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 .
Claim Status
Claims 1, 3-19 and 21-22 are pending following the Reply filed 04/27/2026. Claims 1, 4 and 8 have been amended without introducing new matter. Claim 2 has been cancelled. Claims 9-19 and 21-22 are withdrawn. Claims 1 and 3-8 have been examined on the merits.
Withdrawn
Any objection or rejection of claim 2 is moot because the claim has been cancelled.
The objections of claims 1, 4 and 8 are withdrawn in light of the amendments.
The rejection of claims 1, 3 and 6 under 35 U.S.C. 101 as being directed to a judicial exception (product of nature) is withdrawn in light of the amendments. In particular, the limitations of claim 2 (now cancelled), which was free of this rejection, have been incorporated into independent claim 1. Hence, the claims now require a fusion protein comprising both a VtrA polypeptide and a heterologous CadC transcriptional activator DNA binding domain, which is considered to have markedly different characteristics compared to its closest naturally occurring counterparts (i.e., V. parahaemolyticus VtrA and E. coli CadC from which these polypeptides were derived). See Response to Arguments below for further discussion.
The rejection of claims 1 and 3 under 35 U.S.C. 102 is withdrawn in light of the amendments. In particular, the claims now require an E.coli CadC comprising an amino acid sequence having at least 90% identity with instant SEQ ID NO: 3, which is not taught by the prior art reference used in the rejection. See Response to Arguments below for further discussion.
Maintained rejections and new rejections necessitated by amendment
Claim Rejections - 35 USC § 103
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.
Claim(s) 1 and 3-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Voigt et al. (US 20180073031 A1; previously cited), hereafter, “Voigt”, and further in view of Bonnet et al. (WO 2018224611 A1; cited in the IDS filed 08/01/2023), hereafter, “Bonnet”, and further in view of Rivera-Cancel et al. (cited in the IDS filed 08/01/2023), hereafter, “Rivera”, as further evidenced by UniProt Q87GI4_VIBPA (previously cited).
Regarding claim 1, Voigt teaches that a portion of bile acids synthesized in the liver enter the colon to be modified by the resident gut microbiota, resulting in secondary bile acids, which are implicated to be causative agents for colon and liver cancer, as well as being biomarkers for inflammatory bowel disease (see pg. 1, para. [0004]). Voigt also suggests that determining the presence of bile acid in a biological sample from a patient may be indicative of liver disease or liver dysfunction and be useful when treating such conditions (see pg. 2, paras. [0024], [0026]).
Voigt discloses engineered nucleic acid molecules that act as sensors for bile acids, wherein the nucleotide sequence encodes a bile acid sensor protein that binds to a bile acid (see pg. 1, para. [0009]). Voigt teaches the bile acid sensor comprises a protein from a species of Vibrio, wherein the binding to bile acids leads to a conformational change, leading to the release of DNA and allowing for transcription of the gene by RNA polymerase to take place (see pg. 3, para. [0042]). Voigt discloses exemplary bile acid sensor polypeptides that are derived from Vibrio cholera and Vibrio fischeri (see pg. 3, para. [0042]).
Voigt does not explicitly teach a fusion protein comprising the bile acid sensor protein and a DNA binding domain.
Bonnet teaches that in vitro diagnostic tests (IVDs) are growing in importance in the global health arena because of their noninvasive nature and resulting ease of use and scale; however, conventional detection methods for IVDs are often expensive and complex, and thus difficult to implement in resource-limited settings (see pg. 1, lines 9-12). Bonnet teaches that whole-cell biosensors based on bacteria have proven to be applicable for the detection and quantification of a wide range of analytes, but are limited by slow response times and the inability to engineer ligand-tailored sensors (see pg. 1, lines 16-17 and 27-33).
As a solution to these challenges, Bonnet discloses chimeric receptors that can be used in whole-cell sensors for detecting analytes of interest (see Abstract), wherein the chimeric receptor polypeptide (i.e., fusion protein) comprises: i) a first DNA binding domain, ii) at least one binding domain having specificity for an analyte, and iii) a linker between the DNA binding domain and the analyte-specific binding domain (see pg. 2, lines 14-16). Bonnet teaches the DNA binding domain is a “CadC transcriptional activator” which is a membrane-integrated transcriptional regulator of Escherichia coli, representative of ToxR-like proteins that combine sensory, signal transduction, and DNA-binding activities within a single polypeptide (see pg. 2, line 30 to pg. 3, line 1). Here, the “bile acid sensor protein that binds to a bile acid” taught by Voigt reads on Bonnet’s teaching of a “binding domain having specificity for an analyte”.
Bonnet teaches the CadC transcriptional activator DNA binding domain comprises an amino acid sequence according to SEQ ID NO: 2 (see pg. 3, lines 11-13). As shown in the following alignment, Bonnet’s SEQ ID NO: 2 (bottom) comprises an amino acid sequence that is identical to instant SEQ ID NO: 3 (top):
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Voigt and Bonnet do not teach the analyte-specific binding domain (bile acid sensor) comprising a VtrA polypeptide.
Rivera teaches that some intestinal bacteria are able to use bile salts as a cue for intestinal location to regulate virulence factors, but the mechanisms used for bile acid sensing have been poorly characterized (see pg. 366, col.1, para. 1 to col. 2, para. 2). In Rivera’s study, Vibrio parahaemolyticus was demonstrated to sense bile salts via a heterodimeric receptor formed by the periplasmic domains of inner-membrane proteins VtrA and VtrC, and Rivera discloses that proteins with the same domain arrangement are widespread in Vibrio and related bacteria (see Abstract). Rivera teaches that ToxR and ToxS in V. cholerae adopt the same domain topology as VtrA and VtrC in V. parahaemolyticus, and ToxR has also been reported to respond to the presence of bile (see pg. 369, col. 1, para. 3 to col. 2, para. 1). Rivera also teaches that evidence suggests that ToxR plays a secondary role by enhancing VtrA’s transcription factor activity (see pg. 369, col. 2, para. 2). Rivera discloses that the V. parahaemolyticus strain used in the study was “RIMD2210633” (see pg. 368, col. 1, para. 1).
UniProt entry Q87GI4_VIBPA is identified as a putative transcriptional regulator ToxR (see pg. 1, line 6, “DE”) derived from Vibrio parahaemolyticus strain RIMD 2210633 (see pg. 1, line 8, “OS”). As shown in the following alignment, Q87GI4_VIBPA (bottom) comprises an amino acid sequence that is identical to instant SEQ ID NO: 1 (top):
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It would have been obvious at the time of filing for a person of ordinary skill in the art to have combined the teachings of Voigt, Bonnet and Rivera to have arrived at the claimed invention for at least the following reasons: (1) Voigt and Bonnet both teach compositions and methods for the detection of analytes using bacterial polypeptides; (2) Voigt and Rivera teach bacterial polypeptides which sense bile acids; (3) Bonnet and Rivera teach ToxR-like proteins, such as the CadC transcriptional activator, which relays the sensing of an analyte with DNA-binding/transcriptional activities; (4) Rivera demonstrates that VtrA is used by Vibrio parahaemolyticus to sense bile salts and suggests ToxR-like proteins may enhance VtrA transcription factor activity; and (5) Bonnet teaches fusion proteins comprising a DNA binding domain connected to an analyte-specific binding domain for improved in vitro testing. Hence, one would have been motivated to combine these teachings in order to provide an improved chimeric polypeptide capable of more effectively responding to the presence of bile acids in a sample to determine or monitor a liver or bowel disease. As Rivera teaches VtrA to be used by Vibrio to sense bile salts, one would have immediately envisaged using the VtrA polypeptide as a bile acid sensor, as taught by Voigt, and as the analyte-specific binding domain of the fusion protein taught by Bonnet. Further, the sequence for this polypeptide was readily available in public databases at the time of filing and could have been easily identified based on Rivera’s disclosure. Because these polypeptides are taught by the prior art to inherently possess the required mechanisms for sensing bile acids and activating transcription, one would have recognized there to be a reasonable expectation for success when combining these teachings. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 3, Bonnet teaches the chimeric receptor polypeptide comprises a linker between the DNA binding domain and the analyte-specific binding domain, as discussed above. Hence, it would have been obvious to have the VtrA polypeptide fused via a linker to the DNA binding domain.
Regarding claim 4, as shown in the following alignment, Bonnet’s SEQ ID NO: 2 (bottom) further comprises an amino acid sequence that is identical to instant SEQ ID NO: 4 (top):
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Note that Bonnet’s SEQ ID NO: 2 comprises both a DNA binding domain identical to instant SEQ ID NO: 3 from residues 1 to 107 and a linker sequence identical to instant SEQ ID NO: 4 from residues 108 to 155, as shown above. Hence, Bonnet’s DNA binding sequence already comprises the claimed linker represented by instant SEQ ID NO: 4.
Regarding claim 5, note that instant SEQ ID NO: 5 comprises, in sequence from N-terminus to C-terminus, instant SEQ ID NO: 3 (CadC transcriptional activator DNA binding domain), instant SEQ ID NO: 4 (linker), and residues 134 to 253 of SEQ ID NO: 1 (VtrA).
Rivera teaches that VtrA contains an N-terminal DNA-binding domain of the OmpR family that is attached to the inner membrane by a single transmembrane helix, and a C-terminal periplasmic domain (see pg. 367, col. 1, para. 2). Rivera teaches that V. parahaemolyticus was demonstrated to sense bile salts via the C-terminal periplasmic domain of VtrA (see pg. 370, col. 2, para. 2). Hence, a person of skill would have recognized that the transmembrane domain should be included in the fusion protein for anchoring the fusion protein to the cell membrane, and the C-terminal periplasmic domain should be included in the fusion protein for sensing bile acids.
In view of Q87GI4_VIBPA, the “OmpR” type domain (DNA-binding domain) in VtrA ranges from amino acid residue 3 to residue 103, and the helical transmembrane domain ranges from residues 134 to 153 (see pg. 2, lines 6-14). Hence, a person of skill would have recognized that the minimal structure required for VtrA to be functional in the fusion protein would be an amino acid sequence comprising the C-terminus of VtrA beginning at amino acid residue 134, because this region would be expected to contain the required transmembrane and periplasmic domains. This results in the following truncated VtrA sequence:
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Fusing the CadC transcriptional activator taught by Bonnet (SEQ ID NO: 2) with the truncated VtrA sequence above, results in the following fusion protein sequence:
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As shown in the following alignment, instant SEQ ID NO: 5 (top) is identical to the fusion protein sequence above (bottom):
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Thus, it would have been obvious for the fusion protein to have comprised an amino acid sequence with at least 90% identity with instant SEQ ID NO: 5, because this sequence is one that a person of ordinary skill would have necessarily arrived at when constructing a fusion protein to detect bile acids in view of the prior art combination.
Regarding claim 6, Bonnet teaches a further aspect of the invention relates to a nucleic acid encoding for a chimeric receptor of the invention (see pg. 7, lines 7-8; claim 9). Hence, it would have been obvious to have provided a polynucleotide that encodes the fusion protein.
Regarding claim 7, Bonnet teaches an expression cassette comprising the nucleic acid molecule operably linked to control sequences allowing expression in a prokaryotic cell (see pg. 7, lines 1-3).
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Voigt, Bonnet, Rivera and UniProt Q87GI4_VIBPA as applied to claims 1 and 3-7 above, and further in view of Crafton et al. (US 20030017533 A1; previously cited), hereafter, “Crafton”.
Regarding claim 8, Bonnet teaches that “[s]uitable expression control sequences include
promoters that are applicable in the target host organism. Such promoters are well known to the
person skilled in the art for diverse hosts from prokaryotic organisms and are described in the
literature” (see pg. 7, lines 25-29).
Bonnet does not explicitly teach the expression cassette comprising a p14, p10, or p9 promoter.
Crafton teaches isolated polynucleotides comprising C. glutamicum promoters which may be used to regulate, i.e., either increase or decrease gene expression (see Abstract). Crafton teaches that one way to improve the productivity of a microbial strain is to increase the expression of genes that control the production of a metabolite (see pg. 1, para. [0007]). Crafton teaches promoters useful for regulating and enhancing the production of a variety of products in host cells (see pg. 2, para. [0019]) which include the trc promoter represented by SEQ ID NO: 26 (see pg. 21, para. [0153]). As shown in the following alignment, Crafton’s SEQ ID NO: 26 (top) comprises a nucleic acid sequence that is identical to instant SEQ ID NO: 6 (bottom):
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Hence, while Crafton does not refer to this promoter as a “p14” promoter, it comprises the same structure and is therefore equivalent to the promoter of the claim.
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Crafton with that of the aforementioned references, because all references used in the rejection relate to the expression of genes in bacteria. One would recognized from Bonnet that suitable expression control sequences include promoters that are well known in the art, including the promoters taught by Crafton. One would have also recognized that is well within the ordinary skill in the art to select and use such promoters, which Crafton teaches are useful for regulating the expression level of a given gene, such as in the case of the expression cassettes taught by Bonnet. One would have recognized that each of the claimed elements (i.e., promoter, DNA binding domain, etc.) could be combined by known methods and, as each element merely performs the same function as it does separately, the results of the combination would have been predictable with a reasonable expectation of success. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Response to Arguments
Regarding the rejection of claims 1, 3 and 6 under 35 U.S.C. 101 (product of nature), Applicant argues that claim 1 has been amended to require that the DNA binding domain is a heterologous Escherichia coli CadC transcriptional activator DNA binding domain (as previously recited in claim 2 which was not included in this rejection).
Applicant’s arguments have been fully considered and are persuasive.
Furthermore, the prior art of Bonnet teaches that CadC is a membrane-integrated transcriptional regulator derived from Escherichia coli (see pg. 2, lines 30-31), while Rivera teaches VtrA is an inner-membrane protein derived from Vibrio parahemolyticus (see Abstract). Rivera teaches that Vibrio parahemolyticus senses bile salts via a heterodimeric receptor formed by the periplasmic domains of inner-membrane proteins VtrA and VtrC, which form a beta-barrel that binds bile salts in the hydrophobic interior of the periplasmic complex to activate the VtrA cytoplasmic DNA-binding domain (see Abstract). It should be noted that the wild-type VtrA (SEQ ID NO: 1; top) does not comprise a domain having the same structure as the CadC DNA binding domain (SEQ ID NO: 3; bottom), as shown by sequence alignment:
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According to the specification, the binding of bile salts to the fusion protein triggers the oligomerization of the CadC transcriptional activator DNA binding domain which can then activate the expression of at least one further polynucleotide encoding for an output molecule (see pg. 16, lines 1-4), wherein the E. coli CadC system activates transcription upon dimerization (see pg. 30, lines 5-8). Bonnet teaches that E. coli CadC is representative of ToxR-like proteins (see pg. 2, line 30 to pg. 3, line 1) which Rivera discloses can enhance VtrA’s transcription factor activity (see Rivera at pg. 369, col. 2, para. 2).
Per MPEP 2106.04(c)(II)(B), under the markedly different characteristics analysis, appropriate characteristics include the structure and form of the nature-based product, whether chemical, genetic or physical, as well as biological functions or activities. Taken as a whole, the structure and form of the fusion protein is distinct from either of the structures it was derived (i.e., VtrA and CadC), and this combined structure results in a functional difference (i.e., the enhanced transcriptional activity of the fusion protein comprising CadC, which is dimerized in response to the binding to bile salts by VtrA).
Hence, these structural and functional characteristics are considered to have been changed compared to their closest naturally occurring counterparts (i.e., VtrA and CadC).
Therefore, the rejection under 35 U.S.C. 101 has been withdrawn.
Regarding the rejection of claims 1 and 3 under 35 U.S.C. 102, Applicant argues that the UniProt reference provides the sequence of the wildtype VtrA, and independent claim 1 is amended to require a fusion protein having a heterologous DNA binding domain as previously recited in claim 2 which was not included in this rejection. Thus, the UniProt reference does not anticipate the claimed invention.
Applicant’s arguments have been fully considered and are persuasive.
The prior art reference relied upon in the rejection, UniProt Q87GI4_VIBPA, does not include the E.coli CadC binding domain having at least 90% identity with instant SEQ ID NO: 3.
Therefore, the rejection under 35 U.S.C. 102 has been withdrawn.
Regarding the rejections under 35 U.S.C. 103, Applicant argues that Voigt does not teach a fusion protein comprising the bile acid sensor protein and a DNA binding domain.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Voigt teaches bile acid sensor polypeptides, while Bonnet teaches chimeric receptors comprising a DNA binding domain, specifically, a CadC transcriptional activator derived from E. coli, as discussed in the rejection.
Applicant further argues that Bonnet describes chimeric receptors for use in whole-cell sensors for detection of analytes. The chimeric receptor includes i) a DNA binding domain which may be a CadC domain, ii) at least one binding domain having specificity for an analyte, such as a heavy chain variable domain, and iii) a linker that connects the DNA binding and binding domains. One of ordinary skill in the art would recognize that the VHH domain would be needed for specificity and versatility.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's argument that an ordinary artisan would have recognized that the VHH domain exemplified by Bonnet would be required for specificity and versatility, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Further, “[a] reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See MPEP 2123.
In the instant case, Bonnet teaches “a chimeric receptor polypeptide comprising i) a first DNA binding domain, ii) at least one binding domain having specificity for an analyte, and iii) a linker between the DNA binding domain and the binding domain” (see pg. 2, lines 14-16). Bonnet also states that “Exemplary binding domains include an antibody variable domain, a receptor binding domain of a ligand, a ligand binding domain of a receptor or an enzymatic domain” (see pg. 3, lines 21-23). Per MPEP 2123(II), “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).” Therefore, Bonnet’s exemplifying of a “heavy chain variable domain” or VHH does not constitute a teaching away from other embodiments of the disclosure.
Furthermore, Bonnet’s preferred embodiments do not constitute a teaching away from the teachings of the other references used in the rejection. Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, a person of skill would have recognized that Rivera teaches the VtrA polypeptide, which has been reported to have specificity to bile salts, making it useful for their detection, as discussed in the rejection. Bonnet also teaches that the DNA binding domain is an E. coli CadC, representative of ToxR-like proteins (see Bonnet at pg. 2, line 30 to pg. 3, line 1) which Rivera discloses can enhance VtrA’s transcription factor activity (see Rivera at pg. 369, col. 2, para. 2). Here, a person of skill would have recognized that VtrA acts as a receptor for bile salts, an analyte of particular medical interest, and that it could be used as the analyte-specific binding domain of a chimeric receptor polypeptide for detecting bile salts.
Applicant further argues that Rivera-Cancel describes the use of VtrA polypeptides to detect bile salts, however, this reference does not provide any motivation to adapt the system of Bonnet to achieve the claimed invention. Rivera-Cancel lacks any specific guidance or suggestion that the VtrA/VtrC system could be effectively modified to detect a broader or different range of bile salts by replacing the DNA binding domain. As such, there is no clear teaching or motivation that would lead the skilled person to consider this approach, let alone with a reasonable expectation of success.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). As discussed in the rejection: (1) Voigt and Bonnet both teach compositions and methods for the detection of analytes using engineered bacterial polypeptides, with Bonnet teaching the construction of chimeric receptors (fusion proteins) comprising DNA binding domains and analyte-specific binding domains. Here, Bonnet was relied upon to show that the underlying principle of a fusion protein comprising a CadC DNA binding domain for the detection of an analyte was known in the prior art and enabled by the prior art at the time of filing. (2) Voigt and Rivera teach bacterial polypeptides which sense bile acids. Here, Voigt teaches the medical significance of detecting bile salts and provides motivation to use polypeptides derived from Vibrio, while Rivera teaches the Vibrio-derived VtrA polypeptide to be useful for this purpose. (3) Bonnet and Rivera teach ToxR-like proteins, such as the CadC transcriptional activator, which relays the sensing of an analyte with DNA-binding/ transcriptional activities, and (4) Rivera demonstrates that VtrA is used by Vibrio parahaemolyticus to sense bile salts and suggests elements derived from ToxR-like proteins (such as the E. coli CadC taught by Bonnet) may enhance VtrA transcription factor activity, demonstrating a further advantage. Finally, (5) Bonnet teaches fusion proteins comprising a DNA binding domain connected to an analyte-specific binding domain for improved in vitro testing, which provides further motivation to provide the VtrA sensing mechanism as a fusion protein with a DNA binding domain.
In response to applicant's argument that “Rivera-Cancel lacks any specific guidance or suggestion that the VtrA/VtrC system could be effectively modified to detect a broader or different range of bile salts by replacing the DNA binding domain”, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the instant case, Rivera teaches that enteric pathogens have evolved to “hijack” bile as an intestinal signal to regulate virulence factors and demonstrates that Vibrio parahemolyticus senses bile salts via a heterodimeric receptor formed by VtrA and VtrC (see Abstract). A person of skill would have recognized that the VtrA/VtrC system could be utilized for the same purpose as the polypeptides disclosed by Voigt for sensing bile salts.
Regarding “a reasonable expectation of success”, Applicant’s argument merely states that there is “no clear teaching or motivation” to combine the aforementioned references, and fails to present sufficient evidence to show, for example, the amount of unpredictability that would have been involved when combining these teachings. As stated in the rejection, because these polypeptides (i.e., ToxR-like proteins, such as VtrA and CadC) are taught by the prior art to inherently possess the required mechanisms for sensing bile acids in bacteria, one would have recognized there to be a reasonable expectation for success when combining these teachings. Furthermore, it is evidenced by the prior art used in the rejection that chimeric proteins comprising analyte-specific binding elements (e.g., VtrA/VtrC) further comprising DNA binding domains for transcriptional activity (e.g., CadC) in order to detect an analyte of interest (e.g., bile salts), as taught by Bonnet, are well within the ordinary skill in the art to construct and use, particularly when the structure and function of each of these elements has been established and is known in the art.
Applicant further argues that only the present inventors have shown that the claimed fusion protein which combines a VtrA polypeptide with a CadC DNA binding domain may be used for a broad detection profile of bile salts (see Figure 3). Notably, the system exhibits high specificity and sensitivity toward secondary conjugated bile salts, particularly glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA).
In response to applicant's argument that “the system exhibits high specificity and sensitivity toward secondary conjugated bile salts, particularly glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA)”, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
See also MPEP 2112(IV) which states:
"[I]n order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art." Id. at 1195-96, 112 USPQ2d at 1952. But see, Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020).
For the reasons discussed above, there would have been sufficient motivation to combine the teachings of the prior art references to have arrived at the claimed fusion protein, and there would have been a reasonable expectation that the resulting polypeptide would be useful for detecting bile acids. Having arrived at the same structure as the claims, the resulting product would have necessarily possessed the same properties.
However, it should also be noted that the functional properties upon which applicant relies (i.e., “high specificity and sensitivity toward secondary conjugated bile salts”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Nonetheless, these properties are presumed to be inherent, for the reasons discussed above.
Conclusion
No claims are allowed.
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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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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