DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 02/24/2026 is acknowledged. Claims 1-4,19-25,27 and 29 were cancelled. Claims 5,7,13,14,18 and 28 were amended.
Applicant elected Group 3 (Claims 5-18 and 28) in the reply filed on 09/10/2025 and the election has been treated as an election without traverse (MPEP § 818.01(a)). Applicant canceled the non-elected claims.
Applicant elected SEQ ID NO: 48 for Species C in the reply filed on 09/10/2025 and has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 5-18 and 28 are pending and under examination.
Priority
This application is a 371 of PCT/EP2021/066224, filed 06/16/2021, and claims benefit of EP 20305662.7, filed 06/17/2020.
Withdrawn Objections and Rejections
Applicant’s arguments, see page 6, filed 02/24/2026, with respect to the objections to the abstract, drawings, claims 5 and 7, and the 35 U.S.C. 112(b) rejection of claims 13,14 and 18 have been fully considered and are persuasive due to the amendments to the abstract, drawings and respective claims correcting the issues. The objections to the abstract, drawings and claims, and 35 U.S.C. 112(b) rejection of claims 13,14 and 18 has been withdrawn.
New Rejections-Necessitated by Amendment
Claim Rejections - 35 USC § 112
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 5-18 and 28 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 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 5-18 and 28 introduce new matter as the claims recite the limitation: “wherein the TcpP polypeptide does not include a cytoplasmic domain”. There is no support in the specification for this limitation. The limitation of: “wherein the TcpP polypeptide does not include a cytoplasmic domain”, was not described in the specification as filed, and person skilled in the art would not recognize in the applicant' s disclosure a description of the invention as presently claimed. Applicant states on page 7 of the response that as shown on page 5 of the application, SEQ ID NO: 1 provides the sequence for TcpP including the cytoplasmic, transmembrane and periplasmic domains. As discussed in lines 17-18 of page 5, the polypeptide of the invention includes only the transmembrane and periplasmic domains (see also Figure 1 where the cytoplasmic domain is shown in the normal V. cholerae TcpP peptide but it is replaced with CadC in an example fusion peptide of the invention).
The examiner believes Applicant intended to point to page 4 of the as-filed specification rather than page 5. Page 4, lines 17-18 say, “In particular, the TcpP protein comprises a transmembrane domain and a periplasmic sensing domain. An exemplary amino acid sequence of TcpP is shown as SEQ ID NO: 1”. Disclosing that the TcpP protein comprises a transmembrane domain and a periplasmic sensing domain is not the same as saying the TcpP protein does not include a cytoplasmic domain. The specification uses “comprises” and therefore is not limited to only including a transmembrane domain and a periplasmic domain and can include other components and sequences. In addition, the sequence shown as SEQ ID NO: 1 says that the transmembrane domain is indicated in bold, italic and underlined. The periplasmic sensing domain is indicated in bold and double underlined. There is no indication in this sequence what portion of SEQ ID NO: 1 is the cytoplasmic domain. The only other mention of a cytoplasmic domain in the disclosure is on page 5 and pertains to CadC transcriptional activator, “Specifically, CadC is composed of a C-terminal periplasmic pH-sensing domain, a single transmembrane helix and an N-terminal cytoplasmic winged helix-turn-helix DNA binding domain”, and “Thus the expression of “E. coli CadC transcriptional activator DNA binding domain” refers to the cytoplasmic domain of CadC that is capable of restoring its function via oligomerization of its C-terminal fusion domain” (page 5, lines 10-17). Therefore, there is no mention in regards to TcpP and its cytoplasmic domain or lack thereof.
It is also not clear from Fig. 1 that there is no cytoplasmic domain, either in the Figure itself or the description of the figure on page 33 of the as-filed specification. The description states ”schematic diagram of isolation and rewiring the bile salt sensing module-transmembrane and periplasmic domain of TcpP and TcpH from pathogen V. cholerae into modularized E. coli synthetic receptor platform. The sensing domain TcpP detecting bile salts is plugged into a synthetic receptor which activates GFP expression when bile salts are present”. Nothing in this shows or indicates there is no cytoplasmic domain of TcpP. Disclosing that the TcpP comprises a transmembrane and periplasmic domain does not exclude the cytoplasmic domain. One of ordinary skill in the art would not recognize based on this disclosure that the TcpP polypeptide does not include a cytoplasmic domain as the amended claims now recite. MPEP 2173.05(i) pertaining to negative limitations states that “The mere absence of a positive recitation is not basis for an exclusion”. This part of the MPEP makes it clear that a positive recitation can provide basis for a negative limitation. However, as stated above, the specification does not include a positive recitation of a cytoplasmic domain within the TcpP polypeptide.
Therefore, it is the Examiner' s position that the disclosure does not reasonably convey that the inventor had possession of the subject matter of the amendment at the time of filing of the instant application.
Maintained Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 5-8,12,13 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al. (ACS Synthetic Biology, Published 25 Sept 2017; 7, pages 166-175) in view of Haas et al. (Molecular Microbiology, Published online 4 Nov 2014, 96(1), 4-13), Hase et al. (Proc Natl Acad Sci U.S.A. 20 Jan 1998; 95(2): 730-734), and GenBank Accession Number: ACK75639.1 (24 July 2016).
Claim Interpretation: The language in claim 5, “wherein the TcpP polypeptide has a sequence as set forth in SEQ ID NO: 34 wherein…” is being interpreted as open ended claim language. There is no definition in the specification regarding “has a sequence”, and is therefore being interpreted as “having” or “comprising” rather than “consists of”. In addition, dependent claim 9 recites wherein the linker consists of the amino acid sequence as set forth in SEQ ID NO: 46”, thereby supporting that “has” is open claim language.
The instant specification defines TcpP as the toxin coregulated pilus biosynthesis protein P of Vibrio cholerae, and which is a transmembrane transcription factor, and it has been shown that a set of bile salts cause dimerization of the transmembrane transcription factor TcpP by inducing intermolecular disulfide bonds in its periplasmic domain, and in particular the TcpP protein comprises a transmembrane domain and a periplasmic sensing domain (page 4, lines 14-19).
Regarding amended claim 5, based on the broadest reasonable interpretation, the claim does not exclude the cytoplasmic domain from the fusion protein, just from the TcpP polypeptide claimed as having a sequence set forth in SEQ ID NO: 34, which is amino acids 1-79 of SEQ ID NO: 34. Therefore, SEQ ID NO: 34 is defined as the TcpP polypeptide in claim 5, and therefore, art that teaches the same sequence as SEQ ID NO: 34 still reads on the claim as amended, even if it is part of a larger sequence, as the additional sequences can read on other components of the fusion protein. The claims do not require a particular order or arrangement of the components of the fusion protein, and can include additional sequences in addition to what is claimed.
Regarding claims 5-7, Chang et al. taught bacterial biosensors have been widely used for environmental monitoring but are now being translated into the field of healthcare to detect pathological biomarkers and diagnose diseases (Page 166, left column, first paragraph). Chang et al. taught synthetic receptors should use versatile ligand binding domains (LBDs) for which recognition specificity can be easily programmed for various applications, and therefor aimed at designing a modular bacterial receptor platform using single-domain antibodies as LBDs and following several specifications: (i) receptor activation controls gene expression, so that synthetic gene networks can be connected to ligand detection for further signal processing (ii) the receptor mechanism is scalable so that several orthogonal receptors can be designed following the same principle; and (iii) the receptor system can be applied to engineer either cytosolic sensors (for membrane permeable molecules) or transmembrane receptors (for detection of ligands in the extracellular environment (pages 166-167).
Chang et al. taught on page 167,
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Chang et al. taught an engineered transmembrane receptor comprising CadC-VHH fusion proteins (page 169, left column and Figure 3A).
Chang et al. does not teach that the fusion protein comprises a TcpP polypeptide wherein the TcpP polypeptide does not include a cytoplasmic domain, and wherein the TcpP polypeptide has a sequence as set forth in SEQ ID NO: 34 wherein X47 represents N,D,W,Y,T,V or F, X48 represents Y or F; X49 represents E,G,V,I,L,S or K; X50 represents Q,V,H,A,T,D, L or S.
However, before the effective filing date, Haas et al. taught that TcpP fusion proteins were known in the art. Haas et al. taught the V. cholerae virulence pathway involves an unusual transcription step: the bitopic inner-membrane proteins TcpP and ToxR activate toxT transcription, however the molecular mechanisms by which membrane-localized activators engage the transcription process has yet to be uncovered in live cells, and therefore report examining the dynamics of TcpP proteins in live V. cholerae cells (Abstract). Haas et al. taught a TcpP-PamCherry fusion expressed from an arabinose-inducible promoter in V. cholerae, for use in visualization and localization studies and that the protein fusion is functional in V. cholerae and that the labeled system is comparable to the wild-type system which as a fully functional ToxR regulon (Results, page 5).
Additionally, Hase et al. taught the amino-terminal region of TcpP shows sequence homology to the DNA-binding domains of several regulatory proteins, including ToxR from V. cholerae and PsaE from Yersinia pestis. Like ToxR, TcpP activates transcription of the toxT gene, an essential activator of tcp operon transcription (Abstract). Hase et al. taught a model where both ToxR/S and TcpP/H are involved in sensing various environmental and internal stimuli and are required for the production of TCP in V. cholerae by cooperating in the activation of the toxT promoter. Both TcpP and ToxR appear to be homologous membrane regulatory proteins (page 734, left column).
Haas et al. and Hase et al. do not teach wherein the TcpP polypeptide does not include a cytoplasmic domain, and wherein the TcpP polypeptide has a sequence as set forth in SEQ ID NO: 34 wherein X47 represents N,D,W,Y,T,V or F, X48 represents Y or F; X49 represents E,G,V,I,L,S or K; X50 represents Q,V,H,A,T,D, L or S.
Before the effective filing date, the GenBank Accession Number: ACK75639.1 was publicly available and taught the sequence of toxin co-regulated pilus biosynthesis protein P of Vibrio cholerae shown below.
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Sequence-to-sequence alignment of the above sequence of ACK75639.1 with instant SEQ ID NO: 34 is shown below wherein Qy is instant SEQ ID NO: 34 and Db nucleotides 143-221 of ACK75639.1:
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Therefore, before the effective filing date, GenBank Accession Number: ACK75639.1 taught a TcpP polypeptide that has a sequence as set forth in instant SEQ ID NO: 34 wherein X47 represents N, X48 represents Y, X49 represents E, and X50 represents Q. As stated in the claim interpretation section above, claim 5 does not recite that the fusion protein does not include a cytoplasmic domain, and the claim defines the TcpP polypeptide as SEQ ID NO: 34 (amino acids 1-79 of SEQ ID NO: 34). Therefore, this art teaches the identical sequence of the TcpP polypeptide that is claimed. The amino acids of positions 1-142 of GenBank Accession Number: ACK75639.1 can be included as an additional sequence that is part of the fusion protein.
Regarding claim 8, Chang et al. taught an engineered transmembrane receptor comprising CadC-VHH fusion proteins composed of CadC DBD, CadC juxtamembrane domain (JM), the Leu(16) transmembrane region, CadC wild type external linker region, and the VHH LBDs (page 169, left column and Figure 3A).
Chang et al. taught optimizing the transmembrane receptor signal-to-noise ratio through linkers engineering, and that the best results were obtained using the CadC variant incorporating the full length JM and no external linker, which displayed a significant reduction of self-activation (page 170, left column). Chang et al. taught this data demonstrate that the response properties of synthetic transmembrane receptors can be optimized by varying the amino acid sequences of receptor linker regions (page 170, right column).
Regarding claim 12, Chang et al. taught sequences for CadC and VHHs are provided in the supporting information and that all constructs were cloned into the low-copy plasmid pSB4K5 (Materials and Methods, page 172). Therefore, Chang et al. taught a polynucleotide encoding the fusion protein.
Regarding claim 13, Chang et al. taught placing the expression of the CadC-VHH fusion protein under control of the pLacO1 promoter (page 169, left column, Figure 3B).
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Regarding claims 15-17, Chang et al. taught using E. coli as a model system, both transmembrane and cytosolic receptors were engineered using a VHH for ligand detection and demonstrate the scalability of the platform by using DNA binding domains of two different transcriptional regulators, and provide a method to optimize receptor behavior by finely tuning protein expression levels and optimizing interdomain linker regions and the deployment of these receptors into various hosts to detect ligands for which no receptor is found in nature (Abstract). Chang et al. taught plasmids encoding the different receptors were transformed into chemically competent E. coli NEB10β (page 172, right column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have substituted the VHH portion of the fusion protein of Chang et al. with a TcpP polypeptide that has a sequence of instant SEQ ID NO: 34 as taught by GenBank Accession Number: ACK75639.1, according to the teachings of Hase et al. and Haas et al. with a reasonable expectation of success. There would be a reasonable expectation of success as this would have amounted to simple substitution of one known element for another to obtain predictable results, and because GenBank Accession Number: ACK75639.1 taught the same amino acid sequence of the TcpP polypeptide as required by instant claim 5. One of ordinary skill in the art would have been motivated to do so because Chang et al. provides the motivation for further modification of their synthetic receptors, as Chang et al. taught that synthetic receptors should use versatile ligand binding domains (LBDs) for which recognition specificity can be easily programmed for various applications and the receptor mechanism is scalable so that several orthogonal receptors can be designed following the same principle; and (iii) the receptor system can be applied to engineer either cytosolic sensors (for membrane permeable molecules) or transmembrane receptors (for detection of ligands in the extracellular environment (pages 166-167). Haas et al. taught a TcpP-PamCherry fusion for use in visualization and localization studies, and Hase et al. taught a model where both ToxR/S and TcpP/H are involved in sensing various environmental and internal stimuli and are required for the production of TCP in V. cholerae by cooperating in the activation of the toxT promoter (page 734, left column).
Accordingly, the limitations of claims 5-7,12 and 13 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to provide the modified fusion protein of Chang et al., Haas et al., Hase et al. and GenBank Accession Number: ACK75639.1 with the TcpP polypeptide fused via a linker to the CadC polypeptide based on the teachings of Chang et al. with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so because Chang et al. taught CadC fusion proteins with various linkers and taught optimizing the transmembrane receptor signal-to-noise ratio through linkers engineering (page 170, left column), and the data demonstrates that the response properties of synthetic transmembrane receptors can be optimized by varying the amino acid sequences of receptor linker regions.
Accordingly, the limitations of claim 8 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to provide a prokaryotic host cell, which is Escherichia coli genetically engineered with the polynucleotide encoding the modified fusion protein of Chang et al., Haas et al., Hase et al. and GenBank Accession Number: ACK75639.1 with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so because Chang et al. taught using E. coli as a model system, that CadC-VHH fusion proteins were engineered for ligand detection and demonstrate the scalability of the platform by using DNA binding domains of two different transcriptional regulators including CadC and taught plasmids encoding the different receptors were transformed into chemically competent E. coli NEB10β (page 172, right column).
Accordingly, the limitations of claims 15-17 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., Haas et al., Hase et al. and GenBank Accession Number: ACK75639.1 as applied to claims 5-8,12,13 and 15-17 above, and further in view of GenBank Accession Number: AEJ59541.1 (04 Nov 2011).
Claim Interpretation: Regarding claim 9, the examiner is interpreting “consists of” in claim 9 as requiring that sequence to be present with no additions/substitutions within that sequence, and that since the fusion protein recites “comprises”, these claims do not exclude additional amino acids from being present in the fusion protein.
The teachings of Chang et al., Haas et al., Hase et al., and GenBank Accession Number: ACK75639.1 as applicable to claims 5-8,12,13 and 15-17 have been described above.
Regarding the linker, Chang et al. taught an engineered transmembrane receptor comprising CadC-VHH fusion proteins composed of CadC DBD, CadC juxtamembrane domain (JM), the Leu(16) transmembrane region, CadC wild type external linker region, and the VHH LBDs (page 169, left column and Figure 3A).
Chang et al. taught optimizing the transmembrane receptor signal-to-noise ratio through linkers engineering (page 170, left column), and that the response properties of synthetic transmembrane receptors can be optimized by varying the amino acid sequences of receptor linker regions (page 170, right column).
Chang et al., Haas et al., Hase et al., and GenBank Accession Number: ACK75639.1 (TcpP) do not teach a linker as set forth in SEQ ID NO: 46, or that the fusion protein comprises the amino acid sequence as set forth in SEQ ID NO: 47 or SEQ ID NO: 48.
However, before the effective filing date, the amino acid sequence of transcriptional activator CadC [Escherichia coli] of GenBank Accession No: AEJ59541.1 was publicly available. A Blast search of instant SEQ ID NO: 46 resulted in a 100% match of amino acids 1-48 of SEQ ID NO: 46 to amino acids 108-155 of transcriptional activator CadC [Escherichia coli] of GenBank Accession No: AEJ59541.1
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The amino acid sequence of GenBank Accession No: AEJ59541.1 is shown below:
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Therefore, GenBank Accession No: AEJ59541.1 taught the amino acid sequence as set forth in instant SEQ ID NO: 46 as there are no additions/substitutions within that sequence taught by GenBank that corresponds to all of the amino acids of SEQ ID NO: 46.
It would have been obvious to one of ordinary skill in the art, to combine the CadC transcriptional activator DNA binding domain of Chang et al., the transcriptional activator CadC [Escherichia coli] of GenBank Accession No: AEJ59541.1, and the TcpP of GenBank Accession Number: ACK75639.1 to form a fusion protein to arrive at instant claim 9 with a reasonable expectation of success. There would be a reasonable expectation of success, as this would have amounted to combining known elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Chang et al. taught an engineered transmembrane receptor comprising CadC-VHH fusion proteins composed of CadC DBD, CadC juxtamembrane domain (JM), the Leu(16) transmembrane region, CadC wild type external linker region, and the VHH LBDs (page 169, left column and Figure 3A), and taught optimizing the transmembrane receptor signal-to-noise ratio through linkers engineering (page 170, left column), and that the response properties of synthetic transmembrane receptors can be optimized by varying the amino acid sequences of receptor linker regions (page 170, right column). Since Chang et al. taught using a CadC linker region for the engineered transmembrane receptor biosensor and taught optimization by varying the amino acid sequence of receptor linker regions, an ordinary artisan would have been motivated to try any known CadC amino acid sequence, including that of CadC [Escherichia coli] of GenBank Accession No: AEJ59541.1, in order to provide an optimized linker for use in the engineered receptor biosensor.
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., Haas et al., Hase et al., GenBank Accession Number: ACK75639.1 and GenBank Accession Number: AEJ59541.1 (04 Nov 2011) as applied to claim 9 above, and further in view of GenBank HAI8857886.1 (Publicly available 28 April 2020).
Claim Interpretation: Claims 10-11 recite “comprises the amino acid sequence”, and therefore additional amino acids can be present in the sequence. It is noted that an alignment between sequences showed that instant SEQ ID NO: 45 (CadC) corresponds to amino acids 1-107 of instant SEQ ID NOs: 47 and 48, instant SEQ ID NO: 46 (the linker) corresponds to amino acids 108-155 of instant SEQ ID NOs: 47 and 48, and instant SEQ ID NO: 34 (TcpP) corresponds to amino acids 156-234 of instant SEQ ID NOs: 47 and 48.
The teachings of Chang et al., Haas et al., Hase et al., GenBank Accession Number: ACK75639.1 (TcpP), and GenBank Accession Number: AEJ59541.1 (transcriptional activator CadC [Escherichia coli]) as applicable to claim 9 has been described above.
Chang et al., Haas et al., Hase et al., GenBank Accession Number: ACK75639.1(TcpP), and GenBank Accession Number: AEJ59541.1 (transcriptional activator CadC [Escherichia coli]) do not teach the fusion protein comprises the amino acid sequence as set forth in SEQ ID NO: 47 or SEQ ID NO: 48.
As noted in the claim interpretation section above, instant SEQ ID NOs: 45,46 and 34 make up instant SEQ ID NOs: 47 and 48.
A Blast search of instant SEQ ID NO: 45 resulted in a 100% match to DNA-binding transcriptional activator CadC [E. coli].
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The sequence of CadC of GenBank HAI8857886.1 was publicly available before the effective filing date and is shown below:
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The alignment of instant SEQ ID NO: 45 and the sequence of GenBank HAI8857886.1 is shown below:
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to use the publicly available CadC transcriptional activator DNA binding domain of GenBank HAI8857886.1 as the sequence of the CadC DNA binding domain of Chang et al., and to combine with the transcriptional activator CadC [Escherichia coli] of GenBank Accession No: AEJ59541.1, and the TcpP of GenBank Accession Number: ACK75639.1 to form a fusion protein to arrive at SEQ ID NOs: 47 and 48 of instant claims 10 and 11 respectively, with a reasonable expectation of success, as this would have amounted to substituting one known CadC for another known CadC sequence, and combining known elements according to known methods to yield predictable results.
One of ordinary skill in the art would have been motivated to use the publicly available CadC transcriptional activator DNA binding domain of GenBank HAI8857886.1 as the sequence of the CadC DNA binding domain of Chang et al., and to combine with the transcriptional activator CadC [Escherichia coli] of GenBank Accession No: AEJ59541.1, and the TcpP of GenBank Accession Number: ACK75639.1 to form a fusion protein to arrive at SEQ ID NOs: 47 and 48 because the sequence of the DNA-binding transcriptional activator CadC of E. coli was publicly available before the effective filing date and is a 100% match to instant SEQ ID NO: 45, and Chang et al. taught an engineered transmembrane receptor comprising CadC-VHH fusion proteins composed of CadC DBD, CadC juxtamembrane domain (JM), the Leu(16) transmembrane region, CadC wild type external linker region, and the VHH LBDs (page 169, left column and Figure 3A), and taught optimizing the transmembrane receptor signal-to-noise ratio through linkers engineering (page 170, left column), and that the response properties of synthetic transmembrane receptors can be optimized by varying the amino acid sequences of receptor linker regions (page 170, right column). Since Chang et al. taught using a CadC linker region for the engineered transmembrane receptor biosensor and taught optimization by varying the amino acid sequence of receptor linker regions, an ordinary artisan would have been motivated to try any known CadC amino acid sequence, including that of CadC [Escherichia coli] of GenBank Accession No: AEJ59541.1, in order to provide an optimized linker for use in the engineered receptor biosensor. One of ordinary skill in the art would have been motivated to use the sequence of GenBank HAI8857886.1 of CadC in the fusion protein because the sequence of the DNA-binding transcriptional activator CadC of E. coli was publicly available before the effective filing date and is a 100% match to instant SEQ ID NO: 45.
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., Haas et al., Hase et al. and GenBank Accession Number: ACK75639.1 as applied to claims 5-8,12,13 and 15-17 above, and further in view of D’Elia et al. (US 20060205044, Published 14 September 2006).
The teachings of Chang et al., Haas et al., Hase et al., and GenBank Accession Number: ACK75639.1 as applicable to claims 5-8,12,13 and 15-17 have been described above.
Chang et al., Haas et al., Hase et al., and GenBank Accession Number: ACK75639.1 do not teach wherein the promoter is selected from the group consisting of p14, p10 and p9 promoter having respectively a nucleic acid sequence as set forth in SEQ ID NO: 58, SEQ ID NO: 59 and SEQ ID NO: 60.
Before the effective filing date, D’Elia et al. taught a strain of E. coli where at least one strain contains at least one gene operably associated with at least one non-native promoter, and the strain overproduces L-threonine, L-methionine, L-homoserine, L-isoleucine, and/or L-lysine (paragraph 0032). D’Elia et al. taught a promoter of SEQ ID NO: 5 (paragraph 0050) which has 100% identity to instant SEQ ID NO: 58. See alignment below, wherein Qy is instant SEQ ID NO: 58 and Db is SEQ ID NO: 5 of D’Elia et al.:
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have provided the promoter of SEQ ID NO: 5 of D’Elia et al. in an expression cassette comprising the polynucleotide encoding the fusion protein operably linked to the promoter of SEQ ID NO: 5 of D’Elia et al. allowing expression in a prokaryotic host cell. There would be a reasonable expectation of success because Chang et al., Haas et al. and Hase et al. all taught using promoters, and D’Elia et al. teach the use of the promoter in a prokaryotic cell, E. coli. One of ordinary skill in the art would have been motivated to do so because D’Elia et al. teach E. coli where at least one strain contains at least one gene operably associated with at least one non-native promoter, and the strain overproduces L-threonine, L-methionine, L-homoserine, L-isoleucine, and/or L-lysine (paragraph 0032), and teach a promoter of SEQ ID NO: 5 comprising the same sequence as instant SEQ ID NO: 58.
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., Haas et al., Hase et al. and GenBank Accession Number: ACK75639.1 as applied to claims 5-8,12,13 and 15-17 above, and further in view of NCBI Reference Sequence: WP_000549073.1 (publicly available 10 July 2019).
The teachings of Chang et al., Haas et al., Hase et al., and GenBank Accession Number: ACK75639.1 as applicable to claims 5-8,12,13 and 15-17 have been described above.
Additionally, Hase et al. teach that TcpH, with its large periplasmic domain and inner membrane anchor, has a structure similar to that of ToxS and was shown to enhance the activity of TcpP, and proposed that TcpP/TcpH constitute a pair of regulatory proteins functionally similar to ToxR/ToxS and PsaE/PsaF that are required for toxT transcription in V. cholerae. (Abstract, page 730; page 733, left column). Hase et al. taught a model where both ToxR/S and TcpP/H are involved in sensing various environmental and internal stimuli and are required for the production of TCP in V. cholerae by cooperating in the activation of the toxT promoter. Both TcpP and ToxR appear to be homologous membrane regulatory proteins; similarly, although TcpH and ToxS are not homologous, their predicated topology suggests that they too reside within the inner membrane and have similar topologies (Page 734, left column). Thus, it is conceivable that our observed requirement for both TcpP/H and ToxR/S for optimal expression of the toxT gene may reflect the interaction of these membrane regulatory proteins with each other in a complex. Alternatively, these pairs of regulatory proteins may activate different promoters upstream of toxT in a manner that produces the observed cooperativity between TcpP/H and ToxR/S (page 734, right column).
Chang et al., Haas et al., Hase et al., and GenBank Accession Number: ACK75639.1 do not teach the TcpH polypeptide having an amino acid sequence as set forth in SEQ ID NO: 2.
However, the amino acid sequence of the TcpH polypeptide was publicly available before the effective filing date. A Blast search of instant SEQ ID NO: 2 resulted in a 100% match to toxin-coregulated pilus protein TcpH [Vibrio cholerae] of NCBI Reference Seq WP_000549073.1. See below:
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340
718
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The amino acid sequence of toxin-coregulated pilus protein TcpH [Vibrio cholerae] of WP_000549073.1 is shown below.
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57
506
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Alignment of instant SEQ ID NO: 2 and the above amino acid sequence of WP_000549073.1 is shown below (Qy is instant SEQ ID NO: 2, and Db is WP_000549073.1).
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236
591
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to provide the prokaryotic host cell genetically engineered with the polynucleotide encoding the modified fusion protein of Chang et al., Haas et al., Hase et al. and GenBank Accession Number: ACK75639.1 with an additional polynucleotide encoding the TcpH polypeptide having the amino acid sequence of NCBI Reference Seq WP_000549073.1. with a reasonable expectation of success. There would be a reasonable expectation of success because Chang et al. pertained to synthetic receptor biosensors, Haas et al. taught a TcpP-PamCherry fusion for use in visualization and localization studies, and Hase et al. taught TcpP/H is involved in sensing environmental and internal stimuli, and therefore all pertain to testing/sensing. One of ordinary skill in the art would have been motivated to do so because Hase et al. taught TcpH was shown to enhance the activity of TcpP, and proposed that TcpP/TcpH constitute a pair of regulatory proteins functionally similar to ToxR/ToxS and PsaE/PsaF that are required for toxT transcription in V. cholerae and taught a model where both ToxR/S and TcpP/H are involved in sensing various environmental and internal stimuli and are required for the production of TCP in V. cholerae by cooperating in the activation of the toxT promoter.
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., Haas et al., Hase et al. and GenBank Accession Number: ACK75639.1 as applied to claims 5-8,12,13 and 15-17 above, and further in view of GenBank HAI8857886.1 (Publicly available 28 April 2020).
The teachings of Chang et al., Haas et al., Hase et al., and GenBank Accession Number: ACK75639.1 as applicable to claims 5-8,12,13 and 15-17 have been described above.
Chang et al., Haas et al., Hase et al., and GenBank Accession Number: ACK75639.1 do not teach wherein the E. coli CadC transcriptional activator DNA binding domain comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 45.
A Blast search of instant SEQ ID NO: 45 resulted in a 100% match to DNA-binding transcriptional activator CadC [E. coli].
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281
694
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The sequence of CadC of GenBank HAI8857886.1 was publicly available before the effective filing date and is shown below:
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60
512
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The alignment of instant SEQ ID NO: 45 and the sequence of GenBank HAI8857886.1 is shown below:
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183
594
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, that the E. coli CadC transcriptional activator DNA binding domain used in the fusion protein of Chang et al., Haas et al., Hase et al., and GenBank Accession Number: ACK75639.1, would have been had the amino sequence taught by GenBank HAI8857886.1 with a reasonable expectation of success, as this would have amounted to substituting one known CadC for another known CadC sequence. One of ordinary skill in the art would have been motivated to do so because the sequence of the DNA-binding transcriptional activator CadC of E. coli was publicly available before the effective filing date and is a 100% match to instant SEQ ID NO: 45.
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 02/24/2026 have been fully considered but they are not persuasive.
Applicant argues on page 7 of response that claim 5 has been amended to require that the TcpP polypeptide does not include a cystoplasmic domain and points to page 5, in which SEQ ID NO: 1 provides the sequence for TcpP including the cytoplasmic, transmembrane and periplasmic domains. As discussed in lines 17-18 of page 5, the polypeptide of the invention includes only the transmembrane and periplasmic domains (see also Figure 1 where the cytoplasmic domain is shown in the normal V. cholerae TcpP peptide but it is replaced with CadC in an example fusion peptide of the invention). Applicant argues on pages 7-8 that as claim 5 excludes the cytoplasmic domain of TcpP and Haas teaches a full length TcpP peptide including the cytoplasmic domain, even if one where to combine Chang and Haas, one would not arrive at the instant invention. Applicant argues that GenBank Accession No. ACK75639.1 does not compensate for the deficiencies of Chang, Haas and Hase as this is relied upon for teaching the full length sequence of the TcpP peptide.
This is not found persuasive. The examiner believes Applicant intended to point to page 4 of the as-filed specification rather than page 5. Page 4, lines 17-18 say, “In particular, the TcpP protein comprises a transmembrane domain and a periplasmic sensing domain. An exemplary amino acid sequence of TcpP is shown as SEQ ID NO: 1”. The specification uses “comprises” and therefore is not limited to only including a transmembrane domain and a periplasmic domain and can include other components and sequences. As stated above in the claim interpretation section, the claims do not exclude the cytoplasmic domain from the fusion protein itself, just from the TcpP polypeptide claimed as having a sequence set forth in SEQ ID NO: 34, which is amino acids 1-79 of SEQ ID NO: 34. Therefore, SEQ ID NO: 34 is defined as the TcpP polypeptide in claim 5, and art that teaches the same sequence as SEQ ID NO: 34 still reads on the claim as amended, even if it is part of a larger sequence, as the additional sequences can read on other components of the fusion protein. The claims do not require a particular order or arrangement of the components of the fusion protein, and can include additional sequences in addition to what is claimed including parts of the sequence of GenBank Accession No. ACK75639.1 and Haas.
Applicant argues on page 7 that Chang describes a CadC-VHH fusion protein which forms homodimers upon ligand binding to block expression of a reporter gene and Haas describes a full length TcpP peptide including the cytoplasmic domain, fused to PamCherry in the periplasmic domain (Figure 1). Haas teaches that the TcpP peptide associates with another membrane protein ToxR to activate ToxT transcription and does not teach that a TcpP peptide can be used to detect ligands by forming a homodimer. Thus there would be no motivation to substitute the VHH domain of Chang with a TcpP peptide as taught by Haas as one of ordinary skill in the art would not recognize that a TcpP peptide could be utilized in the ligand detecting method of Chang. Applicant argues that Hase teaches that TcpP has a sequence homology to ToxR membrane protein, but this teaching is irrelevant to the claimed invention which does not include a ToxR sequences. Applicant argues on page 8 that only the present inventors have found that fusing the periplasmic and transmembrane domains of TcpP to a heterologous DNA binding domain would be useful as a bacterial biosensor for detecting bile salts upon dimerization. Applicant argues the remaining secondary references do not compensate for the deficiencies of Chang, Haas, Hase and GenBank.
This is not found persuasive. Hase et al. was used to provide motivation for TcpP to be used in sensing, as the office action on page 11 stated that Hase et al. taught a model where both ToxR/S and TcpP/H are involved in sensing various environmental and internal stimuli. Haas was used to showed that TcpP/fusion proteins were known in the art. Therefore, the examiner disagrees that there is no motivation to substitute the VHH domain of Chang with a TcpP peptide as taught by Haas, since Hase et al. provides motivation for TcpP to be used for sensing environmental and internal stimuli, and would have a reasonable expectation of success. Regarding Applicants argument that only the present inventors have found that fusing the periplasmic and transmembrane domains of TcpP to a heterologous DNA binding domain would be useful as a bacterial biosensor for detecting bile salts upon dimerization, this is not found persuasive. The instant claims are product claims and merely claim a fusion protein, polynucleotide, expression cassette and prokaryotic host cell. No detecting methods or sensors are claimed. "the patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002). Note: MPEP 2111.02
In addition, it is well settled that "any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007). As long as some suggestion to combine the elements is provided by the prior art as a whole, the law does not require that they be combined for the reason or advantage contemplated by the inventor. In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992); In re Kronig, 539 F.2d 1300, 1304 (CCPA 1976). MPEP 2143.01 and 2144 (IV). The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
Applicant argues on page 8 of response that the remaining secondary references do not compensate for the deficiencies of Chang, Haas, Hase and Genbank as these references were only relied upon for allegedly teaching the subject matter of the dependent claims.
However, the response to the arguments pertaining to Chang, Haas, Hase and Genbank and the interpretation of the instant claims have been explained above. As there are no new arguments pertaining to the remaining secondary references, the 103 rejections of claims 9-11,14,18 and 28 are likewise maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 5-17 and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-11 of copending Application No.18/275,331 (‘331) in view of Haas et al. (Molecular Microbiology, Published online 4 Nov 2014, 96(1), 4-13), Hase et al. (Proc Natl Acad Sci U.S.A. 20 Jan 1998; 95(2): 730-734), and GenBank Accession Number: ACK75639.1 (24 July 2016).
Claim 1 of ‘331 recites a fusion protein wherein a VtrA polypeptide having an amino acid sequence having at least 90% identity with the amino acid sequence that ranges from the amino acid residue at position 134 to the amino acid residue at position 253 in SEQ ID NO: 1 is fused to a DNA binding domain which is an E. coli CadC transcriptional activator DNA binding domain that comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 3. Instant claim 5 recites a fusion protein comprising a TcpP polypeptide that has a sequence as set forth in SEQ ID NO: 34, fused to a heterologous polypeptide, with instant claim 6 reciting the heterologous polypeptide is a DNA binding domain, and instant claim 7 reciting the heterologous polypeptide is an E. coli CadC transcriptional activator DNA binding domain.
Claim 1 of ‘331 does not recite the fusion protein comprises a TcpP polypeptide having a sequence as set forth in SEQ ID NO: 34 as recited in instant claim 5.
However, Haas et al., Hase et al. and GenBank Accession Number: ACK75639.1 cures this deficiency.
The teachings of Haas et al., Hase et al. and GenBank Accession Number: ACK75639.1 have been described above in the 103 rejections.
Claim 2 of ‘331 recites the DNA binding domain is an E. coli CadC transcriptional activator DNA binding domain that comprises an amino acid sequence having at least 90% identity with SEQ ID NO: 3. SEQ ID NO: 3 in claim 2 of ‘331 is 100% identical and is the same length as instant SEQ ID NO: 45 in instant claim 28.
Claim 3 of ‘331 recites the VtrA polypeptide is fused either directly or via a linker to the DNA binding domain, and instant claim 8 recites the TcpP polypeptide is also fused either directly or via a linker to the heterologous polypeptide.
Claim 4 of ‘331 recites the linker comprises the amino acid sequence as set forth in SEQ ID NO: 4, which is 100% identical to and of the same length of instant SEQ ID NO: 46 in instant claim 9.
Claim 5 of ‘331 recites the fusion protein of claim 1 comprising an amino acid sequence having at least 90% identity with the amino acid sequence as set forth in SEQ ID NO: 5. Instant claims 10-11 recite the fusion protein that comprises the amino acid sequence as set forth in SEQ ID NO: 47, and that comprises the amino acid sequence set forth in one of SEQ ID NO: 48.
Claim 6 of ‘331 recites a polynucleotide that encodes for the fusion protein and instant claim 12 also recites a polynucleotide that encodes for the fusion protein; claim 7 of ‘331 recites an expression cassette comprising the polynucleotide of claim 6 operably linked to a promoter and/or control sequences allowing expression in a prokaryotic host cell, with instant claim 13 also reciting an expression cassette comprising the polynucleotide of claim 5 operably linked to control sequences allowing expression in a prokaryotic host cell.
Claim 8 of ‘331 also recites the promoters are p14, p10 or p9 as set forth in SEQ ID NOs: 6,7 and 8, which are the same promoters and sequences as recited in instant claim 14.
Claims 9-11 of ‘331 recite a prokaryotic host cell genetically engineered with the polynucleotide of claim 6 or an expression cassette comprising the polynucleotide, with claims 10-11 reciting the species of host cells, and which are the same host cells as recited in instant claims 15-17.
It would have been obvious to one of ordinary skill in the art to have modified the claims of ‘331 by substituting the VtrA polypeptide portion of the fusion protein with a TcpP polypeptide of GenBank Accession Number: ACK75639.1, according to the teachings of Hase et al. and Haas et al. with a reasonable expectation of success in order to produce a TcpP fusion polypeptide. There would be a reasonable expectation of success as this would have amounted to simple substitution of one known element for another to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because GenBank Accession Number: ACK75639.1 (TcpP) was publicly available before the effective filing date, and Haas et al. taught TcpP fusion proteins were known (a TcpP-PamCherry fusion for use in visualization and localization studies), and Hase et al. taught a model where both ToxR/S and TcpP/H are involved in sensing various environmental and internal stimuli and are required for the production of TCP in V. cholerae by cooperating in the activation of the toxT promoter (page 734, left column). Combining the sequence of GenBank Accession Number: ACK75639.1 (TcpP), and the linker of SEQ ID NO: 4 of ‘331 and the CadC transcriptional activator DNA binding domain comprising SEQ ID NO: 3 of ‘331 would have resulted in a fusion protein comprising instant SEQ ID NOs: 47 and 48.
Accordingly, the limitations of claims 5-17 and 28 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
This is a provisional nonstatutory double patenting rejection.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 12 of copending Application No.18/275,331 (‘331) in view of Haas et al. (Molecular Microbiology, Published online 4 Nov 2014, 96(1), 4-13), Hase et al. (Proc Natl Acad Sci U.S.A. 20 Jan 1998; 95(2): 730-734), and GenBank Accession Number: ACK75639.1 (24 July 2016) as applied to claims 5-17 and 28 above, and further in view of NCBI Reference Sequence: WP_000549073.1 (publicly available 10 July 2019).
The claims of ‘331 and teachings of Haas et al., Hase et al, and GenBank Accession Number: ACK75639.1 have been described above.
Claim 12 of ‘331 recites the prokaryotic host cell of claim 9 that comprises a polynucleotide that encodes for the VtrC polypeptide having an aa sequence as set forth in SEQ ID NO: 2. Instant claim 18 also recites a prokaryotic host cell but requires a polynucleotide that encodes for a TcpH polypeptide having an aa sequence as set forth in SEQ ID NO: 2.
NCBI Reference Seq WP_000549073.1 cures this deficiency, the teachings of which have been described in the above 103 rejections.
It would have been obvious to one of ordinary skill in the art before the effective filing date to provide the prokaryotic host cell genetically engineered with the polynucleotide encoding the modified fusion protein of ‘331, Haas et al., Hase et al. and GenBank Accession Number: ACK75639.1 with an additional polynucleotide encoding the TcpH polypeptide having the amino acid sequence of NCBI Reference Seq WP_000549073.1 with a reasonable expectation of success, as this would have amounted to combining known elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Hase et al. taught TcpH was shown to enhance the activity of TcpP, and proposed that TcpP/TcpH constitute a pair of regulatory proteins functionally similar to ToxR/ToxS and PsaE/PsaF that are required for toxT transcription in V. cholerae and taught a model where both ToxR/S and TcpP/H are involved in sensing various environmental and internal stimuli and are required for the production of TCP in V. cholerae by cooperating in the activation of the toxT promoter.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 02/24/2026 have been fully considered but they are not persuasive.
Applicant states they will address the double patenting rejections when the final outcome of the claims in the present or copending application is determined and cites MPEP 804.
As the claims remain rejected based on new matter and 35 U.S.C. 103, the above double patenting rejections are maintained with the same reasonings and arguments regarding the 103 rejections above.
Conclusion
Claims 5-18 and 28 are rejected.
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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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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