DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of invention Group I (claim(s) 1-7 drawn to modified cells for use in a method for identifying modulators of IL-17 receptors) in the reply filed on 2/05/2026 is acknowledged.
3. The election without traverse filed 2/05/2025 is acknowledged. Claims 8-20 are withdrawn. Claims 1-7 are pending and under examination.
Information Disclosure Statement
4. The information disclosure statement (IDS) 1/26/2026 and the references cited therein have been considered, unless indicated otherwise.
Claim Rejections - 35 USC § 112
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.
5. The term “a protease that is functional on the protease recognition site” in claim 1 (section ii) is a relative term which renders the claim indefinite. The term “functional on” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The word at least introduces a range of possibilities and even wider in some interpretations which causes ambiguity. The rationale for avoiding such phrasing comes down to accuracy, reproducibility and the proper
representation of uncertainty.
6. The term “configured as a first fusion protein and second fusion protein” in claim 1 (section i and ii) is a relative term which renders the
claim indefinite. The term “configured as” is not defined by the claim, the specification does not
provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art
would not be reasonably apprised of the scope of the invention. The word at least introduces a
range of possibilities and even wider in some interpretations which causes ambiguity. The
rationale for avoiding such phrasing comes down to accuracy, reproducibility and the proper
representation of uncertainty.
7. The term “a promoter that is functional with transcriptional transactivator” in claim 1 (section iii) is a relative term which renders the claim indefinite. The term “functional with” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The word at least introduces a range of possibilities and even wider in some interpretations which causes ambiguity. The rationale for avoiding such phrasing comes down to accuracy, reproducibility and the proper representation of uncertainty.
8. The term “functional with” in claim 4 is a relative term which renders the claim indefinite. The term “functional with” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The word at least introduces a range of possibilities and even wider in some interpretations which causes ambiguity. The rationale for avoiding such phrasing comes down to accuracy, reproducibility and the proper representation of uncertainty.
9. The term “functional to cleave” in claim 5 is a relative term which renders the claim indefinite. The term “functional to cleave” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The word at least introduces a range of possibilities and even wider in some interpretations which causes ambiguity. The rationale for avoiding such phrasing comes down to accuracy, reproducibility and the proper representation of uncertainty.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
5. Claims 1-7 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
The instant claims are drawn to modified cells for use in a method for identifying modulators of interleukin 17 (IL-17) receptors, wherein; the modified cells express an IL-17 receptor that forms a heteromer comprising separate proteins upon activation by ligand binding, wherein at least one of the proteins that forms the heteromer is configured as a first fusion protein that includes a protease recognition site and a transcription transactivator segment, said protease recognition site being configured to liberate the transcription transactivator upon protease cleavage of the protease recognition site; ii) wherein the cells express an activating protein configured as a second fusion protein, wherein the second fusion protein localizes to the heteromer when formed, and wherein the second fusion protein comprises an activating protein and a protease that is functional on the protease recognition site; iii) wherein the cells further comprise a sequence encoding a reporter protein that is operably linked to a promoter that is functional with the transcriptional transactivator once liberated from the first fusion protein such that expression of the reporter protein driven by the liberated transcriptional activator signifies activation of the receptor; wherein the heteromer comprises a heterodimer; wherein the IL- 7 receptor can be activated by IL- 7A, IL- 7F, IL- 7E, IL- 7C, or a combination thereof; wherein the first fusion protein comprises a transcription transactivator that is functional with a tetracycline responsive element; wherein the second fusion protein comprises an Act1-tobacco etch virus (TEV) protease that is functional to cleave the first fusion protein to thereby liberate the transcription transactivator; wherein the reporter protein participates in production of an optically detectable signal; wherein the optically detectable signal is a fluorescent or chemiluminescent signal.
The specification teaches variants of the described IL-17 receptor proteins and the described fusion proteins. The specification teaches the amino acid sequences that are 80%-99% similar in amino acid sequence across the entire length of the described proteins. The specification teaches homologous variants have at least 80%, 85%, 95%, or 99% identity relative to the described sequences across the entire length of a referenced sequence. The specification teaches the modified cells are modified such that they express a IL-17 receptor that forms a heteromer upon activation by ligand binding. The specification teaches the modified cells also comprise a sequence that encodes a reporter protein that is operably linked to a promoter that is functional with the transcriptional transactivator once liberated from the first fusion protein. The specification teaches that the disclosure includes pluralities of modified cells that express the same or different IL-17 receptors that comprise the first and second fusion proteins. The specification teaches the linker can comprise anywhere from 3-20 amino acids. The specification teaches the promoter can be an endogenous promotor, a part of a contiguous polynucleotide sequence integrated into a chromosome of the modified cells, or a part of a viral vector or other polynucleotide delivery construct. The specification teaches the protease and protease recognition signal are not particular limited to using TEV protease and others may be substituted. The specification teaches the reporter protein participates in producing a detectably signal which is optically detectable and the signal may comprise UV light, visible light or far red light. The specification teaches the detectable signal produced by a fluorescent protein which can include green fluorescent protein, enhanced GFP, mCherry, blue fluorescent protein and mVenus.
The claims lack written description because without knowing the structure of the claimed modified cells that express an L-17 receptors that forms a heteromer, one would not be able to adequately describe the claimed fusion polypeptide construct. The claims recite generic and incompletely described modified cells expressing IL-17 receptor with fusion polypeptide components comprising a first fusion protein that includes a protease recognition site and a transcription transactivator segment, a second protein comprising an activating protein and a protease and reporter protein. The skilled artisan would not be reasonably apprised of the structure of the claimed fusion polypeptide without adequate descriptions of its component parts or overall makeup. The generically claimed fusion proteins and reporter protein do not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicant was in possession of the full scope of the fusion polypeptides as recited in the claims, as written. The claims state that the modified cells that express an L-17 receptors that forms a heteromer is capable of identifying modulators of interleukin 17 receptors; however, this definition provides no name for the encompassed polypeptide or the specific structure of the fusion proteins having the recited function. Similarly, the claims teach that the heteromer comprises a heterodimer, wherein the IL-17 receptor can be activated by IL-17A, IL-17F, IL-17E, or IL-17C, wherein the first fusion protein comprises a transcription transactivator that is functional with a tetracycline responsive element, or wherein the second fusion protein comprises an TEV protease. However, the generic recitation of these limitations is not a description of the modified cells expressing an IL-17 receptor. The claims teach that the cells further comprise a sequence encoding a report protein without providing the sequence within the claim. The claims further teach the reporter protein participates in production of an optically detectable signal wherein the signal is fluorescent or chemiluminescent signal. However, this is not a description of the reporter protein sequence itself. Thus, the claims modified cells expressing IL-17 receptor with fusion polypeptide components solely by their function and/or partial structure.
Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed agent may generically describe the agent’s function, it does not describe the agent itself. A definition by function does not suffice to define the genus because it is only an indication of what the agent does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of agents is highly variable (i.e., each fusion polypeptide would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed agonists have no correlation between their structure and function and the specification fails to provide adequate written description to support the genus of fusion polypeptides encompassed by the claims.
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). As noted above, the claims are not limited to the disclosed modified cells expressing an IL-17 receptor with fusion polypeptide components and encompass a vast genus of fusion proteins comprising any first fusion protein, any second fusion protein, and any report protein Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Given the vast number of agents that are encompassed by the claims, the disclosure of a few species is not sufficiently representative of the broad genus of agonists encompassed by the claims. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed agents, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601,1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2dl961,1966 (1997); In re Gosteli, 872 F.2dl008,1012,10 USPQ2dl614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al. and Burgess et al. but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted.
Applicant has provided little or no descriptive support beyond the mere presentation of generic or partially named structures to enable one of ordinary skill in the art to determine the actual structural composition of the claimed genus of modified cells expressing an IL-17 receptors with fusion polypeptides. Although the prior art outlines art-recognized procedures for producing and screening for recombinant proteins this is not sufficient to impart possession of the genera of fusion polypeptides to Applicant. Even if a few structurally identifiable composition components were described in the specification, they may not be sufficient, as the ordinary artisan would not necessarily immediately recognize how to put them together in such a way as to form a completely constructed fusion protein such that one would be able to distinguish it from the fusion polypeptides of the prior art. Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of fusion polypeptides as claimed.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
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.
6. Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Barnea, et al. (as recited in the IDS) (G. Barnea, W. Strapps, G. Herrada, Y. Berman, J. Ong, B. Kloss, R. Axel, & K.J. Lee, The genetic design of signaling cascades to record receptor activation, Proc. Natl. Acad. Sci. U.S.A. 105 (1) 64-69, https://doi.org/10.1073/pnas.0710487105 (2008) in view of Toy, et al. (Dean Toy, David Kugler, Martin Wolfson, Tim Vanden Bos, Jesse Gurgel, Jonathan Derry, Joel Tocker, Jacques Peschon, Cutting Edge: Interleukin 17 Signals through a Heteromeric Receptor Complex, The Journal of Immunology, Volume 177, Issue 1, July 2006, Pages 36–39, https://doi.org/10.4049/jimmunol.177.1.36)
The instant claims are drawn to modified cels for use in a method for identifying modulators of interleukin 17 receptors wherein the modified cells express an IL-17 receptor that forms a heteromer comprising a first fusion protein, a second fusion protein and a reporter protein.
Barnea, et al. teach modified cells for use in identifying modulators of receptors. Barnea, et al. teach that a transcription factor is tether to a membrane-bound receptor with a linker containing a cleavage site for a specific protease, and that the activation of the receptor recruits a signaling protein fused to the protease that then cleaves and releases the transcription factor to activate reporter genes in the nucleus (abstract). Barnea, et al. further teach that this strategy is used to identify a ligand for an orphan receptor, confirming the utility of the assay for identifying receptor modulators (abstract). Barnea, et al. teach that the first fusion protein consists of the receptor joined at cytoplasmic C terminus to the transcriptional activator tTA, with a specific 7-aa cleavage site for the TEV protease interposed between the report and tTA (GPCRs section, paragraph 1), which corresponds to the first fusion protein of claim 1 comprising a protease recognition site configured to liberate the transcription transactivate upon protease cleavage. Barnea, et al. further teach that a second fusion protein consists of the TEV protease linked to b-aresstin2, wherein arrestin localizes to the activated receptor upon ligand-depending activation (GPCR second, paragraph 2), which corresponds to the second fusion protein of claim 1 comprising an activating protein and a protease functional on the protease recognition site that localizes to the heteromer when formed. Barnea, et al. further teach that ligand-dependent recruitment of the arrestin-TEV protease fusion to the receptor fusion and subsequence proteolytic cleavage frees tTA to enter the nucleus and activate reporter genes, and that the cell line contains a stably integrated tTA-dependent luciferase reporter, which corresponds to the reporter protein operably linked to a promoter functional with the liberated transcriptional activator of claim 1.
Barnea, et al. does not explicitly teach applicant of this system to an IL-17 receptor that forms a heteromer comprising separate fusion protein upon activation.
Toy, et al. teach that the biologic activity of IL-17 is dependent on a complex composed of IL-17RA and IL-17RC, constituting a heteromeric receptor complex comprising separate proteins (abstract). Toy, et al. further teach that IL-17RA and IL-17RC are capable of associating in vitro, supporting a model in which IL-17 and IL-17F signaling is mediated by a heteromeric receptor complex containing, minimally, IL-17RA and IL-17RC chains (IL-17RA and IL-17RC physically associate section).
Barnea, et al. teach their TANGO assay has the ability to monitor activity of a receptor of interest. Barnea, et al. further teach that Tango can be used more broadly to detect protein– protein interactions. One of ordinary skill in the art could reasonably have IL-17 as a receptor of interest to be applied to the TANGO assay architecture with a reasonable expectation of success. Barnea, et al. teach that the TANGO system is broadly applicable to receptors signal through protein-protein interactions, and Toy, et al. establishes that IL-17RA forms exactly such an interaction dependent heteromeric complex upon ligand binding. One of ordinary skill in the art would have been motivated to apply the Barnea, et al. assay platform to the IL-17 receptor system taught by Toy, et al. for purpose of identifying IL-17 receptor modulators, as IL-17 signaling was a recognized therapeutic target at the time. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.).
Regarding instant claim 2, Barnea, et al. teach heterodimer formation between two distinct receptor subunits. Toy, et al. teach the IL-17RA/IL-17RC heterodimer. The combination of Barnea, et al. and Toy, et al. renders claim 2 obvious for the same reasons set up above for claim 1.
Regarding instant claim 3, Toy, et al. teach activation of the IL-17RA/RC complex by these specific ligands (IL-17A, IL-17F, IL-17E, IL-17C, or combination). The combination of Barnea, et al. and Toy, et al. renders claim 3 obvious for the same reasons set up above.
Regarding instant claim 4, Barnea, et al. teach the use of tTA/TRE as the transcriptional transactivator/promoter system in the TANGO assay which established the tTA/TRE system as a well-known tool for inducible reporter expression. The use of tTA-TRE as the transcription readout system is therefore taught by Barnea, et al. and its incorporation in to the claimed system would have been obvious to one of ordinary skin in the art as a routine implementation of the known tTA/TRE system already employed in the TANGO platform.
Regarding instant claim 5, Barnea, et al. which teaches TEV protease as the operative protease in the TANGO system.
Instant claim 1 recites “Modified cells for use in a method for identifying the modulators of Interleukin 17 receptors”. With respect to this limitation, it should be remembered that a recitation of the intent use of the claims invention must result in a structural different between the claimed invention and the prior art is order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Conclusion
7. No claims are allowed
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
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