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 .
DETAILED ACTION
The preliminary amendment filed 12/12/2022 is entered. Claims 10-11 and 18 are canceled. Claims 1-9, 12-17 and 19-23 are pending.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-9, 12 and 15) in the reply filed on 12/05/2025 is acknowledged. The traversal is on the ground(s) that the special technical feature of elected Group I is present and in common with Groups II and IV, and for this reason Groups II and IV should be rejoined. See the last paragraph on page 2 and the second paragraph on page 3 of the remarks filed 12/05/2025. This is not found persuasive because the technical feature of a sialoglycan-binding probe is not a special technical feature as it does not make a contribution over the prior art in view of Srivastava (2019). As such, Groups I-IV lack unity a posterori as set forth in the requirement for restriction/election mailed on 08/27/2025.
The requirement is still deemed proper and is therefore made FINAL.
Claims 13-14, 16-17, and 19-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Accordingly, claims 1-9, 12 and 15 are under consideration in this action.
Priority
The instant claims are entitled to an effective filing date of 06/12/2020.
Information Disclosure Statement
A list of references spans pages 58-77 of the specification filed 12/12/2022. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
The specification recites the amino acid sequence “YTRY” (4aa) without a sequence identifier. This sequence can be found throughout the specification, including: on page 1 in line 20, on page 2 in line 15, on page 4 in line 19, on page 7 in line 12, and on page 10 in line 2.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Figure 4D includes 6 amino acid sequences without sequence identifiers. To obviate this objection, figure 4D or the description thereof can be amended to include the following identifiers: Hsa (SEQ ID NO: 1), NCTC (SEQ ID NO: 2), SK679 (SEQ ID NO: 3), SrpA (SEQ ID NO: 4), GspB (SEQ ID NO: 5), and SK150 (SEQ ID NO: 6)
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Drawings
The black and white drawings filed 12/12/2022 are objected to under 37 CFR 1.83(a) because they fail to show:
“Hsa-like adhesins (blue)” in page 3 line 22;
“GspB-like adhesins (green)” page 3 line 23;
“S. mitis SF100 adhesin (magenta)” page 3 line 24;
“blue” and “red” page 3 line 30;
“cyan” and “blue” page 4 line 1;
“green” and “light green” page 4 line 2;
“blue” and “green” page 4 line 13;
“tan”, “green”, “blue” and/or “yellow” page 4 lines 19-20 and 27-28;
“red” page 5 lines 1, 9 and 16 and page 6 line 18;
“navy” page 5 line 2;
“light green” page 5 lines 4, 8 and 11-12;
“blue” page 5 line 16;
“green, blue, yellow”, “cyan”, “salmon”, “red” page 7 lines 11-14;
“red”, “blue, “blue-gray”, “green”, “purple” and “lavender” page 7 lines 19-22.
“dark blue”, “red”, “blue”, “transparent green” page 7 lines 25-31;
“red, orange, yellow and green, where red” see page 8 lines 11-22; and
“blue”, “green” and “yellow” page 8 lines 7-8
as described in the specification filed 12/12/2022. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
On page 3 in line 29 “Fgiures” should be replaced with “Figures”.
On page 4 in line 5 the specification recites “UB10712 (also referred to as NCTC10712)” and it is unclear whether “NCTC” in figures 4A and 4D is the same as NCTC10712. To obviate this objection, either the recitation “UB10712 (also referred to as NCTC10712)” can be replaced with “UB10712 (also referred to as NCTC10712 or NCTC)”, or Figures 4A and 4D can be amended to replace “NCTC” with “NCTC10712”.
On page 4 in lines 11-12 the specification recites “Figure 4C shows sequence alignment of the Siglec domain of SRR adhesins”. However, this description applies to Figure 4D, not 4C. Therefore, “Figure 4C” in line 11 of page 4 should be replaced with “Figure 4D”.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites the motif “YTRY” in line 2, which should be identified with a sequence identifier number (SEQ ID NO) because the motif sequence has 4 specifically defined and enumerated amino acids.
Appropriate correction is required.
Examiner Comment
“Siglec-like serine-rich repeat adhesin” is an art recognized term. Sialic acid binding immunoglobulin-like lectin (Siglec)-like adhesins are found within the larger family of serine-rich repeat (SRR) adhesins, as evidenced by Bensing (bioRxiv 796912; 2019; as provided with the IDS filed 03/22/2023). See the right column on page 1. Therefore, a Siglec-like adhesin is considered a serine-rich adhesin. Siglec-like adhesins are bacterial adhesins that are structurally similar to mammalian Siglecs. See page 12 line 28 to page 13 line 4 of the instant specification. Siglec-like SRR adhesins include tandem Siglec and Unique domains. See figure 2 and paragraph 12 on page 3. The CD, EF and FG loops are in the variable(V)-set Ig fold of an adhesin. See figure 4D of the instant specification.
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 1-9, 12 and 15 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 claims contain 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, at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a genus of adhesins that bind to sialoglycan. Claim 1 requires the adhesin to be a sialic acid binding immunoglobulin-like lectin (Siglec)-like serine-rich (SRR) repeat adhesin comprising a YTRY motif and a mutation in the CD, EF, or FG loop in the variable(V)-set Ig fold. Besides the YTRY motif, the amino acid sequence of the Siglec-like SRR adhesin is not limited. As such, the claims encompass a variety of mutant sequences. Although dependent claims 3, 5 and 7 recite point mutations, the recited mutations are not particularly limited because the adhesin protein sequence required to be mutated is not limited. Claims 8, 9 and 12 limit the sialoglycan to which the probe binds without providing any additional structural limitation associated with such binding. Claim 15 requires the probe to be chimeric, such that it includes the CD, EF, or FG loop of Hsa. However, the structure of the non-loop regions is not limited in anyway. The specification does not disclose a representative number of species of the claimed genus by reduction to practice, and does not provide adequate guidance with regard to the structural features of the adhesin that is required to provide the recited sialoglycan-binding properties. Therefore, one of skill cannot immediately envision which adhesins will have the required functional characteristics, and one could not conclude that Applicant was in possession of the claimed genus of adhesins at the time the filing, as discussed more fully below.
For claims drawn to a genus, MPEP § 2163(3)(a)(ii) indicates 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, reduction to drawings, 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 applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant specification teaches mutating 5 Siglec-like adhesins sequences including: Hsa (Hsasiglec+unique (SEQ ID NO: 1)) from Streptococcus gordonii strain Challis, Hsa-like adhesin from S. gordonii strain UB10712 (UB10712siglec+unique (SEQ ID NO: 2)), Hsa-like adhesin from S. sanguinis strain SK678 (SK678siglec+unique (SEQ ID NO: 3)), GspB adhesin from S. gordonii strain M99 (GspBsiglec+unique (SEQ ID NO: 5)) and GspB-like adhesin from S. gordonii strain SK150 (SK150siglec+unique (SEQ ID NO: 6)). See table 4, figure 4D and paragraphs 63-64 on pages 22-23. As shown in table 4, the specification teaches the following relevant Hsasiglec+unique mutations: D356Q, D356R and L363G in the FG loop, N333P in the EF loop, and G287A/G288P and E286R mutations in the CD loop. The specification teaches that the N333P and the G27A/G288P mutations exhibit significant reduction in binding. See page 40 paragraph 138. The specification teaches mutating UB10712--siglec+unique at E285R in the CD loop, and Q354D in the FG loop. See NCTC of figure 4D for the UB10712 sequence. The specification teaches mutating SK678siglec+unique at E302R and at Q371D, which may be in the CD loop and FG loop respectively but it is unclear because the SK678 sequence in figure 4D does not include E at position 302 or Q at position 371. The specification teaches L442Y/Y443N mutations in the CD loop of GspB siglec+unique, and Y300L/N301Y mutations in the CD loop of SK150 siglec+unique. Furthermore, the specification teaches chimeric UB10712--siglec+unique and SK678siglec+unique adhesins with the CD, EF and/or FG loops of Hsa, and the chimeric GspBsiglec+unique adhesin with the CD, EF and/or FG loops of SK150 siglec+unique. Thus, the specification reduces to practice a total of 30 mutations across the CD, EF and FG loops of 5 different Siglec-like adhesins, which represents a fraction of the potential possible mutations encompassed by the claims.
MPEP 2163(3)(a)(ii) states that “the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation. Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date”. Considering the lack of guidance provided in the specification, one would appraise support from the state of the art to extrapolate the correlation between the Siglec-like serine-rich structure of the adhesin and the sialoglycan-binding function.
With respect to the state of the art on Siglec-like SRR adhesins, Bensing (bioRxiv 796912; 2019) teaches that the sequences of Siglec-like adhesins are quite variable, as are the host sialoglycans to which they bind. See the first full paragraph on page 2. Bensing teaches that the YTRY motif is located on the F-strand of the V-set Ig fold and contributes to binding. However, the role of the three loops [CD, EF and FG] in glycan affinity and selectivity is unknown. See paragraph spanning pages 2-3. Stubbs (J Biol Chem. 2020 Oct 23;295(43):14737-14749; as cited in the IDS filed 03/22/2023), a past filing date reference, teaches that streptococcal Siglec-like adhesins hydrogen-bond with sialic acid via a semiconserved YTRY sequence motif. The Thr-Arg makes multiple key side-chain hydrogen-bonding contacts to the sialic acid of host sialoglycan, and therefore appears to be the most important residues for binding. However, Stubbs also suggests that sialoglycan binding and selectivity are affected by the three adjacent loops of high sequence diversity. See the left column on page 14738. Stubbs acknowledges that the function of the unique domain in the Siglec-like SRR adhesins is unknown. See the last sentence on page 14737. Stubbs teaches a binding region from S. sanguinis SK1 that differs structurally from Siglec-containing binding regions in that it contains two copies of the Siglec and Unique domains. Stubbs discloses that the SK1 binds to sialoglycans. See the last paragraph on page 14738 and the third paragraph on page 14739. Thus, Siglec-like SRR adhesins are structurally diverse. Although Bensing and Stubbs suggest that the semiconserved YTRY motif is essential for sialoglycan binding, the references also acknowledge that the motif alone may not be the only contributing factor of sialoglycan binding.
With respect to the state of the art on the sialoglycans to which Siglec-like SRR adhesins bind, Bensing teaches that in oral streptococci, Siglec-like adhesins bind to carbohydrates containing a terminal Siaα2-3Gal (i.e. α2,3 sialoglycan) See the right column on page 1. Stubbs teaches that Tyr of the YTRY motif contributes to α2,3-sialoglycan binding. See the first paragraph on page 14738. Bensing and Stubbs are silent regarding bacterial Siglec-like adhesins that bind to α2,6 sialoglycan. Bensing(2004) (Infect Immun 72; as cited in the IDS filed 03/22/2023) teaches that GspB facilitates binding to carbohydrates bearing sialic acid in either α(2-3) or α(2-6) linkages, with a slight preference for α(2-3) linkages. See the abstract. However, Bensing(2004) discloses that S. gordonii DL1 Challis could bind to sialic acid configured in α(2-3), but not α(2-6), linkages and that binding to α(2-3)-linked sialic acid was dependent on the expression of Hsa. See the first paragraph of the results section.
As evidenced by Stubbs, to date, the extent to which other structures, besides the YTRY motif, impact sialoglycan binding is unknown. Considering the structural diversity amongst Siglec-like SRR adhesins, as evidenced by Bensing and Stubbs, one skilled in the art at the time of filing could not have reasonably predicted which mutated adhesins would be capable of sialoglycan binding based solely on the YTRY structure. The instant specification reduces to practice 30 mutations across the CD, EF and FG loops of 5 different Siglec-like adhesins. This represents a small fraction of the possible number of species within the breadth of the claims. Each of claims 8, 9 and 12 requires a distinct sialoglycan selectivity, each correlated with different amino acid substitutions according to Bensing; yet, the claims encompass a broader genus of adhesin structures than Applicant could have reasonably been in possession of.
In view of the prior art, the instant disclosure does not satisfy the written description requirement because the species disclosed do not adequately represent the substantial variation within the claimed genus. As discussed above, the breadth of potential structures embraced by the claims is substantial.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3, 5, 7, and 9 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.
Claims 3, 5, and 7 are indefinite because the claims recite substitutions and position numbers without providing the reference sequence. Specifically, claim 3 recites “the mutation in the CD loop comprises a E285R, E286R, G287A, G288P, E298R, L442Y and/or Y443N substitution”. However, it is unclear which CD loop sequence is being referenced in claim 3. Claim 5 recites “the mutation in the EF loop comprises a N333P substitution”, but the sequence of the EF loop is not defined. Claim 7 recites “the FG loop comprises a Q345D, D356Q, D356R, and/or L363G substitution”, but the FG loop sequence is not set forth in the claim. As such, it is unclear which sequences claims 3, 5 and 7 intend to reference.
Claim 9 depends from claim 5 and is rejected for the reason set forth above.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
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.
Claims 1-9 and 12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product, which is a judicial exception, without significantly more. Each step described below is in reference to the subject matter eligibility test for products and processes (MPEP 2106).
Claim 1 recites a “sialoglycan-binding probe” in line 1. Therefore, claims 1-9, 12 and 15 are directed to a composition of matter, which is one of the statutory categories (Step 1:Yes).
Claim 1 recites an “engineered sialoglycan-binding probe comprising a Siglec-like serine-rich repeat adhesin comprising a YTRY motif and a mutation in the CD, EF, or FG loop in the V-set IG fold”. The term “engineered” does not limit the structure of the claimed probe product in anyway. As such, the claim requires a Siglec-like SRR adhesin comprising a YTRY motif and any natural or unnatural mutation in the CD, EF, or FG loop. As explained by evidentiary reference Fares (Trends in Microbiology, 2025), lectins are found in all biological systems. See the first paragraph on page 839. Fares discloses that the GspB, HSA, SrpA, HSA-like, and SK1 lectins are Siglec-like adhesins from Streptococcus gordonii, S. sanguinis and S. mitis. See table 2. Fares teaches that Streptococci exploit the mutability of these adhesins through genetic recombination. See the last passage on page 842. Furthermore, Bensing(2022) (Nature Communications, 2022 13(1), 2753) teaches that the CD, EF and FG loops are regions with the largest natural sequence variation. Natural evolutionary changes in Siglec-like binding region (SLBR) sequences might involve point mutations. See the last passage on page 7. Furthermore, in figure 4, Bensing (2022) teaches the conserved YTRY motif. Compared to closest naturally occurring counterpart, there is no structural difference between the natural product (i.e. the naturally mutated Siglec-like adhesins) and the instantly claimed product. Because there is no indication in the record that the instantly claimed probe has a markedly different characteristic in structure, function, or other properties as compared to its natural counterpart the claims are directed to a natural-product, which is a judicial exception (Step 2A Prong 1: Yes).
The additional claimed elements separately and accumulatively fail to integrate the product of nature into practical application. Claims 1, 2, 4 and 6 do not include any additional elements besides the natural product. Although claims 2, 4 and 6 specifically require a mutation in the CD, EF or FG loop respectively, the claims do not limit the structure of that mutation in anyway. Therefore, the claims encompass the natural sequence variations amongst the CD, EF and FG loops. Claim 3 requires the mutation in the CD loop to comprise a E285R, E286R, G287A, G288P, E298R, L442Y and/or Y443N substitution. However, these substitutions are recited with a high level of generality, because the starting sequence of the CD loop is not limited or specified in the claim. Therefore, claim 3 provides insufficient specificity to add anything of significance to the judicial exception because at best the claim merely implies that the composition can contain point mutations of E to R, G to A, G to P, L to Y, or Y to N in the CD loop region. Similarly, claim 5 requires the EF loop mutation to comprise a N333P substitution, and claim 7 requires the FG loop mutation to comprise a Q354D, D356Q, D356R and/or L363G substitution. However, claims 5 and 7 do not specify which sequence(s) is/are being referenced. Therefore, claims 3, 5 and 7 cannot integrate the judicial exception into a practical application because the claims may merely be describing the natural sequence variations. Claims 8, 9 and 12 limit the sialoglycans to which the probe binds. Claim 8 requires the probe to have binding selectivity for α2,3 sialoglycans. However, the instant specification teaches that streptococci contain Siglec-like bacterial adhesins that selectively recognize α2,3 sialoglycans. See page 14 lines 3-4. Claim 9 requires the probe to selectively bind to tri-and/or tetra-saccharides, 6S-sLex or 6’S-sLex. However, table 4 of the instant specification indicates that wild-type Hsasiglec+unique, UB10712siglec+unique, and SK678siglec+unique bind 6S-sLex. See pages 30-31. Furthermore, claim 12 requires the probe to have binding selectivity for α2,6 sialoglycans. However, the specification suggests that any probe of table 4 binds to α2,6 sialoglycans, and table 4 includes wild-type adhesins, e.g. Hsasiglec+unique. See page 3 line 5 and table 4. As such, claims 8, 9 and 12 do not add any elements to the natural product judicial exception because the claims merely describe the natural binding properties of Siglec-like adhesins. Accumulatively, the additional limitations in claims 1-9 and 12 do not impose any meaningful limitation over the nature based judicial exception, so the claim as a whole is not integrated into a practical application (Step 2A Prong 2: No).
The additional elements fail to amount to an inventive concept. Bensing (2019, as referenced above) teaches adhesin variants with mutations including Hsasiglec+unique variants with mutations that include: L363G, D356Q and D356R in the FG loop, N333P in the EF loop, and G287A/G288P and E286R in the CD loop. NCTC10712--siglec+unique mutations including E285R in the CD loop, and Q354D in the FG loop. GspB siglec+unique mutations including L442Y/Y443N in the CD loop. SK150 siglec+unique mutations including Y300L/N301Y in the CD loop. See table S3 of Bensing. Thus, the additional mutation elements of instant claims 3, 5 and 7 were well-known in the at the time of filing (Step 2B: No).
Claim Interpretation
Claim 1 is a sialoglycan-binding probe comprising a Siglec-like serine-rich repeat adhesin comprising a YTRY motif and a mutation in CD, EF or FG loop of the V-set Ig fold. The mutations in the CD, EF and FG loops are not limited, and encompass any natural or unnatural sequence variations within the loops. In other words, the instantly claimed CD, EF and/or FG loop sequences need to be changed as compared to any other CD, EF and/or FG loop sequence respectively.
In claim 9, 6S-sLex is 6-sulfated sialyl-Lewis X where the sulfate at carbon 6 of GlcNAc, whereas in 6’S-sLex the sulfate is at carbon 6 of galactose.
Claim 12 requires the probe to bind to α2,6 sialoglycan. According to the instant specification the probes disclosed in table 4 bind to such sialoglycans. These probes include wild-type and mutant Hsa, NCTC, SK678, SrpA, GspB and SK150; the mutations in table 4 include point mutations identical to that of instant claims 3, 5 and 7. See page 3 lines 4-5 and table 4. As such, α2,6 sialoglycan binding is considered to be inherent to Hsa, NCTC, SK678, SrpA, GspB and SK150, absent evidence to the contrary.
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.
Claims 1-9, 12 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bensing (bioRxiv 796912v1, published 10/07/2019; IDS 12/12/2022).
[AltContent: textbox (Table S3 and Figure S4D of Bensing)]Regarding claim 1, Bensing teaches bacterial Siglec-like serine-rich (SRR) adhesins from S. gordonii Challis (Hsa), S. mitis NCTC10712, S. sanguinis SK678, S. gordonii M99 (GspB) and S. sanguinis SK150. See figure S2. In table S3, Bensing teaches adhesin variants. Amongst these variants, Bensing teaches the following Hsasiglec+unique mutations: L363G, D356Q and D356R in the FG loop, N333P in the EF loop, and G287A/G288P and E286R in the CD loop. Bensing teaches the following NCTC10712--siglec+unique mutations: E285R in the CD loop, and Q354D in the FG loop. Bensing teaches GspB siglec+unique L442Y/Y443N mutations in the CD loop, and SK150 siglec+unique Y300L/N301Y mutations in the CD loop. Bensing also teaches replacing the one or all of the CD, EF and FG loops of NCTC10712--siglec+unique, SK678siglec+unique and GspB siglec+unique.
Regarding claim 2, Bensing teaches the following CD loop mutations: G287A/G288P and E286R in Hsa, E285R in NCTC10712--siglec+unique, L442Y/Y443N in GspB siglec+unique and Y300L/N301Y in SK150 siglec+unique. See table S3 and figure S4D.
Regarding claim 3, Bensing teaches E285R, E86R, G287A/G288P,and L442Y/Y443N substitutions in the CD loop. See table s3 and figure S4D.
Regarding claims 4-5, Bensing teaches a N333P mutation in the EF loop of Hsasiglec+unique. See table S3 and figure S4D.
Regarding claim 6, Bensing teaches the following FG loop mutations: L363G, D356Q and D356R in Hsasiglec+unique, and Q354D in NCTC10712--siglec+unique. See table S3 and figure S4D.
Regarding claim 7, Bensing teaches Q354D, D356Q, D356R, and L363G. See table S3 and figure S4D.
Regarding claim 8, Bensing teaches that HsaSiglec+Unique binds detectably to a broad range of Siaα2-3Galβ1-3/4HexNAc glycans (i.e. α2,3 sialoglycan). See the last passage in the left column on page 2. Furthermore, Bensing teaches that the GspBL442Y/Y443N shows increased binding to 3’sLn (i.e. an α2,3 sialoglycan). See the first passage on page 4 and table S3. Furthermore, the NCTC10712Q345D variant becomes more selective for 3’sLn. See the second paragraph on page 4.
Regarding claim 9, Bensing teaches that the CD loop variants of NCTC10712Siglec+Unique and SK678Siglec+Unique become highly selective for 6S-sLeX via a substantial increase in binding for this sulfated tetrasaccharide and a decrease in binding to other glycans. See the second paragraph on page 4 and Figs. 5A and 5B. Furthermore, the HsaE286R, HsaD356R, and HsaD356Q variants show increased binding to 6S-sLeX compared to wild-type. See the second and third paragraph on page 4, figures 5A, 5B, and S11.
Regarding claim 12, Bensing teaches Hsa, NCTC10712, SK678, GspB and SK150 adhesins. See figure S2 and the sequences in figure S4D. Furthermore, Bensing teaches the adhesin variants, as discussed above. Bensing is silent regarding the α2,6 sialoglycan binding ability of the adhesin variants. However, MPEP 2112.01(I) states that “[w]here the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established”. In the instant case, Bensing teaches Siglec-like variants that are structurally identical to the claimed probes, so α2,6 sialoglycan binding is inherent.
Regarding claim 15, Bensing teaches engineering chimeras with the backbone of one adhesin and the loops of a closely-related adhesins. Bensing teaches NCTC10712HSA-Loops, SK678HSA-Loops, SK678HSA-CD-Loop , SK678HSA-EF-Loop SK678HSA-FG-Loop, NCTC10712HSA-CD-Loop, NCTC10712HSA-EF-Loop, NCTC10712HSA-FG-Loop. See the first paragraph in the right column on page 3 and table S3.
Claims 1, 2, 4, 6, and 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bensing2 (Glycobiology 2016 Nov;26(11):1222-1234; IDS 03/22/2023).
Regarding claim 1, Bensing2 teaches the Siglec-like binding region (BR) sequences of GspB, Hsa, 10712 and SK678, all of which include the YTRY motif. See figure 3. Bensing2 teaches that the BR of GspB consists of Cna, Siglec and Unique domains. The Y443 (i.e. a residue in the CD loop of GspB) residue is in the Siglec domain. Bensing2 teaches deleting each domain. See the last passage on page 1222.
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[AltContent: textbox (Edited version of figure 3(B) of Bensing(2016) to show the CD Loop)]Regarding claim 2, Bensing2 teaches deleting each domain of GspB. Bensing discloses that the Y443 residue (i.e. in the CD loop) is in the Siglec domain. See the last passage on page 1222. Furthermore, in figure 3(B), Bensing2 teaches a sequence alignment between GspB, Hsa, 10712 and SK678. The thick box in the image below shows the sequence variations between the CD loops of different Siglec-like BRs.
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[AltContent: textbox (Edited version of figure 3(B) of Bensing(2016) to show the EF Loop)]Regarding claim 4, in figure 3(B), Bensing2 teaches a sequence alignment between GspB, Hsa, 10712 and SK678. The thick box in the image below shows the sequence variations between the EF loops of different Siglec-like BRs.
Regarding claim 6, in figure 3(B), Bensing2 teaches a sequence alignment between GspB, Hsa, 10712 and SK678. The thick box in the image below shows the sequence variations between the FG loops of different Siglec-like BRs.
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[AltContent: textbox (Edited version of figure 3(B) of Bensing(2016) to show the FG Loop)]
Regarding claim 8, Bensing2 teaches that Hsa has high affinity for multiple glycans with terminal α2–3-linked sialic acids. See the last passage in the left column on page 1226.
Regarding claim 9, Bensing2 teaches that SK678BR and NCTC10712BR bind to 6S-sLex. See the right column on page 1229.
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657