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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3-9, 11-12, 14-36, 38-61, and 73-75 were previously pending in the instant application.
Claims 44-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Receipt of the claim amendments filed 10 February, 2026 is acknowledged. Claims 7, 25, 33, 35, 36, 51, and 53 are cancelled. Claims 1, 3-6, 8, 9, 11, 12, 14-18, 21-24, 27, 34, 38, 48-50, 52, 55-61, 73, and 75 are amended. Claims 1, 54, 57, and 73 are independent claims.
Applicant’s election without traverse of the species of HEK293E cells and the species of SEQ ID NO: 23 in the reply filed on 16 June, 2025 was previously acknowledged. SEQ ID NO: 23 was indicated as free of the prior art of record in the non-final rejection mailed 10 September, 2025. Therefore, the species election over the species of FimH sequences is hereby withdrawn.
Therefore, claims 1, 3-6, 8-9, 11-12, 14-24, 26-32, 34, 38-43, 46-50, 52, 54-61, and 73-75 are pending and under examination in the instant Official Action of which claims 73-74 were previously indicated as allowed in the non-final rejection mailed 10 September, 2025.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/IB2020/060081, filed 28 October, 2020, which claims priority to United State Provisional Application Nos. 63081629, filed 22 September, 2020, 63045038, filed 26 June, 2020, and 62929505 filed 01 November, 2019. Acknowledgment is made of applicant’s claim for priority.
It is noted that the acknowledgement of a claim for foreign priority under 35 U.S.C. 119 (a)-(d) in the non-final rejection mailed 10 September, 2025 was incorrect. Applicant has not asserted a foreign priority claim.
The earliest possible priority for the instant application is 01 November, 2019.
Drawings
The drawings submitted on 28 April, 2022 are accepted by the Examiner.
Withdrawn Objections/Rejections in view of Applicant’s Amendments/Arguments
Claim Objections
The objection to claims 1, 7, 24, 25, 27-28, 34, 35, and 57 for containing Abbreviations/acronyms not spelled out upon their first encounter in the claims is withdrawn in view of Applicant’s amendments to the claims. Applicant has cancelled or else spelled out all abbreviations/acronyms.
The objection to claim 53 has been rendered moot by Applicant’s cancelling of claim 53.
Claim Interpretation
Independent claim 1 is directed to a recombinant mammalian cell. The recitation of “wherein the recombinant mammalian cells in culture express more grams of mutant FimH polypeptide per liter of cultured cells as compared to the grams of wild type FimH polypeptide expressed by wild-type E. coli cells per liter of cultured cells” in the claim is a property of the product claimed. It is noted that where 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 re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). Thus, for the purpose of applying prior art, a disclosure of an identical or substantially identical product is presumed to inherently possess the claimed properties. See MPEP 2112.01. The same is noted of the properties recited in instant claims 26, 38, and 46.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 3-6, 8-9, 11-12, 14-24, 26-32, 34, 38-43, 46-50, 52, 54-61, and 75 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 is withdrawn in view of Applicant’s amendments to the claims.
Applicant has amended claim 1 to require that the mutant FimH be a FimH polypeptide having 95% identity to SEQ ID NO: 2, wherein the polynucleotide encoding the FimH further encode a heterologous signal sequence, as well as requiring that the recombinant mammalian cells express more grams of the FimH than the level of expression of wild-type FimH in wild type E. coli. Thus, “derived from” is sufficiently definite as recited in the claims.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 3-6, 8-9, 11-12, 17-18, 21-35, 38-43, 46-47, 52, 54-58, and 60-61 under 35 U.S.C. 103 as being unpatentable over WO 02/04496 A2 (hereinafter “Medimmune”) (of record) in view of Hartmann et al. European Journal of Organic Chemistry 2011.20‐21 (2011): 3583-3609. (hereinafter “Hartmann”), Sauer et al. Nature communications 7.1 (2016): 10738. (hereinafter “Sauer”) (of record: IDS filed 15 November, 2022), Kober et al. Biotechnology and bioengineering 110.4 (2013): 1164-1173., WO2011/053281 (hereinafter “Chen”), Mauro et al. BioDrugs 32.1 (2018): 69-81. (hereinafter “Mauro”), and Dyson et al. Advanced technologies for protein complex production and characterization (2016): 217-224. (hereinafter “Dyson”) is withdrawn in view of Applicant’s amendments to the claims.
Applicant has amended claim 1 to require “the mutant polypeptide does not comprise an N-glycosylation site at a position selected from the group consisting of position N7, position N235, and position N228” and “the mutant FimH polypeptide has at least 95% sequence identity to the sequence of SEQ ID NO: 2”. Medimmume does not teach a polypeptide which falls within amended claim 1. Hartmann, Sauer, Kober, Mauro, Chen, and Dyson do not teach such a polypeptide either.
Maintained Rejections in view of Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 112
Claims 1, 3-6, 8-9, 14-16, 19-24, 26-33, 34, 38-43, 46-50, 52, 54-58, and 60-61 remain rejected and claims 11-12, and 17-18 are newly 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 claim(s) contains 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection has been modified as necessitated by Applicant’s amendments to the claims.
The amended claims are broadly directed to a genus of recombinant mammalian cells comprising a genus of polynucleotides encoding mutant Fimbrial H (FimH) polypeptides wherein the mutant polypeptides do not comprise an N-glycosylation site at a position selected from the group consisting of position N7, position N235, and position N228, wherein the mutant FimH polypeptide has at least 95% sequence identity to the sequence of SEQ ID NO: 2, further encoding a heterologous signal sequence and wherein the cells possess the function of increased expression in the mammalian cells relative to the periplasm of a wild-type E. coli cell. Dependent claims set forth specific point mutations within FimH but none of these claims further specifies the sequence surrounding said mutations other than that the total sequence is a FimH polypeptide. None of the instant claims tie a corresponding structure within the mutant FimH polypeptides to the function claimed. Thus, the instant claims lack a structure-function relationship between the FimH polypeptides and the increased expression in mammalian cells.
Applicants are claiming an undefined number of polypeptides having 95% identity to SEQ ID NO: 2 and having the function of increased expression in mammalian cells relative to the expression of wild type FimH in a wild-type E. coli cell. The specification teaches that “recombinant production of FimH remains challenging” and that “protein expression and purification is not a routine process” (Specification, [0009]). The specification teaches wild-type J96 strain FimH with and without the native leader sequence (SEQ ID NO: 1 and 2 respectively), and teaches 4 versions of this FimH sequence with leader sequences (SEQ ID NO: 5-8) (5-6 being mutants and 7-8 being “fragments”) and the corresponding, mature versions of those versions lacking a leader sequence (SEQ ID NO: 20, 23-24, and 26) (Specification, [0047]). The mutations in the specific 2 mutants taught correspond with the mutations claimed and they are all taught as mutations on the base, J96, sequence (Specification, [0047]). Thus, the specification only teaches four specific versions of FimH wherein 2 of the versions are J96 strain FimH possessing several defined mutations. The specification does not teach any mutations other than those possessed within SEQ ID NOs: 5-6 nor any specific “fragments” other than those taught in SEQ ID NOs: 7-8. The working examples teach that N-terminal processing for FimH with the native leader was not shown in EXP1293 HEK cells (Specification, [0416]-[0421]). The working examples reference Figures 4-6 but these figures merely show SDS-PAGE results without any clear analysis of differential expression between mammalian cells and wild-type E. coli cells (Specification, [0423]-[0427]). Thus, it is unclear which of the 8 versions of FimH taught in the specification actually have the increased expression in mammalian cells function claimed.
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 inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). Further, 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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). See MPEP 2163(II)(A)(3)(a)(ii).
In disclosing only two mutants of FimH and only two “fragments” of FimH, applicant has not disclosed a representative number of species for the entire genus claimed because the claimed genus covers species in which the mutants of FimH differ by 17 of the 330 total amino acid residues and the “fragments” of FimH differ by 10 of the 188 amino acid residues. A skilled artisan would understand that any protein having a substitution of 10 or 17 amino acids in a 188 or 330 amino acid long sequence to a contiguous stretch of prolines would cease to have much in common with the unsubstituted variant, and that the same can be said for amino acids having large aliphatic side chains like tryptophan, and that such FimH variants would have an unpredictable expression level in culture. Hence, the structure/function correlation of a polypeptide is unpredictable, and a skilled artisan would recognize that the vast genus claimed as elected encompasses FimH polypeptides whose claimed function would be hindered if not abolished by specific amino acid substitutions.
The skilled artisan understands that one nucleotide change in a DNA molecule or one amino acid change in the polypeptide encodes by the DNA molecule could result in loss of it’s biological activity as demonstrated in the generation of sickle-cell anemia wherein one specific amino acid mutation gives rise to the inherited disease (Voet et al., Biochemistry, John Wiley and Sons, 1990, p. 126-129). Further, the skilled artisan also understands that the significance of particular amino acids within a peptide cannot be predicted a priori but must be determined from case to case by painstaking experimental study (Rudinger, J., Peptide Hormones. Palgrave, London, 1976. 1-7. (Page 6, “Conclusions”)) and that it is not known whether there exists an algorithm for predicting the structure of a given protein from its amino acid sequence alone (Ngo et al., The protein folding problem and tertiary structure prediction. Boston, MA: Birkhäuser Boston, 1994. 433-506. (page 492, second full paragraph)). The specification is silent as to what residues outside of the specific few mutations taught can be changed while still retaining increased expression in mammalian cells let alone how much of a FimH can be changed while still retaining the classification as a FimH polypeptide. Thus, a skilled artisan would understand from the teachings of Voet, Rudinger, and Ngo that the results of changing any given amino acid within SEQ ID NO: 5-8, 20, 23-24, and 26 outside of the specific mutations taught within said sequences would be unpredictable and that it would require significant experimentation to determine which variants of these polypeptides would still possess the claimed function.
The claims encompass any FimH polypeptide with 95% sequence identity to SEQ ID NO: 2. SEQ ID NO 2 is 330 amino acids long. That 5 percent variance results in a situation in which if a 17 contiguous amino acid region were independently varied among the 20 different naturally occurring amino acids, there would be 1.31 x 1022 (2017 ) different possible molecules. In fact, since variations could occur anywhere within SEQ ID NO: 2, the actual number of different molecules encompassed by the claims is orders of magnitude higher than 2017. For the “fragments” (SEQ ID NO: 7-8), that 5 percent variance results in a situation in which if a 10-contiguous amino acid region within SEQ ID NO: 7-8 were independently varied among the 20 different naturally occurring amino acids, there would be 1.02 x 1013 (2010 ) different possible molecules. In fact, since variations could occur anywhere within SEQ ID NO: 7-8 and the claims are not even limited to a fragment of any particular length, the actual number of different molecules encompassed by the claims is orders of magnitude higher than 2010. Computer software may provide means for identification of such element, but it is not itself an adequate written description of the structure of the claimed invention. Thus, Applicant has not disclosed a representative number of species for the entire genus of sequences claimed.
Response to Arguments
Applicant argues that amended claim 1 “recites numerous structural and sequence limitations with regard to FimH polypeptide and the polynucleotide encoding the same. Furthermore, Applicant has demonstrated the connection between these structural limitations and increased expression of the FimH polypeptide”. Applicant points to Examples 2, 4, 6, and 8 for support for these arguments (Remarks, at page 12). These arguments have been fully considered but have not been found persuasive for the following reasons.
As discussed in the above rejection, the specification does not teach any mutations other than those possessed within SEQ ID NOs: 5-6 nor any specific “fragments” other than those taught in SEQ ID NOs: 7-8. The working examples teach that N-terminal processing for FimH with the native leader was not shown in EXP1293 HEK cells (Specification, [0416]-[0421]). The working examples reference Figures 4-6 but these figures merely show SDS-PAGE results without any clear analysis of differential expression between mammalian cells and wild-type E. coli cells (Specification, [0423]-[0427]). Thus, it is unclear which of the 8 versions of FimH taught in the specification actually have the increased expression in mammalian cells function claimed. To any extent a structure/function relationship may be established, it appears to only be with the specific 2 mutant FimH (SEQ ID NOs: 5-6) and the specific fragments (SEQ ID NOs: 7-8) exemplified in the specification because these are the only species of FimH polypeptides of which Applicant has provided any meaningful exemplification of their relative expression in mammalian cells. Thus, Applicant’s arguments have been fully considered but have, respectfully, not been found persuasive.
Conclusion
Claims 1, 3-6, 8-9, 11-12, 14-24, 26-33, 34, 38-43, 46-50, 52, 54-58, and 60-61 are rejected.
Claim 59 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Allowable Subject Matter
Claims 73-75 are allowed.
The following is an examiner’s statement of reasons for allowance:
SEQ ID NOs: 5, 6, 7, 8, 20, 23, 24, and 26 are all free of the prior art of record.
The closest sequence to instant SEQ ID NO: 5 is reference SEQ ID NO: 140 found in US2024-0115688 (see below). This reference is not prior art because it was filed after the effective filing date of the claimed invention.
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The closest sequence to instant SEQ ID NO: 6 is reference SEQ ID NO: 140 found in US2024-0115688 (see below). This reference is not prior art because it was filed after the effective filing date of the claimed invention.
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The closest sequence to instant SEQ ID NO: 7 is reference SEQ ID NO: 33 found in US2024-0115688 (see below). This reference is not prior art because it was filed after the effective filing date of the claimed invention.
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406
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The closest sequence to instant SEQ ID NO: 8 is reference SEQ ID NO: 34 found in US2024-0115688 (see below). This reference is not prior art because it was filed after the effective filing date of the claimed invention.
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The closest sequence to instant SEQ ID NO: 20 is reference SEQ ID NO: 515 from US 63345610. The reference sequence and the instant sequence are a 100% match but the reference is not prior art because it was filed after the effective filing date of the claimed invention.
The closest sequence to instant SEQ ID NO: 23 is disclosed in WO0204496. This reference is prior art to the claimed invention but the sequences are not a 100% match (see below).
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503
636
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The closest sequence to instant SEQ ID NO: 24 is reference SEQ ID NO: 1 found in US20030027979 (see below). This reference is prior art but the sequences are not a 100% match.
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339
649
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The closest sequence to instant SEQ ID NO: 26 is reference SEQ ID NO: 40 found in US20020150587. This reference is prior art but the sequences are not a 100% match (see below).
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Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MARIA G LEAVITT can be reached at 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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