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 .
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.
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Feb. 14, 2026 has been entered. All arguments and the affidavit/Declaration under 37 CFR §1.132 have been fully considered.
Status of the Claims
Claims 1-14 and 23-32 are currently pending.
Claims 24-28 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 15-22 are cancelled.
Claims 1-14, 23 and 29-32 have been considered on the merits.
Claim Rejections - 35 USC § 112
New claim rejections under 35 USC § 112(b) have been added due to reconsideration.
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 1-14, 23 and 29-32 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “strong promoter” in claim 1 is a relative term which renders the claim indefinite. The term “strong promoter” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification only states that “any suitable strong promoter may be used, the selection of which may be readily made by the skilled person” (0128 of published application). There is no further description of what makes a promoter strong and the only example for a strong promoter is the chicken β-actin promoter as defined by instant claims 1 and 3.
All other claims depend directly or indirectly from rejected claims and are, therefore, also rejected under USC 112 for the reasons set forth above.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are revised due to reconsideration of the prior art.
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 1-5, 8-14, 23 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Bird et al. (WO 2018/172795 A1) as evidenced by NCBI BLASTN (Alignment of instant SEQ ID NO: 7 with Bird SEQ ID NO. 27, Date: May 1, 2026, Camacho et al. BMC Bioinformatics, 2009) in view of Gadalla et al. (Molecular Therapy, 2013) (ref. of record) and Rodrigues et al. (Cell Reports, 2016).
With respect to claim 1, Bird teaches a polynucleotide containing a nucleotide sequence encoding methyl CpG binding-protein 2 (MeCP2) operably linked to a promoter and a 3’ untranslated region (3’UTR) (abstract and pg. 3 lines 1-13). With respect to claims 1 and 4, Bird teaches polynucleotide where the 3’UTR is approximately 205 bp (Fig. 14).
With respect to claim 1, Bird teaches that the 3’UTR containing an endogenous MeCP2 3’UTR containing the distal MeCP2 polyadenylation signal and a number of clustered putative regulatory elements and in addition to containing a select panel of binding sites for miRNAs known to regulate MeCP2 (pg. 42 lines 28-32 and pg. 46 lines 2-9). Bird teaches the polypeptide containing one or binding sites for miR-19, miR-22, miR-132 and miR-124 with an AU rich element and where the MeCP2 expression cassette is no more than 5 kb or 2.2 kb in length (pg. 2 line 34 to pg. 3 line 13, pg. 4 lines 1-5, and pg. 5 lines 29 to pg. 6 line 23). Bird teaches the expression cassette containing a 3’UTR referred to as RDH1pA containing binding sites for miR-19, miR-22, miR-132 and miR-124 with an AU rich element, where the 3’UTR is about 115 bp or less than 1 kb (Fig. 14, approximately 2084 bp-2199 bp). Accordingly, Bird teaches that the 3’UTR contains truncated MeCP2 3’UTR regions that are less than 1000 bp in length. Furthermore, SEQ ID NO. 27 of Bird, which is the sequence of the miR-22 binding site, completely aligns with a portion of instant SEQ ID NO. 7 as evidenced by NCBI Blast alignment:
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With respect to claim 2, Bird teaches the MeCP2 nucleotide sequences, SEQ ID NO. 3 and 21, encode an amino acid sequence that shares 100% homology with SEQ ID NO. 1 (please see Result 2 of Search Results of Geneseq for alignment). With respect to claim 5, Bird teaches the nucleotide sequence further comprising a polyadenylation sequence operably linked to the nucleotide sequence encoding MeCP2 (pg. 35 lines 15-31 and Fig. 13).
With respect to claims 8 and 9, Bird teaches a viral vector containing the polynucleotide (pg. 3 lines 15-22). With respect to claim 10, Bird teaches the vector is a viral vector particle (pg. 7 lines 32-34). With respect to claim 11, Bird teaches viral vector particle is an AAV vector particle that contains a AAV9 capsid (pg. 6 lines 34-36). With respect to claim 23, Bird teaches the vector is AAV, a retroviral vector, a lentiviral vector or a adenoviral vector (pg. lines 15-22).
With respect to claim 12, Bird teaches a cell containing the AAV virion containing the MeCP2 nucleotide sequence (pg. 7 lines 1-14 and pg. 21 lines 2-11). With respect to claim 13, Bird teaches a pharmaceutical composition containing the nucleic acid or AAV virion with a pharmaceutically acceptable carrier (pg. 7 lines 20-23). With respect to claim 14, Bird teaches that the composition can be delivered by a peripheral or central (systemic or local delivery); and intravenous and intrathecal (pg. 7 lines 25-30)
Bird does is silent as to the strength of the promoter and does not teach that the promoter is a strong promoter as recited in claim 1. Similarly, Bird does not teach that the promoter is a chicken β-actin (CBA) promoter as recited in claim 3. However, Gadalla teaches a similar polynucleotide with a nucleotide sequence encoding MeCP2 operably linked to a chicken β-actin promoter (abstract). Gadalla further teaches that the exogenous derived MeCP2 under the CBA promoter was expressed at approximately 1-1.25 times native levels in mice (pg. 18 Col. 2 para. 1). Accordingly, one of ordinary skill in the art would have been motivated to modify the polynucleotide of Bird so that the promoter is the CBA promoter, which is a strong promoter according to claims 1 and 3, for the benefit of having MeCP2 expression close to naturally occurring levels when expressed in an organism as taught by Gadalla. It would have been obvious to one of ordinary skill in the art to substitute the promoter of Bird with other known promoters, like CBA, that have been successfully used for expressing MeCP2 as taught by Gadalla. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the polynucleotide containing a nucleotide sequence encoding for MeCP2, since CBA promoters operably linked to a nucleotide sequence encoding for MeCP2 were known and were known to be successfully expressed in mice as taught by Gadalla.
Bird does not teach that the truncated 3’UTR is truncated at the 3’ end as recited in claim 29.
However, Rodrigues teaches a polynucleotide containing a sequence encoding a polynucleotide containing a nucleotide sequence encoding for a luciferase reporter and a 3’ untranslated region (3’UTR) where the 3’UTR is a truncated MeCP2 3’UTR that is 149 bp, is less than 1000 bp in length, and which is truncated at the 3’ end (abstract and Fig. 3A). Rodrigues further teaches that MECP2 transcripts undergo alternative polyadenylation generating mRNAs with four possible 3’UTR lengths ranging from 130 to 8600 nucleotides and where the truncations are at the 3’ end (pg. 722 Col. 2 para. 1). Rodrigues teaches that the 3’UTR plays a pivotal role in the post-transcriptional control of MECP2 (pg. 720-722 bridging para.). In further support, Bird teaches that “the skilled person will be capable of designing other elements of the expression cassette to achieve appropriate expression of the MeCP2 transgene in the desired target cell type” (pg. 35 lines 15-17).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the polynucleotide of Bird so that the 3’UTR is a truncated MeCP2 3’UTR at the 3’ end for the benefit of altering the translational expression of the gene depending on the desired level and location of expression of the gene as taught by Rodrigues. It would have been obvious to one of ordinary skill in the art to modify the polynucleotide of Bird so that the 3’UTR is a truncated MeCP2 3’UTR and truncated at the 3’ end, since similar polynucleotides containing a nucleotide sequence encoding a protein operably linked to a promoter and a 3’UTR were known to have 3’UTR which are truncated 3’UTR of MeCP2 and truncated at the 3’ end as taught by Rodrigues and Bird teaches a 3’UTR which contains a truncated version of the 3’UTR of MeCP2. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the polynucleotide of Bird, since the truncated MeCP2 3’UTR is a portion of the endogenous 3’UTR for the gene being encoded by the polynucleotide, Rodrigues teaches a polynucleotide with an expression cassette containing truncated MeCP2 3’UTRs which are truncated at the 3’ end, and Bird teaches polynucleotides containing a nucleotide sequences encoding MeCP2 operably linked to a promoter and a 3’UTR where the 3’UTR contains a truncated sequence of the endogenous MeCP2.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 6 and 7 are rejected under 35 U.S.C. 103(a) as being unpatentable over Bird as evidenced by NCBI BLASTN in view of Gadalla and Rodrigues (as applied to claims 1-5, 8-14, 23 and 29 above), and further in view of Zhou et al. (Neuron, 2006).
The teachings of Bird, Gadalla, and Rodrigues can be found in the previous rejection above.
Although, Bird teaches polynucleotide where the 3’UTR containing miRNA binding sites (pg. 3 lines 1-13), Bird does not teach the polynucleotide further comprises a nucleotide sequence encoding an inhibitor of MeCP2 expression as recited in claim 6, or where the inhibitor is an ShRNA, siRNA, miRNA or antisense DNA/RNA as recited in claim 7.
However, Zhou teaches a similar polynucleotide encoding a shRNA and MeCP2, where the shRNA is directed against the expression of endogenous MeCP2 causing the reduction of endogenous MeCP2 expression and expression of the functional exogenous MeCP2 (Fig. 5A and legend and pg. 261 Col. 1 para. 2). Zhou teaches that the efficient knockdown of endogenous MeCP2 protein by the shRNA construct allows for appropriate expression levels of the functional exogenous MeCP2 (pg. 262 para. 1). Zhou further explains that by having the polynucleotide encoding MeCP2 further contain a sequence encoding a shRNA the probability that the exogenously introduced MeCP2 will efficiently replace the endogenous MeCP2 protein increases by reducing the levels of endogenous MeCP2 protein (pg. 261 Col. 2 para. 2). Zhou teaches that an appropriate level of MeCP2 protein is needed for appropriate dendritic morphology in mice and it is possible restore dendritic morphology by introducing into Mecp2-l/y null mice the polynucleotide including the shRNA and MeCP2 protein (pg. 262 para. 1).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the polynucleotide of Bird so that it includes an inhibitor of MeCP2 expression, such as a shRNA, for the benefit of preventing endogenous MeCP2 expression so that the appropriate level of exogenous functional MeCP2 is expressed as taught by Zhou. It would have been obvious to one of ordinary skill in the art to include in the polynucleotide of Bird a sequence encoding an inhibitor of MeCP2 expression, such as a shRNA, since similar polynucleotides were known in the art and were known to successfully allow appropriate expression levels of the introduced exogenous MeCP2 as taught by Zhou. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the polynucleotide containing a nucleotide sequence encoding for MeCP2, since sequences encoding inhibitors of endogenous MeCP2 expression were known to be included in polynucleotides containing a nucleotide sequence encoding for MeCP2 and were known to be successfully expressed in mice as taught by Zhou.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 30-32 are rejected under 35 U.S.C. 103(a) as being unpatentable over Bird as evidenced by NCBI BLASTN in view of Gadalla and Rodrigues (as applied to claims 1-5, 8-14, 23 and 29 above), and further in view of Coy et al. (Human Molecular Genetics, 1999).
The teachings of Bird, Gadalla, and Rodrigues can be found in the previous rejection above.
None of Bird, Gadalla or Rodrigues teach the polynucleotide where the 3’UTR comprises a nucleotide sequence having at least 70% sequence identity to any one of SE ID Nos 6-8 as recited in claim 30, comprises the nucleotide sequence of SEQ ID NO 6 as recited in claim 31, or comprises the nucleotide sequence of SEQ ID NO 6 as recited in claim 32.
However, Coy teaches that the mouse 3’UTR of MeCP2 contains SEQ ID NO. 6, where SEQ ID NO. 6 algins 100% with nucleotides 1491-1713 of the mouse 3’UTR sequence disclosed in Coy (Search Results, Aug. 28, 2025, GenEmble, Result Number 3 for SEQ ID NO. 6). Coy teaches that the human 3’UTR of MeCP2 contains SEQ ID NO. 7, where SEQ ID NO. 7 algins with nucleotides 1537-1760 of the human 3’UTR sequence disclosed in Coy (Search Results, Aug. 28, 2025, GenEmble Result Number 7 for SEQ ID NO. 7). In addition, Coy teaches a sequence in the 3’UTR of MeCP2 with 77.8% sequence identity with SEQ ID NO. 8, where SEQ ID NO. 8 algins with 1537-1669 of the human 3’UTR sequence disclosed in Coy (Search Results, Aug. 28, 2025, GenEmble Result Number 13 for SEQ ID NO. 8).
In further support, as stated above, Bird teaches a polynucleotide with a 3’UTR containing an endogenous MeCP2 3’UTR containing the distal MeCP2 polyadenylation signal and a number of clustered putative regulatory elements and in addition to containing a select panel of binding sites for miRNAs known to regulate MeCP2 (pg. 42 lines 28-32 and pg. 46 lines 2-9). Additionally, Bird teaches that “the skilled person will be capable of designing other elements of the expression cassette to achieve appropriate expression of the MeCP2 transgene in the desired target cell type” (pg. 35 lines 15-17). In additional support, Rodrigues teaches a polynucleotide containing a sequence encoding a polynucleotide containing a nucleotide sequence encoding for a luciferase reporter and a 3’ untranslated region (3’UTR) where the 3’UTR is a truncated MeCP2 3’UTR that is 149 bp, is less than 1000 bp in length, and which is truncated at the 3’ end (abstract and Fig. 3A). Rodrigues further teaches that the 3’UTR plays a pivotal role in the post-transcriptional control of MeCP2 (pg. 720-722 bridging para.). Rodrigues teaches using the polynucleotide with the luciferase reporter with different segments of the MeCP2 ‘3-UTR to determine how the different regions affect the post-transcriptional regulation of the coding sequence or characterize the sequence elements capable of regulating mRNA stabilization and translation in hESCs and neurons (pg. 723-724 bridging para. and Fig. 3A).
Accordingly, one of ordinary skill in the art would have been motivated to modify the polynucleotide taught by the combined teachings of Bird, Gadalla, and Rodrigues so that the 3’UTR comprises SEQ ID NO. 6, SEQ ID NO. 7 or SEQ ID NO. 8 for the benefit of providing known sequences for controlling the post-transcriptional regulation of the mRNA transcript. It would have been obvious to one of ordinary skill in the art to use a known fragment of the human 3’UTR, since fragments of the MeCP2 3’UTR were known to be used in such polynucleotides as taught by Bird and Rodrigues and SEQ ID NO 6-8 are known sequences of a portion of either the mouse or human MeCP2 3’UTR and Bird teaches that the skilled artisan would be capable of designing other elements of the expression cassette to achieve appropriate expression. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of in making such a modification to the polynucleotide taught by the combined teachings of Bird, Gadalla, and Rodrigues, since the sequences were known to be a part of either the mouse or human MeCP2 3’UTR and both Bird teach the successful use of fragments of the MeCP2 3’UTR in a polynucleotide encoding the MeCP2 gene, Bird and Rodrigues teach that the 3’UTR plays a role in regulating the post-transcriptional control of MeCP2, and Rodrigues teaches fragments of the MeCP2 3’UTR in an expression cassette for determining their regulatory function.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Feb. 14, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant states, as explained in the Declaration under Rule 37 CFR 1.132 by Vania Broccoli, Ph.D., that the present invention is the development of an instability-prone MeCP2 (“iMecp2”) transgene cassette that prevents supraphysiological MeCP2 protein levels in transduced neural tissues and that the application demonstrates successful results with intravenous injections of an iMeCP2-encoding vector in a mouse model of Rett syndrome (Remarks pg. 5 para. 4). However, these arguments were not found to be persuasive, since the prior art teaches the claimed polynucleotide and the data is not commensurate in scope with the claim invention. The claimed polynucleotide is broader than the polynucleotide for generating the data in the specification. The data in Example 1 show a particular polynucleotide containing specific sequences for the nucleotide sequence encoding MeCP2, a particular promoter (chicken-β-actin), a particular 3’UTR sequence (that is about 200 bp) and a particular vector (AAV9 PHP.eB) there is improved locomotor activity, coordination, lifespan and normalization of altered gene expression and mTOR signaling in MeCP2 mutant mice models (0013-0015, 0331-0332, 0397 and Example 1). It is unclear if the same effects would be achieved with different sequences encompassed by the claimed invention, for instance, if the polynucleotide has a different promoter, a different 3’UTR sequence and/or a different vector. The applicant has provided no reasoning why the allegedly unexpected results shown in the specification should be extrapolated across the entire set of claimed polynucleotides.
Applicant argues that Dr. Broccoli explains that even though Rodrigues teaches truncated MeCP2 3’-UTRs, Rodrigues only measures the effects of the truncated MeCP2 3’-UTRs on the expression of the luciferase gene and that effect of the 3’-UTR depends on the coding sequence (Remarks pg. 5 last para.). Applicant argues that Dr. Broccoli further explains that the coding sequence affects the translation efficiency, ribosome density, elongation kinetics and translation termination and in turn determines the extent to which the positive and negative regulatory elements in the 3’-UTR promote or inhibit translation (Remarks pg. 6 para. 1). Applicant argues that Dr. Broccoli explains, for example, that positive regulatory elements may affect translation of poorly translated genes more strongly than they affect genes that already strongly translated and negative regulatory elements affect strongly translated genes to a greater extent than genes that are poorly translated. Applicant argues that because of this conclusions cannot be drawn on how the 3’-UTRs would affect MeCP2 expression based on their impacts on luciferase expression (Remarks pg. 6 para. 2). Applicant further argues that the findings in Rodrigues do not provide an indication how the 3’-UTRs would affect MeCP2 mRNA stability based on their impacts on luciferase mRNA stability (Remarks pg. 6 para. 3). However, these arguments were not found to be persuasive, since the Applicant has not provided any evidence that the coding sequence affects the impact of the 3’UTR. In contrast, Rodrigues uses the luciferase reporter (as the coding sequence) with different segments of the MeCP2 ‘3-UTR to determine how the different regions affect the post-transcriptional regulation of the coding sequence or characterize the sequence elements capable of regulating mRNA stabilization and translation in hESCs and neurons (pg. 723-724 bridging para. and Fig. 3A). Therefore, Rodrigues supports the notion that the 3’UTR regulatory elements or regions would have similar affects on mRNA stabilization and translation of different coding sequences.
Applicant argues that Broccoli explains that Example 1 shows that MeCP2 mRNA levels in neurons transduced with viral vectors containing a truncated MeCP2 3’-UTR which contain most of the known regulatory elements from the long 8.6 kb long 3’UTR remains unstable (Remarks pg. 6 para. 4). Applicant argues in contrast Rodrigues indicates that luciferase mRNA levels were the same when either 42655-5677 MeCP2 3’-UTR or the GADPH 3’-UTR is used (Remarks pg. 6 last para.). Applicant argues that Rodrigues does not make a comparison of the different truncated MeCP2 3’-UTR with the full length MeCP2 3’-UTR, so it is unclear how these fragments differ compared to the full length 3’UTR (Remarks pg. 7 para. 1). However, these arguments were not found to be persuasive, the fragment shown in Example 1 that has this desired effect is much smaller than 1000 bp. As stated above, the data in Example 1 show a particular polynucleotide containing specific sequences for the nucleotide sequence encoding MeCP2, a particular promoter (chicken-β-actin), a particular 3’UTR sequence (that is about 200 bp) and a particular vector (AAV9 PHP.eB) there is improved locomotor activity, coordination, lifespan and normalization of altered gene expression and mTOR signaling in MeCP2 mutant mice models (0013-0015, 0331-0332, 0397 and Example 1). Additionally, the claims do not define the 3’UTR comprised in the claimed polynucleotide and 3’UTR is 8.6 kb so the truncated 3’UTR can be any sequence within this region that is less than 1000 bp. This includes a sequence of only 1 bp in length. Therefore, not any fragment of the endogenous 3’UTR MeCP2 that is less than 1000 bp can be considered to have this effect on the expression of the MeCP2 coding sequence.
Applicant argues that a person skilled in the art would have no reason to consider replacing the 3’UTR taught in Bird with one of the MeCP2 3’-UTR fragments taught by Rodrigues, since the effects of the MeCP2 3’-UTR fragments on MeCP2 expression are not known or disclosed (Remarks pg. 7 para. 2). However, this argument was not found to be persuasive, since Rodrigues is using the luciferase reporter gene to determine how the fragments would affect MeCP2 expression (pg. 723-724 bridging para. and Fig. 3A).
Applicant argues that Zhou does not remedy the deficiencies of Bird, Gadalla and Rodrigues (Remarks pg. 8 para. 1). However, this argument was not found to be persuasive, since the arguments with respect to the rejections over Bird, Gadalla and Rodrigues were not found to be persuasive as explained above.
Applicant argues that Coy does not teach a truncated MeCP2 3’-UTR and Zhou does not remedy the deficiencies of Bird, Gadalla and Rodrigues (Remarks pg. 8 para. 4). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Coy is being relied upon for the teaching of the SEQ ID NO. 6-8 are known sequences found in the 3’UTR of MeCP2 and Bird and Rodrigues are being used for the teachings of using truncated sequences of the 3’UTR in an expression cassette. Applicant addressed each prior art reference separately and only with regard to the specific limitations of that reference. However, when the prior art references are taken as a whole, they teach that the skilled artisan knows each step of the method as currently claimed.
Response to Evidentiary Declaration under 37 CFR §1.132
The declaration of Vania Broccoli, Ph.D. filed on Feb. 14, 2026 under 37 CFR §1.132 has been considered but is ineffective to overcome the rejections of claims 1-14, 23 and 29-32 under 35 U.S.C. §103 over Bird in view of Gadalla, Rodrigues, Zhou and Coy. Most of Dr. Broccoli’s statements are address in the response to Applicant’s remarks above and are repeat here.
Dr. Broccoli states that they have shown successful functionality of the instability-prone MeCP2 (“iMeCP2”) transgene cassette which prevents supraphysiological MeCP2 protein levels in transduced neural tissues in the MeCP2 mutant mice (a Rett syndrome model) and showed that there were no severe toxicity effects in either female MeCP2 mutant or wild-type mice (Declaration para. 4). Dr. Broccoli also states that both male and female MeCP2 mutant mice had significant ameliorated disease progression when intravenous injections of an iMeCP2-encoding vector were administered (Declaration para. 4). These statements were not found to be persuasive, since the prior art teaches the claimed polynucleotide and the data is not commensurate in scope with the claim invention. The claimed polynucleotide is broader than the polynucleotide for generating the data in the specification. The data in Example 1 show a particular polynucleotide containing specific sequences for the nucleotide sequence encoding MeCP2, a particular promoter (chicken-β-actin), a particular 3’UTR sequence (that is about 200 bp) and a particular vector (AAV9 PHP.eB) there is improved locomotor activity, coordination, lifespan and normalization of altered gene expression and mTOR signaling in MeCP2 mutant mice models (0013-0015, 0331-0332, 0397 and Example 1). It is unclear if the same effects would be achieved with different sequences encompassed by the claimed invention, for instance, if the polynucleotide has a different strong promoter, a different 3’UTR sequence and/or a different vector. Dr. Broccoli has provided no reasoning why the allegedly unexpected results shown in the specification should be extrapolated across the entire set of claimed.
Dr. Broccoli states that the results Rodrigues reports for short 3’UTRs with report genes cannot be used to accurately predict the effects the same 3’UTRs would have on another gene such as MeCP2, since mRNA stability is linked to various factors (Declaration para. 6). Dr. Broccoli states that it is well-known that the effects of 3’UTRs depends on the coding sequence that they are coupled with and that the coding sequence affects the translation efficiency, ribosome density, elongation kinetics and translation termination and in turn determine the extent to which the positive and negative regulatory elements in the 3’-UTR promote or inhibit translation (Declaration para. 7). Dr. Broccoli states conclusions on how certain 3’UTRs affect MeCP2 expression based on their impact on luciferase expression and therefore the findings in Rodrigues do provide an indication of how the truncated 3’UTRs would affect MeCP2 mRNA stability since they only looked at luciferase mRNA stability (Declaration para. 8-9). However, these statements were not found to be persuasive, since Dr. Broccoli has not provided any clear evidence that the coding sequence affects the impact of the 3’UTR. In contrast, Rodrigues uses the luciferase reporter (as the coding sequence) with different segments of the MeCP2 ‘3-UTR to determine how the different regions affect the post-transcriptional regulation of the coding sequence or characterize the sequence elements capable of regulating mRNA stabilization and translation in hESCs and neurons (pg. 723-724 bridging para. and Fig. 3A). Therefore, Rodrigues supports the notion that the 3’UTR regulatory elements or regions would have similar effects on mRNA stabilization and translation of different coding sequences.
Dr. Broccoli explains that Example 1 shows that MeCP2 mRNA levels in neurons transduced with viral vectors containing a truncated MeCP2 3’-UTR which contain most of the known regulatory elements from the long 8.6 kb long 3’UTR remains unstable whereas Rodrigues indicates that luciferase mRNA levels were the same when either 42655-5677 MeCP2 3’-UTR or the GADPH 3’-UTR is used (Declaration para. 11). Dr. Broccoli explains that Rodrigues does not make a comparison of the different truncated MeCP2 3’-UTR with the full length MeCP2 3’-UTR, so it is unclear how these fragments differ compared to the full length 3’UTR (Declaration para. 12). However, these statements were not found to be persuasive, the fragment shown in Example 1 that has this desired effect is much smaller than 1000 bp. As stated above, the data in Example 1 show a particular polynucleotide containing specific sequences for the nucleotide sequence encoding MeCP2, a particular promoter (chicken-β-actin), a particular 3’UTR sequence (that is about 200 bp) and a particular vector (AAV9 PHP.eB) there is improved locomotor activity, coordination, lifespan and normalization of altered gene expression and mTOR signaling in MeCP2 mutant mice models (0013-0015, 0331-0332, 0397 and Example 1). Additionally, the claims do not define the 3’UTR comprised in the claimed polynucleotide and 3’UTR is 8.6 kb so the truncated 3’UTR can be any sequence within this region that is less than 1000 bp. This includes a sequence of only 1 bp in length. Therefore, not any fragment of the endogenous 3’UTR MeCP2 that is less than 1000 bp can be considered to have this effect on the expression of the MeCP2 coding sequence.
Conclusion
No claims are allowed.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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