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/US2022/023029 filed on 04/01/2022 and claims domestic benefit to US provisional application no. 63/170,250 filed on 04/02/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/25/2024, 06/20/2024, 11/27/2024, and 03/07/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of the Claims
The preliminary claim amendments filed on 01/08/2024 is acknowledged. Claims 1-2, 5, 8, 10-15, 17-19, 22, 28, 30, 38, 44, and 51 are amended. Claims 3-4, 6-7, 9, 16, 20-21, 23-27, 29, 31-37, 39-43, 45-50, 52-74, and 76-96 are cancelled.
Accordingly, claims 1-2, 5, 8, 10-15, 17-19, 22, 28, 30, 38, 44, 51, and 75 are pending and being examined on the merits herein.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 15, 18, 28, 38, 44, and 51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Oberli et al. (Chem Biol, 2011 in IDS filed 03/25/2024).
Oberli teaches an oligosaccharide-conjugate vaccine candidate for Clostridium difficile that is antigenic and immunogenic (Abstract).
Oberli teaches the vaccine contained a chemically synthesized PS-II hapten of a cell wall polysaccharide of hypervirulent ribotype 027 of C. difficile (Abstract and Fig. 1 on page 581). Oberli teaches that the synthesized PS-II hapten was conjugated to a diphtheria toxoid variant CRM197, and further discloses that CRM197 was chosen as a carrier because it is a constituent of licensed vaccines (see last paragraph left column page 583). Oberli demonstrates in Fig. 4 on page 585 that the PS-II hapten was conjugated to CRM 197 via a squaric acid diester moiety to link the primary amine end of the PS-II to a lysine residue on the CRM 197 (first paragraph right column page 583).
Oberli discloses that on average four PS-II haptens were loaded onto the diphtheria toxoid, which indicates the ratio of PS-II and the carrier CRM 197 was 4:1 and meets the limitation of the recited ratio in instant claim 1.
Oberli immunized two female mice using their PS-II CRM197 conjugate vaccine by injecting 15 ug of the vaccine three times subcutaneously at 2 week intervals (see second paragraph right column page 583). As demonstrated in Fig. 5 on 586, antibody titers were monitored, and the two immunized mice produced IgG antibodies that bound specifically the PS-II hapten, demonstrating that the synthesized PS-II hapten is immunoreactive. Oberli discloses that an increase in the level of anti PSII hapten specific IgG antibodies over time was observed in Mouse 2805 (see second paragraph right column page 583).
Here, Oberli demonstrates a PS-II CRM197 conjugate that had roughly a 4:1 ratio of PS-II:CRM197, and further demonstrates administering this vaccine to mice, which induced antibody titers specific to the PS-II hapten.
Therefore, instant claims 1, 15, 18, 28, 38, and 51 are anticipated.
In regards to instant claim 44, the vaccine of Oberli would necessarily have less than 5% by weight of a C. difficile impurity because the PS-II of Oberli was chemically synthesized using monosaccharide building blocks and was not extracted from C. difficile.
Therefore, instant claim 44 is also anticipated.
Claim(s) 1, 8, 15, 18-19, 28, 38, and 51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Adamo et al. (ACS Chemical Biology, 2012 in PTO-892).
Adamo discloses native PSII and phosphorylated synthetic hexasaccharide conjugate to CRM197 as vaccine candidates show below (Abstract):
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The PSII structure shown above meets the limitation of the PSII recited in instant claim 19.
Adamo discloses that native PSII is a polyanionic polysaccharide (second paragraph left column page 1421), and that PSII from the R20291 strain (ribotype 027) was used (right column page 1422). Adamo discloses that PSII having a DP of 8, 11, and 21 conjugated to the CRM197 carrier at 2.07, 1.31, and 0.61 saccharide loading (mol/mol) (last paragraph left column page 1424 and Table 2 page 1425). The PS-II was conjugated by a selective modification of the reducing mannose end to generate aldehyde groups, reduction of PSII with NaBH4, followed by a controlled periodate oxidation to give aldehyde groups for subsequent coupling to the lysine residues of CRM197 via reductive amination as seen in Scheme 3 on page 1425.
As demonstrated in Figure 2 on page 1425, mice were immunized (2.5 ug dosage) with the PSII-CRM197 conjugate and induced IgG antibody titer specific for PS-II (also see right column page 1424).
Therefore, instant claims 1, 8, 15, 18-19, 28, 38, and 51 are anticipated.
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.
Claim(s) 1-2, 5, 10-14, 17, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Oberli et al. (Chem Biol, 2011 in IDS filed 03/25/2024) in view of Scarselli et al. (US20150132333A1 in PTO-892)
The teachings of Oberli are as described above and teach the composition of claim 1 as discussed above. Furthermore, Oberli discloses that their conjugate used to immunize mice were in complete Freund’s adjuvants (see section “Immunization” left column page 587).
Oberli, however, does not disclose a composition further comprising a second and third polypeptide as recited in instant claims 2 and 5.
Scarselli discloses recombinant fragments of C. difficile TcdA and TcdB that may be used in the development of vaccines against C. difficile associated disease (Abstract).
Scarselli discloses their immunogenic composition comprises a ToxB (TcdB)-GT antigen comprising a polypeptide comprising an amino acid sequence 80% or more identical to a fragment of at least 7 consecutive amino acids of SEQ ID NO:18 or SEQ ID NO: 60 wherein the fragment comprises an epitope of SEQ ID NO:18 or SEQ ID NO: 60; and a ToxA (TcdA)-P5-6 antigen comprising an amino acid sequence 80% or more identical to SEQ ID NO:11 (claim 1). Scarselli discloses that their composition can further comprise one or more additional antigens such as a full length TcdB antigen (Toxoid B) (SEQ ID NO: 2) and a full-length TcdA antigen (Toxoid B) (SEQ ID NO:1) and others (claim 33). Here, SEQ ID NO: 2 and SEQ ID NO: 1 of Scarselli contains the same sequences in instant SEQ ID NO: 1 and SEQ ID NO: 4, respectively. Scarselli discloses that at least two of the antigens comprise a hybrid (fused) polypeptide (claim 35).
Scarselli discloses their compositions comprise additional adjuvants including aluminum salts, complete Freund’s adjuvant, and others (paragraph 0196). Scarselli discloses that the use of an aluminum hydroxide and/or aluminum phosphate adjuvant is particular preferred, and antigens are generally adsorbed to these salts (paragraph 0212).
Scarselli discloses that a combination of full length inactivated Toxoid A and Toxoid B was used as a positive control, and that this combination may be considered to represent a “gold standard” against which the combinations of the invention may be compared (paragraph 0371). Scarselli demonstrates that hamsters were immunized with each Toxoid at 5 ug dosages adjuvanted with MF59 (paragraph 0372), and that immunization with full length Toxoid A and B protected 83% of hamsters against the B1 strain (paragraph 0374).
It would have been prima facie obvious before the effective filing date of the claimed invention to have combined the 15ug PS-II CRM197 conjugate composition of Oberli with the immunogenic compositions of Scarselli such as the composition comprising Toxoid A + Toxoid B at 5 ug each to arrive at the claimed invention. One of ordinary skill in the art would have combined these compositions because both Oberli and Scarselli teach compositions that are useful for the same purpose as a vaccine against C. difficile infection. See MPEP 2144.06.
In regards to instant claim 10, it would have been prima facie obvious before the effective filing date of the claimed invention to have fused a toxoid A antigen and a toxoid B antigen as disclosed in Scarselli in the combined compositions of Oberli and Scarselli described above. One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results because Scarselli provides guidance of forming hybrid (fused) polypeptides with any two of the toxoid A and toxoid B antigens disclosed in Scarselli.
In regards to instant claim 22, it would have been prima facie obvious before the effective filing date of the claimed invention to have include aluminum hydroxide and/or aluminum phosphate adjuvants as disclosed in Scarselli in the combined compositions of Oberli and Scarselli described above. One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results because Scarselli provides guidance of preferably including aluminum hydroxide and/or aluminum phosphate adjuvants into C. difficile vaccine compositions.
Claim(s) 1 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Adamo et al. (ACS Chemical Biology, 2012 in PTO-892) in view of Levine et al. (US20130129776A1 in PTO-892).
The teachings of Adamo are as described above and teach the composition of instant claim 1 as discussed above. Furthermore, Adamo demonstrates in Scheme 2 on page 1423 that the synthetic hexasaccharides were conjugated via di-N-hydroxy-succinimidyl adipate ester linker.
Even though Adamo teaches the use of a succinimide linker to conjugate the native PS-II to the CRM-197 carrier protein, Adamo does not teach the linker comprises a thiosuccinimide or thioester.
Levine discloses vaccines comprising a hapten antigen conjugated to a carrier antigen, wherein at least one of the hapten antigens or carrier antigens is characteristic of the Salmonella enterica serovar. (Abstract). Levin discloses that the hapten is a polysaccharide from the Salmonella enterica serovar (COPS) (claim 4), and the carrier is a phase 1 flagella protein (FliC) or an antigenic fragment or derivative thereof from the Salmonella enterica serovar (claim 3).
Levine discloses that the hapten and carrier can be conjugated using known techniques and methods via coupling of available functional groups (such as amino, carboxyl, thio and aldehyde groups) (paragraph 0151). Levine discloses that the hapten and carrier can be chemically manipulated to bear functional groups, and that the presence of functional groups such as amino groups, carboxyl groups, aldehydes, hydrazides, epoxides, and thiols can facilitate covalent conjugation (paragraph 0152). Levine discloses that the use of various conventional crosslinking agents to conjugate the hapten and carrier including N-hydroxysuccinimide ester, GMBS (N-(-maleimidobutyryloxy)succinimide ester), and others (paragraphs 0157-0158).
Levine demonstrates the conjugation of COPS by aminooxy thio-ether chemistry, resulting in conjugates in which the carboxyl group present at the KDO terminus on COPS are conjugated at the polysaccharide terminus to one or more available lysine residues on the protein (paragraph 0280 and 0295). Here, COPS was thiolated via diaminooxy cysteamine, and the flagellin carrier was activated using sulfo-GMBS linker, and then conjugated together. The coupling chemistry described here results in a linker comprising a thiosuccinimide since the carboxyl group of the COPS is thiolated, and the carrier contains GMBS (succinimide ester linker).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the PS-II CRM197 conjugate of Adamo by using the aminooxy thio-ether conjugation chemistry of Levine to arrive at the claimed invention. One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results because Levine demonstrates the conjugation of the synthetic hexasaccharides and CRM197 carrier using a succinimide linker as well as modifying the natural PS-II to generate aldehyde groups for conjugation to the lysine residue of the carrier protein, and Adamo also discloses the conjugation of a polysaccharide and carrier protein using known conventional conjugation techniques including the aminooxy thio-ether chemistry to conjugate a modified polysaccharide to the lysine residues on the protein.
Claim(s) 75 is rejected under 35 U.S.C. 103 as being unpatentable over Dhere et al. (EP3789494A1 in PTO-892).
Dhere discloses a method for obtaining purified bacterial polysaccharides (Abstract).
Dhere discloses the method comprising (a) providing a fermentation harvest comprising bacterial cell, polysaccharide, proteins, nucleic acid and cell debris; and (b) treating the fermentation harvest with an acid to separate the polysaccharide from protein, nucleic acid and cell debris to obtain purified and sized bacterial polysaccharides (claim 1). Dhere discloses the acid used for treatment can be trichloroacetic acid and others (claim 5). Dhere discloses the purified and sized bacterial polysaccharide has protein content less than 3 %, nucleic acid content less than 2 % (claim 2). Here, the trichloroacetic acid treatment meets the limitation of enriching and obtaining an enriched polysaccharide. Dhere discloses that the obtained purified polysaccharide can be from any bacteria including Clostridium difficile and others (paragraph 0062).
Even though Dhere does not demonstrate the purification of a cell-surface polysaccharide from C. difficile, it would have been prima facie obvious before the effective filing date of the claimed invention to have obtained a purified cell-surface polysaccharide from C. difficile as suggested in Dhere using the purification method disclosed in Dhere because Dhere provides guidance that their purification method can be used to obtain a purified polysaccharide from any bacteria including from C. difficile.
Conclusion
No claim is found 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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