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 .
Priority
This application is a 371 of PCT/US2023/060420, filed 1/10/2023. This application claims benefit to U.S. Provisional Application Serial Number 63/298,759, filed 1/12/2022. Claims 1-2, 7-10, 13, 23, 27-28 and 32-41 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-2, 7-10 and 13, in the reply filed on 4/28/2026 is acknowledged.
Claims 23, 27-28 and 32-41 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/28/2026.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-2, 7-10 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Lindquist et al., US 2017/0306386 (US Patent Application Publication cite 1, IDS, 7/8/2024; herein “Lindquist”) in view of Ear et al, 2005 (NPL cite 1, IDS, 7/8/2024).
Lindquist teaches methods of assaying for protein misfolding in a yeast screening system (Abst.) comprising determining the viability [0008-9], i.e., growth rate or relative fitness, of yeast expressing fusion proteins comprising the misfolding protein ([0011], [0017]), mutants of the misfolding protein ([0010], [0012], [0016]) or the wild-type misfolding protein ([0010], [0016]) wherein the viability, i.e., growth rate or relative fitness, of the yeast populations expressing individual fusion proteins comprising misfolding protein mutants are compared to yeast populations expressing fusion proteins comprising wild-type misfolding protein and/or other yeast populations expressing fusion proteins comprising different misfolding protein mutations with or without contacting the yeast populations with a toxicity inducing agent ([0009], [0014], [0019]) wherein the toxicity inducing agent can be 5-fluorocytosine ([0008], [0013], [0018]; Table 3).
Lindquist does not teach that the fusion proteins comprise a first variant of a target protein disposed between segments of a toxic indicator protein wherein the segments induce the first cell population to grow at a lower rate when the target protein is relatively less misfolded than when the target protein is relatively more misfolded; however, a person of ordinary skill in the art at the time of filing would have found it obvious to modify Lindquist’s protein misfolding screen to comprise fusion proteins wherein the misfolding protein, or mutants thereof, are disposed between segments of a fcy1, a toxic indicator protein, wherein a cell population with relatively more misfolded protein will be more viable, as determined by growth rate or relative fitness, that cell populations with relatively less misfolded protein in view of the disclosure of Ear.
Ear teaches negative protein fragment complementation assays wherein cells wherein fcy1 protein fragments brought into proximity with each other reconstitute cytosine deaminase activity in culture systems wherein cells are exposed to 5-fluorocytosine (5FC), a relatively non-toxic prodrug, which is converted to the cytotoxic compound 5-fluorouracil (5FU) by the reconstituted cytosine deaminase activity of the fcy1 protein fragments (Abst.; Fig. 2; pp. 13-15, “yCD Death Selection Assay”); thus, cell populations in which cytosine deaminase activity is reconstituted by complementation of fcy1 protein fragments in the presence of 5FC would exhibit decreased cell viability including a lower growth rate.
Hence, a person of ordinary skill in the art at the time of filing would have found it obvious for the fusion proteins in Lindquist to comprise the misfolding protein or mutants thereof sandwiched between the fcy1 protein fragments disclosed by Ear wherein when the misfolding protein is relatively less misfolded, the fcy1 protein fragments are able to come within proximity of each other and at least partially reconstitute cytosine deaminase activity which would allow the conversion of 5FC to 5FU and decrease cell viability and growth rate; and wherein when the misfolding protein is relatively more misfolded, the fcy1 protein fragments are unable to come within proximity of each other leading to less or no reconstitution of cytosine deaminase activity; thus, conversion of 5FC to 5FU does not occur and the cell population experiences relatively increased cell viability and growth rate.
Lindquist teaches comparing the growth and viability of cells expressing fusion proteins comprising mutants of the misfolding protein to the growth and viability of cells expressing fusion proteins comprising the wild-type misfolding protein and to other mutants with and without the toxicity inducing agent which can be 5-fluorocytosine ([0009-12], [0015-19]; Table 3). Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method made obvious by Lindquist in view of Ear comprising determining a growth rate or relative fitness of at least a first cell population that comprises a first fusion polypeptide comprising a first variant of a target protein disposed between segments of a toxic indicator protein, which segments together induce the first cell population to grow at a lower rate when the target protein is relatively less misfolded than when the target protein is relatively more misfolded; and, determining that the growth rate or fitness of the first cell population varies from a growth rate or fitness of at least a second cell population that comprises a second fusion polypeptide comprising a second variant of the target protein disposed between the segments of the toxic indicator protein, thereby detecting the misfolded target protein; wherein variants of the target protein comprise the mutants and wild-type misfolding proteins set forth by Lindquist; wherein the toxic indicator protein comprises fcy1; and wherein the inducing agent is 5FC; therefore, claims 1-2 and 7-10 are prima facie obvious.
Regarding claim 13, Lindquist teaches that the fusion proteins are encoded by nucleic acid expression plasmids [0071-76]; hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice the method made obvious by Lindquist in view of Ear wherein the fusion proteins are encoded by nucleic acid expression plasmids; therefore, claim 13 is prima facie obvious.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Trent R Clarke whose telephone number is (571)272-2904. The examiner can normally be reached M-F 10-7 MST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie Gordon can be reached at 571-272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TRENT R CLARKE/ Examiner, Art Unit 1651
/DAVID W BERKE-SCHLESSEL/ Primary Examiner, Art Unit 1651
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