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 Application/Amendments/Claims
Applicant’s response filed on 6/15/2026 has been considered. Claims 1-17 and 19 have been canceled. Claims 21-32 have been newly added. Claim 18 has been amended. Claims 18 and 20-32 are pending and are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 63/136,560 and PCT/US2022/012033 filed on 1/12/2021 and 1/11/2022, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 1/12/2021.
Withdrawn Claim Objections and Rejections
The claim objection of claim 18 has been withdrawn given applicants’ amendments which incorporate the limitations of claim 1 into independent claim 18.
The 35 U.S.C. 112(a) written description rejection of claims 18-20 is withdrawn and re-applied in modified form to address applicants claim amendments to independent claim 18 which specifies the actuating protein as a transcription factor and further amendments describing the inactivating protein.
The 35 U.S.C. 102(a)(1) and 102(a)(2) rejection of claims 18-20 is withdrawn and re-applied in modified form to address applicants claim amendments to independent claim 18 which specifies the actuating protein as a transcription factor and further amendments describing the inactivating protein.
Reply to Applicants Arguments
Although the rejections are newly applied, some of applicant’s arguments are relevant and are addressed below.
Applicant argues that the newly amended claims provide a sufficient functional definition of an inactivating protein and target protein such that there is a sufficient written description. Applicant argues that the Examiner has not provided a sufficient explanation of why, once the present invention has been reduced to practice using one set of proteins, it won’t work for other proteins since the invention is not particularly dependent on any protein.
This argument has been fully considered, however, the genus “inactivating protein” and “controller protein” in the newly amended claims refers to genera that are considered extraordinarily broad. Although the specification describes inactivating proteins which may be a protease that cleaves at the protease cleavage site and activates a degron, which causes the degradation of a target protein (Spec, detailed description of the invention). This is not considered a representative number of samples to support the claim to all types of inactivating proteins and controller proteins because of the expansive nature of the genus which encompasses virtually all proteins that accomplish the broad functional objectives.
Applicant further argues that Silverman does not teach a transcription factor that activates expression of both the target protein and the inactivating protein as claimed. Applicant states that the goal of Silverman is to either induce or repress a target protein for screening assays and there would be no point in putting the expression of proteins under the control of the same transcription factor.
It is emphasized that the claims read on a “transcriptional activator” which acts to independently activate the nucleic acid encoding a target protein and inactivating protein in response to an external stimulus, and not a transcription factor.
New Claim Rejections - 35 USC § 112a, 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 18 and 20-32 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. This rejection is supported by Silverman et al. US 2014/0128287, published 5/8/2014, priority date 3/30/2012 (hereinafter Silverman, reference of record). This is a new rejection necessitated by amendment of the claims in the responses filed 6/15/2026.
The genus of “inactivating protein” and “controller protein” refers to genera that are considered extraordinarily broad. It is thought to encompass any inactivating protein which binds to the regulatory motif on the target protein and causes its degradation, sequestration to a sub-cellular location or inhibition in a dominant negative manner. With respect to controller protein, the claims read on a vast number of proteins which bind, blocks or inactivates either the inactivating protein or target protein in response to an external stimulus. The claimed genus of inactivating and controller proteins encompasses a vast number of transcriptional regulators, metabolic regulators, signal transduction proteins, maintenance proteins, and therapeutic proteins which is not adequately supported by the limited number of species described in the instant specification.
For each claim drawn to a genus, the written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or 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 procession of the claimed genius. If a representative number of adequately descried species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, para. 1.
The instant specification exemplifies specific types of inactivating proteins and controller proteins. For example, the specification describes inactivating proteins which may be a protease that cleaves at the protease cleavage site and activates a degron, which causes the degradation of a target protein (Spec, detailed description of the invention). This is not considered a representative number of samples to support the claim to all types of inactivating proteins and controller proteins because of the expansive nature of the genus which encompasses virtually all proteins that accomplish the broad functional objectives. Given the breadth of the genera in contrast to the exemplified and prophetic proportions of the specification, which are largely drawn to specific classes of protease and degrons, the instant specification does not adequately disclose a sufficient number of adequately described species to support the claimed genera. Although claim 27 provides more functional description of the inactivating protein, as stated in the 112(b) rejection below, it remains unclear if one or all of parts (i)-(iii) are required.
Furthermore, the prior art does not support the breadth of applicants claim to all types of inactivating proteins and controller proteins. In particular, the prior art reveals that specific proteins and regulatory motifs work in conjunction and are frequently inoperable. This is supported by Silverman where in specific protease and degron systems are explored to regulate gene circuits. Silverman shows that there is a great deal of unpredictability in the art, wherein only specific inactivating proteins, regulatory motifs and external stimuli are compatible with one another (Silverman, para 61-80). Furthermore, Silverman describes different categories of inactivating proteins (degron, enzymatic inhibitors, structural disruptors of the target protein, long- and short- duration inhibitors, etc.) while it appears applicant only shows possession for a narrow embodiment of protease inhibitors (Silverman, para 73-74,
Thus, although the specification prophetically considers and discloses specific target proteins, inactivating proteins, actuating proteins and controller proteins, the instant specification does not disclose a sufficient number of adequately described species to support the claim to the genus of target proteins, inactivating proteins, actuating proteins and controller proteins.
New Claim Rejections - 35 USC § 112b
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 21, 23 and 24 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 pre-AIA the applicant regards as the invention. This is a new rejection necessitated by amendment of the claims in the responses filed 6/15/2026.
Claim 21 describes “the exogenous stimulus” that binds to the transcriptional factor, induces expression of the transcriptional activator or binds to a transmembrane protein. There is a lack of antecedent basis for the term “the exogenous stimulus” given that claim 18 only describes a firs external stimulus. As a result of this indefinite term, one of ordinary skill in the art would not understand what constitutes the exogenous stimulus and if this is the same as the referenced first external stimulus. A claim is indefinite when it contains words or phrases whose meaning is unclear, see MPEP2173.05(e).
Similarly, claim 23 describes the cell further comprising a controller protein and exposing the cell to “the second external stimulus”. There is a lack of antecedent basis for the term “the second external stimulus” given that claim 18 only describes a transcriptional activator which responds to a first external stimulus. As a result of this indefinite term, one of ordinary skill in the art would not understand what constitutes the second external stimulus. Although claim 24 describes a second exogenous stimulus, it is unclear if this is the same as the second external stimulus referenced in claim 23. Furthermore, it is noted that claim 23 is dependent on claim 18 and not claim 24.
Claim 27 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 pre-AIA the applicant regards as the invention. This is a new rejection necessitated by amendment of the claims in the responses filed 6/15/2026.
Claim 27 describes the method of claim 26, wherein (i) the target protein comprises a caged degron; (ii) the inactivating protein comprises a degron; (iii) the target protein contains an internal degron. Parts (i)-(iii) lack an appropriate “AND/OR” conjugation. Thus, one of ordinary skill in the art would not understand if one or all of parts (i)-(iii) are required to meet the claim limitations. A claim is indefinite when it contains words or phrases whose meaning is unclear, see MPEP2173.05(e).
Claim Interpretation
Claim 18 describes a transcriptional activator that independently activates transcription of the nucleic acid of (a) and (b) in response to a first external stimulus. It is emphasized that the claims do not specify that the nucleic acids (a) and (b) need to be in the same expression construct, only that a transcriptional activator independently activates transcription of both in response to a first external stimulus.
Furthermore, a nucleic acid encoding a target protein that comprises a regulatory motif that is not native to the target protein is interpreted as reading on not part of the protein in its wild type if the protein is otherwise naturally occurring such as a transgene (Spec, detailed description of the invention).
New Claim Rejections - 35 USC § 102
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 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 18 and 20-27 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Silverman et al. US 2014/0128287, published 5/8/2014, priority date 3/30/2012 (hereinafter Silverman, reference of record). This is a new rejection necessitated by amendment of the claims in the responses filed 6/15/2026.
Claim 18: Silverman describes a method comprising exposing a eukaryotic cell to a first external stimulus comprising a hormone (β estradiol) which activates the expression of a target protein and an inactivating protein in a molecular circuit (Silverman, para 13, 77). Silverman describes a nucleic acid encoding a target protein that comprises a regulatory motif that is not native to the target protein, with preferred embodiments to a modified degron hormone binding domain sequence at the initiator codon of the open reading frame (Silverman, para 12, 13, 19 and 25). Silverman describes a nucleic acid encoding an inactivating protein, wherein the inactivating protein binds to the regulatory motif and inactivates the target protein with preferred embodiments to a protease-encoding gene that expresses a protease that is capable of hydrolyzing the target protein to yield a protein having an N-end rule destabilizing amino acid at the amino terminus (Silverman, para 13). In particular, Silverman describes an embodiment wherein a GEV transcriptional activator drives expression of a protease (TEV, inactivating protein) which cleaves a dormant N-degron that has been engineered into the amino acid terminus of a separately-expressed target protein. Cleavage exposes a N-end-rule destabilizing residue, triggering proteasomal degradation of the target (Silverman, para 11-118, 60-62 and Fig 8).
With respect to applicants’ amendments that describe a transcriptional activator that independently activates the transcription of the nucleic acid of (a) and (b) in response to an external stimulus, Silverman describes “adapting other nuclear receptors that work by the same mechanism…so that independent induction of two genes can be accomplished…one can induce synthesis of a target protein by adding one inducer and then destroy at will the protein inducing TEV with the other inducer” (Silverman, para 13 and 72). As stated in the claim interpretation section, claim 18 describes a transcriptional activator that independently activates transcription of the nucleic acid of (a) and (b) in response to a first external stimulus. It is emphasized that the claims do not specify that the nucleic acids (a) and (b) need to be in the same expression construct, only that a transcriptional activator independently activates transcription of both in response to a first external stimulus.
Claim 20: Silverman describes expression in vitro, ex vivo and in vitro (Silverman, para 60).
Claims 21-22: Silverman describes exposing a eukaryotic cell to a first external stimulus comprising a hormone (β estradiol) which activates the expression of a target protein and an inactivating protein in a molecular circuit (Silverman, para 13, 77). Specifically, when the hormone is added, GEV induces the expression of the TEV protease, and once expressed, the protease recognizes and cleaves the dormant N-degron motif on the target protein (Silverman, para 11-18, 60-62).
Claims 23-24: Silverman describes the use of a chimeric hormone transcription factor called GEV which contains a DNA binding domain, a hormone binding domain and a highly electronegative portion of herpes simplex virus protein VP16 which confers strong transcriptional activity (Silverman, para 9). GEV controls both the protease (inactivating protein) and the target protein (Silverman, para 61). Silverman describes the use of various promoters used to control the expression of GEV (Silverman, para 69-70). Silverman describes the use of a second external stimulus which modulates the controller protein, with preferred embodiments to β-estradiol (Silverman, para 9, 166, 179 and claim 3).
Claim 25: Silverman describes specific target proteins including MET31 and MET4, which have been engineered to become target proteins by fusing it to a modified, dormant N-degron sequence so it can be conditionally destroyed (Silverman, para 127-131).
Claim 26-27: Silverman describes engineering a target protein to contain a dormant N-degron at its amino-terminus. Because it is structurally masked, the cellular machinery cannot detect it, allowing the target protein to remain stable and function normally in the cell and acts as a functional equivalent to a “caged degron”. The TEV protease thus acts as a molecular key, precisely cleaving a specific target site on the modified protein (Silverman, para 11, 13, 26).
New 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 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.
Claims 18 and 20-29 are rejected under 35 U.S.C. 103 as being unpatentable over Silverman (supra) in view of Haruki et al. "The anchor-away technique: rapid, conditional establishment of yeast mutant phenotypes." Molecular cell 31.6 (2008): 925-932 (hereinafter Haruki). This is a new rejection necessitated by amendment of the claims in the responses filed 6/15/2026.
A description of Silverman can be found above. Silverman does not describe the inactivating protein comprising a sub-cellular targeting domain that sequesters the target protein or inhibits the target protein in a dominant negative manner.
Claim 28: Haruki describes an anchor-away system that uses an anchoring protein with a dedicated subcellular targeting domain for nuclear depletion (Haruki, abstract and Fig 1). By
Claim 29: Haruki describes trapping the target protein in an inactive or mismatched cellular compartment, thus rapidly creating a conditional null phenotype in a dominant manner, immediately rendering the target protein incapable of interacting with its normal downstream cellular components (Haruki, discussion).
It would have been prima facie obvious to one of ordinary skill in the art to use the anchor-away system described by Haruki to regulate the target protein rather than the degradation-based approach described by Silverman. It would have been a matter of simple substitution of the inactivating protein, using a subcellular targeting domain instead of the protease-based system described by Silverman which destroys the target protein. One would have been motivated to make this substitution given that the approaches are functional equivalents and, in some cases, the objective may be not to degrade the target protein. One would have a reasonable expectation of success since given that dedicated subcellular targeting domains are known in the art and are commonly tethered to an abundant structural anchor like a ribosomal protein for nuclear depletion.
Claims 18 and 20-32 are rejected under 35 U.S.C. 103 as being unpatentable over Silverman (supra) and Haruki (supra) as applied to claims 18 and 20-29 above in further view of Rafiq. "Engineering strategies to overcome the current roadblocks in CAR T cell therapy." Nature reviews Clinical oncology 17.3 (2020): 147-167 (hereinafter Rafiq). This is a new rejection necessitated by amendment of the claims in the responses filed 6/15/2026.
A description of Silverman and Haruki can be found above. Although Silverman generally describes the cell of interest as a eukaryotic cell, the collection of cited art does not specify that the cell is a T cell or stem cell.
Claims 30-32: Rafiq describes the current roadblocks in CAR T therapy and describes methods to dynamically and rapidly control CAR T function (Rafiq, pg 151 col 2). Rafiq provides an example of overcoming the systemic cytokine toxicity of CAR T cells (Rafiq, Fig 2). Rafiq states that in this system, a protease target site and protease are embedded in the CAR construct, together with a degron moiety that promotes degradation of the CAR protein. Rafiq also describes applications towards stem cells (Rafiq, pg 160 col 1).
It would have been prima facie obvious to one of ordinary skill in the art to apply the dynamic regulation approaches described by Silverman to CAR T and stem cells described by Rafiq to reduce toxicity and enhance therapeutic efficacy. It would have been a matter of combining prior art elements according to known methods to yield predictable results since both Rafiq and Silverman describe degron based regulatory feedback systems for target proteins. One would have been motivated to make this combination to reduce toxicity and enhance therapeutic efficacy of CAR T therapies. One would have a reasonable expectation of success since given that the approaches in Silverman were claimed broadly to work in all eukaryotic cells and the positive results from Rafiq further validate their application in CAR T and stem cells. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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