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 .
Claims 1-20 are pending and under examination.
Priority
Applicant' s claim for the benefit of a prior-filed provisional application 63/309,092 filed on 2/11/2022 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Drawings
The drawings filed on 08/09/2024 are accepted.
Specification
The specification filed on 08/09/2024 is accepted.
Claim Objections
Claims 1, 16 and 17 are objected to because of the following informalities:
The Examiner recommends reciting the full name of the receptor (nAChR) and genes followed by their abbreviations in claim 1 (e.g., “a heterologous nucleic acid encoding Choline O-Acetyltransferase (CHAT)”.
The Examiner recommends reciting the abbreviation “(PAM)” in the preamble following the first recitation of “positive allosteric modulators” in claims 16 and 17. Appropriate correction is required.
Claim Interpretation
Claim 3 recites “wherein the a6 subunit of nAChR is an a6/3 chimera in which a full or partial sequence of a second intracellular loop (ICL) of the a6 subunit is replaced by a corresponding sequence of a second ICL of an a3 subunit of nAChR, and wherein the a6/3 chimera and the b2 and b3 subunits of nAChR form a chimeric a6/3b2b3 nAChR.”
Claim 9 recites “The isolated recombinant cell of claim 3, wherein the second ICL of the a6 subunit comprises an amino acid sequence with at least 95% identity to the amino acid sequence of SEQ ID NO: 2 and the second ICL of the a3 subunit comprises an amino acid sequence with at least 95% identity to the amino acid sequence of SEQ ID NO: 4.” This recitation is interpreted to read on isolated recombinant cells where anywhere from one amino acid (e.g., partial) to the full sequence of SEQ ID NO: 2 is replaced by anywhere from one amino acid to the full sequence (e.g., corresponding) of SEQ ID NO: 4. See 112(b) rejection below for further examination/interpretation of the claim language of claims 3 and 9.
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 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.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
Claim 1 recites “An isolated recombinant cell comprising: a) a heterologous nucleic acid encoding an a6 subunit of nAChR; b) a heterologous nucleic acid encoding BARP; c) a heterologous nucleic acid encoding SULT2B1; d) a heterologous nucleic acid encoding LAMP5; e) a heterologous nucleic acid encoding CHAT; and f) a heterologous nucleic acid encoding NACHO.”
The claims are broad for generically reciting the genes/proteins that are encoded by the recited heterologous nucleic acids. Claims 6-15 further limit the sequences of the alpha and beta subunits and genes/proteins. No claim recites more than one subunit or gene/protein sequence (e.g., claim 6 further limits the sequence of the alpha6 subunit, but no claim further limits the sequences of the alpha6, beta2, and beta3 subunits together).
Further, the specification fails to provide guidance for an artisan to determine what alpha6-containing subunits of nAChR may be encoded by a heterologous nucleic acid. The only alpha6-containing nAChR taught in the working example teaches a recombinant cell comprising a heterologous nucleic acid encoding chimeric alpha6/3beta2beta3 nAChR (see pg. 23). No other nAChRs are disclosed in the working example. Otherwise, the specification generically contemplates alpha6-containing nAChRs, but does not further define them structurally.
The art recognizes the importance of the specificity of the alpha6 subunit of nAChR encoded in a recombinant cell.
Hurst, Raymond, Hans Rollema, and Daniel Bertrand. "Nicotinic acetylcholine receptors: from basic science to therapeutics." Pharmacology & therapeutics 137.1 (2013): 22-54. states “Given its unusual expression in the central nervous system, this subunit [alpha6] has received much attention, but difficulties to express the α6 subunit in heterologous systems raised the question whether α6 could participate in, or contribute to, the ligand-binding site. However, the construction of a fusion protein between the α6 and α4 subunit in which the N-terminal domain that contains the major component of the binding site was made from α6 fused with the transmembrane domains (TM1–TM4) of α4, demonstrated that functional α6 containing receptors could be obtained when expressed with β4” (pg. 26, “2.4.The CHRNA6 gene”). In summary, Hurst et al. teaches that alpha6 alone is difficult to express in heterologous systems, but fusion alpha6 subunits produce improved outcomes.
Akaike, Akinori, Shun Shimohama, and Yoshimi Misu. "Nicotinic acetylcholine receptor signaling in neuroprotection." (2018). also teaches that the α6 subunit can form a functional receptor when co-expressed with β4 in vitro, but not alone (pg. 5, para 1). Table 1.1 specifically teaches α6β2β3, α6α4β2β3 as the primary subunit composition of alpha6-containg nAChRs.
Hone, Arik J., et al. "α-Conotoxin PeIA [S9H, V10A, E14N] potently and selectively blocks α6β2β3 versus α6β4 nicotinic acetylcholine receptors." Molecular Pharmacology 82.5 (2012): 972-982. investigated ligands that bind alpha6beta2 nAChRs and the closely related alpha6beta4 subtype in order to distinguish between the two. The authors state “We used rat and mouse 6/3 subunit chimeras to model the alpha6beta2 and alpha6beta4 ligand-binding domain because injection of nonchimeric 6 with 2 and 3 fails to reliably produce functional expression” (pg. 973, col 1, para 3). Hone et al. also notes that chimeric subunits may respond to agents differently. For example, alpha6beta2 and alpha6beta4-containing nAChRs did not share the same response to the toxin PeIA[S9H,V10A,E14N], with the toxin having selectivity for alpha6beta2-containing receptors (and therefore being potentially useful in differentiating between the two subunits) (pg. 980, col 2).
Claims 16-20 are broad for reciting a method for identifying whether a genus of agents have the functional property of being agonists, positive allosteric modulators, or antagonists of alpha6 containing nAChR (claim 16) or alpha6beta2beta3 nAChR (claim 17), which reasonably encompasses a broad range of molecules, compounds, and peptides.
Disclosure of putative structures having a theorized function in the absence of experimental data demonstrating the theorized function is insufficient to demonstrate possession of a representative number of species by disclosure of relevant, identifying characteristics (i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics), sufficient to show the applicant was in possession of the claimed invention.
Whether an agent has the functional characteristic of being an agonist, PAM, or antagonist is determined by function. For example, an agent has the functional characteristic of being an agonist of alpha6 nAChR if it “enhances” the activity of alpha6 nAChR. Pg. 21 of the specification states:
“the term "enhance", "enhanced", "increase", or "increased", when used with respect to a6b2b3 nAChR (including chimeric a6/3b2b3 nAChR as described above) activity refers to an increase in the signaling through the receptor, relative to the corresponding signaling observed in a cell in which an agonist or PAM is not administered.”
“Antagonists, as used herein, refer to molecules/compounds/peptides that serve to block, decrease, or dampen the function of the a6b2b3 nAChR (including chimeric a6/3b2b3 nAChR as described above).”
Although agonists and PAMs are recited as different types of agents in the claims, the claims only recite a way to differentiate agonists and PAMs from antagonists, not agonists from PAMs. The specification differentiates between agonists and PAMs as:
“Agonists, as used herein, refer to molecules/compounds/peptides that serve to enhance the function of the a6b2b3 nAChR (including chimeric a6/3b2b3 nAChR as described above). PAMs, as used herein, refer to molecules/compounds/peptides that enhance the effect of a6b2b3 nAChR's (including chimeric a6/3b2b3 nAChR as described above) response to a ligand without directly activating the receptor.”
According to the specification, a PAM is a species of agonists. However, the specification and claim language do not provide further guidance on how an artisan would determine if an agonist is a PAM (nor what structure a PAM would have that other agonists would not, for example). Further, the specification distinguishes PAMs from agonists in terms of their functionality with alpha6beta2beta3 nAChR, but does not mention alpha6 nAChR (e.g., with alpha6beta2beta3 nAChR being a species of alpha6 nAChR).
The claims fail to recite, and the specification fails to disclose, the structure/function nexus of the vast genus of structures that have the functional property of being an agonist, antagonist, or PAM.
While applicant recite examples of antagonists (pg. 27), possession has not been demonstrated for identifying the generically recited genus of undisclosed structures that necessarily and predictably possess the functional property of being an antagonist of alpha6 nAChR, for example. No examples of agonists or PAMs are provided.
In summary, while the specification includes some characterizations of agonists, positive allosteric modulators, or antagonists of alpha6 containing nAChR (claim 16) or alpha6beta2beta3 nAChR (claim 17), it does not offer further guidance on the metes and bounds of the structure of agents that are agonists, positive allosteric modulators, or antagonists of alpha6 containing nAChR (claim 16) or alpha6beta2beta3 nAChR (claim 17).
Yang, Kc., Jin, Gz. & Wu, J. Mysterious α6-containing nAChRs: function, pharmacology, and pathophysiology. Acta Pharmacol Sin 30, 740–751 (2009). is considered relevant prior art for teaching various ways to determine if an agent is an antagonist of alph6 nAChR. Yang et al. reviewed the functional and pharmacological profiles of α6*-nAChRs. Yang et al. notes “it is still a challenge to develop selective agonists and antagonists for α6*-nAChRs due to the complex subunit combinations of naturally expressed α6*-nAChRs and poor function in heterologous expression systems.” (pg. 743, col 2, para 3). Yang et al. teaches methods for determining if an agent is an antagonist or agonist of alpha6 nAChR include electrophysiological recordings (e.g., patch clamp) and in vivo microdialysis (pg. 744, col 1, para 1). Yang et al. demonstrates that measuring calcium flux of a cell is not the only way to determine whether an agent is an agonist or antagonist (e.g., other function al characteristics may be considered).
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
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 3 and 9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites “wherein the a6 subunit of nAChR is an a6/3 chimera in which a full or partial sequence of a second intracellular loop (ICL) of the a6 subunit is replaced by a corresponding sequence of a second ICL of an a3 subunit of nAChR, and wherein the a6/3 chimera and the b2 and b3 subunits of nAChR form a chimeric a6/3b2b3 nAChR.” It is unclear what the “corresponding” sequence would be. How would an artisan determine if a sequence is corresponding or not? The specification does not provide further guidance on the metes and bounds of “corresponding”. Claim 9 further limits the sequence of alpha6 that is replaced and the sequence of alpha3 that takes its place, raising the question of whether multiple sequences of a3, for example, may replace the same alpha6 sequence (e.g., can multiple sequences of alpha3 correspond to a singular alpha6 sequence?). For examination purposes, an alpha6 subunit where the full or partial sequence of its second ICL is replaced by a second ICL from an alpha3 subunit is interpreted to read on the claim language.
Claim 3, which depends upon claim 1, recites the limitation " wherein the a6/3 chimera and the b2 and b3 subunits of nAChR form a chimeric a6/3b2b3 nAChR" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. The recitation is indefinite because there is no prior reference to b2 and b3 subunits of nAChR in claim 3, and there is nothing implicit in claim 1, from which claim 3 depends upon, that would inherently require the presence of b2 and b3 subunits of nAChR. Therefore, the metes and bounds of the claim is not clearly and precisely defined. It would be remedial to amend claim 3 to depend upon claim 2, which recites b2 and b3 subunits of nAChR.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 16-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claim(s) recite(s) method(s) for identifying agonists, antagonists, or positive allosteric modulators of a6 containing nAChR (a6b2b3 nAChR- claim 17), the method(s) comprising:
a) contacting the isolated recombinant cell of claim 1 with an agent; and
b) determining the activity of the a6 containing nAChR of the isolated recombinant cell, wherein the agent is identified as an agonist or positive allosteric modulator (PAM) if the agent enhances the activity of the a6 (a6b2b3) containing nAChR and the agent is identified as an antagonist if the agent decreases the activity of the a6 containing nAChR as compared to the activity of the a6 (a6b2b3) containing nAChR when the isolated recombinant cell was not contacted with the agent.
According to the 2019 Revised Patent Subject Matter Eligibility Guidelines (2019PEG), the claim is first analyzed to determine if it is directed to one of the acceptable statutory categories of invention (i.e., process, machine, manufacture, or composition of matter). Claims 16 and 17 are drawn to methods for identifying agonists, antagonists, or positive allosteric modulators (i.e., a process). Thus, claims 16 and 17 meet the requirements for step 1 analysis.
Second, the claim is assessed to determine if it is directed to a judicial exception under step 2A. Under 2019PEG, “directed to” is determined via a two-prong inquiry: (1) Does the claim recite a law of nature, a product of nature, a natural phenomenon, or an abstract idea; and (2) Does the claim recite additional element(s) that integrate the judicial exception into a practical application. The phrase, “integration of a practical application”, requires the presence of an additional claim element(s) or a combination thereof to apply, rely on, or use the judicial
exception in a manner that imposes a meaningful limitation on the judicial exception, such that the claim does not monopolize the judicial exception (See MPEP § 2106.05 for examples of
integration of practical application).
Regarding the first prong (1), claims 16 and 17 are directed to methods for identifying agonists, antagonists, or positive allosteric modulators of a6 (a6b2b3) containing nAChR, comprising contacting a cell with an agent and determining the activity of a6 (a6b2b3) containing nAChR following exposure to the agent. The broadest reasonable interpretation of “determining the activity of the a6 containing nAChR of the isolated recombinant cell” encompasses mental processes such as observations, evaluations, and judgements that can be performed in the human mind (i.e., abstract idea). Additionally, the determining step is recited at a high level of generality, and is merely an extra-solution activity (see MPEP 2106.05(g)). There is no claim language that describes how the act of determining the activity is carried out (i.e., further method steps), only that the activity is compared to a control, which is not an active method step (i.e., comparison further describes the result, not the process). Claims 18-20, which depend upon claim 17, further limit what activity is determined (e.g., calcium flux), but again, still encompass abstract ideas that can be performed in the human mind, as there is still no claim language describing the act of determining. As such, claims 16-20 are drawn to an abstract idea and the first prong of the inquiry demonstrates that the claim is directed to a judicial exception.
Regarding the second prong (2), claims 16 and 17 recite the method steps: “contacting the isolated recombinant cell of claim 1 (claim 2) with an agent. The step of contacting a cell, in addition to the step of “determining the activity” of the a6 AChR, fails to integrate the judicial exception into a practical application that is markedly different/substantially more than culturing/exposing a cell to a molecule. Since claims 18-20 only further limit activity is determined, as discussed above, they also fail to integrate the judicial exception into a practical application that is markedly different/substantially more than culturing a tissue sample. Thus, claims 16-20 meet the requirement of step 2A as being directed to a judicial exception.
Third, if a judicial exception is present in the claim, it is further assessed to determine if
the claims recite any additional elements or steps that are sufficient to ensure that the claim as
a whole amounts to significantly more than the judicial exception. As discussed above, the
additional elements recited in the claims are a generically recited contacting step or limit what an activity determined may be, neither of which further limit the abstract idea judicial exception. In addition, the steps and limitation(s) of what activity is determined (and whether the agent is an antagonist, agonist, or PAM) does not impart any particular structural or functional limitation that further limits the generic nature of the abstract idea of determining the activity of a cell, nor further limits the generic recitation of contacting a cell. Thus, claims 16-20 do not meet the requirement for step 2B of the analysis.
In conclusion, claims 16-20 do not meet all the requirements of the 2019PEG subject matter patentability. Therefore, the claim is deemed patent ineligible.
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) 1-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gu et al. 2019 (Gu, Shenyan, et al. "α6-Containing nicotinic acetylcholine receptor reconstitution involves mechanistically distinct accessory components." Cell Reports 26.4 (2019): 866-874.) and further in view of Gu et al. 2020 (Gu, Shenyan, et al. "Hair cell α9α10 nicotinic acetylcholine receptor functional expression regulated by ligand binding and deafness gene products." Proceedings of the National Academy of Sciences 117.39 (2020): 24534-24544.).
Regarding claim 1, Gu et al. 2019 teaches co-transfected HEK293T cells (claims 4 and 5) with α6β2β3 (claim 2) and NACHO, BARP (i.e., GenBank:XM_017026555, shares at least 95% identity with instant SEQ ID NO: 8- claim 11), LAMP5 (i.e., GenBank:NM_012261, shares at least 95% identity with instant SEQ ID NO: 10- claim 13), and SULT2B1 (i.e., GenBank:NM_177973, shares at least 95% identity with instant SEQ ID NO: 9- claim 12) (e.g., Fig. 1B).
Gu et al. 2019 does not teach the recombinant cells also comprising a heterologous nucleic acid encoding CHAT.
An artisan, interested in expressing nAChRs in mammalian cell lines, would be aware of Gu et al. 2020 for investigating how alpha9alpha10 nAChR functional expression is regulated by ligand binding and gene products.
Gu et al. 2020 investigated the regulation of α9α10 nicotinic acetylcholine receptor functional expression by ligand binding. Part of the investigation involved transfecting HEK293T cells with plasmids encoding CHAT (i.e., NM_020984, shares at least 95% identity with instant SEQ ID NO: 11- claim 14), α9α10, and TMIE (e.g., Fig. 3). Additionally, Gu et al. 2020 teachers transfecting HEK cells with TMEM35 (also known as NACHO) (i.e., NM_021637, shares at least 95% identity with instant SEQ ID NO: 12- claim 15) (e.g., pg. 24542, col 1, “Genes and Materials”).
cDNA screenings conducted by Gu et al. found that choline acetyltransferase (ChAT), the biosynthetic enzyme for ACh, synergizes with TMIE or TMEM132e to enable α9α10 receptor function. This synergy reflects the fact that functional α9α10 expression strictly requires ligand-binding, which can be provided by extracellular application of ACh or the membrane impermeable polypeptide antagonist α-bungarotoxin (α-Bgt). (pg. 245335, col 1, para 2).
Gu et al. 2020 note that biochemical and electrophysiological studies of recombinant receptors demonstrate that TMIE functions as an auxiliary subunit that associates stably with α9α10 on the cell surface and modulates channel gating. This is analogous to auxiliary subunit BARP, which modulates mammalian α6β2β3 (e.g., pg. 24540, col 1, para 2).
It would have been obvious to one of ordinary skill in the art at the effective filing date of the current invention to modify the recombinant cell taught by Gu et al. 2019 by adding a heterologous nucleic acid encoding CHAT as taught by Gu et al. 2020. An artisan would have a reasonable expectation for success because both references teach transfecting HEK293T cells with plasmids comprising heterologous proteins and nAChRs, including chimeric nAChRS. Further, Gu et al. 2020 teaches constructing an analogous α9/α6chimera that was cotransfected with CHAT (e.g., Fig.4A). Both α9 wild-type and α9/α6 loop chimera showed enhanced assembly when cotransfected with ChAT or when pre incubated with MLA (Fig. 4C), which permeates cell membranes. (e.g., pg. 245337, col 1, last para). One would be motivated to make this addition to the recombinant cell taught by Gu et al. 2019 because as taught by Gu et al. 2019, BARP promotes a6b2b3 assembly and enhances gating of alpha6beta2beta3 (e.g., 872, col 1, paras 3 and 4). As mentioned above, Gu et al. 2020 relates TMIE’s function as an auxiliary subunit for alpha9alpha10 to BARP’s function for alpha6beta2beta3. Since Gu et al. 2020 found that CHAT synergizes with TMIE to enable α9α10 receptor function, an artisan would similarly be motivated to add CHAT to the recombinant cell of Gu et al. 2019 comprising nucleic acids encoding BARP and alpha6-containing nAChRs.
Regarding claim 3, Gu et al. 2019 teaches an a6 chimera that contains the intracellular loop between TM3 and TM4 from a3. This a6/3b2b3 was transfected into HEK cells with NACHO and with BARP (e.g., pg. 869, col 1). Alpha/3beta2beta3 was not co-transfected into a recombinant cell with BARP, SULT2B1, LAMP5, CHAT, and NACHO.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the alpha6 subunit taught by Gu et al. 2019 with the alpha6/3 chimera also taught by Gu et al. 2019 with a reasonable expectation for success. An artisan would have a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06.
One would be motivated to substitute alpha6 for the alpha6/3 chimera because as taught by Gu et al. 2019, a6/3 chimera in combination with b2 and b3* + NACHO yields robust ACh-evoked currents in transfected HEK cells. Additionally, an a6 chimera that contains the intracellular loop between TM3 and TM4 from a3 enables some functional expression in cell lines (e.g., pg. 869, col 1).
Regarding claim 6, the alpha6 subunit comprises an amino acid sequence with at least 95% identity to SEQ ID NO: 1 (i.e., GenBank: NM_004198) (e.g., pg. e1, CHRNA6 under “Recombinant DNA”).
Regarding claim 7, the beta2 subunit comprises an amino acid sequence with at least 95% identity to SEQ ID NO: 6 (i.e., GenBank: NM_000748) (e.g., pg. e1, CHRNB2 under “Recombinant DNA”).
Regarding claim 8, the beta3 subunit comprises an amino acid sequence with at least 95% identity to SEQ ID NO: 7 (i.e., GenBank: NM_000749) (e.g., pg. e1, CHRNB3 under “Recombinant DNA”).
Regarding claims 9 and 10, Gu et al. 2019 teaches replacing the second ICL of alpha6, represented by a sequence with at least 95% identity to SEQ ID NO: 2 (corresponds to amino acids 338-465 of instant SEQ ID NO: 1), with the second ICL of alpha3, represented by a sequence with at least 95% identity to SEQ ID NO: 4 (corresponds to amino acids 329-464 of instant SEQ ID NO: 3, which represents the alpha3 subunit) , resulting in an alpha6/3 chimera comprising a sequence with at least 95% identity to SEQ ID NO: 5 (e.g., pg. e1, a6/a3chimera (a6-loop 338:465 is replaced with a 3-loop 339:464) under “Recombinant DNA”).
Regarding claim 15, Gu et al. 2019 teaches identifying genes, including NACHO (i.e., TMEM35), by screening Origene’s transmembrane domain collection and a cDNA library from the Broad Institute (e.g., pg. 867, “Genome-wide cDNA Screening Identifies Multiple Accessories for a6* nACh Receptor Reconstitution”, para 3). A search of these databases return GenBank: NM_021637 as the sequence of TMEM35 (see Origene TMEM35 NPL). NM_021637 shares at least 95% identity with instant SEQ ID NO: 12. Therefore, absent evidence on the contrary, an artisan may reasonably conclude that GenBank: NM_021637 was used for NACHO in the experiments conducted in Gu et al. 2019.
Additionally, as mentioned above, Gu et al. 2020 teachers transfecting HEK cells with TMEM35 (also known as NACHO) (i.e., NM_021637, shares at least 95% identity with instant SEQ ID NO: 12) (e.g., pg. 24542, col 1, “Genes and Materials”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the NACHO sequence taught by Gu et al. 2019 with the NACHO sequence taught by Gu et al. 2020 with a reasonable expectation for success. An artisan would have a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06. Further, replacing a sequence with another has long been done in the molecular biology art and would be routine.
Regarding claims 16-20, Gu et al. 2019 teaches performing FLIPR assays for Ca2+ influx in the recombinant HEK cells, including in the presence of agonists, PAMs, and antagonists (e.g., CTX MII) (e.g., Fig 1; pg. e2, “Cell culture and transfection”, “FLIPR assay for Ca2+ influx in HEK cells and neuron”).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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ALLISON M. JOHNSON
Examiner
Art Unit 1638
/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638
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