DETAILED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
2. This application is a 371 of PCT/US2020/014945 filed on 01/24/2020 that is CON of US application 16/512,194 filed on of 07/15/2019.
Election/Restrictions
3. Applicant’s election of Group I inventions in the reply filed on 05/06/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Species election: Applicant elected a species P5 promoter sequence.
Originally, the Group I invention was directed to claims 1-6 and 19.
Applicant cancelled the claim 19.
Applicant introduced two new claims 21 and 22 in Group I.
The new claim 21 is directed to the elected a species P5 promoter sequence.
The new claim 22 is directed to the elected a species P40 promoter sequence.
Examiners Note: Upon further consideration and search, the Group I election of species between P5 or P40 promoter is withdrawn.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 07/12/2022, 01/25/2024, 05/16/2024, 03/16/2026 was filed in time. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
5. Claims 1-18 and 21-22 are pending.
6. Claims 7-18 are withdrawn from consideration.
7. Claims 1-6 and 21-22 are under examination with P5 or P40 promoter sequence.
Status Identifiers (objection)
The amended claim set is objected to for failing to indicate “withdrawn” status in reference to the original/amended/canceled status
Applicant is reminded of the correct format regarding claim status identifiers.
Original, Previously Presented or amended claims which are withdrawn should be indicated as such See e.g. 37 CFR 1.121 and MPEP 714
e.g. 37 CFR 1.121 part (8) (c ) (“… In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).”
See also MPEP (“… For any amendment being filed in response to a restriction or election of species requirement and any subsequent amendment, any claims which are non-elected must have the status identifier (withdrawn). Any non-elected claims which are being amended must have either the status identifier (withdrawn) or (withdrawn – currently amended) and the text of the non-elected claims must be presented with markings to indicate the changes. Any non-elected claims that are being canceled must have the status identifier (canceled).
Claim Interpretation
8. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
The claims 1 is interpreted as directed to a recombinantly-modified adeno-associated virus (AAV) helper vector that comprises an AAV helper function-providing polynucleotide comprising a rep gene operably linked to, a non-native AAV serotype P5 promoter sequence (the elected species is P5 promoter sequence). The” helper vector” is interpreted as plasmid or a nucleic acid encoding a required the essential component (e.g. Rep protein or Rep gene) for replication and packaging of an AAV consistent with the specification.
The claim 3 is interpreted similar to that of claims 1-2 except that instead of Rep gene as recited to claims 1-2 the claim 3 helper vector Cap gene encode Cap protein.
The claim 4 is clearly directed to AAV helper vector as a plasmid vector.
Claims 5-6 and 21 are, inter alia, directed to the recombinantly-modified adeno-associated virus (AAV) helper vector under P5 or P40 promoter of claim 1. Claim 22 is directed to inter alia, directed to the recombinantly-modified adeno-associated virus (AAV) helper vector under P40 promoter of claim 3.
The specification para [0001] recites that present invention is directed to recombinantly-modified adeno-associated virus (AAV) helper vectors that are capable of increasing the packaging efficiency of recombinantly-modified adeno-associated virus (rAAV) and their use to improve the packaging efficiency of such rAAV. It is therefore interpreted that the claimed composition comprising a recombinantly modified adeno-associated virus (AAV) helper vectors are a plasmid or DNA or a nucleic acid, and the claimed AAV helper vector is not used as synonymous to a recombinant AAV virus or a recombinant AAV virus vector because the specification does not provide a clear definition. In addition, the claims 1-6 and 21-22 do not recite all the required AAV genetic elements for production or rescue of an rAAV virus or rAAV virus vector as recited in specification Example 1 para [0099] and Examples 2-5. For examination purpose, in view of the working examples 1-5 in the specification, the claims 1-6 and 21-22 are interpreted to comprise the viral and helper elements to enable to produce or rescue rAAV virus or rAAV virus vector in a cell culture. The intended use of the claimed rAAV vector is achieved by presence of said non-native AAV serotype P5 or P40 promoter sequence causes said cells to produce said rAAV at an increased production titer relative to that which would be attained if said AAV helper function-providing polynucleotide contained native serotype P5 and P40 promoters.
Claim Rejections - 35 USC § 102 (modified)
9. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
10. Claims 1-6 and 21-22 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Tieu et al 2014 (US20140155471A1, published 06/05/2014), as evidenced by
Balakrishnan et al 2014 (Current gene therapy, 14(2), 86-100).
Claim 1: A recombinantly-modified adeno-associated virus (AAV) helper vector that comprises an AAV helper function-providing polynucleotide comprising a rep gene operably linked to a non-native AAV serotype P5 or P40 promoter sequence.
Regarding claim 1: Tieu et al 2014 discloses a recombinant adeno-associated virus (rAAV) vector, methods of treating a neurological disease or injury in a subject comprising administering to the subject a recombinant adeno-associated virus (rAAV) vector comprising a DRP1-encoding nucleic acid, wherein the DRP1 encoded by the nucleic acid comprises a mutation compared to wild-type DRP1 (see, abstract). The rAAV vector ……….. comprises a promoter functionally linked to the DRP1 encoding nucleic acid (see, para [0032]). The promoter can be any desired promoter, selected by known considerations, such as the level of expression of a nucleic acid functionally linked to the promoter …., promoters can include, an AAV promoter from any AAV serotype, such as an AAV p5 promoter, an AAV p19 promoter or an AAVp40 promoter (see, para [0033]). A composition comprising... rAAV virions (See, para [0038]); a method... comprising... a recombinant adeno-associated virus, rAAV, vector (See, para [0004]); an rAAV virion is produced in a suitable host cell with an AAV vector, AAV helper functions and accessory functions introduced therein, (See, para [0035]); the rAAV vector can comprise a nucleic acid encoding AAV2 and a nucleic acid encoding one or more capsids from another serotype, for example, from AAV1, AAV5 or AAV8 capsid (See, para [0029]); promoters can include... an AAV promoter from any AAV serotype, such as an AAV p5 promoter... or an AAV p40 promoter (See, para [0033]); AAV ITRs, together with the AAV rep coding region (rep gene), provide for the efficient excision and rescue from, and integration of a nucleotide sequence interposed between two flanking ITRs into a mammalian cell genome (See, para [0034]); the vector can comprise a nucleic acid from an AAV1, AAV2, AAV3, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 or AAV11 genome the recombinant vector can also be a pseudotyped vector, comprising nucleic acid sequences from more than one AAV serotype (See, para [0029]).
Balakrishnan et al 2014 providence evidence through review on basic biology of AAV genome organization and replication that Rep gene is functionally and operably linked to a promoter p5 at 5’ end of Rep gene (See, Fig. 3).
Tieu et al 2014 disclosed The rAAV vector ……….. comprises a promoter functionally linked to the DRP1 encoding nucleic acid (see, para [0032]). The promoter can be any desired promoter, selected by known considerations, such as the level of expression of a nucleic acid functionally linked to the promoter …., promoters can include, an AAV promoter from any AAV serotype, such as an AAV p5 promoter, an AAV p19 promoter or an AAVp40 promoter (see, para [0033]). Therefore, it is implicit that AAV p5 promoter is operably lined (functionally linked) to both the Rep gene and DRP1-encoding nucleic acid.
Thus, as recited supra the instant claim 1 is anticipated by Tieu et al 2014 (US20140155471A1) as evidenced by Balakrishnan et al 2014.
Claim 2: The recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein said AAV helper function-providing polynucleotide vector comprises a non-native AAV serotype P5 promoter sequence.
Regarding Claim 2: Tieu et al 2014 discloses the recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein said AAV helper function-providing polynucleotide vector comprises a non-native AAV serotype P5 promoter sequence by disclosing promoters can include an AAV promoter from any AAV serotype, such as an AAV p5 promoter (See, para [0033]); the vector can comprise a nucleic acid from an AAV1, AAV2, AAV3, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 or AAV11 genome the recombinant vector can also be a pseudo-typed vector, comprising nucleic acid sequences from more than one AAV serotype (See, para [0033]).
Claim 3: The recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein said AAV helper function-providing polynucleotide further comprises a cap gene operably linked to a non-native AAV serotype P5 or P40 promoter sequence.
Regarding Claim 3: Tieu et al 2014 discloses the recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein said AAV helper function-providing polynucleotide vector comprises a non-native AAV serotype P5 promoter sequence (promoters can include an AAV promoter from any AAV serotype, such as an AAV P5 promoter (See, para [0033]); the vector can comprise a nucleic acid from an AAV1, AAV2, AAV3, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 or AAV11 genome the recombinant vector can also be a pseudotyped vector, comprising nucleic acid sequences from more than one AAV serotype (See, para [0033]); the rAAV vector can comprise a nucleic acid encoding AAV2 and a nucleic acid encoding one or more capsids from another serotype, for example, from AAV1, AAV5 or AAV8 capsid, the rAAV vector can also comprise a nucleic acid encoding a capsid sequence(s) from any AAV that has been modified to facilitate vector targeting. For example, a sequence encoding a peptide that targets a particular cell type can be inserted in a nucleic acid encoding a capsid sequence to allow targeting of the vector to a specific cell type or to a cell type that has a different tropism from the tropism of the AAV backbone of the vector, “insertional mutagenesis of the adeno-associated virus type 2 (AAV2) capsid gene and generation of AAV2 vectors targeted to alternative cell-surface receptors (See, para [0029]).
Claim 4: The recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein said vector is a plasmid vector.
Regarding Claim 4: Tieu et al 2014 discloses the recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein said vector is a plasmid vector (the rAAV vector can comprise a plasmid, the plasmid can be any plasmid that is compatible with an AAV vector, for example, a pFBGR plasmid, as described in the Examples (See, para [0032], claims 5-6).
Claim 5: The recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein said non-native AAV serotype P5 or P40-promoter sequence replaces a native AAV serotype promoter sequence.
Regarding Claim 5: Tieu et al 2014 discloses the recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein said non-native AAV serotype P5 or P40 promoter sequence replaces a native AAV serotype promoter sequence by disclosing promoters can include an AAV promoter from any AAV serotype, such as an AAV P5 promoter... or an AAV p40 promoter (See, para [0033]); the vector can comprise a nucleic acid from an AAV1, AAV2, AAV3, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 or AAV11 genome the recombinant vector can also be a pseudotyped vector, comprising nucleic acid sequences from more than one AAV serotype (See, para [0029]).
Claim 6: The recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein said vector additionally comprises a non-AAV helper function- providing polynucleotide.
Regarding Claim 6: Tieu et al 2014 discloses the recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein said vector additionally comprises a non-AAV helper function-providing polynucleotide by disclosing the rAAV vector comprises a dynamin-related protein, DRP1, encoding nucleic acid (See, para [0030], [0004], [0034], abstract, claims 5, 9).
Claim 21: The recombinantly-modified adeno-associated virus (AAV) helper vector of claim 1, wherein:
(A) the rep gene is an AAV1 rep gene, and the non-native AAV serotype P5 promoter sequence is a promoter sequence from AAV2, AAV7, or AAV8;
(B) the rep gene is an AAV2 rep gene, and the non-native AAV serotype P5 promoter sequence is a promoter sequence from AAV1, AAV3, AAV5, AAV7, or AAV8;
(C) the rep gene is an AAV5 rep gene, and the non-native AAV serotype P5 promoter sequence is a promoter sequence from AAV7;
(D) the rep gene is an AAV6 rep gene, and the non-native AAV serotype P5 promoter sequence is a promoter sequence from AAV1, AAV3, AAV7, or AAV8; or
(E) the rep gene is an AAV7 rep gene, and the non-native AAV serotype PS promoter sequence is a promoter sequence derived from AAV7.
Regarding claim 21: Tieu et al 2014 discloses a recombinant adeno-associated virus (rAAV) vector, a composition comprising... rAAV virions (See, para [0038]); a method... comprising... a recombinant adeno-associated virus, rAAV, vector (See, para [0004]); an rAAV virion is produced in a suitable host cell with an AAV vector, AAV helper functions and accessory functions introduced therein, (See, para [0035]); the rAAV vector can comprise a nucleic acid encoding AAV2 and a nucleic acid encoding one or more capsids from another serotype, for example, from AAV1, AAV5 or AAV8 capsid (See, para [0029]); promoters can include... an AAV promoter from any AAV serotype, such as an AAV p5 promoter... or an AAV p40 promoter (See, para [0033]); AAV ITRs, together with the AAV rep coding region (rep gene), provide for the efficient excision and rescue from, and integration of a nucleotide sequence interposed between two flanking ITRs into a mammalian cell genome (See, para [0034]); the vector can comprise a nucleic acid from an AAV1, AAV2, AAV3, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 or AAV11 genome, the recombinant vector can also be a pseudotyped vector, comprising nucleic acid sequences from more than one AAV serotype (See, para [0029]).
Claim 22: The recombinantly-modified adeno-associated virus (AAV) helper vector of claim 3, wherein:
(A) the cap gene is an AAV1 cap gene, and the non-native AAV serotype P40 promoter sequence is a promoter sequence from AAV2;
(B) the cap gene is an AAV2 cap gene, and the non-native AAV serotype P40 promoter sequence is a promoter sequence from AAV1 or AAV8;
(C) the cap gene is an AAV5 cap gene, and the non-native AAV serotype P40 promoter sequence is a promoter sequence from AAV2; or
(E) the cap gene is an AAV7 cap gene, and the non-native AAV serotype P40 promoter sequence is a promoter sequence derived from AAV2.
Regarding claim 22: Tieu et al 2014 discloses a recombinant adeno-associated virus (rAAV) vector can comprise a nucleic acid from the genome of any adeno-associated virus serotype. For example, the vector can comprise a nucleic acid from an AAV1, AAV2, AAV3, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 or AAV11 genome. The recombinant vector can also be a pseudotyped vector, comprising nucleic acid sequences from more than one AAV serotype. For example, the rAAV vector can comprise a nucleic acid encoding AAV2 and a nucleic acid encoding one or more capsids from another serotype, for example, from AAV1, AAV5 or AAV8 capsid. See, for example, “Time course of transgene expression after intrastriatal pseudotyped rAAV2/1, rAAV2/2. rAAV2/5, and rAAV2/8 transduction in the rat”. The rAAV vector can also comprise a nucleic acid encoding a capsid sequence(s) from any AAV that has been modified to facilitate vector targeting. For example, a sequence encoding a peptide that targets a particular cell type can be inserted in a nucleic acid encoding a capsid sequence to allow targeting of the vector to a specific cell type or to a cell type that has a different tropism from the tropism of the AAV backbone of the vector. See, for example, Shi et al., “Insertional mutagenesis of the adeno-associated virus type 2 (AAV2) capsid gene and generation of AAV2 vectors targeted to alternative cell-surface receptors,”. Mutational analysis of the adeno-associated virus type 2 (AAV2) capsid gene and construction of AAV2 vectors with altered tropism. An AAV capsid sequence can also be modified to encode an antibody or a fragment thereof that recognizes a cell surface marker. An AAV capsid sequence can also be modified to encode a ligand that recognizes a cell Development of novel cell surface CD34-targeted recombinant adeno-associated virus vectors for gene therapy surface receptor in order to direct delivery of the vector to specific cell types (See, para [0029]).
Claim Rejections - 35 USC § 103 (modified)
11. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
12. Claims 1-6 and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Tieu et al 2014 (US20140155471A1, published 06/05/2014); and further in view of Balakrishnan et al 2014 (Current gene therapy, 14(2), 86-100), Pereira et al 1997 (J Virol. 1997 Feb;71(2):1079-88), Murphy et al 2007 (J Virol. 2007 Apr;81(8):3721-30), Li et al 1997 (J Virol. 1997 Jul;71(7):5236-43), and Holehonnur et al 2014 (BMC Neurosci. 2014 Feb 18; 15: 28).
Claims 1-6 and 21-22: The disclosures of Tieu et al 2014 (US20140155471A1) and evidence provided by Balakrishnan et al 2014 regarding recombinant- AAV vectors that teaches claims 1-6 and 21-22 as recited supra in 35 U.S.C. 102 rejection is incorporated here in its entirety and the teachings of Tieu et al as recited supra render obvious the instant claims 1-6 and 21.
Tieu et al 2014 disclosed The rAAV vector ……….. comprises a promoter functionally linked to the DRP1 encoding nucleic acid (see, para [0032]). The promoter can be any desired promoter, selected by known considerations, such as the level of expression of a nucleic acid functionally linked to the promoter …., promoters can include, an AAV promoter from any AAV serotype, such as an AAV p5 promoter, an AAV p19 promoter or an AAVp40 promoter (see, para [0033]).
Tieu et al 2014 does not explicitly teach a phrase “a non-native” AAV P5 promoter. Tieu et al 2014 although does not explicitly teach operable linking, Tieu et al 2014 teaches a nucleic acid to be expressed is functionally linked to the promoter, and the promoters can include, an AAV promoter from any AAV serotype, such as an AAV p5 promoter, an AAV p19 promoter or an AAVp40 promoter.
It is also implicit that AAV p5 promoter is operably linked (functionally linked) to both the Rep gene and DRP1-encoding nucleic acid.
Balakrishnan et al 2014 is in the art and teaches in a review the basic biology of AAV genome organization and replication that Rep gene is functionally and operably linked to an AAV P5 promoter (See, Fig. 3).
Pereira et al 1997 is in the art and teaches adeno-associated virus (AAV) uses three promoters, p5, p19, and p40, to regulate viral gene expression. The p5 and p19 promoters direct the synthesis of the viral regulatory proteins, Rep78 and -68 and Rep52 and -40, respectively (See, abstract, entire article).
Murphy et al 2007 is in the art and teaches Adeno-Associated Virus Type 2 p5 Promoter and the regulation of P5 promoter by the large Rep proteins, p68 and p78, function as master controllers of the adeno-associated virus type 2 (AAV2) life cycle, involved in transcriptional control, in latency, in rescue, and in viral DNA replication. The p5 promoter may be the nucleic acid complement to the large Rep proteins. It drives expression of the large Rep proteins (See, abstract, entire article).
Li et al 1997 teaches role for highly regulated rep gene expression in adeno-associated virus (AAV) vector production. The study focused on the generation of high-titer vectors by using the two-plasmid helper-vector system in adenovirus (Ad)-infected cells. To examine the effects of the AAV replication (rep) genes on recombinant AAV (rAAV) vector production, a series of AAV helper plasmids that contain strong heterologous promoters in place of the endogenous p5 promoter were constructed. Although high-level rep gene expression was achieved, rAAV DNA failed to replicate in the absence of Ad infection. Moreover, unregulated overexpression of Rep78/68 led to substantially lower rAAV yields in the presence of Ad (104-5) versus 107-8). In contrast, under similar conditions, reduced Rep78/68 expression resulted in much higher rAAV yields (109). Molecular characterization showed that overexpression of the rep gene decreased rAAV DNA replication and severely inhibited capsid (cap) gene expression. Interestingly, a reduced rep level enhanced cap gene expression and supported normal rAAV DNA replication. These studies suggest a critical role for regulated rep gene expression in rAAV production and thus signifies critical role of P5 promoter (See, abstract, entire article).
Holehonnur et al 2014 is in the art and teaches AAV serotypes produce
differing titers (See, abstract, entire article), viral titers are also affected by capsid protein.
Therefore, it was known in the art that AAV serotypes differ in viral titers, and it is necessary to obtain high titers of AAV for gene therapy (See, abstract, Figure 2, entire article).
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to modify the prior art teachings of Tieu et al 2014 with additional teachings of Balakrishnan et al 2014, Pereira et al 1997, Murphy et al 2007, Li et al 1997, and Holehonnur et al 2014 to arrive at the inventions of claims 1-6 and 21-22. The motivation would be to increase the recombinant AAV vector titers for efficacious gene therapy and commercial success. One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claims 1-6 and 21-22 given the applied prior art teachings in the art. See, MPEP 2143, Rationales A-G that support the conclusion of obviousness. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007).
Double Patenting
13. 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
14. The instant claims 1-6 and 21-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 12-13 of the patented reference of prior U.S. Patent No. US10557149B1 by Wang et al 2020 (published 02/11/2020) and further in view of Tieu et al 2014 (US20140155471A1, published 06/05/2014); and further in view of Balakrishnan et al 2014 (Current gene therapy, 14(2), 86-100), Pereira et al 1997 (J Virol. 1997 Feb;71(2):1079-88), Murphy et al 2007 (J Virol. 2007 Apr;81(8):3721-30), Li et al 1997 (J Virol. 1997 Jul;71(7):5236-43), and Holehonnur et al 2014 (BMC Neurosci. 2014 Feb 18; 15: 28).
Although the claims at issue and patented reference claims are not identical, they are not patentably distinct from each other because both the patented claims and instant claims are directed to a recombinantly-modified adeno-associated virus (AAV) helper vector that comprises an AAV helper function-providing polynucleotide, wherein said polynucleotide comprises a non-native AAV serotype P5 or P40 promoter sequence (see, US10557149B1 by Wang et al 2020, claims 1 and 12).
The reference patented claims of Wang et al 2020 US10557149B1 do not explicitly recite AAV helper function-providing polynucleotide comprising a rep gene operably linked to a non-native AAV serotype P5 or P40 promoter sequence, and also does not show the contrary evidence of not said operable linking.
Tieu et al 2014 disclosed The rAAV vector, inter alia, ……….. comprises a promoter functionally linked to the DRP1 encoding nucleic acid (see, para [0032]). The promoter can be any desired promoter, selected by known considerations, such as the level of expression of a nucleic acid functionally linked to the promoter …., promoters can include, an AAV promoter from any AAV serotype, such as an AAV p5 promoter, an AAV p19 promoter or an AAVp40 promoter (see, para [0033]). Therefore, it is implicit that AAV p5 promoter is operably lined (functionally linked) to both the Rep gene and DRP1-encoding nucleic acid.
Balakrishnan et al 2014 is in the art and teaches in a review the basic biology of AAV genome organization and replication that Rep gene is functionally and operably linked to a promoter p5 (See, Fig. 3, entire article).
Based on the combined teachings of Wang et al 2020 (U.S. Patent No. US10557149B1), Tieu et al 2014, Balakrishnan et al 2014, Pereira et al 1997, Murphy et al 2007, Li et al 1997, and Holehonnur et al 2014 as applied and recited supra in obviousness rejection, it would have been obvious to one of the ordinary skills to modify the instant claims 1-6 and 21-22 to recite or comprise a rep gene operably linked to a non-native p5 promoter for increased production of recombinant AAV for commercial success.
15. The instant claims 1-6 and 21-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 15-20 of Wang et al 2021 U.S. Patent No. US11001859B2 (published 05/11/2021) and further in view of Tieu et al 2014 (US20140155471A1, published 06/05/2014); and further in view of Balakrishnan et al 2014 (Current gene therapy, 14(2), 86-100), Pereira et al 1997 (J Virol. 1997 Feb;71(2):1079-88), Murphy et al 2007 (J Virol. 2007 Apr;81(8):3721-30), Li et al 1997 (J Virol. 1997 Jul;71(7):5236-43), and Holehonnur et al 2014 (BMC Neurosci. 2014 Feb 18; 15: 28).
Although the instant claims 1-6 and 21-22, and the patented claims (claims 1-6 and 15-20) are not identical, they are not patentably distinct from each other because both the patented claims and instant elected claims are directed to a recombinant-modified AAV helper-vector that comprises a transgene cassette that is flanked by inverted terminal repeated sequences, an rAAV helper vector that comprises an AAV helper function-providing polynucleotide, wherein said polynucleotide comprises an AAV P5 promoter sequence, an AAV P40 promoter sequence, an AAV Cap encoding sequence, and an AAV Rep encoding sequence; wherein said AAV Rep encoding sequence is under the transcriptional control of said AAV P5 promoter sequence, and expresses said AAV Rep52 protein and said AAV Rep78 protein in said transfected cells, and wherein said AAV P5 promoter sequence is not native (non-native) to said AAV Rep encoding sequence and/or said AAV P40 promoter sequence is not native (non-native) to said AAV Cap encoding sequence (see claims 1, 15).
Balakrishnan et al 2014 is in the art and teaches in a review the basic biology of AAV genome organization and replication that Rep gene is functionally and operably linked to a promoter p5 (See, Fig. 3).
The reference patented claims of Wang et al 2021 US11001859B2 do not explicitly recite AAV helper function-providing polynucleotide comprising a rep gene operably linked to a non-native AAV serotype P5 or P40 promoter sequence, and also does not show the contrary evidence of not said operable linking.
Tieu et al 2014 disclosed The rAAV vector ……….. comprises a promoter functionally linked to the DRP1 encoding nucleic acid (see, para [0032]). The promoter can be any desired promoter, selected by known considerations, such as the level of expression of a nucleic acid functionally linked to the promoter …., promoters can include, an AAV promoter from any AAV serotype, such as an AAV p5 promoter, an AAV p19 promoter or an AAVp40 promoter (see, para [0033]). Therefore, it is implicit that AAV p5 promoter is operably lined (functionally linked) to both the Rep gene and DRP1-encoding nucleic acid.
It would have been obvious to one of the ordinary skills in the art before the effective filing date of the instant application to apply the teachings of patented reference claims of 1-6 and 15-20 of Wang et al 2021 U.S. Patent No. US11001859B2 in view of Tieu et al 2014, Balakrishnan et al 2014, Pereira et al 1997, Murphy et al 2007, Li et al 1997, and Holehonnur et al 2014 as applied and recited supra in obviousness rejection to arrive at the instant elected claims 1-6 and 21-22. The motivation would be to produce a recombinantly-modified adeno-associated virus (AAV) helper vectors that are capable of increasing the packaging efficiency of recombinantly-modified adeno-associated virus (rAAV) and their use to improve the packaging efficiency of such rAAV (See, US11001859B2, abstract, claims 1-6 and 15-20). One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of instant elected claims 1-6 and 21-22 given the applied teachings of Wang et al 2021 U.S. Patent No. US11001859B2, Tieu et al 2014 (US20140155471A1) and the applied additional prior arts with a motivation to develop the claimed composition of rAAV with increased titer for efficacious gene therapy and commercial success.
Response to Arguments
16. Applicant's arguments filed on 10/28/2025 have been fully considered but they are not persuasive.
Applicant’s argument: Applicants main argument is that the prior arts applied for 35 U.S.C. 102 anticipation and 35 U.S.C. 103 obviousness rejections based on the primary reference Tieu et al does not disclose or suggest anywhere an "AAV helper function-providing polynucleotide comprising a rep gene operably linked to a non-native AAV serotype P5 or P40 promoter sequence," as featured in claim 1.
Applicant argued that secondary references in 35 U.S.C. 103 obviousness rejection do not overcome the deficiency of Tieu et al.
In Response:
35 U.S.C. 102 anticipation: Tieu et al implicitly disclosed that AAV helper function-providing polynucleotide comprising a rep gene operably linked to a non-native AAV serotype P5 or P40 promoter sequence as evidenced by Balakrishnan et al 2014 for 35 U.S.C. 102 anticipation.
35 U.S.C. 103 obviousness: As recited supra the office action is modified, by including additional prior arts as recited supra in the office action are applied to the modified 35 U.S.C. 103 obviousness rejection. The combined prior art teaching has rendered obvious the instant claims 1-6 and 21-22 under examination.
Applicant's arguments filed on 10/28/2025 have been fully considered but they are not persuasive.
Secondary evidence
Applicant’s argument:
Even if, arguendo, a prima facie case of obviousness were established (which Applicant does not concede), Applicant submits that one of ordinary skill in the art would not have reasonably expected the advantages provided by the claimed rAAV helper vector, in which the P5 and/or P40 promoter sequences that are natively associated with the Rep proteins encoded by such rAAV are replaced or augmented with AAV P5 and/or P40 promoters that are associated with the Rep proteins of an rAAV of different serotype. These AAV helper vectors are capable of increasing the packaging efficiency of rAAV. See the as-filed Specification, paragraph [0020]. As shown in Example 1, a non-native AAV serotype P5 promoter operably linked to the rep gene surprisingly increased rAAV production titer. See id., paragraph [00101] and Figure 12B. Such advantageous results could not have been contemplated by one of ordinary skill in the art reading the cited references.
In Response:
The 35 U.S.C. 102 anticipation rejection and 35 U.S.C. 103 obviousness rejection as recited supra has rendered obvious the independent claim 1 and dependent claims (the claimed rAAV composition) as recited in the office action. Therefore, when the composition is rendered obvious having the claimed structure the applicant’s argued function of increased rAAV production titer by the claimed composition of rAAV is reasonably expected to be achievable.
Applicant's arguments filed on 10/28/2025 have been fully considered but they are not persuasive.
17. Double Patenting Rejections
Applicant’s argument:
The applicant has traverses (i) Statutory 101 double patenting rejection in view of as claims 1-6 of U.S. Patent No. 10557149 B1 ("the '149 patent") is traversed. NFOA, pp. 14-15, and (ii) nonstatutory double patenting rejection of claims 21 and 22 over claims over claims 1-6 of U.S. Patent No. 11,001,859 B2. NFOA, pp. 15- 16.
In Response:
The statutory double patenting rejection in view of as claims 1-6 of U.S. Patent No. 10557149 B1 ("the '149 patent") is withdrawn.
The instant office action is modified to render obvious the elected claims 1-6 and 21-22 under 35 U.S.C. 103 as recited supra by applying additional reference(s) and teachings as recited in the office action.
The modified double patenting rejections are based on the ground of nonstatutory double patenting as recited supra.
Applicant's arguments filed on 10/28/2025 have been fully considered but they are not persuasive in view of the instant modified office action that rely on additional references and teachings to render obvious the instant elected claims.
Conclusion
18. No claim is allowed.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600
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