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 .
Status of Claims
2. Claims 1-11, 13-15, 17-20, 22 and 24 are currently pending. Claims 12, 21, 16, 23 and 25 are cancelled. Applicant’s election without traverse of Group I in the reply filed on 12/30/2024 is acknowledged. Claim 24 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/30/2024. Claims 1-11, 13-15, 17-20, and 22 are under examination.
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.
3. Claims 10-11 and 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 10, the claim recites “such as” in line 1. This is exemplary language.
Regarding claim 11, the claim recites “e.g.” in line 1. This is exemplary language.
Claim 13 depends from claim 11, and is therefore included in this rejection.
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.
3. Claim(s) 1-4, 6-11, 13-15, 19-20, and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Underwood et al. (“A quantitative assay to study protein: DNA interactions, discover transcriptional regulators of gene expression, and identify novel anti-tumor agents.” J Vis Exp. 2013) in view of Hirst et al. (WO-9913069-A1) and in view of Berkhout et al. ("Tet-On Systems For Doxycycline-inducible" Gene Expression. Curr Gene Ther. 2016.)
Regarding claim 1, Underwood teaches a method for screening for an antagonist of a DNA binding protein. (Underwood et al. Abstract). Underwood teaches “Based on analyses of kinetic measurements 7, increasing the amounts of the CADD5221975 inhibitor resulted in a dose-dependent, sigmoidal inhibition curve, with inhibitor concentrations above 10-3 M effectively inhibiting DNA binding, while concentrations below 10-11 M showed very little inhibition. The EC50 (concentration at which inhibitor caused a 50% reduction in the binding of RUNX2 to DNA) was 10 nM for this compound. The statistical analyses for this assay have been published previously 6 and, for simplicity, only one well of a triplicate series of wells is shown in representative Figures 2 and 3.” (Underwood et al. Representative Results). This teaching of Underwood et al. is interpreted as teaching a compound that is capable of inhibiting DNA-binding protein. Additionally, Underwood et al. teaches test compounds capable of inhibiting DNA-binding activity. (Underwood et al. Discussion). Underwood et al. teaches providing a cell (preparation of cells- Abstract),
Regarding claim 1, Underwood et al. does not teach a reporter expression cassette comprising a binding site for a DNA binding protein or “wherein an increase in expression of the reporter expression product in the presence of the test compound indicates that the test compound is capable of inhibiting DNA-binding activity of the DNA-binding protein”.
However, Hirst et al. teaches a method for screening for inhibitors of that interfere with protein-protein interactions of transcriptional repressors (page 9, paragraph 2). Hirst teaches that inhibition of the transcriptional repressor causes a reporter gene to be expressed (page 9, paragraph 2). Therefore, Hirst teaches that a compound that causes a reporter gene to be expressed means that the compound was capable of inhibiting the activity of the transcriptional repressor. Hirst teaches a reporter expression cassette comprising a binding site for a DNA-binding protein (binding site for GAL4 DNA-binding domain), a TATA box and a reporter gene (Hirst et al. figure 10; page 36, line 9 - page 39, line 20); binding of the DNA-binding protein (here complete complex) inhibits expression of the reporter expression product, and the binding site is located in the transcribed sequence of the reporter cassette.
Regarding claim 1, Hirst teaches does not teach that the method is for screening for compounds that inhibit “DNA-binding activity” specifically.
However, Berkhout et al. teaches Tet-On Systems. Specifically, Fig. 1A plus effector of Berkout et al. demonstrates that binding of Tc or dox triggers a conformational switch in TetR that prevents tetO binding and results in the activation of TetA and TetR production. This is interpreted as Berkout et al. teaching an increase in expression of a reporter expression product in the presence of a test compound that inhibits DNA binding activity of the DNA-binding protein. The figure is reproduced below for ease:
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have had a method of screening for an antagonist of a DNA-binding protein, as taught by Underwood et al., comprising a reporter expression cassette, as taught by Hirst et al, with an E-box target DNA sequence fused to a repressor for transcriptional activation, as taught by Berkhout et al.. because Berkhout et al. provides a method of repressing transcription activation and Hirst et al. provides a reporter expression cassette method. Each of Underwood, Hirst, and Berkhout are directed to related methods for detecting activity of proteins involved in regulating transcription including either DNA binding proteins or protein-binding proteins. Therefore, one of ordinary skill in the art of screening for inhibitors of proteins would have looked to these other disclosures for guidance for assays for measuring such inhibitory activity. Although Underwood’s method is for screening for inhibitors of DNA binding proteins and Hirst teaches screening for inhibitors of protein-protein interactions with the readout of a reporter gene expression, Berkhout’s disclosure bridges the gap between these references because it discloses the use of inhibitors of DNA binding activities of transcriptional repressors as detected by measuring gene expression. Accordingly, one of ordinary skill in the art would have had a reasonable expectation of success in modifying Underwood’s method for screening for inhibitors of DNA binding activity by using a reporter gene expression system in which an increase in reporter gene expression indicates that the compound has DNA binding activity. In addition, substituting Hirst’s reporter gene assay in place of Underwoods ELISA assay would have merely amounted to a simple substitution of one known method for detecting transcriptional regulatory protein activity for another. One would have been motivated to have done so because, rather than merely detecting protein binding to a target DNA, Hirst’s method is a functional assay because it involves measuring reporter gene expression, which is more biologically relevant.
Regarding claim 2, Hirst et al. teaches reporter proteins (page 29).
Regarding claim 3, Hirst et al. teaches cell survival protein. (page 5).
Regarding claim 4, Hirst et al. teaches cell survival proteins (page 9). Hirst et al. teaches endogenous genes, specifically “ The 'prey' fusion protein causes repression of reporter genes that would otherwise be active, such as the GAL4-dependent reporter genes GAL1 -CAN1 , GAL1 -URA3, the endogenous GAL1 gene, and a GALl -LacZ fusion gene. Using these reporter genes, inhibition of GAL4-dependent reporter gene expression may be indicated by growth on canavanine, 5-FOA, and 2-deoxygalactose, and formation of blue colonies on X-gal, respectively.” (Hirst et al. Description).
Regarding claim 6, Hirst et al. teaches between 1 and 5 binding sites.
Regarding claim 7, Hirst et al. teaches binding sites that are located in protein coding sequences (page 6).
Regarding claim 8, Hirst et al. teaches the DNA binding protein being a transcription factor (page 3).
Regarding claim 9, Hirst et al. teaches a DNA binding protein being a leucine zipper ([002]).
Regarding claim 10, Hirst et al. teaches E.coli (page 19).
Regarding claim 11, Hirst et al. teaches eukaryotic cells. (page 12).
Regarding claim 13, Underwood et al. teaches “ To prepare nuclear protein for DNA binding assays, culture human cells that express RUNX2 (endothelial, osteosarcoma, breast cancer cells) in appropriate media 6.” (Underwood et al. Cell Culture and Nuclear Protein Isolation).
Regarding claim 14, Berkhout et al. teaches “Also when the rtTA and Ptet-reporter cassettes were stably integrated in the cellular genome through lentiviral vector transduction (Fig. 5D) (Berkhout et al., Stably Transduced Cells).
Regarding claim 15, Hirst et al. teaches peptidic test compounds (page 22). Therefore, it would have been obvious to one of ordinary skill in the art to have used peptidic test compounds in the method of Underwood et al.
Regarding claim 19, Hirst et al. teaches administration of test compounds.
Regarding claim 20, Berkhout et al. teaches Tet-On which is a peptidic system. Therefore, Berkhout et al. teaches this limitation.
Regarding claim 22, it would have been obvious to one of ordinary skill in the art to have tried this combined method of Underwood et al., Hirst et al., and Berkhout et al., because it has been shown to have worked within cells and a cell-free method could be easier to use.
5. Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Underwood et al. (“A quantitative assay to study protein: DNA interactions, discover transcriptional regulators of gene expression, and identify novel anti-tumor agents.” J Vis Exp. 2013) in view of Hirst et al. (WO-9913069-A1) in view of Berkhout et al. ("Tet-On Systems For Doxycycline-inducible" Gene Expression. Curr Gene Ther. 2016.) in further view of Hanahan et al. ( US-5631133-A) Regarding claim 17, Underwood in view of Hirst in view of Berkhout teaches the method of claim 15.
Regarding claim 17, Underwood in view of Hirst in view of Berkhout does not teach wherein the test compound is a peptidic test compound expressed intracellularly from a test compound expression cassette.
However, Hanahan et al. teaches “contacting a test cell with a biologically active compound, wherein the test cell is transformed with the expression cassette of step (i) and the intracellular hormone receptor expression cassette” (Hanahan et al. Claims).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have a test compound expressed intracellularly from a test compound expression cassette, as taught by Hanahan et al. in the method of Underwood in view of Hirst et al. in view of Berkhout et al. directed to peptidic test compounds and expression cassette because one would have wanted to have a test compound already proven to be expressed intracellularly. 6. Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Underwood et al. (“A quantitative assay to study protein: DNA interactions, discover transcriptional regulators of gene expression, and identify novel anti-tumor agents.” J Vis Exp. 2013) in view of Hirst et al. (WO-9913069-A1) in view of Berkhout et al. ("Tet-On Systems For Doxycycline-inducible" Gene Expression. Curr Gene Ther. 2016.) in further view of Berman et al. (US-5674984-A).
Regarding claim 18, Underwood in view of Hirst in view of Berkhout teaches the method of claim 15.
Regarding claim 18, Underwood in view of Hirst in view of Berkhout does not teach wherein the method comprises administration of a cross-linking agent into a cell in order to introduce a cross-link between two amino acid residues.
However, Berman et al. teaches “Polymers generally are covalently linked to the peptide herein through a multifunctional crosslinking agent which reacts with the polymer and one or more amino acid or sugar residues of protein. However, it is within the scope of this invention to directly crosslink the polymer by reacting a derivatized polymer with the peptide, or vice versa.” (Berman et al. [0014]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered a crosslinking agent, as taught by Berman et al. to introduce a cross-link between two amino acid residues in the combined method of Underwood in view of Hirst in view of Shin as it would have been expected to have created a derivatized polymer with the peptide or vice versa. Thus, interpreted as producing a helix-constrained compound.
7. Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Underwood et al. (“A quantitative assay to study protein: DNA interactions, discover transcriptional regulators of gene expression, and identify novel anti-tumor agents.” J Vis Exp. 2013) in view of Hirst et al. (WO-9913069-A1) in view of Berkhout et al. ("Tet-On Systems For Doxycycline-inducible" Gene Expression. Curr Gene Ther. 2016.) in further view of GenBank: AFQ55276.1 Accession. (Year: 2013))
Regarding claim 5, Underwood et al. in view of Hirst et al. in view of Shin et al teaches claim 3.
Regarding claim 5, Underwood et al. in view of Hirst et al. in view of Shin et al. does not teach SEQ ID NO:1.
However, GenBank: AFQ55276.1 has a 100% match to SEQ ID NO:1 and teaches that SEQ ID NO:1 is a URT reporter protein [URT cloning vector pKP77].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used a known reporter protein, as taught by GenBank: AFQ55276.1 in the method directed to screening for an antagonist of a DNA binding protein because one would have wanted to have had a known reporter protein that has already been demonstrated to have been used in the field of the art. One would have had a reasonable expectation of success as the combined method of Underwood et al. in view of Hirst et al. in view of Shin et al is already directed to using a reporter protein and it would have been a simple substitution of one known reporter protein for another to achieve predictable results.
CONCLUSION
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MORGAN TAYLOR LINDGREN BALTZELL whose telephone number is (571)270-3350. The examiner can normally be reached Monday-Friday 8:00am-5:30pm.
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/MORGAN TAYLOR LINDGREN BALTZEL/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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