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 .
Election/Restrictions
Applicant's election with traverse of Group I, and species TNFR-1 in the reply filed on 2/27/2026 is acknowledged. The traversal is on the ground(s) that the analysis for restriction fails to recognize eh unifying inventive concept. Applicant asserts that Group I-IV and all recited species in claim 4 share an inventive concept: a split protein cytokine receptor assembly that utilizes ligand-induced, irreversible protease cleavage of a linker to release a transcription factor, which is the core contribution over prior art and is common to the system. Applicant argues that this shared technical feature is not taught by Brines. Applicant argues that Brines describes a system relying on natural signaling cascade or “two hybrid” assays where signal depends on the reversible reconstitution of transcription factor halves, whereas the present claims rely on physical severing of a linker, which is irreversible. Applicant argues that the cleavage mechanism allows for a table signal that allows for long term tracing of cells, whereas Brines’ readouts are transient and decay if the ligand dissociates. Applicant states that the special technical feature is the protease-cleavage system itself, the allowability of the generic claims in Group I must result in the withdrawal of the restriction requirement for entire application. Applicant argues since claim 1 is a generic claim encompassing all species of claim 4, the allowance of claim 1 requires the examination and rejoinder of all species dependent therefrom.
The above argument has been fully considered and deemed partially persuasive. The special technical feature between Groups I-IV is a first fusion protein comprising a first subunit of a cytokine receptor and a second domain that comprises a transcription activator with a cleavable linker in between; and a second fusion protein that comprises a first domain comprising a second subunit of the cytokine receptor and a second domain comprising a catalytic domain of a protease; and a reporter gene operably linked to a transcription factor regulatory elements wherein the DNA binding domain of a transcription factor recognizes and binds the TFRE. The cytokine modulator system taught by Brines differs from this technical feature because Brines teaches the DNA binding domain and the transcriptional activation domain is split and fused to two different receptor subunit rather than fused to one subunit of the cytokine receptor, and no protease cleavage is required upon ligand binding to produce a reporter signal. However, Lee (US 8,017,289) teaches a linker linking the first and second domain (a cytokine receptor and a transcription activator) with a protease linker, and a second interaction partner fusion comprising a protease and a linker (abstract, Figure 1 and col.3, lines 24-41). It would have been obvious to an ordinary skilled in the art that the system of Brines may be modified to place both DNA binding domain and DNA activation domain with the same subunit with cleavage linker in between and a second subunit fused to protease so that the transcription activator produces a signal readout upon ligand binding based on the teaching from Lee. Therefore, this technical feature cannot link the invention as a whole to form a single general inventive concept under PCT Rule 13.1.
The requirement is still deemed proper and is therefore made FINAL.
Upon further consideration and for the purpose of compact examination, the invention of Groups II and III are rejoined, and the species election is withdrawal.
The restriction requirement between the product and method claims will be revisited when allowable subject is identified.
Accordingly, claims 1, 2, 4-10, 12, 14-19 and 21 are currently under examination. Claims 22-23 and 25 are withdrawn from consideration for being directed to non-elected subject matter.
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 18 and 21 are rejected under 35 USC §101 because the claimed invention is directed to non-statutory subject matter. The term “cell” as defined by the specification at page 12 paragraph [0058] states that the cell maybe present in a mammal (line 8). Since mammal includes a human being, said cell becoming integrated into the human being and therefore being an inseparable part of the human itself. The scope of the claim, therefore, encompasses a human being, which is non-statutory subject matter. As such, the recitation of the limitation “isolated” would be remedial. See 1077 O.G. 24, April 21, 1987.
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.
Claim 19 is 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.
The recitation of “a polynucleotide at least two of the first fusion polypeptide, the second fusion polypeptide and the reporter gene of claim 1” renders the claim indefinite because it is unclear whether the polynucleotide encodes two copies of the entire system as claimed in claim 1, or at least two components (ab, bc or ac) of the system claimed in claim 1.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 4, 10, 12, 16-19 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brines (IDS) and Lee (US 8,017,398).
Claim 1 is drawn to a reporter system comprising: a) a first fusion protein comprising a first subunit of a cytokine receptor and a second domain that comprises a transcription activator with a cleavable linker in between; b) a second fusion protein that comprises a first domain comprising a second subunit of the cytokine receptor and a second domain comprising a catalytic domain of a protease; and c) a reporter gene operably linked to a transcription factor regulatory elements wherein the DNA binding domain of a transcription factor recognizes and binds the TFRE.
Brines teaches a method of using tissue protective cytokine receptor complexes to identify compounds that have tissue protective activity, i.e. a ligand (paragraph [0008]). Brines teaches a method of detecting a compound that modulates a tissue protective activity, comprising contacting a test compound with a cell that comprising, (i) a nucleic acid sequence comprising a reporter gene operably linked to a binding site specific for a DNA binding domain of a transcriptional activator; (ii) a first fusion protein comprising the DNA binding domain of the transcriptional activator, and a first tissue cytokine receptor polypeptide or a fragment thereof, and (iii) a second tissue protective cytokine receptor and an activation domain of the transcriptional activator, and detecting reporter gene expression in the presence or absence of a compound that modulates a tissue protective activity (paragraph [0019]). Brines teaches that the tissue protective cytokine receptor complex comprises a heteromultimer, wherein the receptor pair is EPO receptor and a βc receptor, or other receptor such as GM-CSF, IL-3, IL-5 (paragraph [0054]).
The teaching from Brines differs from the claimed system of claim 1 is that Brines teaches the DNA binding domain and the activation domain of a transcription activator are fused to different subunit of the cytokine receptor, whereas the claimed system fuses the transcription activator with one subunit of the cytokine receptor and a protease fuses with a second subunit cytokine receptor.
Lee teaches a method of determining a test compound modulates a specific protein/protein interaction, wherein the determination is made possible via the use of two recombinant molecules, one of which contains the first protein a cleavage site for proteolytic molecule, and an activator of a gene, the second recombinant molecule includes the second protein and the proteolytic molecule. If the test compound binds to the first protein, a reaction is initiated whereby the activator is cleaved and activates a reporter gene (abstract). Lee gives an example of a 7 transmembrane receptor linked to transcription factor tTA (comprises both DNA binding domain and activation domain) via a protease cleavage site, wherein the second protein is Arrestin linked to a TEV protease, and a reporter gene that comprises a tTA regulatory element (Figure 1, and col.3, lines 24-41). Lee teaches that the invention contemplates the use of any two proteins for which a physical interaction is known or suspected, whereas the two proteins will exists as fusion proteins, a first test protein fused to a transcription factor, and the second test protein fused to a protease that recognizes a cleavage site in the first fusion protein, cleavage of which releases the transcription factor (col.14, lines 62-67). Lee teaches that activities of a variety of receptor including cytokine receptor and tumor necrosis factor and leptin receptors (col.15, lines 28 and 30-31) may be used in this system. Lee also teach other test protein pairs includes components of signal transduction cascades and dimerizing proteins (col.15, lines 64-67).
The teaching from Lee differs from the claimed system of claim 1 only in that Lee does not teach the two fusion polypeptide that interacts with each other are subunits of a cytokine receptor.
It would have been obvious to an ordinary skilled in the art that the system taught by Brines for identifying a cytokine receptor modulator may be modified by placing the entire transcription activator in the first cytokine receptor with a protease cleavable linker, and replacing the second fusion receptor partner with a protease that cleaves the linker to release the transcription factor based on the teaching from Lee. The ordinary skilled in the art would recognize the advantage of inclusion of a single transcription activator in one subunit of a cytokine receptor to be more efficient for transcription activation than have DNA binding domain and activation domain separately attached to two fusion receptor. The ordinary skilled in the art would have reasonable expectation of success to make such a reporter system because Lee teaches that protease cleavage method may be performed with a wide variety of protein pairs, including dimerizing proteins (which includes cytokine receptors) following combined teaching from Brines and Lee. Therefore, the claimed invention of claim 1 would have been prima facie obvious to an ordinary skilled in the art at the time the application was made.
Regarding claim 2, Lee teaches a linker DNA sequence encoding NSSGGNSGS (col.33, lines 45-47), which meets the limitation of a flexible linker because it is a short peptide comprises mostly serine and glycine (see teaching from Chen IDS, page 4, section 3.1 flexible linkers).
Regarding claim 4, Lee teaches TNFR receptor (col.15, line 31).
Regarding claim 10, Lee teaches tTA and GAL4 as transcription activator (col.16, line 28-30).
Regarding claim 12, Lee gives a specific example of using tobacco etch virus nuclear inclusion A protease (col.16, lines 46-47).
Regarding claim 16, Brines teaches inducible promoters may be used (paragraph [0110]).
Regarding claim 17, Brines teaches reporter genes may be GFP, CFP, RFP, β-galactosidase, CAT (paragraph [0129]).
Regarding claims 18 and 21, Brines teaches the host cell expressing the cytokine receptor complexes include a wide variety of cell types, preferably derived from neuronal tissue (paragraph [0102] and [0104]).
Regarding claim 19, Brines teaches vectors encoding the receptor complexes, which are a polynucleotide encoding the first and second fusion polypeptide and the reporter gene (paragraph [0097]). The claim is interpreted as a polynucleotide encoding at least two components of the fusion polypeptides and reporter gene.
Claim(s) 5-9, 14 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brines and Lee, as applied to claims 1 and 4 above, and further in view of Gu (IDS).
The teaching from Brines and Lee has been discussed above. However, neither reference teaches the cytokine receptor or subunits thereof is IL-17R, specifically IL-17RA, B and C.
Gu teaches IL-17 family plays crucial roles in host defense against microbial organisms in the development of inflammatory diseases (abstract). Gu teaches IL-17 signaling is mediated through IL-17RA, RB, RC, RD and RE, wherein IL-17RA alone is insufficient to mediate IL-17 signaling, but requires the formation of heterodimer with IL-17RC, IL17RB or IL017 RE (Figure 1 and legend, and page 2, last paragraph).
It would have been obvious to an ordinary skilled in the art that the system for identifying cytokine receptor modulator rendered obvious by combined teaching from Brines and Lee may be modified to use IL-17R subunits in making the two fusion polypeptide based on the teaching from Gu. The ordinary skilled in the art reading Gu would recognize that IL-17 mediates host defense against microbial organism, and would have been motivated to use IL-17R subunits to make fusion proteins to identify compounds that would be beneficial to activate the host defense against microbial pathogen. Since the system rendered obvious by Brines and Lee is versatile and may use a wide variety of cytokine receptors that forms dimer upon ligand activation, the -ordinary skilled in the art would recognize that IL-17RA/RB, and IL-17RA/RC pair would be suitable to make fusion polypeptide that comprises transcription activator and protease. Therefore, the claimed invention of claims 5-9 and 14-15 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/Primary Examiner, Art Unit 1637
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