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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114 was filed in this application after appeal to the Patent Trial and Appeal Board, but prior to a decision on the appeal. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114.
Applicant’s submission filed on 8/22/2025 has been entered.
Claims status
Claims 25 and 26 is/are cancelled. Claims 1, 4, 7, 22, 29, 46, 172-183 is/are currently pending and is/are under examination.
Claim Suggestion
Claim 22 recites “wherein said first nucleic acid sequences and said second nucleic acid sequences are present within one AAV vector”. Claim 22 depends from Claim 4 which is instantly amended to recite “wherein said first nucleic acid sequence and said second nucleic acid sequence are separated by a P2A linker […] or an […] (IRES) sequence”. Thus, since amended claim 4 already requires the first nucleic acid sequences and the second nucleic acid sequences to be present within one vector, recitation of the same in Claim 22 is redundant. Claim 22 may be amended as follows: “wherein said first nucleic acid sequences and said second nucleic acid sequences are
Claim Rejections - 35 USC § 112(b)
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.
Previous rejections of Claims 1, 7, 46, 172-177, 180-183 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention are withdrawn in light of amendment to claims 1, specifically amending the SEQ ID NOs. in (b).
Claim 29 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 29 requires the first nucleic acid sequences and the second nucleic acid sequences to be separated by the IRES sequence. Claim 29 depends from claim 22 that requires the first nucleic acid sequences and the second nucleic acid sequences to be a P2A linker. It is unclear if claim 29 requires the IRES sequence to be in addition to or as an alternate to the P2A linker sequence. Claim 22 depends from Claim 4 that recites that the IRES sequence and the P2A linkers as alternatives (see the use of ‘or’ in line 9 of claim 4). Considering claim 22 already limits the linker sequence to P2A, it is unclear how claim 29 could further limit the linker sequence of P2A to an IRES sequence. Thus, the claim appears to broaden the limitation pertaining to the linker of claim 22 (addressed below in 112d rejection). For the purpose of compact prosecution, the claim(s) 29 is/are interpreted as dependent from claim 4.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 29 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 29 requires the first nucleic acid sequences and the second nucleic acid sequences to be separated by the IRES sequence. Claim 29 depends from claim 22 that requires the first nucleic acid sequences and the second nucleic acid sequences to be separated by a P2A linker and claim 22 depends from claim 4 that recites that the IRES sequence and the P2A linker as alternatives (see the use of ‘or’ in line 9 of claim 4). In light of the indefiniteness issues noted above, in case claim 29 is further including an IRES sequence in a vector already comprising a P2A linker, claim 29 broadens the AAV vector of claim 22 and claim 4.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
Claim 4 is directed to a product which is a composition comprising only an AAV vector with the specifically recited structural elements in (i, ii, a-e). Claim 4 also recites “wherein a glial cell comprising the one or more AAV vectors is converted into a functional neuron after expression of the hNeuroD1 sequence and the hDlx2 sequence”. Since the composition of claim 4 is not a glial cell comprising the AAV vector and a glial cell is not a structural element of the recited composition, this ‘wherein’ clause is interpreted to recite an intended use of the composition ‘for converting glial cells into functional neurons’.
Regarding ‘wherein’ clauses, MPEP 2111.04 provides that “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”. Furthermore, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim (see MPEP 2111.02(II)).
Of note, the structural elements of the AAV vector of claim 4 are identical to the structural elements of claim 1, thus a prior art(s) that would render claim 1 unpatentable also renders claim 4 unpatentable.
Claim Rejections - 35 USC § 103
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.
Claims 1, 4, 7, 22, 29, 46, 172-183 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 2017/0239373 A1, Publication date 08/24/2017; ref of record) in view of GenBank: LT738798.1 (NCBI, available since 15-Feb-2017; ref of record), GenBank: HQ258018.1 (NCBI, available since 25-July-2016; ref of record), Fan (Plasmids 101: Multicistronic Vectors, Addgene Blog, Published September 9, 2014; ref of record), Lee et al (Glia, Volume 56, April 2008; ref of record), Powell et al (Discov Med., Volume 19, January 2015; ref of record), Boulaire et al (Advanced Drug Delivery Reviews, Volume 61, April 2009; ref of record), Wu et al (Mol. Therapy, vol. 16 no. 2, 280–289 Feb. 2008; ref of record), Wang et al (Gene Therapy (2006) 13, 1447–1456; ref of record), Baeuerle et al (WO-2020219563-A1, Published October 29, 2020; ref of record) as evidenced by Cell biolab pAAV-MCS Expression vector sequence (pAAV-MCS), AmCyan-P2A-mCherry vector sequence (P2A sequence), pWPI vector sequence (IRES sequence), pGfaABC1D-nLac vector sequence (truncated hGFAP promoter), pRc/CMV2 vector sequence (CMV enhancer), pCI-Neo vector sequence (chimeric intron), pcDNA3.1 vector sequence (bGH poly A).
Chen teaches a composition comprising an AAV vector(s) comprising a human NeuroD1 encoding nucleic acid sequence and a human Dlx2 encoding nucleic acid sequence separated by a P2A linker, further comprising a hGFAP promoter for conversion of glial cells into functional neurons ([0009], [0054], [0056], [0069], Example 1, 3; Figure 1, 4); (required for claims 1, 4, 22).
Regarding hNeuroD1 and hDlx2 sequences, Chen teaches vectors comprising nucleic acid sequences that encode SEQ ID no. 1, the amino acid sequence of hNeuroD1 (identical to instant SEQ ID no. 10 which is encoded by the instantly claimed SEQ ID no. 6) and SEQ ID no. 2, the amino acid sequence of hDlx2 (identical to instant SEQ ID no. 14 which is encoded by the instantly claimed SEQ ID no. 13) ([0009], lines 13-33). Chen does not explicitly teach the exact nucleic acid sequences used in their vectors that encode the amino acid sequence of hNeuroD1 and the amino acid sequence of hDlx2, thus Chen does not teach SEQ ID NO. 6 and 13. However, these sequences are available to an ordinary artisan via the publicly available GenBank from National Center for Biotechnology Information (NCBI). Sequences LT738798.1 and HQ258018.1, available through GenBank, teach nucleic acid sequences that encode hNeuroD1 and hDlx2 respectively and are 100% identical to instant SEQ ID No. 6 and 13 respectively (See Sequence Alignments section below).
Regarding linkers between sequences encoding different polypeptides, Chen teaches several linkers, such as P2A, E2A and IRES, for separating nucleic acid sequences that encode different polypeptides [0054, 0056, 0057, 0069, 0071, 0072]. Chen uses these linkers interchangeably. For example, Chen discloses pNG2-NeuroD1-IRES-GFP in [0054] and NG2-NeuroD1-P2A-GFP in [0056], each for the co-expression of NeuroD1 and GFP from the same vector but separated by different linkers that are alternatives. Chen teaches the use of P2A between sequences encoding hNeuroD1 and hDlx2 [0056] (required for claim 22, 181, 183).
Although Chen does not explicitly teach the use of IRES between the sequences encoding hNeuroD1 and hDlx2, these sequences are alternatives known in the art. According to MPEP 2144.06(II), substituting equivalents known for the same purpose present a strong evidence of obviousness (See Smith v. Hayashi, 209 USPQ 754 (Bd. of Pat. Inter. 1980) (The mere fact that phthalocyanine and selenium function as equivalent photoconductors in the claimed environment was not sufficient to establish that one would have been obvious over the other. However, there was evidence that both phthalocyanine and selenium were known photoconductors in the art of electrophotography. "This, in our view, presents strong evidence of obviousness in substituting one for the other in an electrophotographic environment as a photoconductor." 209 USPQ at 759.). The claimed linker sequences are alternatives in the art is exemplified by Chen itself, wherein these linker sequences are used as alternatives for the same purpose of separating nucleic acid sequences that encode different polypeptides. Thus, in teaching P2A between sequences encoding hNeuroD1 and hDlx2, Chen renders its alternative IRES as prima facie obvious (as required for claim 29 in view of 112b issue noted above and claims 180 and 182).
Further, Chen does not explicitly teach the exact nucleotide sequences for the P2A, or IRES linkers. Fan teaches the use of IRES and 2A peptides (P2A, T2A, E2A) in multicistronic vectors (How do multicistronic vectors work?) and teaches various vectors that are provided by Addgene (a commercial vendor) from which the sequence for any of these linkers can be extracted via PCR (second Table). For example, P2A sequence 100% identical to instant SEQ ID no. 15 can be extracted from AmCyan-P2A-mCherry vector; this vector was taught by Fan in second Table (see attached sequence of this vector in PTO-892). See 100% identity between SEQ ID no. 15 aligned with P2A sequence from AmCyan-P2A-mCherry vector below (required for claims 1, 4, 22, 181, 183). Similarly, IRES sequence can extracted from pWPI vector; this vector was taught by Fan in second Table (see attached sequence of this vector in PTO-892). See 100% identity between SEQ ID no. 3 aligned with IRES sequence from pWPI vector below (required for claim 1, 4, 29 in view of 112b issue noted, 180 and 182).
Regarding use of various gene expression regulatory elements, Chen teaches “promoter sequences, enhancer sequences, response elements, signal peptides, internal ribosome entry sequences, polyadenylation signals, terminators, or inducible elements that modulate expression ( e.g., transcription or translation) of a nucleic acid” maybe used as regulatory elements [0035]. Chen explicitly teaches hGFAP promoter for the expression of the hNeuroD1 and hDlx2 polypeptides [0056, 0078]. Chen also teaches that promoter sequences such as EF1a and CMV can also be used in their vector [009, 035].
Regarding the GFAP promoter sequence, Chen teaches a full length hGFAP promoter ([0035], last line and [0056], AAV production) but does not teach a truncated promoter with a sequence of SEQ ID No. 26 as claimed. This deficiency is rectified by Lee that teaches a truncated hGFAP promoter 100% identical to SEQ ID NO: 26 (see Sequence alignments below, pGfaABC1D-nLac plasmid sequence referenced by Lee is attached in PTO-892 and available via Addgene). Furthermore, Lee teaches that their truncated hGFAP promoter is not only shorter and thus beneficial in size limited applications but, also has two-fold greater activity without any loss in specificity (Abstract).
Regarding the CMV enhancer of SEQ ID No. 11 and a WPRE regulatory element of SEQ ID No. 29, Chen does not teach these specific regulatory elements.
Regarding intronic sequences, Chen teaches a human βglobin intron (comprised in the pAAV-MCS used by Chen to generate their AAV vectors, [0056]; see pAAV-MCS sequence in PTO 892). Chen does not teach a chimeric intron of SEQ ID No. 5 which comprises a portion of human β-globin intron fused with a immunoglobin heavy chain acceptor.
Regarding polyA sequences, Chen teaches hGH as a polyA signal, however Chen does not teach bGH of SEQ ID No. 30 as polyA signals.
However, use and sequences of each of these regulatory elements in AAV vectors (CMV enhancer, WPRE, chimeric introns, bGH polyA) to alter transgene expression dependent on experimental needs are well-known in the art.
Powell teaches the use of enhancers, WPREs, intronic sequences and polyA sequences in AAV expression cassettes to increase transgene expression, specifically teaching the use of CMV enhancers, WPREs, chimeric intron comprising a portion of human β-globin intron fused with a immunoglobin heavy chain acceptor and bGH polyA (Abstract, pages 4-6, Tables 1-3). Regarding the CMV enhancer, Powell teaches several references that lead to the conclusion that “the CMV enhancer increases transgene expression under different cell-specific promoters and different cell types making it a broadly applicable tool to increase transgene expression levels” (page 6, para 1). Regarding WPRE, Powell teaches that WPRE not only promote transgene expression but also prevent transgene silencing in vivo (page 4, para 2). Regarding chimeric intron, Powell teaches that “an intron can be a valuable element to include in an expression cassette to increase transgene expression” (page 6, para 1; Table 3). Regarding polyA regulatory elements, Powell teaches that at least for neurons bGHpolyA is a strong polyA signal and when combined with WPRE results in increased transgene expression (page 5, para 1-2; Table 2). Critically, Powell teaches that bGH is a stronger polyA signal as compared to hGH polyA, as used by Chen (Table 2).
Additionally, Boulaire also teaches several viral regulatory elements such as human CMV enhancer, ITRs and WPRE to improve gene expression in brain cells (section 3.4), specifically teaching that a CMV enhancer combined with GFAP promoter increases gene expression “by 10-fold in the rat brain when compared to the baculoviruses with the GFAP promoter alone” (page 596, right column, para 4, lines 5-9). Boulaire also teaches WPREs in AAVs to increase transgene expression (page 598, left column, para 1, line 4-5) and note that when combined with neural specific promoters have been shown to increase transgene expression by 26-fold (page 598, right column, last line).
Although Powell and Boulaire do not explicitly teach the exact nucleotide sequences for a CMV enhancer, WPRE, chimeric introns or bGH polyA - such sequences are known in the art.
For example, Wang teaches vectors comprising CMV enhancer sequence derived from pRc/CMV2 plasmid that is 100% identical to SEQ ID No. 11 (See Sequence Alignments section, pRc/CMV2 plasmid sequence referenced by Wang is attached in PTO-892 and available via Invitrogen; required for claims 1, 4).
Baeuerle teaches vectors comprising WPRE sequence 100% identical to SEQ ID No. 29 (See Sequence Alignments section; SEQ ID No. 139 in Baeuerle, required for claims 1, 4).
Wu teaches vectors comprising chimeric intron sequence derived from pCI-Neo plasmid that is 100% identical to SEQ ID No. 5 (See Sequence Alignments section; pCI-Neo plasmid sequence referenced by Wu is attached in PTO-892 and available via Promega;, required for claims 1, 4). Wu also teaches vectors comprising bGH polyA derived from pcDNA3.1 plasmid that is 100% identical to SEQ ID No. 30 (See Sequence Alignments section; pcDNA3.1 plasmid sequence referenced by Wu is attached in PTO-892 and available via Invitrogen; required for claims 1, 4).
Regarding AAV serotypes and AAV ITR sequences, especially AAV2 ITR sequences of SEQ ID No. 1 or 5, Chen teaches “viral vector can be an adeno-associated viral vector (e.g., an adeno-associated virus serotype 2 viral vector, an adeno-associated virus serotype 5 viral vector, or an adeno-associated virus serotype 9 viral vector)” [0009] (required for claims 7, 172, 173, 174 and 178). Chen uses the pAAV-MCS vector to generate their AAV which comprises two AAV2 ITRs with sequences 100% identical to SEQ ID No. 1 and 9 (see pAAV-MCS sequence in PTO-892 and Sequence Alignments section; required for claims 46, 175, 179). Chen teaches the use of AAV serotype 5 or 9 as their vector [0009]. ITRs are cis-acting regions that flank the rep and cap genes of adeno-associated viruses; these genes are replaced by transgenes of interest to form an AAV vector with ITR sequences from the AAV flanking the transgenes of interest (See teachings about ITRs from Boulaire in section 3.4.2). Therefore, Chen’s teaching of AAV serotype 5 or 9 as their vector implicitly teaches AAV serotype 5 or 9 ITRs (required for claims 176, 179).
In summary, Chen teaches a polycistronic AAV vector encoding hNeuroD1 and hDlx2, sequences separated by a linker such as P2A and, operably linked to a GFAP promoter and other regulatory elements such as a human βglobin intron and hGH polyA.
Chen teaches that hNeuroD1 and hDlx2 when expressed together in astrocytes using the GFAP promoter converts them into neurons (Example 1, 3; meets the wherein clause of claim 4). Chen does not teach a truncated GFAP promoter however Lee rectifies this deficiency.
Chen teaches the use of 2A and IRES linkers as alternatives to separate polypeptide encoding nucleic acid sequences such as of hNeuroD1 and hDLX2 encoding sequences. Furthermore, Chen teaches regulatory elements such as “promoter sequences, enhancer sequences, response elements, signal peptides, internal ribosome entry sequences, polyadenylation signals, terminators, or inducible elements that modulate expression ( e.g., transcription or translation) of a nucleic acid” maybe used in their vectors [0035].
Although, Chen does not teach the exact nucleotide sequences for hNeuroD1, hDlx2, GFAP, P2A, IRES nor does it teach some of the regulatory elements specifically recited in the claims (truncated GFAP, WPRE, CMV enhancer, chimeric intron, bGH polyA), the nucleotide sequences for hNeuroD1, hDlx2, P2A, IRES have been publicly available (GenBank: LT738798.1, GenBank: HQ258018.1, Fan) and use of each of the recited regulatory elements to increase transgene expression is well known in the art (Lee, Powell, Boulaire, Wang, Wu and Baeuerle). Therefore, each of the regulatory elements specifically recited in the claims are readily present in a toolbox of an ordinary artisan in the field of viral vectors and are known for increasing transgene expression.
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the vector of Chen to comprise the nucleotide sequences for hNeuroD1, hDlx2 taught by GenBank: LT738798.1, GenBank: HQ258018.1, linker sequences taught by plasmids (AmCyan-P2A-mCherry vector sequence, pWPI) taught by Fan, truncated GFAP promoter taught by Lee and regulatory elements such as CMV enhancer, WPRE, bGH polyA and chimeric introns as taught by Powell, Boulaire, Wang, Wu and Baeuerle.
An ordinary artisan using the invention of Chen to convert astrocytes to neurons would be motivated to include the nucleotide sequences of hNeuroD1, hDlx2 taught by GenBank: LT738798.1, GenBank: HQ258018.1 to generate Chen’s vector because although Chen teaches that their vectors comprise sequences encoding hNeuroD1, hDlx2, Chen does to explicitly provide these sequences. Similarly, an ordinary artisan using the invention of Chen to convert astrocytes to neurons would be motivated to include the nucleotide sequences of P2A, or IRES linkers taught by plasmids (AmCyan-P2A-mCherry vector sequence, pWPI) taught by Fan because although Chen teaches that their vectors comprise linker sequences, Chen does to explicitly provide these sequences. An ordinary artisan would be motivated to substitute Chen’s full length promoter with Lee’s promoter because Lee teaches that their truncated hGFAP promoter is not only shorter and thus beneficial in size limited applications but, also has two-fold greater activity without any loss in specificity (Abstract). Finally, an ordinary artisan would be motivated to include CMV enhancer, WPRE , chimeric intron and bGH polyA signal in Chen’s vector to result in an improved AAV vector with increased transgene expression because Powell and Boulaire teach the use of CMV enhancers, WPREs, intronic sequences and polyA sequences in AAV expression cassettes increase transgene expression.
An ordinary artisan would reasonably expect to include each of the specifically recited sequences such as those of hNeuroD1, hDlx2, P2A, T2A, IRES, CMV enhancer, WPRE, chimeric introns and bGH polyA signal in Chen’s vector to arrive at the instantly claimed vector because these sequences are well-known in the art and an ordinary artisan routinely derives these sequences from publicly available plasmids to generate viral vectors. Since Chen teaches that hNeuroD1 and hDlx2 when expressed together in astrocytes using the GFAP promoter converts them into functional neurons, an ordinary artisan would reasonably expect that a viral vector that drives hNeuroD1 and hDlx2 expression in astrocytes would convert the astrocytes to functional neurons.
PNG
media_image1.png
200
400
media_image1.png
Greyscale
Finally, regarding the organization of the regulatory elements, the transgenes and the linkers recited in claims 180-183, since use of each of these elements is well known, an ordinary artisan would organize the recited regulatory elements, the transgenes and the linkers in the order recited in claims 180-183. For example, see Figure 1 from Powell (copied below) which provides a basic organization of a generic viral vector wherein enhancer (CE) is followed by promoter followed by intron (I) followed by the transgene which would comprise the polypeptides and linkers and, finally a polyA (pA).
Sequence alignments
PNG
media_image2.png
1374
826
media_image2.png
Greyscale
PNG
media_image3.png
1278
1064
media_image3.png
Greyscale
PNG
media_image4.png
755
768
media_image4.png
Greyscale
PNG
media_image5.png
143
796
media_image5.png
Greyscale
PNG
media_image6.png
879
810
media_image6.png
Greyscale
PNG
media_image7.png
546
790
media_image7.png
Greyscale
PNG
media_image8.png
845
838
media_image8.png
Greyscale
PNG
media_image9.png
296
791
media_image9.png
Greyscale
PNG
media_image10.png
546
777
media_image10.png
Greyscale
Response to Arguments
Applicant's arguments filed 8/22/2025 regarding the U.S.C. 103 rejection of the claims have been fully considered but they are not persuasive.
Applicant argue that “the combined disclosure of these references fail to provide a person of ordinary skill in the art with the pre-requisite motivation to arrive at the claimed invention, much less to do so with a reasonable expectation of success” (page 10, para 1).
In support, Applicant first allege improper hindsight reasoning and then accepting their own allegation conclude that “the Office has not demonstrated why a person of ordinary skill would have selected these regulatory elements from the vast array of available options” and “mere existence in separate references does not suggest combining them in the exact arrangement required by the claims.” (page 10, para 2).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). To this end, the primary prior art of Chen teaches the key elements of the claims i.e. AAV vector encoding hNeuroD1 and hDlx2 separated by a P2A or alternatively an IRES linker wherein the transgenes are operably linked to a glial promoter GFAP and the vector comprises regulatory elements such as human βglobin intron and hGH polyA. The rejection provides teachings from the prior art references that motivate an artisan to include the truncated GFAP promoter, CMV enhancer, WPRE, chimeric intron and bGH polyA in Chen’s vectors. For examples, the rejection states “Lee teaches that their truncated hGFAP promoter is not only shorter and thus beneficial in size limited applications but, also has two-fold greater activity without any loss in specificity (Abstract)”. This is a clear motivation to include the truncated hGFAP promoter in place of Chen’s full length hGFAP promoter. Similarly, the rejection states “Regarding the CMV enhancer, Powell teaches several references that lead to the conclusion that “the CMV enhancer increases transgene expression under different cell-specific promoters and different cell types making it a broadly applicable tool to increase transgene expression levels” (page 6, para 1). Regarding WPRE, Powell teaches that WPRE not only promote transgene expression but also prevent transgene silencing in vivo (page 4, para 2). Regarding chimeric intron, Powell teaches that “an intron can be a valuable element to include in an expression cassette to increase transgene expression” (page 6, para 1; Table 3). Regarding polyA regulatory elements, Powell teaches that at least for neurons bGHpolyA is a strong polyA signal and when combined with WPRE results in increased transgene expression (page 5, para 1-2; Table 2). Critically, Powell teaches that bGH is a stronger polyA signal as compared to hGH polyA, as used by Chen (Table 2). Additionally, Boulaire also teaches several viral regulatory elements such as human CMV enhancer, ITRs and WPRE to improve gene expression in brain cells (section 3.4), specifically teaching that a CMV enhancer combined with GFAP promoter increases gene expression “by 10-fold in the rat brain when compared to the baculoviruses with the GFAP promoter alone” (page 596, right column, para 4, lines 5-9). Boulaire also teaches WPREs in AAVs to increase transgene expression (page 598, left column, para 1, line 4-5) and note that when combined with neural specific promoters have been shown to increase transgene expression by 26-fold (page 598, right column, last line)”. Thus, the rejection provides ample teachings from the prior art that motivate an artisan to include the claimed regulatory sequences.
Next, Applicant allege without evidence that “given the numerous options of regulatory elements known in the art, the scenario at hand does not involve a ''finite number of identified, predictable solutions." On the contrary, in order to arrive at the claimed invention, the skilled artisan would have to pick and choose these elements and specific sequences from a "toolbox" having a large number of possible options but with no guidance. Hence, the Office's position that such a process would have been obvious for the skilled artisan appears to lack factual and rational basis.” (page 10, para 4)
In response, at first it must be noted that an ‘obvious to try’ rationale (such as rationale E in MPEP 2143) was not used for the instant rejection. Teachings, motivation and reasonable expectations were established using the prior art. Further, Applicant have not provided any evidence for their allegation that the regulatory elements used in AAV vectors are not reasonably predictable and their use in the claimed vector resulted in an unexpected outcome. Additionally, as noted in the response to the first argument, the rejection details teachings from the prior art references that motivate an artisan to include the claimed regulatory sequences. The prior art cited in the rejection provides ample guidance for the use of the claimed regulatory sequences.
Finally, the Applicant allege that “the Office has not demonstrated that a person of ordinary skill would have reasonably expected success in combining the claimed elements to achieve effective astrocyte-to-neuron conversion” (page 10, last para) while “the present specification contains actual experimental data demonstrating superior results that, through in vitro and in vivo testing, the claimed vectors have shown remarkable effectiveness in both transgene expression and cellular conversion” (page 11, para 1). Applicant point to Example 24 and 25 in support.
In response, the claims are directed to a product and “astrocyte-to-neuron conversion” although an intended use, is not a required element in the claims. Importantly, Chen shows that vectors that induce the expression of hNeuroD1 and hDlx2 in glia result in the astrocyte-to-neuron conversion, including in vivo (Examples 1-3; [0068-73, 0077-79]). There is no evidence that inclusion or substitution of other regulatory elements in Chen’s vector would disrupt the functioning of the vector such that NeuroD1 and Dlx2 are not expressed. The art of AAV vectors was mature at the time of filing. To this end, Chen teaches the use of different regulatory elements. Critically, in light of Chen’s teachings, the specification fails to establish a result that could be considered unexpected or superior. For example, example 24 (Figures 41-56) is an in vitro assay testing astrocyte-to-neuron conversion using 8 vectors with different combinations of regulatory elements. Results for AAV9-P112 are shown in Figures 41-42, for AAV9-P122 in Figures 44-45, AAV9-P124 in Figures 47-48, AAV9-P20 in Figures 50-51, AAV9-P31 in Figure 53, AAV9-P123 in Figure 54, AAV9-P113 in Figure 55, AAV9-P111 in Figure 56. These figures show that each of these vectors result in expression of NeuroD1 and Dlx2 24 hour to 6 days post-transfection. Only AAV9-P112, AAV9-P122, AAV9-P124, AAV9-P20 were tested for astrocyte-to-neuronal conversion at the 3 week timepoint and data shows that each of these vectors tested resulted in some success in conversion to about the same degree without any vector showing any clear unexpected or superior results. No quantification is provided to make such an assessment. Expression of NeuroD1 and Dlx2 was expected to result in astrocyte-to-neuronal conversion based on Chen’s teachings. In example 25 (Figure 57-61) only AAV9-P112 and AAV9-P122 were tested, without any rationale for selecting these vectors out of the numerous others tested previously. Herein again, both vectors perform the same and as expected (Figures 59 and 61). Of note neither of AAV9-P112 and AAV9-P122 that Applicant claim “exhibit exceptional performance in astrocyte-to-neuron conversion in cultured rat astrocytes” and “demonstrated remarkable specificity and efficiency in converting astrocytes to neurons” in vivo comprise each of the regulatory elements claimed. Specifically these vectors lack the WPRE. There is no evidence in the specification that the any of vectors tested and the specifically claimed vectors have a property that could be considered unexpected. Each of these results disclosed are predictable based on teachings of the prior art. MPEP 716.02(b) guides that “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.").” Applicant have not established that any difference exists between the claimed vectors and Chen’s vector, with or without combination with teachings of the secondary references, such the results presented are unexpected to an unobvious extent and, also both statistically and practically significant.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras Jr. can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MATASHA DHAR/Examiner, Art Unit 1632