figure 17). Fiebig teaches the oligosaccharide moiety [[Wingdings font/0xE0]6)-α-D-Gal-(1-4)- α-Neu5Ac-(2[Wingdings font/0xE0]]n (see, e.g., Fiebig, [0405]). Fiebig teaches glycosylating the sugar acceptor with repeating galactose and sialic acid residues (see, e.g., Fiebig, [0405]). Moreover, Fiebig teaches extracellular polysaccharide capsules comprising heteropolymers of repeating units (see, e.g., Fiebig, [0405]). Additionally, Fiebig teaches that the degree of polymerization ranges from 10 to 60 (see, e.g., Fiebig, [0007], [0042]), and a polydispersity index ranging from about 1 to about 1.3 (see, e.g., Fiebig, [0441], Table 4).
Regarding claim 7 pertaining to the polydispersity index, Fiebig teaches a polydispersity index ranging from 1.01 to about 1.15 (see, e.g., Fiebig, [0441], Table 4).
Regarding claim 13 pertaining to the galactose and sialic acid donors, Fiebig teaches that the galactose donor is UDP-Gal (see, e.g., Fiebig, [0323]) and that the sialic acid donor is CMP-Neu5Ac (see, e.g., Fiebig, [0336], [0419], Figure 17).
Regarding claim 17 pertaining to glycosylating the sugar acceptor with alternating galactose and sialic acid residues, Fiebig teaches glycosylating the sugar acceptor with repeating galactose and sialic acid residues (see, e.g., Fiebig, [0405]). Fiebig teaches the reaction mixture comprises UDP-Gal (see, e.g., Fiebig, [0323]) and CMP-Neu5Ac (see, e.g., Fiebig, [0336], Figure 17). Additionally, Fiebig teaches that the ratio of UGP-Gal + CMP-Neu5Ac to sugar acceptor ranges from 100:1 to 200:1 (see, e.g., Fiebig, [0539]).
Regarding claim 25 pertaining to the pH, Fiebig teaches that the reaction mixture has a pH of 8.0 (see, e.g., Fiebig, [0034]).
Regarding claim 26 pertaining to a method for preparing a bacterial capsular saccharide product, Fiebig teaches that the method is conducted in vitro (see, e.g., Fiebig, abstract).
Regarding claim 29 pertaining to the sialic acid donor, Fiebig teaches that the sialic acid donor is CMP-Neu5Ac (see, e.g., Fiebig, [0336], [0419], Figure 17).
However, Fiebig does not teach: wherein the glycosylation occurs within a single or alternating polymerization step (claims 1 and 17); or wherein the acceptor comprises a purification handle (claim 22).
Lau’s general disclosure relates to “the promiscuous acceptor substrate specificity of two bacterial β1–4-galactosyltransferases and their application in efficient one-pot multienzyme chemoenzymatic synthesis of β1–4-linked galactosides containing sulfated GlcNAc” (see, e.g., Lau, pg. 6066, col. 1). Moreover, Lau discloses that Neisseria meningitidis β1-4-galactosyltransferase (β1–4GalT) can use both GlcNAc- and Glc-terminated glycans as acceptor substrates (see, e.g., Lau, pg. 6067, col. 1). Furthermore, Lau discloses that “bacteria express β1–4GalT for the formation of capsular polysaccharides (CPS) and lipopolysaccharides (LPS)” (see, e.g., Lau, pg. 6066, col. 2)
Regarding claims 1 and 17 pertaining to glycosylating the sugar acceptor with galactose residues, Lau teaches the use of β1-4-galactosyltransferases for catalyzing the transfer of galactose residues onto oligosaccharides (see, e.g., Lau, Introduction, pg. 6067). Moreover, Lau teaches “β1–4-Galactosyltransferases (β1–4GalTs) are enzymes that catalyze the transfer of galactose (Gal) from sugar nucleotide UDP-Gal to N-acetylglucosamine (GlcNAc)” (see, e.g., Lau, Introduction, pg. 6066). Furthermore, Lau teaches the use of β1–4GalTs from Neisseria meningitidis serogroup B (see, e.g., Lau, pg. 6066).
Hanashima’s general disclosure relates to synthesis of α(2,3)- or α(2,3)-sialylated biantennary glycans with a soluble polymer support strategy in combination with a resin-capture release protocol (see, e.g., Hanashima, abstract). Moreover, Hanashima discloses the use of sialyltransferases to transfer sialic acid residues to oligosaccharides (see, e.g., Hanashima, pg. 4222, col. 1). Furthermore, Hanashima discloses the use of a purification handle to separate products from reaction mixtures, or distinguish assembled oligomers from shorter products (see, e.g., Hanashima, pg. 4220, col 1).
Regarding claims 1 and 17 pertaining to glycosylating the sugar acceptor with sialic acid residues, Hanashima teaches “the use of glycosyl-transferases to introduce the terminal Neu5Ac residues and penultimate Gal of the (1,6) branch. An initial glycosylation with either (2,6)- or (2,3)-sialyltransferase should provide monosialylated heptasaccharide 5 or 6, which can then serve as substrates of sequential galactosylation–sialylation” (see, e.g., Hanashima, pg. 4220, col. 1).
Regarding claim 22 pertaining to the purification handle, Hanashima teaches “a unique resin capture–release purification, which uses a chloroacetyl group as the purification handle” (see, e.g., Hanashima, pg. 4220, col 1).
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Fiebig’s bacterial capsular saccharide product, wherein the sugar acceptor is glycosylated with galactose and sialic acid residues, as taught by Lau and Hanashima, respectively. One would have been motivated to do so because Lau teaches that “bacteria express β1–4GalT for the formation of capsular polysaccharides (CPS) and lipopolysaccharides (LPS)” (see, e.g., Lau, pg. 6066, col. 2), and Hanashima teaches “cell-surface glycoproteins and glyco-sphingolipids, sialic acid containing glycan chains are involved in a variety of important physiological events such as cell–cell recognition, adhesion, and signal transduction” (see, e.g., Hanashima, pg. 4218). Moreover, Fiebig teaches a sugar acceptor moiety [[Wingdings font/0xE0]6)-α-D-Gal-(1-4)- α-Neu5Ac-(2[Wingdings font/0xE0]]n (see, e.g., Fiebig, [0405]), wherein UDP-Gal is used as the galactose donor (see, e.g., Fiebig, [0323]) and CMP-Neu5Ac is used as the sialic acid donor (see, e.g., Fiebig, [0336], [0419], Figure 17). Furthermore, one of ordinary skill in the art would readily understand that β1–4-Galactosyltransferase, as taught by Lau, and (2,6)- or (2,3)-sialyltransferase, as taught by Hanashima, can be added to a one-pot reaction mixture in order to glycosylate the sugar acceptor in a single polymerization step, or the β1–4-Galactosyltransferase and (2,6)- or (2,3)-sialyltransferase can be added in alternating steps in order to glycosylate the sugar acceptor with galactose and sialic acid in alternating steps. Therefore, based on the teachings of Fiebig, Lau, and Hanashima, it would have been obvious to glycosylate the sugar acceptor with galactose and sialic acid residues, wherein the glycosylation can be in alternating or a single polymerization step. One would have expected success because Fiebig, Lau, and Hanashima all teach glycosylation of capsular saccharides.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of preparing a bacterial capsular saccharide product, as taught by Fiebig, wherein the sugar acceptor comprises a purification handle, as taught by Hanashima. One would have been motivated to do so because Hanashima teaches that purification handles can be used to separate products from reaction mixtures, or distinguish assembled oligomers from shorter products (see, e.g., Hanashima, pg. 4220, col 1). Moreover, Fiebig teaches the purification of the sugar acceptor carbohydrate (e.g. purified capsular polysaccharides of NmA) (see, e.g., Fiebig, [0031]). Therefore, based on the teachings of Fiebig and Hanashima, it would have been obvious to produce a bacterial capsular saccharide product using a purification handle because the purification handle can be used to purify the sugar acceptor. One would have expected success since Fiebig and Hanashima both teach the synthesis of cell-surface glycans.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Fiebig, Lau, and Hanashima as applied to claims 1, 7, 13, 17, 22, 25-26, and 29 above, and further in view of Higa (US 2016/0289726; Date of Publication October 6, 2016 – previously cited).
The teachings of Fiebig, Lau, and Hanashima, herein referred to as modified-Fiebig-Lau-Hanashima, are discussed above as it pertains to a method of preparing a bacterial capsular saccharide product.
However, modified-Fiebig-Lau-Hanashima does not teach: wherein the sugar acceptor comprises a sialic acid residue at its non-reducing end or a galactose residue at its non-reducing end (claim 19).
Higa’s general disclosure relates to a method of producing a glycoprotein with a complex sugar chain (see, e.g. Higa, abstract). Higa also discloses “a method of producing a glycoprotein, the method comprising the steps of: introducing a gene encoding a desired protein and a gene encoding an antibody that inhibits a decomposing enzyme preventing formation of a desired complex-type sugar chain in the desired protein into an insect organism or insect cells; and obtaining a desired protein having a desired complex-type sugar chain from the insect organism or insect cells” (see, e.g., Higa, [0010]).
Regarding claim 19 pertaining to a galactose reside, Higa teaches “galactose at the non-reducing end of a complex-type sugar chain” (see, e.g., Higa, [0026]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare a bacterial capsular saccharide product, as taught by modified-Fiebig-Lau-Hanashima, wherein the sugar acceptor comprises a galactose residue at its non-reducing end, as taught by Higa. One would have been motivated to do so to prepare a bacterial capsular saccharide product because sialic acid can be added to the galactose at the non-reducing end of a complex sugar chain in an α-2,3 linkage or α-2,6 linkage, as taught by Higa (see, e.g., Higa, [0026]). Additionally, Higa teaches that the sugar chain forming process occurs at the non-reducing end (see, e.g., Higa, [0004]-[0005]). Moreover, modified-Fiebig-Lau-Hanashima teaches glycosylation of the sugar acceptor with galactose and sialic acid residues (see, e.g., Lau, Introduction, pg. 6066-6067) (see, e.g., Hanashima, pg. 4220, col. 1) because glycosylation of the sugar acceptor in capsular saccharides is important for various cellular and physiological events (see, e.g., Hanashima, pg. 4218). Therefore, based on the teachings of modified-Fiebig-Lau-Hanashima and Higa, it would have been obvious to produce a bacterial capsular saccharide product with a galactose residue at its non-reducing end. Furthermore, utilization of a galactose reside at the non-reducing end would be advantageous or beneficial for modified-Fiebig-Lau-Hanashima’s purpose of producing a bacterial capsular saccharide product. One would have expected success since modified-Fiebig-Lau-Hanashima and Higa both teach the synthesis of complex sugars.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Fiebig, Lau, and Hanashima as applied to claims 1, 7, 13, 17, 22, 25-26, and 29 above, and further in view of Sanapala (Expedient Route To Access Rare Deoxy Amino L‑Sugar Building Blocks for the Assembly of Bacterial Glycoconjugates; 2016 – previously cited).
The teachings of Fiebig, Lau, and Hanashima, herein referred to as modified-Fiebig-Lau-Hanashima, are discussed above as it pertains to a method of preparing a bacterial capsular saccharide product.
Regarding claim 21 pertaining to the oligosaccharide moiety, Fiebig teaches the oligosaccharide moiety [[Wingdings font/0xE0]6)-α-D-Gal-(1-4)- α-Neu5Ac-(2[Wingdings font/0xE0]]n (see, e.g., Fiebig, [0405]).
However, modified-Fiebig-Lau-Hanashima does not teach: the sugar acceptor moiety structure (claim 21).
Sanapala’s general disclosure relates to “general and expedient methodology to access a variety of unusual deoxy amino L-sugars starting from readily available L-rhamnose and L-fucose via highly regioselective, one-pot double serial and double parallel displacements of the corresponding 2,4-bistriflates using azide and nitrite anions as nucleophiles” (see, e.g., Sanapala, abstract). Sanapala discloses that “The methodology will expedite assembly of bacterial glycoconjugates and speed up the vaccine development” (see, e.g., Sanapala, Conclusion, pg. 4945). Moreover, Sanapala discloses that “Bacterial glycoproteins and oligosaccharides contain several rare deoxy amino L-sugars which are virtually absent in the human cells” (see, e.g., Sanapala, abstract).
Regarding claim 21 pertaining to the sugar acceptor moiety, Sanapala teaches the formula HO(CH2)3NHCbz (see, e.g., Sanapala, Scheme 5, pg. 4944), whose structure corresponds to the instantly claimed sugar acceptor structure. Additionally, Sanapala teaches that HO(CH2)3NHCbz is an amino linker that acts as a sugar acceptor (see, e.g., Sanapala, Scheme 6, pg. 4945).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine modified-Fiebig-Lau-Hanashima’s oligosaccharide moiety, with Sanapala’s sugar acceptor. One would have been motivated to do so because Sanapala teaches that the HO(CH2)3NHCbz is an amino linker that acts as a sugar acceptor for the synthesis of polysaccharides (see, e.g., Sanapala, Schemes 5-6, pgs. 4944-4945). Moreover, modified-Fiebig-Lau-Hanashmia teaches the use of sugar acceptors for receiving the sugar moiety and building bacterial capsular polysaccharides (see, e.g., Fiebig, abstract). Therefore, based on the teachings of Wang and modified-Fiebig-Lau-Hanashima, it would have been obvious to combine an oligosaccharide moiety with a sugar acceptor structure because this would allow for the production of bacterial capsular polysaccharides. One would have expected success because modified-Fiebig-Lau-Hanashima and Wang both teach production of oligosaccharides and sugar acceptors.
Claims 23-24 and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Fiebig, Lau, and Hanashima as applied to claims 1, 7, 13, 17, 22, 25-26, and 29 above, and further in view of Chen (US 2017/0204444; Date of Publication: July 20, 2017 – previously cited).
The teachings of Fiebig, Lau, and Hanashima, herein referred to as modified-Fiebig-Lau-Hanashima, are discussed above as it pertains to a method of preparing a bacterial capsular saccharide product.
However, modified-Fiebig-Lau-Hanashima does not teach: wherein the reaction mixture comprises a CMP-sialic acid synthetase (claim 23); or wherein the CMP-sialic acid synthetase is NmCSS (claim 24); or further comprising forming a reaction mixture including a CMP-sialic acid synthetase, cytidine triphosphate, and Neu5Ac under conditions suitable to form the CMP-Neu5Ac (claim 30); or further comprising forming a reaction mixture including a sialic acid aldolase, pyruvic acid, and N-acetylmannosamine, under conditions suitable to form the Neu5Ac (claim 31).
Chen’s general disclosure relates to “a one-pot multi-enzyme method for preparing UDP-sugars from simple sugar starting materials” (see, e.g., Chen, abstract). Moreover, Chen discloses “a method of preparing an oligosaccharide. The method includes forming a first reaction mixture containing a first sugar, an acceptor sugar, a glycosyltransferase, a nucleotide-sugar pyrophosphorylase, and an enzyme selected from a kinase and a dehydrogenase” (see, e.g., Chen, [0011]). Furthermore, Chen discloses a method of preparing a sialylated oligosaccharide having at least two sialic acid moieties. The method includes forming a reaction mixture containing: a substrate sugar; cytidine-5′-monophospho-sialic acid (CMP-sialic acid or CMP-Sia) or derivatives” “using the one-pot multi-enzyme methods of the invention” (see, e.g., Chen, [0012]). Additionally, Chen discloses methods for the production of CMP-Neu5Ac and Neu5Ac (see, e.g., Chen, [0142]-[0143]), which allows for production of sialylated oligosaccharides.
Regarding claims 23-24 pertaining to NmCSS, Chen teaches “a one-pot two-enzyme sialic acid activation and transfer system containing Neisseria meningitidis CMP-sialic acid synthetase (NmCSS)” (see, e.g., Chen, [0521]).
Regarding claim 30 pertaining to forming CMP-Neu5AC, Chen teaches a reaction mixture comprising “forming a reaction mixture including a CMP-sialic acid synthetase, cytidine 5′-triphosphate, and N-acetylneuraminic acid (Neu5Ac) or a Neu5Ac analog, under conditions suitable to form CMP-Neu5Ac or a CMP-Neu5Ac analog” (see, e.g., Chen, [0142]).
Regarding claim 31 pertaining to forming Neu5Ac, Chen teaches “the method also includes forming a reaction mixture including a sialic acid aldolase, pyruvic acid or derivatives thereof, and N-acetylmannosamine or derivatives thereof, under conditions suitable to form Neu5Ac or a Neu5Ac analog” (see, e.g., Chen, [0143]).
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of preparing a bacterial capsular saccharide product, as taught by modified-Fiebig-Lau-Hanashima, wherein the CMP-sialic acid synthetase is NmCSS, as taught by Chen. One would have been motivated to do so because Chen teaches that NmCSS is used to produce a sialylated bacterial capsular saccharide product (see, e.g., Chen, [0012]) because sialic acid-containing capsular polysaccharides are found on some pathogenic bacteria and can serve as virulence factors (see, e.g., Chen, [0007]). Moreover, Chen teaches that CMP-sialic acid synthetase, which can be derived from N. meningitidis, is used to produce CMP-sialic acid (see, e.g., Chen, [0142]), which is a sialic acid donor, as taught by modified-Fiebig-Lau-Hanashima (see, e.g., Fiebig, [0336], [0419], Figure 17). Therefore, based on the teachings of modified-Fiebig-Lau-Hanashima and Chen, it would have been obvious to produce a bacterial capsular saccharide product with NmCSS because NmCSS can produce CMP-sialic acid, which is the sialic acid donor used when producing the bacterial capsular saccharide product.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of preparing a bacterial capsular saccharide product, as taught by modified-Fiebig-Lau-Hanashima, with the method of producing CMP-Neu5Ac, as taught by Chen. One would have been motivated to do so because Chen teaches that CMP-Neu5Ac is used to produce an sialylated oligosaccharide (see, e.g., Chen, [0142]). Moreover, modified-Fiebig-Lau-Hanashima teaches that CMP-sialic acid is the sialic acid donor used when producing the bacterial capsular saccharide product (see, e.g., Fiebig, [0336], [0419], Figure 17). Therefore, based on the teachings of modified-Fiebig-Lau-Hanashima and Chen, it would have been obvious to one of ordinary skill in the art to form a reaction mixture to produce CMP-Neu5Ac because CMP-Neu5Ac is the sialic acid donor used to sialylated oligosaccharides.
It would have been thirdly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of preparing a bacterial capsular saccharide product, as taught by modified-Fiebig-Lau-Hanashima, with the method of producing Neu5Ac, as taught by Chen. One would have been motivated to do so because Chen teaches that Neu5Ac is used to produce CMP-Neu5Ac, wherein CMP-Neu5Ac is the sialic acid donor used to sialylated oligosaccharides (see, e.g., Chen, [0142]), and modified-Fiebig-Lau-Hanashima teaches that CMP-sialic acid is the sialic acid donor used when producing the bacterial capsular saccharide product (see, e.g., Fiebig, [0336], [0419], Figure 17). Therefore, based on the teachings of modified-Fiebig-Lau-Hanashima and Chen, it would have been obvious to form a reaction mixture to produce Neu5Ac because Neu5Ac can be used to produce CMP-Neu5Ac, which is the sialic acid donor for production of sialylated oligosaccharides. One would have been motivated to do so because modified-Fiebig-Lau-Hanashima and Chen both teach a method of preparing oligosaccharides from simple sugars.
Claims 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Fiebig (US 2017/0037440; Date of Publication: February 9, 2017 - previously cited) in view of Lau (Highly efficient chemoenzymatic synthesis of β1-4-linked galactosidases with promiscuous bacterial β1-4-galactosyltransferases; 2010 – cited in the IDS filed on 05/20/2022 – previously cited), Hanashima (Divergent Synthesis of Sialylated Glycan Chains: Combined Use of Polymer Support, Resin Capture-Release, and Chemoenzymatic Strategies; 2005 – previously cited), and Higa (US 2016/0289726; Date of Publication October 6, 2016 – previously cited).
Fiebig’s general disclosure relates to “in vitro methods for producing Neisseria meningitidis capsular polysaccharides which have a defined length. The present invention also relates to compositions comprising at least one capsule polymerase, at least one donor carbohydrate and at least one acceptor carbohydrate, wherein the ratio of donor carbohydrate to acceptor carbohydrate is a ratio from 10:1 to 400:1. Moreover, the present invention provides truncated versions of the capsule polymerases of Neisseria meningitidis serogroups A and X” (see, e.g., Fiebig, abstract). Moreover, Fiebig discloses a sugar acceptor moiety [[Wingdings font/0xE0]6)-α-D-Gal-(1-4)- α-Neu5Ac-(2[Wingdings font/0xE0]]n (see, e.g., Fiebig, [0405]), wherein UDP-Gal is used as the galactose donor (see, e.g., Fiebig, [0323]) and CMP-Neu5Ac is used as the sialic acid donor (see, e.g., Fiebig, [0336], [0419], Figure 17).
Regarding claim 32 pertaining to a method of preparing a bacterial capsular saccharide product, Fiebig teaches methods for producing capsular polysaccharides (see, e.g., Fiebig, abstract, [0021]), wherein the composition comprises “at least one capsule polymerase, at least one donor carbohydrate and at least one acceptor carbohydrate” (see, e.g., Fiebig, abstract). Moreover, Fiebig teaches the presence of a bacterial capsular saccharide synthase (see, e.g., Fiebig, [0012], [0409]). Fiebig teaches that the reaction is regulated to allow for the production of capsular polysaccharides (see, e.g., Fiebig, [0021]). Fiebig teaches glycosylating the sugar acceptor with repeating galactose and sialic acid residues (see, e.g., Fiebig, [0405]). Moreover, Fiebig teaches extracellular polysaccharide capsules comprising heteropolymers of repeating units (see, e.g., Fiebig, [0405]). Additionally, Fiebig teaches that the degree of polymerization ranges from 10 to 60 (see, e.g., Fiebig, [0007], [0042]), and a polydispersity index ranging from about 1 to about 1.3 (see, e.g., Fiebig, [0441], Table 4).
Regarding claim 33 pertaining to the synthase, Fiebig teaches the presence of a bacterial capsular saccharide synthase (see, e.g., Fiebig, [0012], [0409]).
Regarding claim 34 pertaining to the synthase, Fiebig teaches Neisseria meningitidis SiaDW (NmSiaDw) (see, e.g., Fiebig, [0012], [0409]).
However, Fiebig does not teach: wherein the glycosylation occurs within a single polymerization step (claim 32); or wherein the sugar acceptor comprises a sialic acid residue at its non-reducing end (claim 32).
Lau’s general disclosure relates to “the promiscuous acceptor substrate specificity of two bacterial β1–4-galactosyltransferases and their application in efficient one-pot multienzyme chemoenzymatic synthesis of β1–4-linked galactosides containing sulfated GlcNAc” (see, e.g., Lau, pg. 6066, col. 1). Moreover, Lau discloses that Neisseria meningitidis β1-4-galactosyltransferase (β1–4GalT) can use both GlcNAc- and Glc-terminated glycans as acceptor substrates (see, e.g., Lau, pg. 6067, col. 1). Furthermore, Lau discloses that “bacteria express β1–4GalT for the formation of capsular polysaccharides (CPS) and lipopolysaccharides (LPS)” (see, e.g., Lau, pg. 6066, col. 2)
Regarding claim 32 pertaining to glycosylating the sugar acceptor with galactose residues, Lau teaches the use of β1-4-galactosyltransferases for catalyzing the transfer of galactose residues onto oligosaccharides (see, e.g., Lau, Introduction, pg. 6067). Moreover, Lau teaches “β1–4-Galactosyltransferases (β1–4GalTs) are enzymes that catalyze the transfer of galactose (Gal) from sugar nucleotide UDP-Gal to N-acetylglucosamine (GlcNAc)” (see, e.g., Lau, Introduction, pg. 6066). Furthermore, Lau teaches the use of β1–4GalTs from Neisseria meningitidis serogroup B (see, e.g., Lau, pg. 6066).
Hanashima’s general disclosure relates to synthesis of α(2,3)- or α(2,3)-sialylated biantennary glycans with a soluble polymer support strategy in combination with a resin-capture release protocol (see, e.g., Hanashima, abstract). Moreover, Hanashima discloses the use of sialyltransferases to transfer sialic acid residues to oligosaccharides (see, e.g., Hanashima, pg. 4222, col. 1). Furthermore, Hanashima discloses the use of a purification handle to separate products from reaction mixtures, or distinguish assembled oligomers from shorter products (see, e.g., Hanashima, pg. 4220, col 1).
Regarding claim 32 pertaining to glycosylating the sugar acceptor with sialic acid residues, Hanashima teaches “the use of glycosyl-transferases to introduce the terminal Neu5Ac residues and penultimate Gal of the (1,6) branch. An initial glycosylation with either (2,6)- or (2,3)-sialyltransferase should provide monosialylated heptasaccharide 5 or 6, which can then serve as substrates of sequential galactosylation–sialylation” (see, e.g., Hanashima, pg. 4220, col. 1).
Higa’s general disclosure relates to a method of producing a glycoprotein with a complex sugar chain (see, e.g. Higa, abstract). Higa also discloses “a method of producing a glycoprotein, the method comprising the steps of: introducing a gene encoding a desired protein and a gene encoding an antibody that inhibits a decomposing enzyme preventing formation of a desired complex-type sugar chain in the desired protein into an insect organism or insect cells; and obtaining a desired protein having a desired complex-type sugar chain from the insect organism or insect cells” (see, e.g., Higa, [0010]).
Regarding claim 32 pertaining to a galactose reside, Higa teaches “galactose at the non-reducing end of a complex-type sugar chain” (see, e.g., Higa, [0026]).
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Fiebig’s bacterial capsular saccharide product, wherein the sugar acceptor is glycosylated with galactose and sialic acid residues, as taught by Lau and Hanashima, respectively. One would have been motivated to do so because Lau teaches that “bacteria express β1–4GalT for the formation of capsular polysaccharides (CPS) and lipopolysaccharides (LPS)” (see, e.g., Lau, pg. 6066, col. 2), and Hanashima teaches “cell-surface glycoproteins and glyco-sphingolipids, sialic acid containing glycan chains are involved in a variety of important physiological events such as cell–cell recognition, adhesion, and signal transduction” (see, e.g., Hanashima, pg. 4218). Moreover, Fiebig teaches a sugar acceptor moiety [[Wingdings font/0xE0]6)-α-D-Gal-(1-4)- α-Neu5Ac-(2[Wingdings font/0xE0]]n (see, e.g., Fiebig, [0405]), wherein UDP-Gal is used as the galactose donor (see, e.g., Fiebig, [0323]) and CMP-Neu5Ac is used as the sialic acid donor (see, e.g., Fiebig, [0336], [0419], Figure 17). Furthermore, one of ordinary skill in the art would readily understand that β1–4-Galactosyltransferase, as taught by Lau, and (2,6)- or (2,3)-sialyltransferase, as taught by Hanashima, can be added to a one-pot reaction mixture in order to glycosylate the sugar acceptor in a single polymerization step, or the β1–4-Galactosyltransferase and (2,6)- or (2,3)-sialyltransferase can be added in alternating steps in order to glycosylate the sugar acceptor with galactose and sialic acid in alternating steps. Therefore, based on the teachings of Fiebig, Lau, and Hanashima, it would have been obvious to glycosylate the sugar acceptor with galactose and sialic acid residues, wherein the glycosylation can be in alternating or a single polymerization step. One would have expected success because Fiebig, Lau, and Hanashima all teach glycosylation of capsular saccharides.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare a bacterial capsular saccharide product, as taught by Fiebig, wherein the sugar acceptor comprises a galactose residue at its non-reducing end, as taught by Higa. One would have been motivated to do so to prepare a bacterial capsular saccharide product because sialic acid can be added to the galactose at the non-reducing end of a complex sugar chain in an α-2,3 linkage or α-2,6 linkage, as taught by Higa (see, e.g., Higa, [0026]). Additionally, Higa teaches that the sugar chain forming process occurs at the non-reducing end (see, e.g., Higa, [0004]-[0005]). Moreover, modified-Fiebig-Lau-Hanashima teaches glycosylation of the sugar acceptor with galactose and sialic acid residues (see, e.g., Lau, Introduction, pg. 6066-6067) (see, e.g., Hanashima, pg. 4220, col. 1) because glycosylation of the sugar acceptor in capsular saccharides is important for various cellular and physiological events (see, e.g., Hanashima, pg. 4218). Therefore, based on the teachings of Fiebig and Higa, it would have been obvious to produce a bacterial capsular saccharide product with a galactose residue at its non-reducing end. Furthermore, utilization of a galactose reside at the non-reducing end would be advantageous or beneficial for Fiebig purpose of producing a bacterial capsular saccharide product. One would have expected success since Fiebig and Higa both teach the synthesis of complex sugars.
Examiner’s Response to Arguments
Applicant's arguments filed 11/24/2025 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments pertaining to the teachings of Lau (remarks, pages 9-10), this argument is not persuasive for multiple reasons:
First, Lau teaches the use of β1-4-galactosyltransferases for catalyzing the transfer of galactose residues onto oligosaccharides (see, e.g., Lau, Introduction, pg. 6067). Moreover, Lau teaches “β1–4-Galactosyltransferases (β1–4GalTs) are enzymes that catalyze the transfer of galactose (Gal) from sugar nucleotide UDP-Gal to N-acetylglucosamine (GlcNAc)” (see, e.g., Lau, Introduction, pg. 6066). Furthermore, Lau teaches the use of β1–4GalTs from Neisseria meningitidis serogroup B (see, e.g., Lau, pg. 6066). Hanashima teaches “the use of glycosyl-transferases to introduce the terminal Neu5Ac residues and penultimate Gal of the (1,6) branch. An initial glycosylation with either (2,6)- or (2,3)-sialyltransferase should provide monosialylated heptasaccharide 5 or 6, which can then serve as substrates of sequential galactosylation–sialylation” (see, e.g., Hanashima, pg. 4220, col. 1). Moreover, Hanashima discloses the use of sialyltransferases to transfer sialic acid residues to oligosaccharides (see, e.g., Hanashima, pg. 4222, col. 1). Therefore, the combined prior art of Lau and Hanashima were used to show a mechanism by which galactose and sialic acid residues can be added to a sugar acceptor alternatingly if the enzymes used to transfer sialic acid and galactose are provided. Furthermore, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Secondly, regarding Applicant’s arguments that Lau does not teach producing a bacterial capsular saccharide product with a degree of polymerization of 20 to 200, or 5 to 200, this is not persuasive because Lau was not used to teach this limitation. Instead Fiebig was used to teach this limitation, as discussed above.
Regarding Applicant’s arguments pertaining to none of the references disclosing or suggesting a method wherein the sugar acceptor comprises a sialic acid residue on its non-reducing end (remarks, page 10), this argument is not persuasive because Higa teaches “galactose at the non-reducing end of a complex-type sugar chain” (see, e.g., Higa, [0026]). Therefore, Higa was used to teach this limitation in claims 19 and 32.
Conclusion
Claims 1, 7, 13, 17, 19, 21-26, and 29-34 are rejected.
No claims are 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. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653