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 .
Applicant’s arguments and amendments filed on 12/22/2025 have been entered.
Claims 1, 4 and 5 have been amended.
Claim 2 has been cancelled.
In view of Applicants amendments to claim 5, the 112(b) rejection is withdrawn.
In view of Applicants amendments to claim 1, the 102(a)(1) rejection is withdrawn.
Claims 1, 3-9 and 21 are examined in the instant application.
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.
Claim(s) 1, 4-9 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patane M. (U.S. Patent No. 9,409,901 B1, issued 8/9/2026) in view of Sonenberg et al. (WO 2009/076755 A1), Jiang et al. (2003, Cancer Cell Int., Vol. 3:2, pgs. 1-10) and Crino PB (2015, Cold Spring Harbor Perspectives in Medicine, 5:a022442, pgs. 1-17) for reasons of record in the Non-Final Office Action mailed on 9/4/2025 (and repeated below).
Regarding claim 1, Patane M. teaches a method of preventing seizures in a subject comprising contacting a target cells of the subject with an effective amount of a 4EPB-activating agent (col. 1 lines 42-50, col. 4 lines 8-11, col. 6 lines 21-25, col. 8 line 65 bridge col. 9 line 3).
Importantly, Patane taches that their therapy can function as an mTOR inhibitor (col. 44 lines 31-39).
Patane does not teach:
an adenoviral vector with a tissue specific promoter.
a viral vector encoding a constitutively active form of 4EBP;
delivering the activating agent to brain neurons in a subject with focal cortical malformations.
Regarding a viral vector with a tissue specific promoter, Sonenberg et al. teaches
an adenoviral vector comprising a tissue specific promoter encoding 4EBP (pg. 14 lines 4-12).
Sonenberg continues to teach that (emphasis added) “Mammals contain three highly related 4E-BPs that compete with elF4G for a shared binding site on the convex dorsal surface of elF4E. mTOR-mediated phosphorylation of 4E-BP1 (the most characterized 4E-BP), stimulates translation by dissociating 4E-BPs from elF4E. Hypophosphorylated 4E-BP1 binds to elF4E with high affinity (nanomolar range), whereas increased phosphorylation decreases its affinity for elF4E.” (pg. 1 lines 22-27).
Regarding a viral vector encoding a constitutively active form of 4EBP, Jiang
et al. teach developing a mutant 4EBP which is constitutively expressed due to mutation of 5 amino acids that were targeted for phosphorylation, and thus their 4EBP cannot be phosphorylated (pg. 2 col. 1 last parag.).
Jiang continues to teach that through constitutive expression of 4EBP they observed an increase in binding of 4EBP to eIF4E (pg. 6 col. 2 parag. 2).
Regarding mTOR signaling in epilepsy, Crino PB teaches “Malformations of cortical
Development (MCD) are highly associated with medically intractable epilepsy (pg. 1 col. 1 lines 1-3).
Regarding claim 7, Crino continues to teach that “Over the past decade enhanced activation of the mammalian target of rapamycin (mTOR)-signaling cascade has been identified in focal malformations of cortical development (MCD) subtypes, which have been collectively referred to as “mTORopathies.” (Abstract lines 1-3).
Regarding claim 21, Crino continues to teach that There is now solid evidence that hyperactivated mTOR signaling is a feature of several focal MCD subtypes and likely provides a common pathogenic mechanism for the cytoarchitectural abnormalities seen in these MCD” (pg. 3 col. 2 last two lines bridge pg. 4 col. 1 lines 1-3).
Regarding claims 6, 8 and 9, it would be obvious to target neurons in the brains of a patient suffering from seizures since Crino teaches the how mTOR hyperactivity leads to focal cortical malformations that occur entirely in the brain.
Further Crino teaches:
“Perhaps the most significant progress will come from designing targeted epilepsy therapies through inhibition of mTOR (Galanopolou et al. 2012; Wong 2013). Current data suggests that mTOR inhibitors can improve seizure frequency in TSC and PS. Furthermore, mTOR inhibitors in mouse mTORopathy models can improve neurocognitive deficits, and thus these agents could yield novel therapeutic strategies to improve neurobehavioral disabilities.” (pg. 12 col. 2 last parag. bridge pg. 12 col. 1 lines 1-5).
Thus at the time of filing it would have been prima facie obvious to combine the teachings of Patane regarding a method of preventing seizures using a 4EBP-activating agent wit the teachings of Sonenberg regarding the adenoviral expression of 4EBP and with the teachings of Jiang regarding the constitutive expression of 4EBP and with the teachings of Crino regarding the role of mTOR in seizures to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make such a combination since Sonenberg teaches that increased 4EBP will bind to eIF4E and Jiang teaching that blocking phosphorylation of 4EBP via mutation increases its binding to eIF4E. Further motivation is provided by Patane and Crino with Patane teaching that their therapy can be function as an mTOR inhibitor and Crino teaching the nexus of mTOR expression and the onset of focal cortical malformations and the resulting epilepsy.
There would have been a reasonable expectation of success that the adenoviral vector of Sonenberg could be mutated to express a constitutive active form of 4EBP since Jiang teaches the 5 alanine residues to be mutated.
Thus the cited art provides the requisite teachings and motivations to make and use the invention as claimed.
Response to Arguments
Applicant’s Arguments
Applicants argue in amendment that Patane does not describe using the 4E-BP inhibitor in a viral vector comprising a polynucleotide encoding a constitutively active form of 4EBP. The Sonenberg, Jiang, and Crino references do not teach or suggest all of the claim limitations of the invention and do not overcome the deficiencies of Patane. Sonenberg teaches the use of a shRNA to inhibit 4EBP and not a polynucleotide encoding a constitutively active form of 4EBP (4EBPᶜA) to inhibit 4EBP. Jiang fails to overcome the deficiencies of Patane and Sonenberg because Jiang uses a mammalian expression vector in breast cancer cells to express the constitutively active form of 4EBP to cause cell cycle arrest (emphasis added).
Jiang describes that in order "to test the effect of 4EBP-1 on the proliferation of human
breast cancer cells, an expression vector encoding the constitutively active 4EBP-1 mutant
(4EBP-1-5A) was stably transfected into MCF7 cells." from Jiang at page 2 (first paragraph of
results section). Further, Jiang describes that the vector backbone used for stable transfection was
a pERV3 vector used in an inducible mammalian expression system (Jiang, page 7). A stably
transfected expression vector is not a viral vector. Accordingly, Jiang fails to teach or suggest a
viral vector comprising a polynucleotide encoding a constitutively active form of 4EBP.
Crino also fails to overcome the deficiencies of Patane, Sonenberg, and Jiang because
Crino only discusses the use of small molecule m TOR inhibitors (i.e., rapamycin) in targeting
focal cortical malformations. Li fails to teach or suggest the feature of a viral vector comprising a
polynucleotide encoding a constitutively active form of 4EBP.
The combination of the cited documents fail at least the first and second criterion of the KSR test, because the references fail to provide any suggestion or motivation to arrive at the method recited and the references fail to provide a reasonable expectation of success to arrive at the claimed invention.
Patane does not describe using the 4E-BP inhibitor in a viral vector comprising a polynucleotide encoding a constitutively active form of 4EBP. Sonenberg teaches the use of a shRNA to inhibit 4EBP and not a polynucleotide encoding a constitutively active form of 4EBP (4EBPᶜA). Jiang uses a mammalian expression vector in breast cancer cells to express the constitutively active form of 4EBP to cause cell cycle arrest. Crino only discusses the use of small molecule mTOR inhibitors (i.e., rapamycin) in targeting focal cortical malformations. Li fails to teach or suggest the feature of a viral vector comprising a polynucleotide encoding a constitutively active form of 4EBP. Nowhere do the references, alone or combined, teach or suggest the method claimed, namely a viral vector comprising a polynucleotide encoding a constitutively active form of 4EBP. Furthermore, none of the cited art, either alone or in combination discloses all of the elements of the claims as described. Therefore, one of ordinary skill in the art would not have had a reasonable expectation of success in arriving at the instantly claimed methods.
Examiner’s Response
While Applicant’s arguments have been fully considered they are not found persuasive. The claimed invention only has one operable step, contacting a target cell with an effective amount of a 4EBP-activating agent. In this regard Patane teaches preventing seizures by contacting a target cell with an effective amount of a 4EBP-activating agent. At the time of filing Sonenberg teaches adenoviral expression of 4EBP with a tissue specific promoter and Jiang teaches constitutive expression of 4EBP. Significantly, the teachings of Crino teach the ordinary artisan that the signaling pathway for mTOR is the nexus which enables the prevention of seizures and this teaching is in agreement with Sonenberg regarding 4EBP and mTOR. Thus the ordinary artisan is provided at the time of filing all of the teachings to make and practice the claimed method. Thus for the reasons above and of record the rejection is maintained.
Claim(s) 3 remains rejected under 35 U.S.C. 103 as being unpatentable over Patane M. (U.S. Patent No. 9,409,901 B1, issued 8/9/2026) in view of Sonenberg et al. (WO 2009/076755 A1), Jiang et al. (2003, Cancer Cell Int., Vol. 3:2, pgs. 1-10) and Crino PB (2015, Cold Spring Harbor Perspectives in Medicine, 5:a022442, pgs. 1-17) as applied to claims 1, 4-9 and 21 above, and further in view of Li et al. (August 2019, Trends Biochem. Sci., Vol. 44(8), pgs. 659-674) for reasons of record in the Non-Final Office Action mailed on 9/4/2025 (and repeated below).
Patane, Sonenberg, Jiang and Crino are relied upon in teaching a method of preventing seizures using an adenoviral vector encoding a constitutively expressed 4EBP.
Patane, Sonenberg, Jiang and Crino do not teach:
using CRISPR to mutate 4EBP to a constitutively active form,
Regarding the use of CRISPR to mutate 4EBP to a constitutively active form, Li
et al. teach that CRISPR can be used to provide both gain of function and loss of function mutations to a protein of interest through CRISPR editing of sequence (pg. 8 parag. 3).
Thus at the time of filing it would have been prima facie obvious to combine the teachings of Patane, Sonenberg, Jiang and Crino regarding a method of preventing seizures using an adenoviral vector encoding a constitutively expressed 4EBP to arrive at the claimed invention with the teachings of Li regarding using CRISPR to provide a gain of function mutation to a protein of interest to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make such a combination since Li teaches that CRISPR editing of a sequence can provide a gain of function to a desired protein.
There would have been a reasonable expectation of success that the 4EBP of Patane could be edited via CRISPR to be constitutively active since Jiang teaches the five alanine residues that need to be mutated to prevent phosphorylation and provide constitutive function to 4EBP.
Thus the cited art provides the requisite teachings and motivations to make and use the invention as claimed.
Response to Arguments
Applicant’s Arguments
Applicants provide no arguments for this rejection.
Examiner’s Response
The rejection is maintained for the reasons above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID A MONTANARI whose telephone number is (571)272-3108. The examiner can normally be reached M-Tr 8-6.
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DAVID A. MONTANARI
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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