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 amendment filed on 11/04/2025 has been entered.
Amended claims 1-20, 22-25, 32-34 and 36-39 are pending in the present application.
Applicant elected without traverse the Invention of Group I. Applicant also elected without traverse the following species: (i) A vector system containing a first vector and a second vector; (ii) the first reconstitution sequence comprises a splicing donor signal (SD) and the second reconstitution sequence comprises a splicing acceptor signal (SA), optionally each one of first and second reconstitution sequence further comprises a recombinogenic sequence; (iii) SEQ ID NO: 1 as a species of a degradation signal; (iv) SEQ ID NO: 22 as a species of a recombinogenic sequence; and (v) MYO7A as a species of a gene.
Claims 25, 33-34 and 36-39 were withdrawn previously from further considerations because they are directed to non-elected inventions. Additionally, claims 7, 16, 18 and 22-23 were also withdrawn previously from further considerations because they are directed to non-elected species.
Accordingly, amended claims 1-6, 8-15, 17, 19-20, 24 and 32 are examined on the merits herein with the above elected species.
Claim Objections
Claim 6 is objected to because the phrase “a nucleotide sequence encoding (SEQ ID No. 1(CL1)) is not very clear. The examiner suggests to replace the above phrase with - - a nucleotide sequence encoding the CL1 sequence of SEQ ID NO: 1 - - to be consistent with the species election and for overcoming this objection.
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.
Amended claims 1-6, 8-15, 17, 19-20, 24 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Trapani et al. (EMBO Molecular Medicine, Vol. 6, pages 194-211, published online December 16, 2013; IDS) in view of Umezawa et al (US 8,658,777) and Zdanovsky et al. (WO 2004/025264; IDS). This is a slightly modified rejection necessitated by Applicant’s amendment.
With respect to elected species, Trapani et al. disclose a vector system to express a coding sequence of interest (trans-splicing and hybrid vectors including the ABCA4-3xflag and MYO7A-HA coding sequences, see page 195 under heading “Generation of normal, oversize, and dual AAV vectors”). Trapani et al. disclose a first vector comprising a CDS1 and a first reconstitution sequence; and a second vector comprising a CDS2 and a second reconstitution sequence (CDS1 is the 5’CDS and CDS2 is the 3’CDS, see Fig. 1 or excerpt below). Trapani et al. disclose that the first reconstitution sequence comprises a splicing donor (SD) signal and a recombinogenic sequence 3’ relative to SD, and the second reconstitution sequence comprises a splicing acceptor (SA) signal and a recombinogenic sequence that is 5’ relative to SA (AK recombinogenic sequences, see Fig. 1 or excerpt below).
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Trapani et al. further disclose that safety issues must be considered with dual AAV vectors because the possibility that delivery of dual AAV vectors result in production of aberrant or truncated proteins, then proceed disclosing that both vectors produce truncated products in vitro (e.g., HEK293 cells) but not in vivo (e.g., retina of sh1-/- mice) (see at least page 204, left column, second paragraph; AK column-- in excerpt below--of supplemental Fig. 12 for MYO7A proteins produced in infected HEK293 cells; and supplemental Fig. 13).
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Anti-Myo7a antibodies recognize an epitope contained in the 5’-half of the MYO7A coding sequence (A); anti-HA antibodies recognize the HA tag located at the MYO7A C-terminus and therefore contained in the 3’-half vector (B); the upper arrow indicates the full-length MYO7A-HA; the lower arrow indicates the smaller products (<130 KDa) which derive from either single 5’-(A) or 3’-halves (B).
Regarding claim 8, Trapani et al. disclose a first vector comprising a promoter sequence operably linked to the 5’-end of the CDS1 (see hybrid AP and hybrid AK in Fig. 1).
Regarding claim 9, Trapani et al. disclose both the first and second vector further comprise a 5’-inverted terminal repeat nucleotide sequence and a 3’-inverted terminal repeat nucleotide sequence of AAV serotype 2 (see page 204 under heading “Generation of AAV vector plasmids”).
Regarding claim 10, Trapani et al. disclose the recombinogenic sequence of AK (SEQ ID NO: 22) (see page 204, right column, last two complete sentences).
Regarding claim 11, Trapani et al. disclose the coding sequence is split into the first portion and the second portion at a natural exon-exon junction (both ABCA4 and MYO7A CDS split at natural exon-exon junction; page 204, col. 2, para. 2).
Regarding claim 12, Trapani et al. disclose the splicing donor signal comprises a sequence that is 100% identical to SEQ ID NO: 27 (page 204, right column, para. 2).
Regarding claim 13, Trapani et al. disclose the splicing acceptor signal comprises a sequence that is 100% identical to SEQ ID NO: 28 (page 204, right column, para. 2).
Regarding claim 15 and 17, Trapani et al. disclose the coding sequence is the human ABCA4 or MYO7A coding sequence (page 204, right column, top of second para.).
Regarding claim 19, Trapani et al. discloses a first vector that does not comprise a poly-adenylation signal nucleotide sequence (pA on 3’CDS but not 5’CDSD, see Fig. 1).
Regarding claims 20 and 24, Trapani et al. disclose:
the first vector comprises in the 5’-3’ direction: a 5’-ITR sequence; a promoter sequence; a 5’ end portion of a coding sequence of a gene of interest (CDS1) that is operably linked to an under control of said promoter; a nucleotide sequence of a splicing donor signal; a nucleotide sequence of a recombinogenic region; and a 3’-ITR sequence (see hybrid AP and AK AAV vectors in Fig. 1, and page 204 under Materials and Methods).
the second vector comprises in the 5’-3’ direction: a 5’-ITR sequence; a nucleotide sequence of a recombinogenic region; a nucleotide sequence of a splicing acceptor signal; the 3’ end of the coding sequence CDS2; a poly-adenylation signal nucleotide sequence; and a 3’-ITR sequence (see hybrid AP and AK AAV vectors in Fig. 1, and page 204 under Materials and Methods).
Trapani et al. disclose the first and second vectors are an adeno-associated viral (AAV) vector (see page 204 under the heading “Generation of AAV vector plasmids”).
Regarding claim 32, Trapani et al. disclose dual AAV trans-splicing or hybrid vectors as an attractive strategy for gene therapy (see, e.g., abstract) and disclose the diluent PBS to re-suspend the vector solution for injections (see page 205, under heading “AAV vector production and characterization” and page 206 under heading “Subretinal injection of AAV vectors in mice and pigs”).
Trapani et al. do not disclose that both of the first and second vectors further comprise a nucleotide sequence of a degradation signal in a 3’ position relative to the SD and in a 5’ position relative to the SA, and the nucleotide sequence of a degradation signal in the first vector is identical or different from that in the second vector. Trapani et al. also do not disclose that the nucleotide sequence of a degradation signal is localized at the 5’ end or at the 3’ end of the nucleotide sequence of the recombinogenic sequence of both of the first and second vectors. Trapani et al. also do not disclose a protein ubiquitination signal or a sequence encoding CL1 of SEQ ID NO: 1. Trapani et al. further do not disclose the use of an enhancer sequence.
Before the effective filing date of the present application (03/03/2015), Umezawa et al already taught the use of a PEST sequence (known to accelerate degradation of a protein) fused to any one of the ends of the linear fusion protein “Int-C/Luc-C/substrate peptide/Luc-N/Int-N” that results in the rapid degradation of only unspliced products of protein splicing, and allows the accumulation inside the cells of the circular form indicator that is formed by protein splicing with Int-N and Int-C, which then leads to the generation of the linear form of luciferase (Luc-N/Luc-C) upon digestion of the substrate peptide with a co-existed protease to restore the luminescence function as depicted schematically below (see at least Abstract; particularly col. 3, lines 10-46; col. 8, lines 30-39; co. 12, last sentence continues to line 8 on col. 13; and Fig. 1A-B).
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Umezawa et al also taught that the fusion protein “Luc-C/substrate peptide/Luc-N” is in steric structure of a distorted circular form, the bound Luc-N/Luc-C does not have any luminescence function. Umezawa et al also stated “The presence of the PEST sequence is important for high-sensitivity detection since such unspliced precursor protein generates high backgound luminescence” (col. 16, lines 21-24).
Additionally, Zdanovsky et al. disclosed a fusion polypeptide comprising a protein of interest and one or more heterologous protein destabilization sequences, which, when present at the N-terminus or C-terminus of the protein of interest, reduces or decreases substantially the half-life of the protein of interest, wherein the presence of the protein destabilization sequence does not alter other functional properties of the protein of interest; and wherein the protein destabilization sequence includes CL sequences; and a nucleic acid molecule encoding the fusion polypeptide (See at least Abstract; Summary of the Invention; particularly page 5, lines 10-25; page 21, lines 1-31). Zdanovsky et al. disclosed that protein degradation is necessary to rid cells of damaged and non-functioning proteins (i.e. aberrant or truncated products, see page 1, lines 22-29). Zdanovsky et al. also disclosed ubiquitination signals and the destabilization peptide CL1 (see page 3, lines 1-13). Zdanovsky et al. disclosed specifically SEQ ID NO: 12 which is a 100% match to instant SEQ ID NO: 1 (see page 30, lines 13-18). Zdanovsky et al. also disclosed vectors comprising a CL1 degradation signal (see, e.g., page 33). Zdanovsky et al. further taught promoter and enhancer elements that direct transcription of a gene (see page 12 line 24-32).
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the dual vector system of Trapani et al. by also incorporating at least a polynucleotide sequence of a degradation signal such as the CL1 sequence of SEQ ID NO: 1 in a 3’ position relative to the SD (e.g., 5’ end or 3’ end of the nucleotide sequence of the recombinogenic region) in the first vector and in a 5’ position relative to the SA (e.g., 5’ end or 3’ end of the nucleotide sequence of the recombinogenic region) in the second vector to reduce the production or expression of truncated products generated by the 5’-half (first) and the 3’-half (second) vectors (vectors that have not undergone trans-splicing); as well as further incorporating an enhancer nucleotide sequence operably linked to the coding sequence in the first vector for increasing the expression of a desired coding sequence; in light of the teachings of Umezawa et al and Zdanovsky et al as set forth above.
An ordinary skilled in the art would have been motivated to carry out the above modifications to reduce the production or expression of truncated products generated by the 5’-half (first) and the 3’-half (second) vectors (vectors that have not undergone trans-splicing) because: (i) Umezawa et al already taught the concept of using a PEST sequence (known to accelerate degradation of a protein) fused to any one of the ends of the linear fusion protein “Int-C/Luc-C/substrate peptide/Luc-N/Int-N” that results in the rapid degradation of only unspliced products of protein splicing, and allows the accumulation inside the cells of the circular form indicator that is formed by protein splicing with Int-N and Int-C, which then leads to the generation of the linear form of luciferase (Luc-N/Luc-C) upon digestion of the substrate peptide with a co-existed protease to restore the luminescence function; and the presence of the PEST sequence is important for high-sensitivity detection since such unspliced precursor protein generates high backgound luminescence; and (ii) Zdanovsky et al. also recognized the role of protein degradation signals, including the CL-1 degradation signal of SEQ ID NO: 1, in clearing non-functioning proteins and demonstrated that degradation signals can be incorporated into vectors, particularly Trapani et al. already taught the production of truncated products must be considered when assessing the safety issues of dual AAV vectors. An ordinary skill in the art would readily attribute the discrepancy between in vitro and in vivo results regarding to generation of truncated and/or aberrant ABCA4 and MYO7A by similar dual AAV vector constructs in Trapani to different cell types (embryonic kidney cells in vitro vs photoreceptors/retinal pigment epithelial cells in vivo) and/or different animal species (human cells in vitro vs murine cells in vivo); and the modified dual AAV vector system has applications in tissues and animal species other than murine retinal cells. Additionally, the placement of the degradation signals in the vectors as set forth above is only possible and proper such that the degradation signals in both the first and second vectors are removed via splicing upon reconstituting a large gene encoding the elected MYO7A protein; and unlike coding sequences of the truncated products generated by the first and second vectors, the reconstituted full-length coding sequence of MYO7A lacks a degradation signal to be quickly degraded. Moreover, Zdanovsky et al. also taught using suitable enhancers/promoters to permit proper transcription of RNA, particularly Trapani et al. demonstrated different approaches to improve expression level of a coding sequence (e.g. designing and comparing different vector constructs to express ABCA4 or MYO7A, see Fig. 1 and 2).
An ordinary skilled artisan would have a reasonable expectation of success to carry out the above modifications in light of the teachings of Trapani et al, Umezawa et al and Zdanovsky et al; coupled with the level of skill for an ordinary skilled artisan in the relevant art.
The modified vector system resulting from the combined teachings of Trapani et al, Umezawa et al and Zdanovsky et al as set forth above is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments related to the above modified 103 rejection in the Amendment filed on 11/04/2025 (pages 8-16) have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
A. Applicant argued that there is no rationale to combine Umezawa with either Trapani or Zdanovsky.
Specifically, Applicant argued that because the field and purpose of Umezawa (drawn to a synthetic protein construct used for in vitro or “in cell” analysis or protease activity) is distinct from that of the presently claimed subject matter (using dual AAV vectors to direct expression of large transgenes in cells for gene therapy applications) such that an ordinary skill in the art would not have considered Umezawa relevant to the presently claimed invention without the impermissible use of hindsight. Applicant also argued that since Umezawa differs from the presently claimed subject matter in terms of structural characteristics (e.g., the construct of Umezawa is a circular protein construct that is produced by expression of a single linear polynucleotide, followed by protein splicing using inteins; while the presently claimed subject matter relates to the expression of a linear transgene from two separate linear AAV polynucleotides, that are joined using the normal polynucleotide splicing apparatus), the examiner does not provide why there would be a reasonable expectation of success for a degradation signal in different construct types. Moreover, the dual vector system of currently amended claims requires that there are two degradation sequences, one on each vector, while the system of Umezawa only contemplates the provision of one PEST sequence.
First, the Office recognizes the differences between the protein constructs and the protein splicing system via inteins of Umezawa and the dual AAV vector system to express the coding sequence of a gene of interest in a cell of the presently claimed invention. However, the issue is not using or modifying the disclosed protein splicing system with inteins of Umezawa to arrive at the presently claimed dual AAV vector system. This is because the primary Trapani reference already disclosed a similar dual AAV vector system, in which both the first and second vectors do not further comprise a nucleotide sequence of a degradation signal (e.g., the elected CL1 of SEQ ID NO: 1, or other protein ubiquitination signals such as a PEST sequence) in a 3’ position relative to the SD in the first vector and in a 5’ position relative to the SA in the second vector. The Umezawa reference was cited primarily to supplement the teachings of Trapani et al because the reference already disclosed the concept of using a PEST sequence (a degradative ubiquitination signal to accelerate degradation of a protein) fused to any one of the ends of the linear fusion protein “Int-C/Luc-C/substrate peptide/Luc-N/Int-N” that results in the rapid degradation of only unspliced products of the protein splicing, including the unspliced precursor protein that generates high background luminescence. It would have been obvious to one of ordinary skill in the art to modify the dual vector system of Trapani et al. by also incorporating at least a polynucleotide sequence of a degradation signal such as the CL1 sequence of SEQ ID NO: 1 in a 3’ position relative to the SD (e.g., 5’ end or 3’ end of the nucleotide sequence of the recombinogenic region) in the first vector and in a 5’ position relative to the SA (e.g., 5’ end or 3’ end of the nucleotide sequence of the recombinogenic region) in the second vector to reduce the production or expression of truncated products generated by the 5’-half (first) and the 3’-half (second) vectors (vectors that have not undergone trans-splicing).
Second, the activity of a protein ubiquitination signal such as the elected CL1 of SEQ ID NO:1 of the present application and/or the PEST sequence of Umezawa to accelerate degradation of a protein is not dependent on a splicing mechanism as evidenced at least by the teachings of Zdanovsky et al. Zdanovsky et al. already disclosed a fusion polypeptide comprising a protein of interest and one or more heterologous protein destabilization sequences (e.g., CL sequences), which, when present at the N-terminus or C-terminus of the protein of interest, reduces or decreases substantially the half-life of the protein of interest, wherein the presence of the protein destabilization sequence does not alter other functional properties of the protein of interest.
Third, with respect to Applicant’s argument on impermissible hindsight reconstruction Examiner would like to recite a paragraph from in re Oetiker, 977, F.2d 1443, 1448 (Fed. Cir. 1992).
"[T]here must be some teaching, reason, suggestion, or motivation found "in the prior art" or "in the prior art references" to make a combination to render an invention obvious within the meaning of 35 U.S.C. 103 (1998). Similar language appears in a number of opinions and if taken literally would mean that an invention cannot be held to have been obvious unless something specific in a prior art reference would lead an inventor to combine the teachings therein with another piece of prior art. This restrictive understanding of the concept of obviousness is clearly wrong…. While there must be some teaching, reason, suggestion, or motivation to combine existing elements to produce the claimed device, it is not necessary that the cited references or prior art specifically suggest making the combination…. In sum, it is off the mark for litigants to argue, as many do, that an invention cannot be held to have been obvious unless a suggestion to combine the prior art teachings is found in a specific reference."
Although the cited artisans do not specifically point out a motivation to in their disclosure, an ordinarily skilled artisan would have been able to identify the need for the combination of the teachings without the disclosure of the instant application. 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). Please refer to the above modified 103 rejections for more details.
B. Applicant argued that there is no reasonable expectation of success in adapting features of the cyclic luciferase in Umezawa to the presently claimed invention.
Specifically, Applicant argued that since the cyclic luciferase reporter construct of Umezawa is structurally distinct from the dual AAVs of the presently claimed subject matter, one skilled in the art would therefore not be able to reasonably expect that a degradation sequence for a cyclic construct would have an effect in the context of dual AAV vectors. Additionally, Applicant argued that Umezawa relies on protein splicing using split inteins, which is in contrast to the splice donor and splice acceptor sequences used in the presently claimed subject matter; and one cannot predict how a PEST sequence of Umezawa or similar sequence would function in the context of the splice donor and splice acceptor sequence, nor any motivation for not using split inteins. Applicant further argued the split inteins of Umezawa are not necessarily compatible with the dual AAV vectors of the presently claimed subject matter that are processed with nucleotide splicing; and as such it would not have been obvious for one skilled in the art how to overcome this incompatibility nor one skilled in the art would have any motivation for using such as system in a dual AAV vector. Applicant further argued that Umezawa differs from the presently claimed subject matter in that it uses a degradation sequence (i) in the context of protein splicing, and (ii) in the context of splicing between two ends of the same linear molecule; while the present application uses nucleotide degradation sequences and nucleotide sequences encoding degradation sequences (i) in the context of nucleotide splicing, and (ii) in the context of splicing between two independent linear transcripts that are expressed from separate vectors. Applicant argued that the kinetics of protein and nucleotide splicing are different since they operate on separate biochemical mechanisms, and the kinetics of splicing between two ends of the same molecule will be different and likely to be much faster and efficient than splicing between two independently transcribed AAV vector sequences, which have to associate in the cell and then splice.
First, once again the issue is not using or modifying the disclosed protein splicing system with inteins of Umezawa to arrive at the presently claimed dual AAV vector system. This is because the primary Trapani reference already disclosed a similar dual AAV vector system, in which both the first and second vectors do not further comprise a nucleotide sequence of a degradation signal (e.g., the elected CL1 of SEQ ID NO: 1, or other protein ubiquitination signals such as a PEST sequence) in a 3’ position relative to the SD in the first vector and in a 5’ position relative to the SA in the second vector. The Umezawa reference was cited primarily to supplement the teachings of Trapani et al because the reference already disclosed the concept of using a PEST sequence (a degradative ubiquitination signal to accelerate degradation of a protein) fused to any one of the ends of the linear fusion protein “Int-C/Luc-C/substrate peptide/Luc-N/Int-N” that results in the rapid degradation of only unspliced products of the protein splicing, including the unspliced precursor protein that generates high background luminescence. It is apparent that Applicant solely focused on the teachings Umezawa, without taking into account of the combined teachings of Trapani, Umezawa and Zdanovsky references. Please refer to the above 103 rejection for details, including the provided motivations for combining the cited references.
Second, the activity of a protein ubiquitination signal such as the elected CL1 of SEQ ID NO:1 of the present application and/or the PEST sequence of Umezawa to accelerate degradation of a protein is not dependent on a splicing mechanism as evidenced at least by the teachings of Zdanovsky et al. Zdanovsky et al. already disclosed a fusion polypeptide comprising a protein of interest and one or more heterologous protein destabilization sequences (e.g., CL sequences), which, when present at the N-terminus or C-terminus of the protein of interest, reduces or decreases substantially the half-life of the protein of interest, wherein the presence of the protein destabilization sequence does not alter other functional properties of the protein of interest.
Third, please also note that the standard under 35 U.S.C. 103 is a “reasonable” expectation of success.
C. Applicant argued that Trapani fails to provide motivation to seek to reduce the production of truncated aberrant proteins.
Specifically, Applicant argued previously that Trapani initiates a discussion about the possibility of truncates from a dual AAV system being a potential safety concern, however, later in the same paragraph, Trapani discloses that no such truncated proteins were detected in vivo as well as point 7 in the 1.132 Declaration of Prof. Alberto Auricchio. Thus, Trapani as a whole discloses the ordinary person skilled in the art that in vivo, truncated protein products are not produced. Applicant also argued that the person of ordinary skill in the art would preferentially treat in vivo experiments and in vivo animal safety test as representative of the situation in vivo when treating a subject; and prior to the filing date of the present application there was no evidence that truncated protein production was of concern in vivo as evidenced by the disclosure of Trapani. Accordingly, given the teachings of Trapani that truncated products are no issue in vivo, there is no motivation for the person of ordinary skill in the art to change the vector constructs disclosed therein in order to reduce the production of truncated protein products. Applicant further argued that the person of ordinary skill in the art would be at least as likely to consider that the different result in the in vivo system compared to the in vitro experiment is not due to the switch in species/type of cell but due to the switch to a more physiological relevant in vivo model; and the in vivo data therefore cannot be disregarded.
First, with respect to the issue that Trapani teaches that unlike in vitro results in human embryonic kidney 293 (HEK-293) cells (supplementary Figures S7 and S12), only full-length ABCA4 and MYO7A proteins are detected in vivo in the retina, the examiner noted that Trapani’s in vivo results are obtained only in experiments performed in mice (C57BL/6 and sh1-/- mice) via subretinal injection of dual AAV2/8 TS and hybrid AK vectors (supplementary Figures S8 and S13). Accordingly, an ordinary skill in the art would readily attribute the discrepancy between in vitro and in vivo results regarding to generation of truncated and/or aberrant ABCA4 and MYO7A by similar dual AAV vector constructs in Trapani to different cell types (embryonic kidney cells in vitro vs photoreceptors/retinal pigment epithelial cells in vivo) and/or different animal species (human cells in vitro vs murine cells in vivo). This is supported and evidenced by the disclosure of the present application showing subretinal injection of Large White pigs with AAV2/8 dual AAV hybrid AK vectors, of which the inclusion of the CL1 degradation in the 5’-half vectors resulted in a significant reduction of truncated ABCA4 protein (page 51, second last paragraph; and Fig. 5b). Thus, the dual AAV vectors of Trapani are capable of generating truncated/aberrant products at least in retina in pigs. Moreover, please note that the claimed AAV vector system to express the coding sequence of a gene interest in any cell derived from any animal source, not necessarily limited only to retinal cells in mice. Furthermore, Riazuddin et al (Human mutation 29:502-511, 2008) already disclosed recessive mutations of MYO7A can cause either a deaf-blindness syndrome (type I Usher syndrome; USH1B) or nonsyndromic deafness (DFNB2) (see Abstract). Thus, an ordinary skill in the art would have been motivated to modify the dual vector system of Trapani et al. by also incorporating at least a polynucleotide sequence of a degradation signal such as the CL1 sequence of SEQ ID NO: 1 in a 3’ position relative to the SD (e.g., 5’ end or 3’ end of the nucleotide sequence of the recombinogenic region) in the first vector and in a 5’ position relative to the SA (e.g., 5’ end or 3’ end of the nucleotide sequence of the recombinogenic region) in the second vector to reduce the production or expression of truncated products generated by the 5’-half (first) and the 3’-half (second) vectors; particularly Trapani et al. already taught the production of truncated products must be considered when assessing the safety issues of dual AAV vectors.
Second, the Office does not disregard the in vivo data presented in the Trapani reference. However, the in vivo data of the Trapani reference were obtained solely or exclusively in mice (C57BL/6 and sh1-/- mice) via subretinal injection of dual AAV2/8 TS and hybrid AK vectors (supplementary Figures S8 and S13), and not in other animals; and/or the fact that the same dual AAV vector system results in the production of truncated or aberrant products in human HEK293 cells in vitro as demonstrated by the Trapani reference. An ordinary skill in the art would readily recognize that at least the incorporation of a degradative signal in the dual-vector system is a safety feature to be used in tissues and species other than murine retina; particularly for treating at least human patients.
D. Applicant argued that the data in the present application is not prior art and cannot be used to inform or justify what the person of ordinary skill in the art would have known at the filing date.
Specifically, Applicant argued that the Office Action improperly refers to data in the present application for pig retina as justification that the person of ordinary skill in the art would attribute the differences observed in vivo versus in vitro in Trapani et al to the animal species used. Applicant argued that it must be considered what the person of ordinary skill in the art, presented with the information available to them at the time of filing of the application, would have been considered to be obvious. The discovered production of truncated proteins in pig retina is knowledge that can only be drawn from the present application, which was not available to the person of ordinary skill in the art at the priority date. Accordingly, the person of skill in the art would not have considered that truncated products are present in vivo, nor would they have been motivated to try to reduce the hypothetical production of such truncated products expressed from dual AAVs. As a result, the present claims are not obvious.
First, the Office does not rely on the data for pig retina of the present application as a basis for the above 103 rejection of record. Please refer to the above 103 rejection for details. Rather, the Office used such data as evidence that further support the rationale why an ordinary skill in the art would not equate the in vivo data obtained solely or exclusively in mice (C57BL/6 and sh1-/- mice) via subretinal injection of dual AAV2/8 TS and hybrid AK vectors (supplementary Figures S8 and S13) in the primary Trapani reference to extend to all other animals (in vivo); and especially the same dual AAV vector system results in the production of truncated or aberrant products in human HEK293 cells (in vitro) as also demonstrated by the Trapani reference.
Second, please also refer to the Examiner’s responses in the preceding Section C above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Amended claims 1-6, 8-15, 17, 19-20, 24 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14, 16 and 18 of U.S. Patent No. 10,494,645 or claims 1-14, 16, 18, 34-41, 43-46, 48 and 55 of U.S. RE50,283 (previously Application No. 17/541,846) in view of Trapani et al. (EMBO Molecular Medicine, Vol. 6, pages 194-211, published online December 16, 2013; IDS), Umezawa et al (US 8,658,777) and Zdanovsky et al. (WO 2004/025264; IDS). This is a slightly modified rejection necessitated by Applicant’s amendment.
The claims of the present application differ from claims 1-14, 16 and 18 of U.S. Patent No. 10,494,645, or claims 1-14, 16, 18, 34-41, 43-46, 48 and 55 of U.S. RE50,283 in requiring specifically “both of the first and second vector further comprise a nucleotide sequence of degradation signal, said sequence being located in 3’ position relative to the SD and in 5’ position relative to the SA”; and preferably the nucleotide sequence of the degradation signal comprises or consists of a sequence encoding a sequence selected from CL1 (SEQ ID NO: 1).
Before the effective filing date of the present application (03/03/2015), Trapani et al. disclosed a vector system to express a coding sequence of interest (trans-splicing and hybrid vectors including the ABCA4-3xflag and MYO7A-HA coding sequences, see page 195 under heading “Generation of normal, oversize, and dual AAV vectors”). Trapani et al. disclosed a first vector comprising a CDS1 and a first reconstitution sequence; and a second vector comprising a CDS2 and a second reconstitution sequence (CDS1 is the 5’CDS and CDS2 is the 3’CDS, see Fig. 1 or excerpt below). Trapani et al. disclosed that the first reconstitution sequence comprises a splicing donor (SD) signal and a recombinogenic sequence 3’ relative to SD, and the second reconstitution sequence comprises a splicing acceptor (SA) signal and a recombinogenic sequence that is 5’ relative to SA (AK recombinogenic sequences, see Fig. 1 or excerpt below).
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Trapani et al. further disclosed that safety issues must be considered with dual AAV vectors because the possibility that delivery of dual AAV vectors result in production of aberrant or truncated proteins, then proceed disclosing that both vectors produce truncated products in vitro (e.g., HEK293 cells) but not in vivo (e.g., retina of sh1-/- mice) (see at least page 204, left column, second paragraph; AK column-- in excerpt below--of supplemental Fig. 12 for MYO7A proteins produced in infected HEK293 cells; and supplemental Fig. 13).
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Anti-Myo7a antibodies recognize an epitope contained in the 5’-half of the MYO7A coding sequence (A); anti-HA antibodies recognize the HA tag located at the MYO7A C-terminus and therefore contained in the 3’-half vector (B); the upper arrow indicates the full-length MYO7A-HA; the lower arrow indicates the smaller products (<130 KDa) which derive from either single 5’-(A) or 3’-halves (B).
Additionally, Umezawa et al already taught the use of a PEST sequence (known to accelerate degradation of a protein) fused to any one of the ends of the linear fusion protein “Int-C/Luc-C/substrate peptide/Luc-N/Int-N” that results in the rapid degradation of only unspliced products of protein splicing, and allows the accumulation inside the cells of the circular form indicator that is formed by protein splicing with Int-N and Int-C, which then leads to the generation of the linear form of luciferase (Luc-N/Luc-C) upon digestion of the substrate peptide with a co-existed protease to restore the luminescence function as depicted schematically below (see at least Abstract; particularly col. 3, lines 10-46; col. 8, lines 30-39; co. 12, last sentence continues to line 8 on col. 13; and Fig. 1A-B).
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Umezawa et al also taught that the fusion protein “Luc-C/substrate peptide/Luc-N” is in steric structure of a distorted circular form, the bound Luc-N/Luc-C does not have any luminescence function. Umezawa et al also stated “The presence of the PEST sequence is important for high-sensitivity detection since such unspliced precursor protein generates high backgound luminescence” (col. 16, lines 21-24).
Moreover, Zdanovsky et al. disclosed a fusion polypeptide comprising a protein of interest and one or more heterologous protein destabilization sequences, which, when present at the N-terminus or C-terminus of the protein of interest, reduces or decreases substantially the half-life of the protein of interest, wherein the presence of the protein destabilization sequence does not alter other functional properties of the protein of interest; and wherein the protein destabilization sequence includes CL sequences; and a nucleic acid molecule encoding the fusion polypeptide (See at least Abstract; Summary of the Invention; particularly page 5, lines 10-25; page 21, lines 1-31). Zdanovsky et al. disclosed that protein degradation is necessary to rid cells of damaged and non-functioning proteins (i.e. aberrant or truncated products, see page 1, lines 22-29). Zdanovsky et al. also disclosed ubiquitination signals and the destabilization peptide CL1 (see page 3, lines 1-13). Zdanovsky et al. disclosed specifically SEQ ID NO: 12 which is a 100% match to instant SEQ ID NO: 1 (see page 30, lines 13-18). Zdanovsky et al. also disclosed vectors comprising a CL1 degradation signal (see, e.g., page 33). Zdanovsky et al. further taught promoter and enhancer elements that direct transcription of a gene (see page 12 line 24-32).
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the dual construct system in claims 1-14, 16 and 18 of U.S. Patent No. 10,494,645, or claims 1-14, 16, 18, 34-41, 43-46, 48 and 55 of U.S. RE50,283 by also incorporating at least a polynucleotide sequence of a degradation signal such as the CL1 sequence of SEQ ID NO: 1 in a 3’ position relative to the SD (e.g., 5’ end or 3’ end of the nucleotide sequence of the recombinogenic region) in the first vector and in a 5’ position relative to the SA (e.g., 5’ end or 3’ end of the nucleotide sequence of the recombinogenic region) in the second vector to reduce the production or expression of truncated products generated by the 5’-half (first) and the 3’-half (second) vectors; in light of the teachings of Trapani et al, Umezawa et al and Zdanovsky et al as set forth above.
An ordinary skilled in the art would have been motivated to carry out the above modifications to reduce the production or expression of truncated products generated by the 5’-half (first) and the 3’-half (second) vectors (vectors that have not undergone trans-splicing) because: (i) Umezawa et al already taught the concept of using a PEST sequence (known to accelerate degradation of a protein) fused to any one of the ends of the linear fusion protein “Int-C/Luc-C/substrate peptide/Luc-N/Int-N” that results in the rapid degradation of only unspliced products of protein splicing, and allows the accumulation inside the cells of the circular form indicator that is formed by protein splicing with Int-N and Int-C, which then leads to the generation of the linear form of luciferase (Luc-N/Luc-C) upon digestion of the substrate peptide with a co-existed protease to restore the luminescence function; and the presence of the PEST sequence is important for high-sensitivity detection since such unspliced precursor protein generates high backgound luminescence; and (ii) Zdanovsky et al. recognized the role of protein degradation signals, including the CL-1 degradation signal of SEQ ID NO: 1, in clearing non-functioning proteins and demonstrated that degradation signals can be incorporated into vectors, particularly Trapani et al. already taught the production of truncated products must be considered when assessing the safety issues of dual AAV vectors. An ordinary skill in the art would readily attribute the discrepancy between in vitro and in vivo results regarding to generation of truncated and/or aberrant ABCA4 and MYO7A by similar dual AAV vector constructs in Trapani to different cell types (embryonic kidney cells in vitro vs photoreceptors/retinal pigment epithelial cells in vivo) and/or different animal species (human cells in vitro vs murine cells in vivo); and the modified dual AAV vector system has applications in tissues and animal species other than murine retinal cells. Additionally, the placement of the degradation signals in the vectors as set forth above is only possible and proper such that the degradation signals in both the first and second vectors are removed via splicing upon reconstituting a large gene encoding the elected MYO7A protein; and unlike coding sequences of the truncated products generated by the first and second vectors, the reconstituted full-length coding sequence of MYO7A lacks a degradation signal to be quickly degraded.
An ordinary skilled artisan would have a reasonable expectation of success to carry out the above modifications in light of claims 1-14, 16 and 18 of U.S. Patent No. 10,494,645, or claims 1-14, 16, 18, 34-41, 43-46, 48 and 55 of U.S. RE50,283 along with the teachings of Trapani et al, Umezawa et al and Zdanovsky et al; coupled with the level of skill for an ordinary skilled artisan in the relevant art.
The modified vector system resulting from claims 1-14, 16 and 18 of U.S. Patent No. 10,494,645, or claims 1-14, 16, 18, 34-41, 43-46, 48 and 55 of U.S. RE50,283 in combination with the teachings of Trapani et al, Umezawa et al and Zdanovsky et al as set forth above is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Amended claims 1-6, 8-15, 17, 19-20, 24 and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-11 and 19-20 of copending Application No. 17/742,924 in view of Trapani et al. (EMBO Molecular Medicine, Vol. 6, pages 194-211, published online December 16, 2013; IDS), Umezawa et al (US 8,658,777) and Zdanovsky et al. (WO 2004/025264; IDS). This is a slightly modified rejection necessitated by Applicant’s amendment.
The claims of the present application differ from claims 1, 3-11 and 19 of copending Application No. 17/742,924 in requiring specifically “both of the first and second vector further comprises a nucleotide sequence of degradation signal, said sequence being located in 3’ position relative to the SD and in 5’ position relative to the SA”; preferably the nucleotide sequence of the degradation signal comprises or consists of a sequence encoding a sequence selected from CL1 (SEQ ID NO: 1); and an enhancer nucleotide sequence operably linked to the coding sequence in the first vector .
Before the effective filing date of the present application (03/03/2015), Trapani et al. disclosed a vector system to express a coding sequence of interest (trans-splicing and hybrid vectors including the ABCA4-3xflag and MYO7A-HA coding sequences, see page 195 under heading “Generation of normal, oversize, and dual AAV vectors”).Trapani et al. disclosed a first vector comprising a CDS1 and a first reconstitution sequence; and a second vector comprising a CDS2 and a second reconstitution sequence (CDS1 is the 5’CDS and CDS2 is the 3’CDS, see Fig. 1 or excerpt below). Trapani et al. disclosed that the first reconstitution sequence comprises a splicing donor (SD) signal and a recombinogenic sequence 3’ relative to SD, and the second reconstitution sequence comprises a splicing acceptor (SA) signal and a recombinogenic sequence that is 5’ relative to SA (AK recombinogenic sequences, see Fig. 1 or excerpt below).
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Trapani et al. further disclosed that safety issues must be considered with dual AAV vectors because the possibility that delivery of dual AAV vectors result in production of aberrant or truncated proteins, then proceed disclosing that both vectors produce truncated products in vitro (e.g., HEK293 cells) but not in vivo (e.g., retina of sh1-/- mice) (see at least page 204, left column, second paragraph; AK column-- in excerpt below--of supplemental Fig. 12 for MYO7A proteins produced in infected HEK293 cells; and supplemental Fig. 13).
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Anti-Myo7a antibodies recognize an epitope contained in the 5’-half of the MYO7A coding sequence (A); anti-HA antibodies recognize the HA tag located at the MYO7A C-terminus and therefore contained in the 3’-half vector (B); the upper arrow indicates the full-length MYO7A-HA; the lower arrow indicates the smaller products (<130 KDa) which derive from either single 5’-(A) or 3’-halves (B).
Additionally, Umezawa et al already taught the use of a PEST sequence (known to accelerate degradation of a protein) fused to any one of the ends of the linear fusion protein “Int-C/Luc-C/substrate peptide/Luc-N/Int-N” that results in the rapid degradation of only unspliced products of protein splicing, and allows the accumulation inside the cells of the circular form indicator that is formed by protein splicing with Int-N and Int-C, which then leads to the generation of the linear form of luciferase (Luc-N/Luc-C) upon digestion of the substrate peptide with a co-existed protease to restore the luminescence function as depicted schematically below (see at least Abstract; particularly col. 3, lines 10-46; col. 8, lines 30-39; co. 12, last sentence continues to line 8 on col. 13; and Fig. 1A-B).
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Umezawa et al also taught that the fusion protein “Luc-C/substrate peptide/Luc-N” is in steric structure of a distorted circular form, the bound Luc-N/Luc-C does not have any luminescence function. Umezawa et al also stated “The presence of the PEST sequence is important for high-sensitivity detection since such unspliced precursor protein generates high backgound luminescence” (col. 16, lines 21-24).
Moreover, Zdanovsky et al. disclosed a fusion polypeptide comprising a protein of interest and one or more heterologous protein destabilization sequences, which, when present at the N-terminus or C-terminus of the protein of interest, reduces or decreases substantially the half-life of the protein of interest, wherein the presence of the protein destabilization sequence does not alter other functional properties of the protein of interest; and wherein the protein destabilization sequence includes CL sequences; and a nucleic acid molecule encoding the fusion polypeptide (See at least Abstract; Summary of the Invention; particularly page 5, lines 10-25; page 21, lines 1-31). Zdanovsky et al. disclosed that protein degradation is necessary to rid cells of damaged and non-functioning proteins (i.e. aberrant or truncated products, see page 1, lines 22-29). Zdanovsky et al. also disclosed ubiquitination signals and the destabilization peptide CL1 (see page 3, lines 1-13). Zdanovsky et al. disclosed specifically SEQ ID NO: 12 which is a 100% match to instant SEQ ID NO: 1 (see page 30, lines 13-18). Zdanovsky et al. also disclosed vectors comprising a CL1 degradation signal (see, e.g., page 33). Zdanovsky et al. further taught promoter and enhancer elements that direct transcription of a gene (see page 12 line 24-32).
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the dual construct system in claims , 3-11 and 19-20 of copending Application No. 17/742,924 by also incorporating at least a polynucleotide sequence of a degradation signal such as the CL1 sequence of SEQ ID NO: 1 in a 3’ position relative to the SD (e.g., 5’ end or 3’ end of the nucleotide sequence of the recombinogenic region) in the first vector and in a 5’ position relative to the SA (e.g., 5’ end or 3’ end of the nucleotide sequence of the recombinogenic region) in the second vector to reduce the production or expression of truncated products generated by the 5’-half (first) and the 3’-half (second) vectors; as well as further incorporating an enhancer nucleotide sequence operably linked to the coding sequence in the first vector for increasing the expression of a desired coding sequence; in light of the teachings of Trapani et al, Umezawa et al and Zdanovsky et al as set forth above.
An ordinary skilled in the art would have been motivated to carry out the above modifications to reduce the production or expression of truncated products generated by the 5’-half (first) and the 3’-half (second) vectors (vectors that have not undergone trans-splicing) because: (i) Umezawa et al already taught the concept of using a PEST sequence (known to accelerate degradation of a protein) fused to any one of the ends of the linear fusion protein “Int-C/Luc-C/substrate peptide/Luc-N/Int-N” that results in the rapid degradation of only unspliced products of protein splicing, and allows the accumulation inside the cells of the circular form indicator that is formed by protein splicing with Int-N and Int-C, which then leads to the generation of the linear form of luciferase (Luc-N/Luc-C) upon digestion of the substrate peptide with a co-existed protease to restore the luminescence function; and the presence of the PEST sequence is important for high-sensitivity detection since such unspliced precursor protein generates high backgound luminescence; and (ii) Zdanovsky et al. recognized the role of protein degradation signals, including the CL-1 degradation signal of SEQ ID NO: 1, in clearing non-functioning proteins and demonstrated that degradation signals can be incorporated into vectors, particularly Trapani et al. already taught the production of truncated products must be considered when assessing the safety issues of dual AAV vectors. An ordinary skill in the art would readily attribute the discrepancy between in vitro and in vivo results regarding to generation of truncated and/or aberrant ABCA4 and MYO7A by similar dual AAV vector constructs in Trapani to different cell types (embryonic kidney cells in vitro vs photoreceptors/retinal pigment epithelial cells in vivo) and/or different animal species (human cells in vitro vs murine cells in vivo); and the modified dual AAV vector system has applications in tissues and animal species other than murine retinal cells. Additionally, the placement of the degradation signals in the vectors as set forth above is only possible and proper such that the degradation signals in both the first and second vectors are removed via splicing upon reconstituting a large gene encoding the elected MYO7A protein; and unlike coding sequences of the truncated products generated by the first and second vectors the reconstituted full-length coding sequence of MYO7A lacks a degradation signal to be quickly degraded. Moreover, Zdanovsky et al. also taught using suitable enhancers/promoters to permit proper transcription of RNA, particularly Trapani et al. demonstrated different approaches to improve expression level of a coding sequence (e.g. designing and comparing different vector constructs to express ABCA4 or MYO7A, see Fig. 1 and 2).
An ordinary skilled artisan would have a reasonable expectation of success to carry out the above modifications in light of claims 1, 3-11 and 19 of copending Application No. 17/742,924 along with the teachings of Trapani et al, Umezawa et al and Zdanovsky et al; coupled with the level of skill for an ordinary skilled artisan in the relevant art.
The modified vector system resulting from claims 1, 3-11 and 19 of copending Application No. 17/742,924 in combination with the teachings of Trapani et al, Umezawa et al and Zdanovsky et al as set forth above is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection.
In the Amendment filed on 11/04/2025 (middle of page 16), Applicant simply requested that all of the above non-statutory double patenting rejections to be held in abeyance until all other issues in the present application are resolved.
Conclusion
No claim is 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 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 Quang Nguyen, Ph.D., whose telephone number is (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James D. Schultz, Ph.D. may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631