DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1) A request for continued examination under 37 C.F.R 1.114, including the fee set forth in 37 C.F.R 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R 1.114, and the fee set forth in 37 C.F.R 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 C.F.R 1.114. Applicants’ submission filed on 12/09/25 has been entered.
Applicants’ Amendment
2) Acknowledgment is made of Applicants’ amendment filed 12/09/25 in response to the final Office Action mailed 09/10/25.
Status of Claims
3) Claims 32, 44 and 48 have been amended via the amendment filed 12/09/2025.
Claim 35 has been canceled via the amendment filed 12/09/2025.
Claims 32, 36, 39, 42-44 and 48 are pending.
Claims 32, 36, 39, 42 and 43 are under examination.
Prior Citation of Title 35 Sections
4) The text of those sections of Title 35 U.S. Code not included in this action can be found in a prior Office Action References.
Prior Citation of References
5) The references cited or used as prior art in support of one or more rejections in the instant Office Action and not included on an attached form PTO-892 or form PTO-1449 have been previously cited and made of record.
Information Disclosure Statement
6) Acknowledgment is made of Applicants’ information disclosure statement filed 12/30/25. The information referred to therein has been considered and a signed copy is attached to this Office Action.
Rejection(s) Moot
7) The rejection of claim 35 set forth in paragraph 19 of the Office Action mailed 09/10/25 under 35 U.S.C § 101 as being directed to a judicial exception without significantly more is moot in light of Applicants’ cancellation of the claim.
8) The rejection of claim 35 set forth in paragraph 22 of the Office Action mailed 09/10/25 under 35 U.S.C § 102(a)(2) as being anticipated by Dong et al. (US 20200339636 A1, of record) is moot in light of Applicants’ cancellation of the claim.
9) The rejection of claim 35 set forth in paragraph 23 of the Office Action mailed 09/10/25 under 35 U.S.C § 102(a)(1) and 35 U.S.C § 102(a)(2) as being anticipated by Shone et al. (US 20150093389 A1, of record) is moot in light of Applicants’ cancellation of the claim.
10) The rejection of claim 35 set forth in paragraph 25 of the Office Action mailed 09/10/25 under 35 U.S.C § 112(d) or pre-AIA 35 U.S.C § 112, fourth paragraph is moot in light of Applicants’ cancellation of the claim.
Rejection(s) Withdrawn
11) The rejection of claims 32, 36, 39, 42 and 43 set forth in paragraph 19 of the Office Action mailed 09/10/25 under 35 U.S.C § 101 as being directed to a judicial exception without significantly more is withdrawn in light of Applicants’ claim amendments and the new rejection set forth in this Office Action to address the claims as amended.
Applicants refer to claim 32 as amended and state that the claim now explicitly limits the fragment in terms of structure, source, and length, specifically defining a fragment derived from C. difficile TcdB that is at least 98% identical to SEQ ID NO: 3. Applicants direct the Office to the Decision on Appeal for Appeal Proceeding No. 2022-004253 (US Application No. 12/576,750, now US Patent 12,072,338 B2), which addressed claims directed to protein fragments. Applicants state that: (a) the Board at pages 9-10 there reversed the Examiner's § 101 rejection noting that the claimed fragments were not naturally occurring stating: "The mere possibility that the peptides ... might have existed as a natural phenomenon is insufficient to establish that the composition is a product of nature and therefore a judicial exception."; and (b) The Board further emphasized at page 10 4th paragraph that the claimed fragments exhibited markedly different characteristics compared to the native protein supported by specification data by stating:
"We are persuaded that the peptides of SEQ ID NOs: 2 and 16 have markedly different characteristics than the naturally occurring CXCR3 protein based upon multiple lines of evidence."
With these, Applicants state that the present specification at sections [0087] to [0091] describes the TcdB fragments as exhibiting distinct functional and structural properties compared to the full-length holotoxin. Applicants submit that for the same reasons recognized in the cited Decision on Appeal, the claims here are directed to more than a judicial exception and are patent-eligible.
Applicants’ arguments have been carefully considered, but are not persuasive.
Applicants’ current amendments to claim 32 have been noted. However, contrary to Applicants’ assertions, there is no evidence within the as-filed specification that a polypeptide sequence of a fragment of a TcdB holotoxin of C. difficile that is at least 98% identical to SEQ ID NO: 3, i.e., up to 2%, or 1.5%, or 1% non-identical to SEQ ID NO: 3, exhibited markedly different characteristics compared to the native full-length TcdB holotoxin protein of C. difficile. Furthermore, as is evident from the dependent claim 36, the immunogen claimed therein comprises at least one polypeptide according to claim 32. Likewise, the vaccine claimed in claim 39 comprises at least one polypeptide according to claim 32. Therefore, it encompasses and reads on a full-length TcdB holotoxin of C. difficile since a full-length TcdB holotoxin of C. difficile is a naturally occurring immunogen that comprises therein a polypeptide sequence that is 100% or 99.8% identical to the instantly recited SEQ ID NO: 3. See for example, the sequence alignments (A) and (B) provided in the new 35 U.S.C § 101 rejection set forth below in this Office Action. Clearly, the Decision on Appeal for Appeal Proceeding No. 2022-004253 (US Application No. 12/576,750, now US Patent 12,072,338 B2) referred to by Applicants is not applicable in the instant application. Accordingly, the 35 U.S.C § 101 rejection as set forth in this Office Action stands.
Rejection(s) under 35 U.S.C § 102 Maintained
12) 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 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.
13) The rejection of claims 32, 36, 38, 39, 42 and 43 set forth in paragraph 22 of the Office Action mailed 09/10/25 under 35 U.S.C § 102(a)(2) as being anticipated by Dong et al. (US 20200339636 A1, of record) is maintained.
Applicants refer to claim 1 and assert that the amendments to claim 1 explicitly define the source, structure, and length of the claimed fragment, which is fully supported by the Provisional Application. With regard to the support for the pending claims in the U.S. provisional application 62/851,040 filed 05/21/2019, Applicants state that paragraph [0015] of said provisional application explicitly discloses that SEQ ID NO: 3 corresponds to amino acids 1072-1452 of the Clostridium difficile TcdB holotoxin, identifying both the source (TcdB of C. difficile) and the specific structural region (a defined portion of the translocation domain necessary for pore formation) from which the claimed fragment is derived. With regard to the support for the claim limitation “at least 98% identity to SEQ ID NO: 3”, Applicants refer to paragraph [0016] of U.S. provisional application which recites “an isolated polypeptide comprising at least 375 consecutive amino acids of SEQ ID NO: 3”. Applicants state that because SEQ ID NO: 3 is 381 amino acids in length, a 375-amino-acid fragment necessarily retains at least 98% identity to SEQ ID NO: 3. This is stated as providing direct support for the length and sequence identity requirement recited in claim 1 (“a polypeptide sequence that is at least 98% identical to SEQ ID NO: 3”). With these, Applicants conclude that the Provisional Application provides support for a fragment of the C. difficile TcdB holotoxin having the same source (TcdB of C. difficile), the same structural sequence (SEQ ID NO: 3), and a length that inherently satisfies the claimed "at least 98% identical" limitation and therefore, the pending claims are fully supported by and are entitled to the benefit of U.S. Provisional Application No. 62/851,040, filed May 21, 2019. Applicants state that because the Dong prior art was published less than one year before the effective filing date, the Dong prior art is disqualified or exempt as prior art under 35 U.S.C. § 102(b)(1)(A).
Applicants’ arguments have been carefully considered but are not persuasive.
First, Applicants’ multiple references to the amendments to claim 1 are not understood. Claim 1 is neither a part of the instant rejection, nor a pending claim since Applicants have already canceled claim 1.
Second, with regard to Applicants’ arguments in support of the recitation "at least 98% identical to SEQ ID NO: 3", the mentioning of the single isolated polypeptide species comprising at least 375 consecutive amino acids of SEQ ID NO: 3 does not provide descriptive support for the entire genus of at least 98% identical polypeptide sequence. For instance, the genus of a polypeptide sequence ‘at least 98% identity to SEQ ID NO: 3’ is not limited to the single isolated polypeptide species comprising at least 375 consecutive amino acids of SEQ ID NO: 3, but it also encompasses other at least 98% identical polypeptide fragment species having amino acid substitutions and/or deletions anywhere along the length of SEQ ID NO: 3 (i.e., variants having non-consecutive amino acids of SEQ ID NO: 3), for which there is no support in the provisional application. Additionally, it is noted that the PCT application, PCT/US20/34070, with which instant application has a continuation-in-part relationship, has no support for an isolated polypeptide comprising at least 375 consecutive amino acids of SEQ ID NO: 3. Instant claims are not afforded the effective filing date of the provisional application. The disclosure of Dong et al. as set forth anticipates instant claims.
14) The rejection of claims 32, 36, 38, 39, 42 and 43 set forth in paragraph 23 of the Office Action mailed 09/10/25 under 35 U.S.C § 102(a)(1) and 35 U.S.C § 102(a)(2) as being anticipated by Shone et al. (US 20150093389 A1, of record) is maintained.
Applicants point to the recitation in the amended claim 1 “a fragment of a TcdB holotoxin of Clostridium difficile (C. difficile) wherein the fragment is a polypeptide sequence that is at least 98% identical to SEQ ID NO: 3" and contend that SEQ ID NO: 3 comprises 381 amino acids spanning positions 1072-1452 of the translocation domain (TD) of the TcdB holotoxin. Applicants state that this defined fragment is particularly advantageous due to its smaller size, which improves processability compared to larger fragments. Applicants assert that the isolated immunogenic polypeptides are nontoxic making them safer for use, and can be efficiently produced in E. coli with high yield and purity, reducing costs associated with production, formulation, and storage. Applicants further state that the polypeptide according to SEQ ID NO: 3 maintains its native 3D structure, enabling the formation of a 3D epitope where antibodies bind to amino acids that are spatially clustered, though not contiguous in a linear sequence, which characteristic enhances the effectiveness of the polypeptide in stimulating an immune response as a vaccine. Applicants state that by focusing on a smaller, more precise region of TcdB, these immunogens have the potential to evoke a stronger immune response. Applicants assert that the polypeptide according to SEQ ID NO: 3 contains an epitope recognized by an antibody that potently neutralizes TcdB by preventing pore formation, an indispensable activity during TcdB intoxication. Applicants state that by precisely targeting this functionally vulnerable fragment of TcdB, this immunogen is more efficient at triggering the production of neutralizing antibodies. Applicants contend that immunization with a polypeptide according to SEQ ID NO: 3 (e.g., a non-toxic fragment of C. difficile TcdB) induces high antibody levels in mice and antibody levels are boosted by greater than 3 logs and the immune response is specific against a 381 aa immunogen compared to the full-length toxin, which is 2367 aas. Applicants refer to paragraph [0076] and FIG. 6 and state that the induced antibodies against the polypeptide according to SEQ ID NO: 3 are able to act on the full-length toxin and neutralize its toxicity. Applicants assert that the Shone prior art does not have the aforementioned technical features, i.e., an ".... isolated immunogenic polypeptide that is a fragment of a TcdB holotoxin of C. difficile .... wherein the fragment is a polypeptide sequence that is at least 98% identical to SEQ ID NO: 3..." and thus, cannot achieve what can be achieved by the present invention. Applicants refer to the Abstract of Shone et al., which was never used in the rejection of record, and state that the Shone prior art, at most, focuses on larger polypeptides spanning amino acids 700-1500 from a central domain of a C. difficile holotoxin. Applicants opine that such larger polypeptides, even if they would encompass the shorter amino acid fragment of SEQ ID NO: 3, would nevertheless not be considered as isolated immunogenic polypeptides being at least 98% identical to SEQ ID NO: 3. Applicants refer to the Example section and the figures, specifically Example 7 and FIG. 6 of Shone et al. and contend that the Shone prior art examines fragments spanning amino acids 543-1852 (i.e., a ~1300 amino acid fragment) or amino acids 767-1852 (i.e., a ~1000 amino acid fragment) of a C. difficile Toxin B sequence. Applicants state that although the Shone prior art lists numerous random fragments within the central domain (e.g., residues 542-1849 for Toxin A and residues 543-1851 for Toxin B), SEQ ID NO: 3 is only included in larger sequences (>1000 aa). Applicants further state that the shortest sequences containing SEQ ID NO: 3 listed in the Shone prior art span residues 1074-1852 for C. difficile Toxin B and 1074-1850 for C. difficile Toxin A and that these fragments remain twice the size of the polypeptide presently claimed. Applicants note that while larger fragments of a given antigen can potentially contain multiple epitopes, their utility in practice will be limited because antibodies binding to non-essential parts of the toxin will not be able to effectively neutralize the toxin and will consequently reduce the overall efficiency of the immune response. Applicants state that the short polypeptide according to SEQ ID NO: 3 contains a 3D epitope recognized by a potent neutralizing antibody (SEQ ID NO: 10) and the small size of the isolated polypeptides according to SEQ ID NO: 3 allows for more convenient production, formulation and storage of any vaccine comprising such immunogens. Applicants acknowledge that despite the Shone prior art listing larger sequences that may include SEQ ID NO: 3, these fragments cannot attain the efficacy and specificity of the smaller fragment presently claimed.
Applicants’ arguments have been carefully considered, but are not persuasive.
Again, with regard to Applicants’ reference to the amendments to claim 1, it must be noted that claim 1 is neither a part of the instant rejection, nor a pending claim since Applicants have already canceled claim 1.
First, instant claim(s) are not limited to an isolated immunogenic polypeptide consisting of SEQ ID NO: 3. Second, at least one polypeptide of claim 32 is comprised in an immunogen of claim 36 and in a vaccine of claim 39. As set forth previously, Shone et al. (‘389) disclosed several isolated immunogenic TcdB polypeptide fragments each comprising a polypeptide sequence at least 98% identical to the instantly recited SEQ ID NO: 3. Each of the various exemplary SEQ ID NOs: 10, 12, 13, 18 and 20 disclosed by Shone et al. (‘389) and set forth in the rejection of record is a fragment of a TcdB holotoxin of C. difficile and it reads on and anticipates an immunogen that comprises at least one polypeptide fragment of a sequence that is at least 98% identical to SEQ ID NO: 3. Because these SEQ ID NOs disclosed by Shone et al. (‘389) meet the structural requirements of instant claims, they are expected to necessarily have the epitopes and the functional characteristics of Applicants’ SEQ ID number including immunogenicity and vaccine functions. As set forth previously, Shone et al. (‘389) disclosed an immunizing formulation (i.e., a vaccine) comprising the immunogenic polypeptide fragment, for example, SEQ ID NO: 20 therein. See TABLES 1, 3 and 4; Examples 5 and 6; and claim 4. Shone’s toxin B fragments that are shorter than a TcdB holotoxin of C. difficile were indeed recombinantly expressed and purified. See sections [0154]; and at least Examples 1 and 2. Shone’s polypeptides were formulated as vaccines for human use. See sections [0079], [0080] and [0095]. The rejection as set forth stands.
Applicants’ remarks on the disclosure in the Abstract of Shone et al. are misplaced since the rejection of record does not refer to or use Shone’s abstract. Applicants’ statements on fragments of Shone’s Toxin A are not relevant since instant claims are directed to a TcdB fragment(s).
Rejection(s) under 35 U.S.C § 101
15) 35 U.S.C § 101 states:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
16) Claims 32, 36, 39, 42 and 43 are rejected under 35 U.S.C § 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Instant claim 32, as amended, is directed to an isolated immunogenic polypeptide fragment of a TcdB holotoxin, wherein the fragment comprises a polypeptide sequence that is at least 98% identical to a sequence consisting of SEQ ID NO: 3. The dependent claim 36 is directed to an immunogen comprising at least one polypeptide according to claim 32. The dependent claims 39, 42 and 43 are directed to a vaccine comprising an immunogen having at least one polypeptide according to claim 32. The immunogen of the dependent claim 36 comprising at least one polypeptide of according to claim 32 and ‘an immunogen having at least one polypeptide of according to claim 32’ as recited in claim 39 encompass and read on a full-length TcdB holotoxin of C. difficile since said full-length TcdB holotoxin of C. difficile is a naturally occurring immunogen that comprises therein a polypeptide sequence that is 100% or 99.8% identical to the instantly recited SEQ ID NO: 3. See the sequence alignments (A) and (B) set forth below. Because these elements are composed of matter, at least one embodiment encompassed within the broadest reasonable interpretation (BRI) of instant claims is directed to a statutory category, i.e., a composition of matter (Step 1: YES).
(A)
F6JXY1_CLODI
ID F6JXY1_CLODI 2329 AA.
AC F6JXY1
DT 27-JUL-2011, integrated into UniProtKB/TrEMBL.
DT 27-JUL-2011, sequence version 1.
DT 05-FEB-2025, entry version 42.
DE SubName: Full=TcdB {ECO:0000313|EMBL:ADH94625.1}
DE Flags: Fragment
GN Name=tcdB {ECO:0000313|EMBL:ADH94625.1}
OS Clostridioides difficile (Peptoclostridium difficile).
OC Bacteria; Bacillati; Bacillota; Clostridia; Peptostreptococcales;
OC Peptostreptococcaceae; Clostridioides.
OX NCBI_TaxID=1496 {ECO:0000313|EMBL:ADH94625.1}
RN [1] {ECO:0000313|EMBL:ADH94625.1}
RP NUCLEOTIDE SEQUENCE.
RC STRAIN=CH6223 {ECO:0000313|EMBL:ADH94625.1}
RA Rupnik M., Kocuvan A.
RT "Mutation patterns in Clostridium difficile toxin coding regions.";
RL Submitted (MAR-2010) to the EMBL/GenBank/DDBJ databases.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-threonyl-[protein] + UDP-alpha-D-glucose = 3-O-(alpha-D-
CC glucosyl)-L-threonyl-[protein] + UDP + H(+); Xref=Rhea:RHEA:64684,
CC Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:16656, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30013, ChEBI:CHEBI:58223, ChEBI:CHEBI:58885,
CC ChEBI:CHEBI:156085; Evidence={ECO:0000256|ARBA:ARBA00049101};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64685;
CC Evidence={ECO:0000256|ARBA:ARBA00049101};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000256|ARBA:ARBA00001946};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000256|ARBA:ARBA00001936};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000256|ARBA:ARBA00001947};
CC -!- SUBCELLULAR LOCATION: Host cell membrane
CC {ECO:0000256|ARBA:ARBA00004501}; Peripheral membrane protein
CC {ECO:0000256|ARBA:ARBA00004501}; Cytoplasmic side
CC {ECO:0000256|ARBA:ARBA00004501}. Host cytoplasm, host cytosol
CC {ECO:0000256|ARBA:ARBA00023586}. Host endosome membrane
CC {ECO:0000256|ARBA:ARBA00023585}. Secreted
CC {ECO:0000256|ARBA:ARBA00004613}.
CC -!- SIMILARITY: Belongs to the clostridial glucosylating toxin (LCGT)
CC family. {ECO:0000256|ARBA:ARBA00023607}.
DR EMBL; HM062499; ADH94625.1; -; Genomic_DNA.
DR MEROPS; C80.003; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0044164; C:host cell cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0044175; C:host cell endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0016757; F:glycosyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR CDD; cd20502; C80_toxinA_B-like; 1.
DR FunFam; 2.10.270.10:FF:000003; Toxin B; 2.
DR Gene3D; 1.10.10.1780; -; 1.
DR Gene3D; 1.10.274.80; -; 1.
DR Gene3D; 1.10.3730.30; -; 1.
DR Gene3D; 1.20.58.1190; -; 1.
DR Gene3D; 3.40.50.11050; -; 1.
DR Gene3D; 2.10.270.10; Cholin Binding; 6.
DR InterPro; IPR018337; Cell_wall/Cho-bd_repeat.
DR InterPro; IPR020974; CPD_dom.
DR InterPro; IPR038383; CPD_dom_sf.
DR InterPro; IPR029044; Nucleotide-diphossugar_trans.
DR InterPro; IPR024770; TcdA/TcdB_cat.
DR InterPro; IPR024772; TcdA/TcdB_N.
DR InterPro; IPR024769; TcdA/TcdB_pore_forming.
DR Pfam; PF01473; Choline_bind_1; 4.
DR Pfam; PF19127; Choline_bind_3; 1.
DR Pfam; PF11713; Peptidase_C80; 1.
DR Pfam; PF12919; TcdA_TcdB; 1.
DR Pfam; PF12920; TcdA_TcdB_pore; 1.
DR Pfam; PF12918; TcdB_N; 1.
DR SUPFAM; SSF69360; Cell wall binding repeat; 4.
DR SUPFAM; SSF53448; Nucleotide-diphospho-sugar transferases; 1.
DR PROSITE; PS51771; CGT_MARTX_CPD; 1.
DR PROSITE; PS51170; CW; 1.
PE 3: Inferred from homology;
KW Autocatalytic cleavage {ECO:0000256|ARBA:ARBA00022813};
KW Glycosyltransferase {ECO:0000256|ARBA:ARBA00022676};
KW Host cell membrane {ECO:0000256|ARBA:ARBA00022511};
KW Host cytoplasm {ECO:0000256|ARBA:ARBA00023200};
KW Host endosome {ECO:0000256|ARBA:ARBA00023046};
KW Host membrane {ECO:0000256|ARBA:ARBA00022870};
KW Hydrolase {ECO:0000256|ARBA:ARBA00022801};
KW Lipid-binding {ECO:0000256|ARBA:ARBA00023121};
KW Magnesium {ECO:0000256|ARBA:ARBA00022842};
KW Manganese {ECO:0000256|ARBA:ARBA00023211};
KW Membrane {ECO:0000256|ARBA:ARBA00023136};
KW Metal-binding {ECO:0000256|ARBA:ARBA00022723};
KW Protease {ECO:0000256|ARBA:ARBA00022670};
KW Repeat {ECO:0000256|ARBA:ARBA00022737};
KW Secreted {ECO:0000256|ARBA:ARBA00022525};
KW Thiol protease {ECO:0000256|ARBA:ARBA00022807};
KW Toxin {ECO:0000256|ARBA:ARBA00022656};
KW Transferase {ECO:0000256|ARBA:ARBA00022679};
KW Virulence {ECO:0000256|ARBA:ARBA00023026};
KW Zinc {ECO:0000256|ARBA:ARBA00022833}.
FT DOMAIN 548..755
FT /note="Peptidase C80"
FT /evidence="ECO:0000259|PROSITE:PS51771"
FT REPEAT 1967..1986
FT /note="Cell wall-binding"
FT /evidence="ECO:0000256|PROSITE-ProRule:PRU00591"
FT NON_TER 1
FT /evidence="ECO:0000313|EMBL:ADH94625.1"
FT NON_TER 2329
FT /evidence="ECO:0000313|EMBL:ADH94625.1"
SQ SEQUENCE 2329 AA; 264834 MW; E686A726EFDC47BE CRC64.
Query Match 100%; Score 1934; Length 2329; Best Local Similarity 100%;
Matches 381; Conservative 0; Mismatches 0; Indels 0; Gaps 0.
Qy 1 LTTATTAIITSSLGIASGFSILLVPLAGISAGIPSLVNNELVLRDKATKVVDYFKHVSLV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1052 LTTATTAIITSSLGIASGFSILLVPLAGISAGIPSLVNNELVLRDKATKVVDYFKHVSLV 1111
Qy 61 ETEGVFTLLDDKVMMPQDDLVISEIDFNNNSIVLGKCEIWRMEGGSGHTVTDDIDHFFSA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1112 ETEGVFTLLDDKVMMPQDDLVISEIDFNNNSIVLGKCEIWRMEGGSGHTVTDDIDHFFSA 1171
Qy 121 PSITYREPHLSIYDVLEVQKEELDLSKDLMVLPNAPNRVFAWETGWTPGLRSLENDGTKL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1172 PSITYREPHLSIYDVLEVQKEELDLSKDLMVLPNAPNRVFAWETGWTPGLRSLENDGTKL 1231
Qy 181 LDRIRDNYEGEFYWRYFAFIADALITTLKPRYEDTNIRINLDSNTRSFIVPIITTEYIRE 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1232 LDRIRDNYEGEFYWRYFAFIADALITTLKPRYEDTNIRINLDSNTRSFIVPIITTEYIRE 1291
Qy 241 KLSYSFYGSGGTYALSLSQYNMGINIELSESDVWIIDVDNVVRDVTIESDKIKKGDLIEG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1292 KLSYSFYGSGGTYALSLSQYNMGINIELSESDVWIIDVDNVVRDVTIESDKIKKGDLIEG 1351
Qy 301 ILSTLSIEENKIILNSHEINFSGEVNGSNGFVSLTFSILEGINAIIEVDLLSKSYKLLIS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1352 ILSTLSIEENKIILNSHEINFSGEVNGSNGFVSLTFSILEGINAIIEVDLLSKSYKLLIS 1411
Qy 361 GELKILMLNSNHIQQKIDYIG 381
|||||||||||||||||||||
Db 1412 GELKILMLNSNHIQQKIDYIG 1432
(B)
F6JXY5_CLODI
ID F6JXY5_CLODI 2328 AA.
AC F6JXY5
DT 27-JUL-2011, integrated into UniProtKB/TrEMBL.
DT 27-JUL-2011, sequence version 1.
DT 05-FEB-2025, entry version 42.
DE SubName: Full=TcdB {ECO:0000313|EMBL:ADH94629.1}
DE Flags: Fragment
GN Name=tcdB {ECO:0000313|EMBL:ADH94629.1};
OS Clostridioides difficile (Peptoclostridium difficile).
OC Bacteria; Bacillati; Bacillota; Clostridia; Peptostreptococcales;
OC Peptostreptococcaceae; Clostridioides.
OX NCBI_TaxID=1496 {ECO:0000313|EMBL:ADH94629.1}
RN [1] {ECO:0000313|EMBL:ADH94629.1}
RP NUCLEOTIDE SEQUENCE.
RC STRAIN=IS25 {ECO:0000313|EMBL:ADH94629.1}
RA Rupnik M., Kocuvan A.;
RT "Mutation patterns in Clostridium difficile toxin coding regions."
RL Submitted (MAR-2010) to the EMBL/GenBank/DDBJ databases.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-threonyl-[protein] + UDP-alpha-D-glucose = 3-O-(alpha-D-
CC glucosyl)-L-threonyl-[protein] + UDP + H(+); Xref=Rhea:RHEA:64684,
CC Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:16656, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30013, ChEBI:CHEBI:58223, ChEBI:CHEBI:58885,
CC ChEBI:CHEBI:156085; Evidence={ECO:0000256|ARBA:ARBA00049101}
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64685
CC Evidence={ECO:0000256|ARBA:ARBA00049101}
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000256|ARBA:ARBA00001946}
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000256|ARBA:ARBA00001936}
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000256|ARBA:ARBA00001947}
CC -!- SUBCELLULAR LOCATION: Host cell membrane
CC {ECO:0000256|ARBA:ARBA00004501}; Peripheral membrane protein
CC {ECO:0000256|ARBA:ARBA00004501}; Cytoplasmic side
CC {ECO:0000256|ARBA:ARBA00004501}. Host cytoplasm, host cytosol
CC {ECO:0000256|ARBA:ARBA00023586}. Host endosome membrane
CC {ECO:0000256|ARBA:ARBA00023585}. Secreted
CC {ECO:0000256|ARBA:ARBA00004613}.
CC -!- SIMILARITY: Belongs to the clostridial glucosylating toxin (LCGT)
CC family. {ECO:0000256|ARBA:ARBA00023607}.
DR EMBL; HM062503; ADH94629.1; -; Genomic_DNA.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0044164; C:host cell cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0044175; C:host cell endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0016757; F:glycosyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR CDD; cd20502; C80_toxinA_B-like; 1.
DR FunFam; 2.10.270.10:FF:000003; Toxin B; 2.
DR Gene3D; 1.10.10.1780; -; 1.
DR Gene3D; 1.10.274.80; -; 1.
DR Gene3D; 1.10.3730.30; -; 1.
DR Gene3D; 1.20.58.1190; -; 1.
DR Gene3D; 3.40.50.11050; -; 1.
DR Gene3D; 2.10.270.10; Cholin Binding; 6.
DR InterPro; IPR018337; Cell_wall/Cho-bd_repeat.
DR InterPro; IPR020974; CPD_dom.
DR InterPro; IPR038383; CPD_dom_sf.
DR InterPro; IPR029044; Nucleotide-diphossugar_trans.
DR InterPro; IPR024770; TcdA/TcdB_cat.
DR InterPro; IPR024772; TcdA/TcdB_N.
DR InterPro; IPR024769; TcdA/TcdB_pore_forming.
DR Pfam; PF01473; Choline_bind_1; 4.
DR Pfam; PF19127; Choline_bind_3; 1.
DR Pfam; PF11713; Peptidase_C80; 1.
DR Pfam; PF12919; TcdA_TcdB; 1.
DR Pfam; PF12920; TcdA_TcdB_pore; 1.
DR Pfam; PF12918; TcdB_N; 1.
DR SUPFAM; SSF69360; Cell wall binding repeat; 4.
DR SUPFAM; SSF53448; Nucleotide-diphospho-sugar transferases; 1.
DR PROSITE; PS51771; CGT_MARTX_CPD; 1.
DR PROSITE; PS51170; CW; 1.
PE 3: Inferred from homology;
KW Autocatalytic cleavage {ECO:0000256|ARBA:ARBA00022813};
KW Glycosyltransferase {ECO:0000256|ARBA:ARBA00022676};
KW Host cell membrane {ECO:0000256|ARBA:ARBA00022511};
KW Host cytoplasm {ECO:0000256|ARBA:ARBA00023200};
KW Host endosome {ECO:0000256|ARBA:ARBA00023046};
KW Host membrane {ECO:0000256|ARBA:ARBA00022870};
KW Hydrolase {ECO:0000256|ARBA:ARBA00022801};
KW Lipid-binding {ECO:0000256|ARBA:ARBA00023121};
KW Magnesium {ECO:0000256|ARBA:ARBA00022842};
KW Manganese {ECO:0000256|ARBA:ARBA00023211};
KW Membrane {ECO:0000256|ARBA:ARBA00023136};
KW Metal-binding {ECO:0000256|ARBA:ARBA00022723};
KW Protease {ECO:0000256|ARBA:ARBA00022670};
KW Repeat {ECO:0000256|ARBA:ARBA00022737};
KW Secreted {ECO:0000256|ARBA:ARBA00022525};
KW Thiol protease {ECO:0000256|ARBA:ARBA00022807};
KW Toxin {ECO:0000256|ARBA:ARBA00022656};
KW Transferase {ECO:0000256|ARBA:ARBA00022679};
KW Virulence {ECO:0000256|ARBA:ARBA00023026};
KW Zinc {ECO:0000256|ARBA:ARBA00022833}.
FT DOMAIN 547..754
FT /note="Peptidase C80"
FT /evidence="ECO:0000259|PROSITE:PS51771"
FT REPEAT 1966..1985
FT /note="Cell wall-binding"
FT /evidence="ECO:0000256|PROSITE-ProRule:PRU00591"
FT NON_TER 1
FT /evidence="ECO:0000313|EMBL:ADH94629.1"
FT NON_TER 2328
FT /evidence="ECO:0000313|EMBL:ADH94629.1"
SQ SEQUENCE 2328 AA; 265241 MW; F61395A6CFFD11AF CRC64;
Query Match 99.8%; Score 1930; Length 2328; Best Local Similarity 99.5%;
Matches 379; Conservative 2; Mismatches 0; Indels 0; Gaps 0.
Qy 1 LTTATTAIITSSLGIASGFSILLVPLAGISAGIPSLVNNELVLRDKATKVVDYFKHVSLV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1051 LTTATTAIITSSLGIASGFSILLVPLAGISAGIPSLVNNELVLRDKATKVVDYFKHVSLV 1110
Qy 61 ETEGVFTLLDDKVMMPQDDLVISEIDFNNNSIVLGKCEIWRMEGGSGHTVTDDIDHFFSA 120
||||||||||||:|||||||||||||||||||||||||||||||||||||||||||||||
Db 1111 ETEGVFTLLDDKIMMPQDDLVISEIDFNNNSIVLGKCEIWRMEGGSGHTVTDDIDHFFSA 1170
Qy 121 PSITYREPHLSIYDVLEVQKEELDLSKDLMVLPNAPNRVFAWETGWTPGLRSLENDGTKL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1171 PSITYREPHLSIYDVLEVQKEELDLSKDLMVLPNAPNRVFAWETGWTPGLRSLENDGTKL 1230
Qy 181 LDRIRDNYEGEFYWRYFAFIADALITTLKPRYEDTNIRINLDSNTRSFIVPIITTEYIRE 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1231 LDRIRDNYEGEFYWRYFAFIADALITTLKPRYEDTNIRINLDSNTRSFIVPIITTEYIRE 1290
Qy 241 KLSYSFYGSGGTYALSLSQYNMGINIELSESDVWIIDVDNVVRDVTIESDKIKKGDLIEG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1291 KLSYSFYGSGGTYALSLSQYNMGINIELSESDVWIIDVDNVVRDVTIESDKIKKGDLIEG 1350
Qy 301 ILSTLSIEENKIILNSHEINFSGEVNGSNGFVSLTFSILEGINAIIEVDLLSKSYKLLIS 360
|||||||||||||||||||||||:||||||||||||||||||||||||||||||||||||
Db 1351 ILSTLSIEENKIILNSHEINFSGDVNGSNGFVSLTFSILEGINAIIEVDLLSKSYKLLIS 1410
Qy 361 GELKILMLNSNHIQQKIDYIG 381
|||||||||||||||||||||
Db 1411 GELKILMLNSNHIQQKIDYIG 1431
Clearly, the polypeptide as claimed is a naturally occurring product. The claimed product does not fall within at least one of the four categories of patent eligible subject matter because the instant claims read on a product of nature. Thus, for at least one embodiment encompassed within the broadest reasonable interpretation (BRI), the claimed immunogenic polypeptide does not display markedly different characteristics compared to the naturally occurring element or counterpart. Accordingly, the claimed product is a ‘product of nature’ exception, and the claims are directed to a judicial exception (Step 2A Prong One: YES). Judicial exceptions include all natural products including those derived from natural sources such as naturally occurring pathogens found in or derived therefrom, or from nature. This is the case regardless of whether particular words such as ‘isolated’, ‘purified’, ‘recombinant’, or ‘synthetic’ are recited in the claim(s). Next, the claims as a whole are analyzed to determine whether any additional element, or a combination of elements, is sufficient to ensure that the claims amount to significantly more than the exceptions. No additional elements are present with the claimed polypeptide sequence. The claims as a whole do not recite additional elements that integrate the recited judicial exception into a practical application of the judicial exception (Step 2A, Prong 2: NO). The claims as a whole do not include additional elements that are sufficient to amount to significantly more than the judicial exception (Step 2B: NO). The term ‘vaccine’ in claims 39, 42 and 43 is an intended use of the claimed product. A recitation of the intended use of the claimed invention must result in a marked structural difference between the claimed invention and the prior art in order to patentably distinguish it from a product of nature. The immunogenicity or the vaccine characteristic of the claimed polypeptide in the composition is the handiwork of nature and is inseparable therefrom. Therefore, the claims are not directed to a patent eligible subject matter.
The rationale for this determination is formed in view of the 2019 PEG, the 2015 Update of the 2014 Interim Guidance on Patent Subject Matter Eligibility (79 FR 4618) (hereafter Interim Eligibility Guidance) dated 16 December 2014, the Life Sciences Examples issued in May 2016, and in view of Myriad v Ambry, CAFC 2014-1361, -1366, 17 December 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012). The unpatentability of natural products was confirmed by the U.S. Supreme Court in Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U. S. (June13, 2013).
Conclusion
17) No claims are allowed.
Correspondence
18) Any inquiry concerning this communication or earlier communications from the Examiner should be directed to S. Devi, Ph.D., whose telephone number is (571) 272-0854. A message may be left on the Examiner’s voice mail system. The Examiner is on a flexible work schedule, however she can normally be reached Monday to Friday from 7.00 a.m. to 4.00 p.m. (EST). If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's Supervisor, Gary Nickol, can be reached at (571) 272-0835. The fax phone number for the organization where this application or proceeding is assigned (571) 273-8300.
19) Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center or the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
/S. DEVI/
S. Devi, Ph.D.Primary Examiner
Art Unit 1645
February, 2026