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 1-16 are pending and currently under consideration for patentability under 37 CFR 1.104.
Priority
This application claims benefit of Provisional U.S. Application No. 63/380,870 filed on 10/25/2022. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-16 have an effective filing date of 10/25/2022 corresponding to Provisional U.S. Application No. 63/380,870.
Information Disclosure Statement
The information disclosure statements filed on 05/07/2024 (2 information disclosure statements filed on same day) and 10/25/2023 have been considered. Signed copies are enclosed.
Claim Objections
Claim 16 is objected to because of the following informalities: “first biological activity protein binding affinity” in lines 1-2 should read “first biological activity is protein binding affinity”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the phrase "an antibody comprising: a heavy chain variable domain subunit of the allosteric protein" renders the claim indefinite because it is unclear if the antibody or the allosteric protein comprises the heavy chain. Claims 2-16 are included in this rejection as they incorporate and/or depend on claim 1.
For the purposes of claim interpretation, the antibody will be treated as comprising a heavy chain, not the allosteric protein.
Regarding claim 1, the phrase "an antibody comprising… a light chain variable domain subunit of the allosteric protein" renders the claim indefinite because it is unclear if the antibody or the allosteric protein comprises the light chain. Claims 2-16 are included in this rejection as they incorporate and/or depend on claim 1.
For the purposes of claim interpretation, the antibody will be treated as comprising a light chain, not the allosteric protein.
Regarding claims 4-7, the phrase "naturally occurring end terminus" renders the claim indefinite because it is unclear how an end terminus is defined as naturally occurring.
For the purposes of claim interpretation, the phrase "naturally occurring end terminus" will be treated as any N-terminus or any C-terminus.
Claims 4 and 6 recite the limitation "first naturally occurring end terminus" in line 2 of claim 4 and line 2 of claim 6. There is insufficient antecedent basis for this limitation in the claims.
For the purposes of claim interpretation, the limitation "first naturally occurring end terminus" will refer to any N-terminus or any C-terminus that is distinct from the second naturally occurring end terminus (see 112[b] rejection for claims 5 and 7 below).
Claims 5 and 7 recite the limitation "second naturally occurring end terminus" in line 2 of claim 5 and line 2 of claim 7. There is insufficient antecedent basis for this limitation in the claims.
For the purposes of claim interpretation, the limitation "second naturally occurring end terminus" will refer to any N-terminus or any C-terminus that is distinct from the first naturally occurring end terminus (see 112[b] rejection for claims 4 and 6 above).
Regarding claims 8-9, the phrase "rearrangement of a gene coding region" renders the claim indefinite because it is unclear what constitutes rearrangement of a gene coding region.
For the purposes of claim interpretation, the phrase "rearrangement of a gene coding region" will be treated as any deletion, substitution, or addition to a gene coding region.
Regarding claim 10, the phrase "the first biological activity is an enzyme activity having a first level and the second biological activity is the enzyme activity having a second level different than the first level" renders the claim indefinite because it is unclear (i) what constitutes the first and second levels as enzymatic activity can be assessed in numerous ways and (ii) the degree of the difference between the first and second levels.
For the purposes of claim interpretation, (i) the first and second levels will be interpreted as enzymatic activities measured by spectrophotometry, fluorometry, or colorimetric assays and (ii) the first and second levels will be considered different if said measured enzymatic activities have any detectable difference.
Claims 12 and 14-15 recite the limitation "the membrane channel" in line 1 of claim 12, lines 3-4 of claim 14, and line 1 of claim 15. There is insufficient antecedent basis for this limitation in the claims.
For the purposes of claim interpretation, claims 12 and 14-15 will be treated as dependent on claim 11.
Regarding claims 12 and 15, the phrase "domain external to a membrane" renders the claim indefinite because it is unclear if the phrase indicates the domain is not an intramembrane domain or the domain resides on the extracellular side of the membrane.
For the purposes of claim interpretation, the phrase "domain external to a membrane" will be treated as the domain resides on the extracellular side of the membrane.
Regarding claim 12, the phrase "the permeability" renders the claim indefinite because it is unclear what permeability is being referred to. Claim 11, which claim 12 depends on, recites a first and second permeability. Therefore, the phrase "the permeability" could (i) refer to the first or second permeability of claim 11, (ii) refer to a permeability distinct from the first or second permeability of claim 11, or (ii) be a typographical error wherein the correct phrase is “permeability” alone and is indicative of various permeabilities of a membrane channel.
For the purposes of claim interpretation, the phrase "the permeability" will be treated as a typographical error wherein the correct phrase is “permeability” alone and is indicative of various permeabilities of a membrane channel.
Regarding claim 16, the phrase "the first biological activity protein binding affinity having a first level and the second biological activity is the protein binding affinity having a second level different than the first level" renders the claim indefinite because it is unclear (i) what constitutes the first and second levels as protein binding activity can be assessed in numerous ways and (ii) the degree of the difference between the first and second levels.
For the purposes of claim interpretation, (i) the first and second levels will be interpreted as protein binding activities measured by spectrophotometry, fluorometry, colorimetric assays, or surface plasmon resonance and (ii) the first and second levels will be considered different if said measured protein binding activities have any detectable difference.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 10 and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Su et al. (Noncompetitive homogeneous immunodetection of small molecules based on beta-glucuronidase complementation, Analyst, Issue 9, Pg. 2096-2101, 2018; IDS filed on 05/07/2024 with 50 NPL references, Cite No. 2) as evidenced by Tsai and Nussinov (A Unified View of ‘‘How Allostery Works’’, PLoS Comput Biol, 2014, 10[2]: e1003394).
Claims 1, 10, and 16
Regarding claim 1, Su et al. teach a system for responding to the antigen 4-hydroxy-3 nitrophenylacetyl (NP) comprising a multi-subunit protein having inactive and active conformational states (Pg. 2097, Fig. 1d shown below, mutant β-glucuronidase [GUSm] depicted in green and brown go between inactive GUSm dimers and active GUSm tetramer conformational states upon binding the antigen 4-hydroxy-3 nitrophenylacetyl [NP]). The first conformational state is the inactive GUSm dimers when the antigen is not bound and the second conformation state is the active GUSm tetramer when the antigen is bound; inactive and active states are biological activities. This teaching reads on a system for responding to an antigen comprising a multi-subunit protein having a first conformational state associated with a first biological activity and a second conformational state associated with a second biological activity (claim 1).
Regarding claim 1, Su et al. further teach the system comprises an antibody comprising a heavy chain variable domain (VH) fused to the first dimer of GUSm (Pg. 2097, Fig. 1d shown below, VH shown in blue bound to the first dimer of GUSm) and a light chain variable domain fused (VL) to the second dimer of GUSm (Pg. 2097, Fig. 1d shown below, VL shown in purple bound to the second dimer of GUSm). The GUSm dimers are subunits of the multi-subunit proteins, a GUSm tetramer. This teaching reads on the system comprising an antibody comprising a heavy chain variable domain fused to a first subunit of the multi-subunit protein and a light chain variable domain fused to a second subunit of the multi-subunit protein (claim 1).
Regarding claim 10, Su et al. further teach the active GUSm tetramer forms when NP is bound to VH and VL of antibody and inactive GUSm dimers form when NP is not bound to VH and VL of antibody, conferring a higher enzymatic activity to the active GUSm tetramer. (Pg. 2097, Fig. 1d shown below, active GUSm tetramer forms when NP is bound to VH and VL of antibody and inactive GUSm dimers form when NP is not bound to VH and VL of antibody; Pg. 2098, column 1, ¶ 2, lines 1-4, “After mixing the [GUSm dimers]… in the presence or absence of NP, higher enzymatic activity was observed in the reaction mixture with NP”). The levels of enzyme activity were measured using a “chromogenic substrate” (Pg. 2098, column 1, line 4) in a colorimetric assay and have a detectable difference i.e. the level of enzymatic activity is higher when the antigen NP is bound to VH and VL of the antibody compared to when it is not bound. This teaching reads on the first biological activity is an observable enzyme activity when the antigen is bound to the heavy chain variable domain subunit and the light chain variable domain subunit and the second biological activity is an observable enzyme activity when the antigen is not bound to the heavy chain variable domain subunit and the light chain variable domain subunit (claim 10; see 112[b] for claim interpretation).
Regarding claim 16, Su et al. further teach the GUSm dimers have a higher protein binding affinity to itself in the presence of the antigen compared to in the absence of the antigen as demonstrated through the increase in enzymatic activity (Pg. 2096, Abstract, lines 3-4, “the dimerization of dimers, which is a rate-limiting step, can be effectively inhibited by a set of interface mutations” i.e. GUSm dimers are inactive and protein binding affinity to itself is low; Pg. 2098, column 1, ¶ 2 [bottom], lines 19-22, “Comparing the fluorescence signals generated by the binding of the two fusion proteins in the presence and absence of antigen revealed that the highest response, i.e. a 5-fold increase” for the active GUSm tetramer). The levels of enzymatic activity were measured using fluorescence signals i.e. fluorometry generated by the binding of the GUSm dimers and directly correlate to the levels of protein binding affinity. In addition, the levels of protein binding affinity have a detectable difference i.e. the level of protein binding affinity is higher in the presence of the antigen (GUSm tetramer bound to the antigen) as seen through the increase in enzymatic activity compared to in the absence of the antigen (GUSm dimers not bound to the antigen). This teaching reads on a system wherein the first biological activity is protein binding affinity having a first level and the second biological activity is the protein binding affinity having a second level different than the first level (claim 16; see 112[b] for claim interpretation).
Regarding claim 1, Su et al. further teach inactive GUSm dimers bind antigens at a site physically away from the active site (Pg. 2097, Fig. 1d, the antigen binds to the VH and VL of the antibody not the enzymatic protein containing the active site for the substrate) to form an active GUSm tetramer, as seen through the increase in enzymatic activity (see claim 10 rejection above). Su et al. do not explicitly state that GUSm is an allosteric protein.
However, Tsai and Nussinov state “allostery is capable of altering the active state population [of a protein] by some perturbation away from the active site, such as that elicited by ligand binding” (Pg. 1, column 1, last ¶, lines 6-9) thereby “shifting the population from the inactive to the active state” (Pg. 1, column 2, ¶ 1 [middle], lines 12-13). Tsai and Nussinov further state inactive and active states are considered “two conformational states” (Pg. 2, column 2, ¶ 1, lines 1-2; Pg. 2, Fig. 1, x axis is labeled as conformation and plot depicts inactive and active states).
GUSm as taught by Su et al. is inherently allosteric as evidenced by Tsai and Nussinov and reads on the limitation of an allosteric protein (claim 1).
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Claim 2
Regarding claim 2, Su et al. further teach the VH and VL of the antibody is fused to GUSm via a linker polypeptide (Pg. 2097, column 2, ¶ 2, lines 2-4, “interdomain linker GESKLAAA or KL(GGGGS)3AAA was placed after VH or VL, respectively, followed by GUSm”). Linker polypeptides are fused to both VH and VL of the antibody followed by GUSm. This teaching reads on the allosteric multi-subunit protein is fused to the heavy chain variable domain subunit with a linker polypeptide and the allosteric multi-subunit protein is fused to the light chain variable domain subunit with a linker polypeptide.
Claims 3-5
Regarding claims 3-5, Su et al. further teach the multi-subunit protein was produced using “pET32-VH(NP)-GUSm and pET32-VL(NP)-GS3-GUSm vectors” (Pg. 2100, column 1, ¶ 4 [middle], lines 16-17). Vectors are read N-terminus to C-terminus from left to right. Therefore, the C-terminus of the VH of the antibody is fused to the N-terminus of a first GUSm dimer in a head-to-tail manner and the C-terminus of the VL of the antibody is fused to the N-terminus of a second GUSm dimer in a head-to-tail manner. As the C-termini of VH and VL of the antibody are fused to the N-termini of two different GUSm dimers, this teaching reads on the heavy chain variable domain subunit is fused to a first amino-terminal end of the allosteric multi-subunit protein and the light chain variable domain subunit is fused to a second amino-terminal end of the allosteric multi-subunit protein (claim 3). In addition, the N-termini of the GUSm dimers are naturally occurring and distinct from one another based on the claim interpretation given for claims 4-5 in the 112(b) section; as a result, this teaching also reads on the heavy chain variable domain subunit is fused head to tail with a first naturally occurring end terminus of the allosteric multi-subunit protein (claim 4) and the light chain variable domain subunit is fused head to tail with a second naturally occurring end terminus of the allosteric multi-subunit protein (claim 5).
Su et al. further teach their system is an extension of open sandwich enzyme complementation immunoassay (OS-ECIA, similar to an enzyme-linked immunosorbent assay i.e. ELISA), adapting the immunoassay from β-galactosidase to GUS (Pg. 2099, column 2, ¶ 2, lines 1-5, “This system is an extension of open sandwich enzyme complementation immunoassay (OS-ECIA), wherein the approximation-induced reconstitution of multimeric β-galactosidase activity… is monitored”).
Su et al. further teach OS-ECIA “depends on chemiluminescence detection” (Pg. 2099, ¶ 2, lines 5-6) while their system uses “chromogenic and fluorogenic substrates” (Pg. 2099, column 2, ¶ 2, lines 8-9). This teaching indicates the heavy and light variable domains of the antibody can be fused to different reporter proteins, for example β-galactosidase and GUS, depending on the desired readout i.e. how the activity of the reporter protein is measured.
Accordingly, claims 1-5, 10, and 16 are anticipated by Su et al.
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.
Claims 6-9 and 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Su et al. (Noncompetitive homogeneous immunodetection of small molecules based on beta-glucuronidase complementation, Analyst, Issue 9, Pg. 2096-2101, 2018; IDS filed on 05/07/2024 with 50 NPL references, Cite No. 2) in view of Cornell et al. (A biosensor that switches, Nature, Vol 387, 1997; IDS filed on 05/07/2024 with 21 NPL references, Cite No. 6) and Jiang et al. (Crystal structure and mechanism of a calcium-gated potassium channel, Nature, 417, Pg. 515–522, 2002) as evidenced by Tsai and Nussinov (A Unified View of ‘‘How Allostery Works’’, PLoS Comput Biol, 2014, 10[2]: e1003394).
Claim 11 and 14
Su et al. as delineated in the 102 section teach the limitation of a system for responding to an antigen comprising allosteric multi-subunit GUSm fused to the VH and VL of an antibody in an ELISA-based biosensor. Su et al. indicate that the VH and VL of the antibody can be fused to different reporter proteins depending on the desired readout i.e. how the activity of the reporter protein is measured, meaning the identity of the allosteric multi-subunit protein can be changed.
Su et al. is being provided to address how the VH and VL of the antibody is fused to the allosteric multi-subunit protein in a biosensor and give motivation for changing the identity of the allosteric multi-subunit protein. However, Su et al. do not teach the allosteric multi-subunit protein wherein (i) the first biological activity is a membrane channel opening having a first permeability and the second biological activity is the membrane channel opening having a second permeability different than the first permeability (claim 11) and (ii) the first biological activity and the second biological activity are observable by detecting a change in permeability by measuring electrical conductivity caused by a passage of a plurality of potassium ions through the membrane channel (claim 14).
Cornell et al., on the other hand, is provided for its teaching of ion channel-based biosensors being superior to ELISA-based biosensors and its relevance. Cornell et al. teach an ion channel-based biosensor comprising ion channels linked to antibodies (Pg. 580, column 1, Abstract, “biosensing technique in which the conductance of a population of molecular ion channels is switched by the recognition event”; Pg. 580, column 1, ¶ 2, “ion channels linked to antibodies”).
Regarding claim 11, Cornell et al. further teach the ion channel is active when the antigen not bound to the antibodies, allowing ions pass through the channel (i.e. in a permeable state), and the ion channel is inactive when the antigen is bound, preventing ions from passing through the channel (i.e. not in a permeable state) (Pg. 582, Fig. 1a, depicts ion channel switching from active to inactive states with antigen binding and unbinding to the antibody; Pg. 583, column 2, ¶ 1, “In the absence of analyte, the mobile channels crosslink to the immobilized antibody fragments preventing the formation of dimers and turning off the membrane conductance”). This teaching reads on the first biological activity of a protein is a membrane channel opening having a first permeability and the second biological activity of a protein is the membrane channel opening having a second permeability different than the first permeability (claim 11).
Regarding claim 14, Cornell et al. further teach ions passing through the channel is measured via “electrical conduction of the membrane” (Pg. 580, column 1, ¶ 1). This teaching reads on the first biological activity and the second biological activity are observable by detecting a change in permeability by measuring electrical conductivity caused by a passage of a plurality of ions through the membrane channel (claim 14).
Cornell et al. further teach the biosensor is “very flexible” and “can be used with most types of receptor” (Pg. 580, column 1, Abstract), indicating that varying the biosensor is beneficial for changing the ions detected.
Cornell et al. further teach their biosensor is superior to ELISA-based biosensors as it “requires none of the washing or reagents additions” (Pg. 582, column 2, ¶ 1).
Cornell et al. do not teach the ions passing through the channel are potassium ions (claim 14), the ion channel is allosteric, nor how the antibody is fused to the ion channel. However, Su et al. rectify how the antibody is fused.
Jiang et al., in addition, is being provided to for its teaching of an allosteric multi-subunit potassium ion channel that can be incorporated into a biosensor as taught in Su et al. and Cornell et al. Regarding claim 14, Jiang et al. teach a crystal structure of the allosteric calcium-gated potassium ion channel MthK (Pg. 515, Abstract, crystal structure of calcium-gated potassium ion channel MthK; Pg. 521, column 1, ¶ 2, MthK undergoes “ligand-induced conformational changes” i.e. it is allosteric based on calcium binding). This teaching reads on MthK being allosteric and a plurality of potassium ions through the membrane channel (claim 14).
Jiang et al. further teach MthK comprises multiple domains (Pg. 515, Abstract, “Eight RCK domains”). This teaching reads on MthK being a multi-subunit protein.
Jiang et al. do not teach a system for responding to the presence of an antigen wherein the ion channel is fused to an antibody. However, Su et al. and Cornell et al. address this failing and teach said system.
Biosensors comprising allosteric enzymes or ion channels fused to antibodies were known and used prior to the effective filing date of the application. The prior art sources are analogous because Su et al. and Cornell et al. teach biosensors fused to antibodies, which is in the same field of endeavor as the present invention. Concurrently, Cornell et al. teach that biosensors fused to antibodies include interchangeable ion channels and the identity of these ion channels is flexible, thus allowing for the addition of the ion channel MthK disclosed by Jiang et al to such biosensors. Therefore, a person having ordinary skill in the art would reasonably consider using the ion channel MthK as taught by Jiang et al. in the biosensors as taught by Su et al. and Cornell at al.
Since (i) Su et al. teach the heavy and light variable domains of the antibody in their ELISA-based biosensor can be fused to different proteins, (ii) Cornell et al. teach the ion channel in their biosensor is flexible in identity and their biosensor is superior to ELISA-based biosensors as it requires none of the washing or reagents additions, and (iii) Jiang et al. teach the allosteric ion channel MthK detects potassium ions, there is motivation for using MthK in an ion channel biosensor fused to an antibody.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. Cornell et al. teach the ion channel in their biosensor is flexible in identity and their biosensor is superior to ELISA-based biosensors as it requires none of the washing or reagents additions; Jiang et al. teach the allosteric ion channel MthK detects potassium ions) would have led one of ordinary skill to modify the prior art reference (i.e. a biosensor comprising an allosteric enzyme fused to an antibody wherein the antibody is known to be fused to different multi-domain proteins, applicable to MthK) to arrive at the claimed invention.
There is a reasonable expectation of success as biosensors comprising allosteric enzymes or ion channels fused to antibodies were known and used prior to the effective filing date of the application. In addition, the prior art sources are analogous because Su et al. and Cornell et al. teach biosensors fused to antibodies, which is in the same field of endeavor as the present invention. Concurrently, Cornell et al. teach that biosensors fused to antibodies include interchangeable ion channels and the identity of these ion channels is flexible, thus allowing for the addition of the ion channel MthK disclosed by Jiang et al to such biosensors. Therefore, a person having ordinary skill in the art would reasonably consider using the ion channel MthK as taught by Jiang et al. in the biosensors as taught by Su et al. and Cornell at al.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the allosteric potassium ion channel MthK as taught by Jiang et al. in a biosensor comprising an ion channel fused to an antibody as taught by Su et al. and Cornell et al.
Claims 6-9
Regarding claims 6-9, Jiang et al. further teach MthK variants with and without an M107I mutation, corresponding to the addition and deletion of a 26k gene product respectively on the N-terminus (Pg. 517, Fig. 3, [a] shows gene product being deleted and added and [d-e] shows protein products). This teaching reads on a portion of the allosteric multi-subunit protein MthK being removed (claims 6-7) and a rearrangement of a gene coding region creating a new N terminus (claims 8-9; see 112[b] for claim interpretation).
Claim 12
Regarding claim 12, Jiang et al. further teach MthK comprises a domain residing external to a membrane and said domain affects permeability (Pg. 515, Fig. 1, “ligand receptor is usually located at the membrane surface on the extracellular side”; Pg. 515, column 1, ¶ 3, the basic function of the ligand-binding to MthK is to “change its conformation between closed and opened states,” which affects permeability). This teaching reads on the membrane channel further comprises a domain residing external to a membrane wherein the domain affects the permeability of the membrane channel (claim 12).
Claim 13
Regarding claim 13, Jiang et al. further teach MthK is a cytoplasmic gating-ring octamer (Pg. 517, column 1, ¶ 1, “the structure formed by the eight RCK domains as the gating ring” on its intracellular surface i.e. in the cytoplasm). This teaching reads on the allosteric multi-subunit protein comprises MthK, and wherein the MthK further comprises a cytoplasmic gating-ring octamer (claim 13).
Accordingly, claims 6-9 and 11-14 are rendered obvious over Su et al. in view of Cornell et al. and Jiang et al.
Claim 15 rejected under 35 U.S.C. 103 as being unpatentable over Su et al. (Noncompetitive homogeneous immunodetection of small molecules based on beta-glucuronidase complementation, Analyst, Issue 9, Pg. 2096-2101, 2018; IDS filed on 05/07/2024 with 50 NPL references, Cite No. 2) in view of Cornell et al. and Coyote-Maestas et al. (Domain insertion permissibility-guided engineering of allostery in ion channels, Nat Commun, 2019 Jan 17;10[1]:290) as evidenced by Tsai and Nussinov (A Unified View of ‘‘How Allostery Works’’, PLoS Comput Biol, 2014, 10[2]: e1003394).
Claim 15
Su et al. as delineated in the 102 section teach the limitation of a system for responding to an antigen comprising allosteric multi-subunit GUSm fused to the VH and VL of an antibody in an ELISA-based biosensor. Su et al. indicate that the VH and VL of the antibody can be fused to different reporter proteins depending on the desired readout i.e. how the activity of the reporter protein is measured, meaning the identity of the allosteric multi-subunit protein can be changed.
Su et al. is being provided to address how the VH and VL of the antibody is fused to the allosteric multi-subunit protein in a biosensor and give motivation for changing the identity of the allosteric multi-subunit protein. However, Su et al. do not teach the allosteric multi-subunit protein is a membrane channel and its permeabilities nor that the membrane channel does not include a domain external to a membrane (claim 15).
Cornell et al., on the other hand, is provided for its teaching of ion channel-based biosensors being superior to ELISA-based biosensors and its relevance. Cornell et al. as delineated in the previous 103 rejection teach an ion channel-based biosensor comprising ion channels linked to antibodies and its permeabilities, the identity of the ion channel is flexible depending on the desired ions detected, and their biosensor is superior to ELISA-based biosensors.
Cornell et al. do not teach the membrane channel does not include a domain external to a membrane (claim 15), the ion channel is allosteric, nor how the antibody is fused to the ion channel. However, Su et al. rectify how the antibody is fused.
Coyote-Maestas et al., in addition, is being provided to for its teaching of an allosteric multi-subunit potassium ion channel without a domain external to the membrane that can be incorporated into a biosensor as taught in Su et al. and Cornell et al. Coyote-Maestas et al. teach “G-protein-gated inward rectifier K+ ion channel” Kir2.1 is allosteric (Pg. 1, Abstract; Pg. 3, Fig. 1a, depicts Kir2.1 shifting from closed to open conformation upon binding its ligand PIP2).
Regarding claim 15, Coyote-Maestas et al. further teach Kir2.1 comprises multiple domains, with no domains in the extracellular region (Pg. 3, column 1, ¶ 1, Kir2.1 is tetrameric; Pg. 3, Fig. 1a, depicts loop extracellularly but no distinct domain). This teaching reads on the membrane channel does not include a domain external to a membrane (claim 15).
Coyote-Maestas et al. do not teach a system for responding to the presence of an antigen wherein the ion channel is fused to an antibody. However, Su et al. and Cornell et al. address this failing and teach said system.
Biosensors comprising allosteric enzymes or ion channels fused to antibodies were known and used prior to the effective filing date of the application. The prior art sources are analogous because Su et al. and Cornell et al. teach biosensors fused to antibodies, which is in the same field of endeavor as the present invention. Concurrently, Cornell et al. teach that biosensors fused to antibodies include interchangeable ion channels and the identity of these ion channels is flexible, thus allowing for the addition of the ion channel Kir2.1 disclosed by Coyote-Maestas et al. to such biosensors. Therefore, a person having ordinary skill in the art would reasonably consider using the ion channel Kir2.1 as taught by Coyote-Maestas et al. in the biosensors as taught by Su et al. and Cornell at al.
Since (i) Su et al. teach the heavy and light variable domains of the antibody in their ELISA-based biosensor can be fused to different proteins, (ii) Cornell et al. teach the ion channel in their biosensor is flexible in identity depending on the desired ions detected and their biosensor is superior to ELISA-based biosensors as it requires none of the washing or reagents additions, and (iii) Coyote-Maestas et al. teach the allosteric ion channel Kir2.1 with no domains external to the membrane detects potassium ions, there is motivation for using Kir2.1 in an ion channel biosensor fused to an antibody.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. Cornell et al. teach the ion channel in their biosensor is flexible in identity depending on the desired ions detected and their biosensor is superior to ELISA-based biosensors as it requires none of the washing or reagents additions; Coyote-Maestas et al. teach the allosteric ion channel Kir2.1 with no domains external to the membrane detects potassium ions) would have led one of ordinary skill to modify the prior art reference (i.e. a biosensor comprising an allosteric enzyme fused to an antibody wherein the antibody is known to be fused to different multi-domain proteins, applicable to Kir2.1) to arrive at the claimed invention.
There is a reasonable expectation of success as biosensors comprising allosteric enzymes or ion channels fused to antibodies were known and used prior to the effective filing date of the application. In addition, the prior art sources are analogous because Su et al. and Cornell et al. teach biosensors fused to antibodies, which is in the same field of endeavor as the present invention. Concurrently, Cornell et al. teach that biosensors fused to antibodies include interchangeable ion channels and the identity of these ion channels is flexible depending on the desired ions detected, thus allowing for the addition of the ion channel Kir2.1 disclosed by Coyote-Maestas et al to such biosensors. Therefore, a person having ordinary skill in the art would reasonably consider using the ion channel Kir2.1 (with no domain external to the membrane) as taught by Coyote-Maestas et al. in the biosensors as taught by Su et al. and Cornell at al.
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the allosteric potassium ion channel Kir2.1 as taught by Coyote-Maestas et al. in a biosensor comprising an ion channel fused to an antibody as taught by Su et al. and Cornell et al.
Accordingly, claim 15 is rendered obvious over Su et al. in view of Cornell et al. and Coyote-Maestas et al.
Conclusion
Claims 1-16 are pending. Claim 16 is objected to. Claims 1-16 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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