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 instant claims are entitled to an effective filing date of 06/12/2020.
Claims 2-7, 10-11 and 18 are canceled. Claims 1, 8-9, 12-17 and 19-23 are pending. Claims 13-14, 16-17, and 19-23 are withdrawn from consideration as being drawn to a non-elected invention.
Claims 1, 8-9, 12, and 15 are under consideration in this action.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “SEQID” in line 3, which should be replaced with “SEQ ID”.
Claim 15 recites “YTRY” in line 2, which should be replaced with “YTRY (SEQ ID NO: 7)” because the motif should be identified with its sequence identification number.
Appropriate correction is required.
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, 8-9, 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 repeat adhesin comprising a YTRY (SEQ ID NO: 7) motif and a mutation in the CD, EF, or FG loop in the variable(V)-set Ig fold relative to SEQ ID NO: 1; SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6; wherein the mutation in the CD loop comprises a E285R, E286R, G287A, G288P, E298R, L442Y, and/or Y443N substitution; wherein the mutation in the EF loop comprises a N333P substitution; and wherein the mutation in the FG loop comprises Q354D, D356Q, D356R, and/or L363G substitution. Claim 1 does not substantially limit the structure of the required siglec-like serine-rich repeat (SRR) adhesin because the claim only limits 7 residues of the siglec-like SRR adhesin as a whole, i.e. 4 residues for the YTRY motif (SEQ ID NO: 7), 1 residue in the CD loop, one residue in the EF loop and one residue in the FG loop. As such, the claims encompass a variety of mutant sequences. 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 (SEQ ID NO: 7) and CD, EF, and FG point mutation 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.
Response to Arguments
Applicant's arguments filed 08/04/2026 have been fully considered but they are not persuasive.
35 U.S.C. 112(a)
Applicant argues that the amendment to claim 1 obviates the rejection. See p. 7 para. 5.
This argument is not persuasive because claim 1, as amended, encompasses a genus of adhesins. The instant specification reduces to practice mutating Hsasiglec+unique (SEQ ID NO: 1), UB10712siglec+unique (SEQ ID NO: 2), SK678siglec+unique (SEQ ID NO: 3), GspBsiglec+unique (SEQ ID NO: 5) and SK150siglec+unique (SEQ ID NO: 6), i.e. mutating sequences that are 100% identical to SEQ ID NOs: 1,2, 3, 5 and 6. See table 4 on pgs. 31-32 of the specification as filed 08/04/2026. Claim 1, as amended, limits 7 residues of the Siglec-like SRR adhesin amino acid sequence, but claim 1 does not require the amino acid sequence as a whole to be identical or similar to SEQ ID NOs: 1, 2, 3, 5 or 6 in anyway (i.e. the reduced to practice sequences). Therefore, besides the required YTRY motif (SEQ ID NO: 7) and recited point mutations, the Siglec-like SRR adhesin structure is not limited.
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 1, 8-9, and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, as amended, is indefinite because the claim recites substitutions and position numbers without providing the reference sequence. Claim 1 recites “mutations in the CD, EF, or FG loop of the V-set Ig fold relative to SEQ ID NO: 1; SEQ ID NO: 2, SEQID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6; wherein the mutation in the CD loop comprises E285R, E286R, G287A, G288P, E298R, L442Y and/or Y443N substitution; wherein the mutation in the EF loop comprises a N333P substitution; and wherein the mutation in the FG loop comprises a Q354D, D356Q, D356R, and/or L363G substitution” in lines 3-7. It is unclear whether the recited mutations refer to the residue positions of SEQ ID NO: 1, 2, 3, 4, 5, or 6. Only the EF loop of Hsa (SEQ ID NO: 1) includes the recited N333 residue. The CD loop of Hsa (SEQ ID NO: 1) also includes the E286, G287, and G288 residues, but Hsa (SEQ ID NO: 1) does not include any of the other recited residues in the CD loop. Furthermore, the FG loop of Hsa (SEQ ID NO: 1) includes the Q354 residue but Hsa (SEQ ID NO: 1) does not include any of the other recited FG loop residues. As such, it is unclear which residues are required to be mutated.
Claims 8-9, and 12 depend from claim 1 and are rejected for the reason set forth above.
Response to Arguments
35 U.S.C. 112(b)
Applicant's arguments filed 08/04/2026, with respect to the rejection under 35 U.S.C. 112(b), have been fully considered but they do not apply to the new grounds of rejection set forth above.
35 U.S.C. 102(a)(1)
The declaration under 37 CFR 1.130(a) filed 08/04/2026 has disqualified Bensing (bioRxiv 796912v1, published 10/07/2019; IDS 12/12/2022) as prior art under 102(a)(1), because the declaration establishes that the subject matter disclosed in Bensing was obtained directly or indirectly from the inventors of the application, and the declaration provides a reasonable explanation of the additional author’s involvement with the journal article.
Applicant’s arguments, see the remarks the paragraph bridging pgs. 8-9, filed 08/04/2026, with respect to the rejection of claims 1-9, 12 and 15 under 35 U.S.C. 102(a)(1) as being anticipated by Bensing have been fully considered and are persuasive. Applicant asserts that the declaration under 37 USC 1.130 disqualifies Bensing as a prior art reference (paragraph bridging pgs. 8-9).
Accordingly, the rejection of claims 1-9, 12 and 15 under 35 U.S.C. 102(a)(1) as being anticipated by Bensing is withdrawn.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657
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