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 response of 06/18/2026 has been received and entered into the application file.
Claims 1 and 3-4 were cancelled in the claim set filed 06/18/2026.
Claim 41 was added in the claim set filed 06/18/2026.
Accordingly, claims 6-8, 11-14, 18-22, 24-25, 28-29, and 41 are pending and under consideration.
Status of Prior Objections/Rejections
RE: Double Patenting
►Claims 1, 3, 4, 24, and 29 were previously rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 8, 11, and 18 of U.S. Patent No. 12,508,327 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The cancellation of claims 1 and 3-4 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that claim 6 has been amended to be an independent claim that incorporates the recitation of the base claim and intervening claims and further that claim 29 has been amended to depend from claim 6.
In response, this is not found persuasive. The Examiner regrets the improper accounting of double patenting previously set forth. However, as set forth in greater detail below, patent ‘327 recites “a nucleic acid encoding aspartoacylase (ASPA) or a functional fragment thereof, wherein the ASPA or functional fragment thereof comprises an amino acid sequence that is at least 75% identical to the sequence of SEQ ID NO: 1.” Instant SEQ ID NO: 2 translates into a sequence that is 100% identical to SQ ID NO: 1 of patent ‘327. Thus, the nucleic acid recited in patent ‘327 reads on the instantly claimed nucleic acid, while the prior art teaches all other elements of the instant claim set. Accordingly, new grounds of rejection are set forth below.
►Claims 1, 3, 4, 24, and 29 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 10, 13, 15, and 19 of copending Application No. 19/396,542 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The cancellation of claims 1 and 3-4 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that claim 6 has been amended to be an independent claim that incorporates the recitation of the base claim and intervening claims and further that claim 29 has been amended to depend from claim 6.
In response, this is not found persuasive. The Examiner regrets the improper accounting of double patenting previously set forth. However, as set forth in greater detail below, application ‘542 recites “a nucleic acid encoding aspartoacylase (ASPA) or a functional fragment thereof, wherein the ASPA or functional fragment thereof…comprises an amino acid sequence that is at least 75% identical to the sequence of SEQ ID NO: 1.” Instant SEQ ID NO: 2 translates into a sequence that is 100% identical to SQ ID NO: 1 of application ‘542. Thus, the nucleic acid recited in application ‘542 reads on the instantly claimed nucleic acid, while the prior art teaches all other elements of the instant claim set. Accordingly, new grounds of rejection are set forth below.
New/Maintained Grounds of Objection/Rejection
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.
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.
Claims 6-8, 11-14, 18-22, 24-25, 28-29, and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-9, 11, 12, and 18 of U.S. Patent No. 12,508,327 B2 in view of Powell et al., 2016 (hereinafter Powell; of record), US 2015/0238550 A1 (hereinafter McCown), US 2017/0128528 A1 (hereinafter Samulski), Janson et al., 2002 (hereinafter Janson), Leone et al., 2012 (hereinafter Leone), Mendes et al., 2017 (hereinafter Mendes), US 2002/0177222 A1 (hereinafter Li), US 2022/0280657 A1 (hereinafter McDonald; effectively filed 08/12/2019), US 2019/0144884 A1 (hereinafter Tretiakova), WO 2019/076892 A1 (hereinafter Colloca), US 2022/0175965 A1 (hereinafter Clark; effectively filed 12/31/2019), and US 2017/0275649 A1 (hereinafter Vandendriessche).
Instant claim 6 recites “a recombinant adeno-associated virus (rAAV) vector comprising (i) a vector genome, wherein the vector genome comprises a modified nucleic acid encoding aspartoacylase (ASPA) and comprising the nucleic acid sequence of SEQ ID NO: 2 and (ii) a capsid selected from the group consisting of a capsid of Olig001, Olig002, Olig003, AAV1, AAV2, AAV3, AAV3A, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10…and AAV-LK03.” Dependent claim 7 further limits the capsid of said vector to “Olig001, an Olig002, or an Olig003 capsid.”
In comparison, claims 1, 7, and 18 of patent ‘327 all recite “a nucleic acid encoding aspartoacylase (ASPA) or a functional fragment thereof, wherein the ASPA or functional fragment thereof comprises an amino acid sequence that is at least 75% identical to the sequence of SEQ ID NO: 1,” wherein said nucleic acid is carried on an rAAV vector as recited at patented claim 11.
Claim 8 of patent ‘327 requires 100% identity to SEQ ID NO: 1. As shown in the alignment of the Appendix, instant SEQ ID NO: 2 translates into a sequence that is 100% identical to SEQ ID NO: 1 of patent ‘327. Thus, the nucleic acid recited in patent ‘327 reads on the instantly claimed nucleic acid. However, patent ‘327 is silent as to the instantly claimed capsid. This deficiency is cured by Powell. As previously set forth, Powell discloses that the Olig001 capsid is a novel AAV capsid with oligodendrocyte-preferring tropism generated using capsid shuffling and directed evolution (abstract; Figure 1; page 807, column 1, paragraph 2-page 807, column 2, paragraph 1). Thus, Powell discloses that the novel Olig001 capsid generates an AAV vector serotype with tropism for oligodendrocytes, thereby teaching the claim elements not recited in patent ‘327.
Instant claim 8 further limits the claimed capsid to “an Olig001 capsid comprising a viral protein 1 (VP1) and wherein the VP1 comprises the amino acid sequence of SEQ ID NO: 14.” SEQ ID NO: 14 was known in the art prior to the effective filing date of the instant application. McCown discloses chimeric AAV capsid structures capable of preferentially transducing oligodendrocytes over neurons and other cells of the CNS, wherein said AAV capsid structures correspond to SEQ ID NO: 2 and comprise VP1 capsid proteins (paragraphs [0061] and [0063]). As shown in the alignment of the Appendix, instant SEQ ID NO: 14 and SEQ ID NO: 2 of McCown are 100% identical to each other. Thus, the prior art teaches the claim elements not recited in patent ‘327.
Instant claim 11 recites “the vector genome [of the rAAV vector of claim 6] further comprises at least one element selected from the group consisting of at least one AAV inverted terminal repeat (ITR) sequence, an enhancer, a promoter, an exon, an intron, and a poly-adenylation (polyA) signal sequence.” While patent ‘327 does not claim these elements, these are known to be components of rAAV constructs. McCown teaches that rAAV genomes comprise at least one inverted terminal repeat at either the 3’ or 5’ end (paragraph [0055]). Thus, the prior art teaches the claim elements not recited in patent ‘327.
Instant claim 12 recites “the vector genome [of the rAAV vector of claim 6] comprises at least one element selected from the group consisting of at least one AAV2 ITR, a cytomegalovirus (CMV) enhancer, a hybrid form of the CBA promoter (CBh promoter), a chicken B-actin (CBA) exon, a CBA intron, a minute virus of mice (MVM) intron and a bovine growth hormone (BGH) polyA.” While patent ‘327 does not claim these elements, these are known components of rAAV constructs. McCown teaches that rAAV genomes may further comprise polyadenylation signals to appropriately control the expression of the heterologous nucleic acids disclosed therein (paragraph [0104]). However, McCown does not teach that these polyadenylation signals are specifically bovine growth hormone polyadenylation signals. This deficiency is cured by Samulski, which also discloses therapeutic rAAV vectors, wherein said rAAV vectors comprise control elements such as a polyA signal sequence, specifically bovine growth hormone polyA signal sequence such that said polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic RNA (paragraphs [0039] and [0091]). Thus, the prior art teaches the claim elements not recited in patent ‘327.
Instant claim 13 recites “the rAAV vector of claim 6, wherein the vector genome further comprises at least one element selected from the group consisting of…a polyA comprising the nucleic acid sequence of SEQ ID NO: 11.” While patent ‘327 does not claim this element, this is a known polyA signal sequence in the prior art. As set forth above, Samulski discloses therapeutic rAAV vectors, wherein said rAAV vectors comprise control elements such as a polyA signal sequence, specifically bovine growth hormone polyA signal sequence such that said polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic RNA (paragraphs [0039] and [0091]). An exemplary bGH polyA signal sequence is disclosed to be SEQ ID NO: 27 of Samulski (see paragraph [0014]), which comprises 100% identity to instant SEQ ID NO: 11, as shown in the alignment of the Appendix. Thus, the prior art teaches the claim elements not recited in patent ‘327.
With regard to claim 14, which recites “an rAAV vector comprising a vector genome comprising from 5’ to 3’:
an AAV inverted terminal repeat (ITR) comprising the nucleic acid sequence of SEQ ID NO: 5…;
an enhancer comprising the nucleic acid sequence of SEQ ID NO: 6 or SEQ ID NO: 17;
a promoter comprising the nucleic acid sequence of SEQ ID NO: 7;
an exon comprising the nucleic acid sequence of SEQ ID NO: 8 or SEQ ID NO: 18;
an intron comprising the nucleic acid sequence of SEQ ID NO: 9;
an intron comprising the nucleic acid sequence of SEQ ID NO: 10;
a modified nucleic acid encoding aspartoacylase (ASPA) comprising the nucleic acid sequence of SEQ ID NO: 2;
a polyA comprising the nucleic acid sequence of SEQ ID NO: 11; and
an AAV ITR comprising the nucleic acid sequence of SEQ ID NO: 5…”,
as set forth above, instant SEQ ID NO: 2 is not patentably distinct from patent ‘327, as both encode identical protein products. Regarding the remaining claimed rAAV sequences, the prior art teaches all of these sequences.
Regarding the instantly claimed ITR sequences, Li discloses that AAV inverted terminal repeats provide for efficient excision and rescue from, and integration of a nucleotide sequence interposed between two flanking ITRs into a mammalian cell genome (paragraphs [0042] and [0043]). Li further discloses that these ITRs are preferably mutated to comprise a deletion in the D sequence, which is represented by SEQ ID NO: 1 (paragraph [0093]). As shown in the alignment of the Appendix, SEQ ID NO: 1 of Li comprises 100% identity to instant SEQ ID NO: 5.
Regarding the instantly claimed enhancer sequence, McCown discloses that the rAAV vectors taught therein may comprise a variety of enhancer sequences depending on the level and tissue-specific expression desired (paragraphs [0104]-[0106]). However, McCown is silent as to the instantly claimed sequence thereof. This deficiency is cured by McDonald. McDonald discloses rAAV vectors comprising one or more enhancers (paragraphs [0068] and [0136]), wherein said enhancers include a chicken beta-actin fused early enhancer, wherein said enhancer is fused to a CMV promoter (referred to as SEQ ID NO: 44; paragraphs [0071] and [0072]). As shown in the alignment of the Appendix, SEQ ID NO: 44 of McDonald comprises 100% identity to instant SEQ ID NO: 17 and is disclosed to comprise the chicken beta-actin early enhancer.
Regarding the instantly claimed promoter sequence, McCown discloses that the rAAV vectors taught therein may comprise a variety of promoter sequences depending on the level and tissue-specific expression desired (paragraphs [0104]-[0106]). However, McCown is silent as to the instantly claimed sequence thereof. This deficiency is cured by Tretiakova, which discloses rAAV vectors comprising the chicken beta actin promoter corresponding to SEQ ID NO: 16 taught therein (paragraphs [0008] and [0060]). As shown in the alignment of the Appendix, SEQ ID NO: 16 of Tretiakova comprises 100% identity to instant SEQ ID NO: 7.
Regarding the instantly claimed exon sequence, Colloca discloses novel promoter sequences (abstract), wherein said promoter sequences comprise a fragment of the beta-actin sequence corresponding to SEQ ID NO: 9 taught therein. As shown in the alignment of the Appendix, SEQ ID NO: 9 of Colloca comprises 100% identity to instant SEQ ID NO: 8.
Regarding the instantly claimed intron sequence corresponding to SEQ ID NO: 9, Clark discloses polynucleotides and AAV vectors providing for the expression of a transgene in neuron or glial garget cells (abstract), wherein such constructs comprise a promoter, which is itself comprised of an enhancer, a promoter, an exon, and a chimeric intron from the 5’ to 3’ end (paragraph [0135]). This architecture broadly reads on the instantly claimed construct comprising an enhancer, a promoter, and an exon. Clark teaches that SEQ ID NO: 10009 taught therein corresponds to the chimeric intron disclosed therein (paragraph [0136]). As shown in the alignment of the Appendix, SEQ ID NO: 10009 of Clark comprises 100% identity to instant SEQ ID NO: 9.
Regarding the instantly claimed intron sequence corresponding to SEQ ID NO: 10, Vandendriessche teaches therapeutic AAV constructs, wherein said constructs comprise the minute virus of mouse (MVM) intron, wherein the MVM intron corresponds to SEQ ID NO: 54 (paragraph [0032]). As shown in the alignment of the Appendix, SEQ ID NO: 54 of Vandendriessche comprises 100% identity to instant SEQ ID NO: 10.
Regarding the instantly claimed polyA sequence, Samulski further discloses that the rAAV constructs taught therein further comprise a bovine growth hormone polyA signal sequence having the sequence of SEQ ID NO: 27 (paragraphs [0009], [0014], [0020], and [0026]) to drive efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic mRNA (paragraph [0091]). As shown in the alignment of the Appendix, SEQ ID NO: 27 of Samulski comprises 100% identity to instant SEQ ID NO: 11.
Thus, the prior art teaches the claim elements not recited in patent ‘327.
Instant claim 18 recites “a pharmaceutical composition comprising the rAAV vector of claim 6.” Although patent ‘327 does not claim a pharmaceutical composition comprising the rAAV vectors claimed therein, such compositions are known in the art. McCown teaches that rAAV vectors may be provided within a pharmaceutical composition (paragraphs [0187] and [0188]). Thus, the prior art teaches the claim elements not recited in patent ‘327.
Instant claim 19 recites “a method of treating a disease, disorder, or condition associated with deficiency or dysfunction of ASPA, the method comprising administering a therapeutically effective amount of the rAAV vector of claim 6,” wherein the treated disease is Canavan disease per instant claim 20. While the methods of patent ‘327 are drawn to the treatment of amyotrophic lateral sclerosis (ALS), both ALS and Canavan disease are associated with deficient levels or activity of ASPA. Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in patent ‘327.
Instant claim 21 recites “the rAAV vector [of the method of claim 19] is administered directly to the brain and/or central nervous system,” which corresponds to patented claim 12, which recites administration of the rAAV composition taught therein to at least a portion of the brain and spinal cord of the subject. Thus, the instant and patented claims are not patentably distinct.
Instant claim 22 recites “the rAAV vector [of the method of claim 19] is administered to a region of the central nervous system…or wherein the rAAV vector is administered by a method selected from the group consisting of intraparenchymal administration, intrathecal administration, intracerebroventricular administration, intracisternal magna administration, and a combination thereof.” As set forth above, Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Janson cites examples of such therapy in rats, wherein the AAV-ASPA vector was delivered intraparenchymally or intracerebroventricularly to said rats (page 1393, column 1, paragraph 4-page 1393, column 2, paragraph 1). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in patent ‘327.
Instant claims 24 and 25 respectively recite “an isolated host cell comprising the rAAV vector of claim 6” and “the isolated host cell of claim 24, wherein the cell is selected from the group consisting of VERO, WI38, MRC5, A549, HEK293, B-50 or any other HeLa cell, HepG2, Saos-2, HuH7, and HT1080.” Patented claim 9 recites viral transduction of at least one cell with the nucleic acid claimed therein at patented claim 9. Thus, patented claim 9 is not patentably distinct from instant claim 24. Regarding the additional limitations of instant claim 25, Mendes discloses HEK293 cells transfected with an ASPA open reading frame (abstract). Thus, the prior art teaches the claim elements not recited in patent ‘327.
Instant claim 28 recites “the isolated host cell of claim 25, wherein the cell comprises at least one nucleic acid encoding at least one protein selected from the group consisting of an AAV rep protein, an AAV capsid (Cap) protein, an adenovirus (Ad) early region 1A (E1a) protein, an Ad E1b protein, an Ad E2a protein, an Ad E4 protein and a viral associated (VA) RNA,” as set forth above, Samulski discloses therapeutic rAAV vectors. Samulski further discloses packaging cells useful for viral vector replication and packaging, wherein said packaging cells comprise genes encoding AAV Rep and Cap proteins (paragraph [0118]). Thus, the prior art teaches the claim elements not recited in patent ‘327.
Furthermore claim 18 of patent ‘327 recites “a kit for increasing a level or activity of ASPA in a cell of a subject comprising a rAAV1 vector or a virus-like particle, wherein the virus or virus-like particle comprises a nucleic acid encoding ASPA or a functional fragment thereof, wherein the ASPA or functional fragment thereof comprises an amino acid sequence that is at least 75% identical to the sequence of SEQ ID NO: 1, and wherein the ASPA or functional fragment thereof has the enzymatic activity of aspartoacylase.” This kit is not patentably distinct from the kit recited at instant claim 29, which also requires a nucleic acid encoding ASPA or a functional fragment thereof that reads on the nucleic acid of patent ‘327, as set forth above. As set forth in MPEP § 2111.02(II), when a preamble only states a purpose or intended use for the invention, it is not considered to carry patentable weight. Thus, the kit of patent ‘327 is not patentably distinct from the kit recited at instant claim 29.
Regarding the additional limitations of instant claim 41, which requires that the kit further comprise “a label or insert including instructions for using one or more of the kit components,” while the kit recited at patent ‘327 does not explicitly require a label or insert for instructions for use, it is noted that MPEP § 804 II B 1 indicates:
When considering whether the invention defined in a claim of an application would have been anticipated by or is an obvious variation of the invention defined in the claim of a patent or copending application, no part of the reference patent or application may be used as if it were prior art… This does not mean that one is precluded from all use of the reference patent or application disclosure to understand the meaning of the reference claims.
The specification can be used as a dictionary to learn the meaning of a term in the patent claim… Further, those portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent.
Therefore, MPEP § 804 II B 1 indicates that a patent’s disclosure may be considered when determining if an examined claim is an obvious variation of an invention claims in a patent and explicitly indicates that the disclosure of a patent may be considered when determining if a claim in an application is an obvious variation of an invention claimed in the patent.
In the instant case, while the claims of patent ‘327 recite only “a kit,” the specification of patent ‘327 discloses that said kit may comprise instructions for use (column 17, lines 9-14). Thus, instant claim 41 is not patentably distinct from patent ‘327
Given that patent ‘237 recites a nucleic acid encoding aspartoacylase (ASPA) or a functional fragment thereof, wherein the ASPA or functional fragment thereof comprises an amino acid sequence that is at least 75% identical to the sequence of SEQ ID NO: 1, wherein said nucleic acid is carried in an rAAV, and that the cited art discloses all of the instantly claimed rAAV components, as set forth above, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the rAAV recited in patent ‘237 per the teachings of the prior art to predictably arrive at the instant invention of a therapeutic rAAV encoding ASPA. One would have been motivated to make such a modification in order to receive the expected benefit of generating a therapeutic rAAV encoding ASPA for treatment of patients in need thereof.
Claims 6-8, 11-14, 18-22, 24-25, 28-29, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 10, 13, 15, 17, and 19 of copending Application No. 19/396,542 (reference application; corresponds to US 2026/0077060 A1) in view of Powell et al., 2016 (hereinafter Powell; of record), US 2015/0238550 A1 (hereinafter McCown), US 2017/0128528 A1 (hereinafter Samulski), Janson et al., 2002 (hereinafter Janson), Leone et al., 2012 (hereinafter Leone), Mendes et al., 2017 (hereinafter Mendes), US 2002/0177222 A1 (hereinafter Li), US 2022/0280657 A1 (hereinafter McDonald; effectively filed 08/12/2019), US 2019/0144884 A1 (hereinafter Tretiakova), WO 2019/076892 A1 (hereinafter Colloca), US 2022/0175965 A1 (hereinafter Clark; effectively filed 12/31/2019), US 2017/0275649 A1 (hereinafter Vandendriessche), and WO 2020/028751 A2 (hereinafter Sah).
Instant claim 6 recites “a recombinant adeno-associated virus (rAAV) vector comprising (i) a vector genome, wherein the vector genome comprises a modified nucleic acid encoding aspartoacylase (ASPA) and comprising the nucleic acid sequence of SEQ ID NO: 2 and (ii) a capsid selected from the group consisting of a capsid of Olig001, Olig002, Olig003, AAV1, AAV2, AAV3, AAV3A, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10…and AAV-LK03.” Dependent claim 7 further limits the capsid of said vector to “Olig001, an Olig002, or an Olig003 capsid.”
In comparison, copending claims 1 and 13 both recite “a nucleic acid encoding aspartoacylase (ASAP) or a functional fragment thereof, wherein the ASPA or functional fragment thereof…comprises an amino acid sequence at least 75% identical to the sequence of SEQ ID NO: 1.” Claims 3 and 15 require 100% identity to SEQ ID NO: 1. As shown in the alignment of the Appendix, instant SEQ ID NO: 2 translates into a sequence that is 100% identical to copending SEQ ID NO: 1. Thus, the nucleic acid recited in copending application ‘542 reads on the instantly claimed nucleic acid. Furthermore, copending claims 10 and 19 recite that the nucleic acid claimed therein is carried on an rAAV vector.
However, the copending application is silent as to the instantly claimed capsid. This deficiency is cured by Powell. As previously set forth, Powell discloses that the Olig001 capsid is a novel AAV capsid with oligodendrocyte-preferring tropism generated using capsid shuffling and directed evolution (abstract; Figure 1; page 807, column 1, paragraph 2-page 807, column 2, paragraph 1). Thus, Powell discloses that the novel Olig001 capsid generates an AAV vector serotype with tropism for oligodendrocytes, thereby teaching the claim elements not recited in the copending application.
Instant claim 8 further limits the claimed capsid to “an Olig001 capsid comprising a viral protein 1 (VP1) and wherein the VP1 comprises the amino acid sequence of SEQ ID NO: 14.” SEQ ID NO: 14 was known in the art prior to the effective filing date of the instant application. McCown discloses chimeric AAV capsid structures capable of preferentially transducing oligodendrocytes over neurons and other cells of the CNS, wherein said AAV capsid structures correspond to SEQ ID NO: 2 and comprise VP1 capsid proteins (paragraphs [0061] and [0063]). As shown in the alignment of the Appendix, instant SEQ ID NO: 14 and SEQ ID NO: 2 of McCown are 100% identical to each other. Thus, the prior art teaches the claim elements not recited in the copending application.
Instant claim 11 recites “the vector genome [of the rAAV vector of claim 6] further comprises at least one element selected from the group consisting of at least one AAV inverted terminal repeat (ITR) sequence, an enhancer, a promoter, an exon, an intron, and a poly-adenylation (polyA) signal sequence.” While the copending application does not claim these elements, these are known to be components of rAAV constructs. McCown teaches that rAAV genomes comprise at least one inverted terminal repeat at either the 3’ or 5’ end (paragraph [0055]). Thus, the prior art teaches the claim elements not recited in the copending application.
Instant claim 12 recites “the vector genome [of the rAAV vector of claim 6] comprises at least one element selected from the group consisting of at least one AAV2 ITR, a cytomegalovirus (CMV) enhancer, a hybrid form of the CBA promoter (CBh promoter), a chicken B-actin (CBA) exon, a CBA intron, a minute virus of mice (MVM) intron and a bovine growth hormone (BGH) polyA.” While the copending application does not claim these elements, these are known components of rAAV constructs. McCown teaches that rAAV genomes may further comprise polyadenylation signals to appropriately control the expression of the heterologous nucleic acids disclosed therein (paragraph [0104]). However, McCown does not teach that these polyadenylation signals are specifically bovine growth hormone polyadenylation signals. This deficiency is cured by Samulski, which also discloses therapeutic rAAV vectors, wherein said rAAV vectors comprise control elements such as a polyA signal sequence, specifically bovine growth hormone polyA signal sequence such that said polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic RNA (paragraphs [0039] and [0091]). Thus, the prior art teaches the claim elements not recited in the copending application.
Instant claim 13 recites “the rAAV vector of claim 6, wherein the vector genome further comprises at least one element selected from the group consisting of…a polyA comprising the nucleic acid sequence of SEQ ID NO: 11.” While the copending application does not claim this element, this is a known polyA signal sequence in the prior art. As set forth above, Samulski discloses therapeutic rAAV vectors, wherein said rAAV vectors comprise control elements such as a polyA signal sequence, specifically bovine growth hormone polyA signal sequence such that said polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic RNA (paragraphs [0039] and [0091]). An exemplary bGH polyA signal sequence is disclosed to be SEQ ID NO: 27 of Samulski (see paragraph [0014]), which comprises 100% identity to instant SEQ ID NO: 11, as shown in the alignment of the Appendix. Thus, the prior art teaches the claim elements not recited in the copending application.
With regard to claim 14, which recites “an rAAV vector comprising a vector genome comprising from 5’ to 3’:
an AAV inverted terminal repeat (ITR) comprising the nucleic acid sequence of SEQ ID NO: 5…;
an enhancer comprising the nucleic acid sequence of SEQ ID NO: 6 or SEQ ID NO: 17;
a promoter comprising the nucleic acid sequence of SEQ ID NO: 7;
an exon comprising the nucleic acid sequence of SEQ ID NO: 8 or SEQ ID NO: 18;
an intron comprising the nucleic acid sequence of SEQ ID NO: 9;
an intron comprising the nucleic acid sequence of SEQ ID NO: 10;
a modified nucleic acid encoding aspartoacylase (ASPA) comprising the nucleic acid sequence of SEQ ID NO: 2;
a polyA comprising the nucleic acid sequence of SEQ ID NO: 11; and
an AAV ITR comprising the nucleic acid sequence of SEQ ID NO: 5…”,
as set forth above, instant SEQ ID NO: 2 is not patentably distinct from the copending application, as both encode identical protein products. Regarding the remaining claimed rAAV sequences, the prior art teaches all of these sequences.
Regarding the instantly claimed ITR sequences, Li discloses that AAV inverted terminal repeats provide for efficient excision and rescue from, and integration of a nucleotide sequence interposed between two flanking ITRs into a mammalian cell genome (paragraphs [0042] and [0043]). Li further discloses that these ITRs are preferably mutated to comprise a deletion in the D sequence, which is represented by SEQ ID NO: 1 (paragraph [0093]). As shown in the alignment of the Appendix, SEQ ID NO: 1 of Li comprises 100% identity to instant SEQ ID NO: 5.
Regarding the instantly claimed enhancer sequence, McCown discloses that the rAAV vectors taught therein may comprise a variety of enhancer sequences depending on the level and tissue-specific expression desired (paragraphs [0104]-[0106]). However, McCown is silent as to the instantly claimed sequence thereof. This deficiency is cured by McDonald. McDonald discloses rAAV vectors comprising one or more enhancers (paragraphs [0068] and [0136]), wherein said enhancers include a chicken beta-actin fused early enhancer, wherein said enhancer is fused to a CMV promoter (referred to as SEQ ID NO: 44; paragraphs [0071] and [0072]). As shown in the alignment of the Appendix, SEQ ID NO: 44 of McDonald comprises 100% identity to instant SEQ ID NO: 17 and is disclosed to comprise the chicken beta-actin early enhancer.
Regarding the instantly claimed promoter sequence, McCown discloses that the rAAV vectors taught therein may comprise a variety of promoter sequences depending on the level and tissue-specific expression desired (paragraphs [0104]-[0106]). However, McCown is silent as to the instantly claimed sequence thereof. This deficiency is cured by Tretiakova, which discloses rAAV vectors comprising the chicken beta actin promoter corresponding to SEQ ID NO: 16 taught therein (paragraphs [0008] and [0060]). As shown in the alignment of the Appendix, SEQ ID NO: 16 of Tretiakova comprises 100% identity to instant SEQ ID NO: 7.
Regarding the instantly claimed exon sequence, Colloca discloses novel promoter sequences (abstract), wherein said promoter seuqences comprise a fragment of the beta-actin sequence corresponding to SEQ ID NO: 9 taught therein. As shown in the alignment of the Appendix, SEQ ID NO: 9 of Colloca comprises 100% identity to instant SEQ ID NO: 8.
Regarding the instantly claimed intron sequence corresponding to SEQ ID NO: 9, Clark discloses polynucleotides and AAV vectors providing for the expression of a transgene in neuron or glial garget cells (abstract), wherein such constructs comprise a promoter, which is itself comprised of an enhancer, a promoter, an exon, and a chimeric intron from the 5’ to 3’ end (paragraph [0135]). This architecture broadly reads on the instantly claimed construct comprising an enhancer, a promoter, and an exon. Clark teaches that SEQ ID NO: 10009 taught therein corresponds to the chimeric intron disclosed therein (paragraph [0136]). As shown in the alignment of the Appendix, SEQ ID NO: 10009 of Clark comprises 100% identity to instant SEQ ID NO: 9.
Regarding the instantly claimed intron sequence corresponding to SEQ ID NO: 10, Vandendriessche teaches therapeutic AAV constructs, wherein said constructs comprise the minute virus of mouse (MVM) intron, wherein the MVM intron corresponds to SEQ ID NO: 54 (paragraph [0032]). As shown in the alignment of the Appendix, SEQ ID NO: 54 of Vandendriessche comprises 100% identity to instant SEQ ID NO: 10.
Regarding the instantly claimed polyA sequence, Samulski further discloses that the rAAV constructs taught therein further comprise a bovine growth hormone polyA signal sequence having the sequence of SEQ ID NO: 27 (paragraphs [0009], [0014], [0020], and [0026]) to drive efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic mRNA (paragraph [0091]). As shown in the alignment of the Appendix, SEQ ID NO: 27 of Samulski comprises 100% identity to instant SEQ ID NO: 11.
Thus, the prior art teaches the claim elements not recited in the copending application.
Instant claim 18 recites “a pharmaceutical composition comprising the rAAV vector of claim 6.” Although the copending application does not claim a pharmaceutical composition comprising the rAAV vectors claimed therein, such compositions are known in the art. McCown teaches that rAAV vectors may be provided within a pharmaceutical composition (paragraphs [0187] and [0188]). Thus, the prior art teaches the claim elements not recited in the copending application.
Instant claim 19 recites “a method of treating a disease, disorder, or condition associated with deficiency or dysfunction of ASPA, the method comprising administering a therapeutically effective amount of the rAAV vector of claim 6,” wherein the treated disease is Canavan disease per instant claim 20. While the methods of the copending application are drawn to the treatment of amyotrophic lateral sclerosis (ALS), both ALS and Canavan disease are associated with deficient levels or activity of ASPA. Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in the copending application.
Instant claim 21 recites “the rAAV vector [of the method of claim 19] is administered directly to the brain and/or central nervous system,” which corresponds to copending claim and 17, which recites administration of the rAAV composition taught therein to at least a portion of the spinal cord of the subject (i.e. the CNS). Thus, the instant and copending claims are not patentably distinct.
Instant claim 22 recites “the rAAV vector [of the method of claim 19] is administered to a region of the central nervous system…or wherein the rAAV vector is administered by a method selected from the group consisting of intraparenchymal administration, intrathecal administration, intracerebroventricular administration, intracisternal magna administration, and a combination thereof.” As set forth above, Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Janson cites examples of such therapy in rats, wherein the AAV-ASPA vector was delivered intraparenchymally or intracerebroventricularly to said rats (page 1393, column 1, paragraph 4-page 1393, column 2, paragraph 1). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in the copending application.
Instant claims 24 and 25 respectively recite “an isolated host cell comprising the rAAV vector of claim 6” and “the isolated host cell of claim 24, wherein the cell is selected from the group consisting of VERO, WI38, MRC5, A549, HEK293, B-50 or any other HeLa cell, HepG2, Saos-2, HuH7, and HT1080.” Mendes discloses HEK293 cells transfected with an ASPA open reading frame (abstract), while the copending application recites an rAAV comprising said open reading frame (copending claim 19). Thus, the prior art teaches the claim elements not recited in the copending application.
Instant claim 28 recites “the isolated host cell of claim 25, wherein the cell comprises at least one nucleic acid encoding at least one protein selected from the group consisting of an AAV rep protein, an AAV capsid (Cap) protein, an adenovirus (Ad) early region 1A (E1a) protein, an Ad E1b protein, an Ad E2a protein, an Ad E4 protein and a viral associated (VA) RNA,” as set forth above, Samulski discloses therapeutic rAAV vectors. Samulski further discloses packaging cells useful for viral vector replication and packaging, wherein said packaging cells comprise genes encoding AAV Rep and Cap proteins (paragraph [0118]). Thus, the prior art teaches the claim elements not recited in the copending application.
Instant claim 29 recites “a kit for the treatment of Canavan disease (CD), comprising a therapeutically effective amount of the rAAV vector of claim 6,” while instant claim 41 further recites that the kit “comprises a label or insert including instructions for using one or more of the kit components.” As set forth above, the rAAV of instant claim 6 is not patentably distinct from the copending application. Furthermore, the recited preamble of “a kit” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Accordingly, while the copending application does not explicitly recite a kit comprising the claimed rAAV, the copending application does disclose the claimed rAAV, which is the only recited claim limitation with patentable weight at instant claim 29. Regarding the additional limitations of instant claim 41, Sah discloses therapeutic rAAV vectors encoding ASPA, wherein said rAAVs may be packaged into a kit comprising instructions for using the kit (paragraphs [0223], [0486], and [0489]). Thus, the prior art teaches the claim elements not recited in the copending application.
Given that the copending application recites a nucleic acid encoding aspartoacylase (ASPA) or a functional fragment thereof, wherein the ASPA or functional fragment thereof comprises an amino acid sequence that is at least 75% identical to the sequence of SEQ ID NO: 1, wherein said nucleic acid is carried in an rAAV, and that the cited art discloses all of the instantly claimed rAAV components, as set forth above, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the rAAV recited in the copending application per the teachings of the prior art to predictably arrive at the instant invention of a therapeutic rAAV encoding ASPA. One would have been motivated to make such a modification in order to receive the expected benefit of generating a therapeutic rAAV encoding ASPA for treatment of patients in need thereof.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 6-8, 11-14, 18-22, 24-25, 28-29, and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-8, and 11 of U.S. Patent No. 9,700,604 B2 in view of Powell et al., 2016 (hereinafter Powell; of record), US 2015/0238550 A1 (hereinafter McCown), US 2017/0128528 A1 (hereinafter Samulski), Janson et al., 2002 (hereinafter Janson), Leone et al., 2012 (hereinafter Leone), Mendes et al., 2017 (hereinafter Mendes), US 2002/0177222 A1 (hereinafter Li), US 2022/0280657 A1 (hereinafter McDonald; effectively filed 08/12/2019), US 2019/0144884 A1 (hereinafter Tretiakova), WO 2019/076892 A1 (hereinafter Colloca), US 2022/0175965 A1 (hereinafter Clark; effectively filed 12/31/2019), US 2017/0275649 A1 (hereinafter Vandendriessche), and WO 2020/028751 A2 (hereinafter Sah).
MPEP 804 II B 1 states:
The specification can be used as a dictionary to learn the meaning of a term in the patent claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999)… Further, those portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent. In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970).
The following rejections are in view of the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc, v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims.
Instant claim 6 recites “a recombinant adeno-associated virus (rAAV) vector comprising (i) a vector genome, wherein the vector genome comprises a modified nucleic acid encoding aspartoacylase (ASPA) and comprising the nucleic acid sequence of SEQ ID NO: 2 and (ii) a capsid selected from the group consisting of a capsid of Olig001, Olig002, Olig003, AAV1, AAV2, AAV3, AAV3A, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10…and AAV-LK03.” Dependent claim 7 further limits the capsid of said vector to “Olig001, an Olig002, or an Olig003 capsid.”
In comparison, claims 1 and 11 of patent ‘604 both recite “an isolated nucleic acid comprising a first sequence that encodes ASPA,” while patented claims 6 and 7 further recite that the isolated nucleic acid claimed therein is in an AAV vector comprising a regulatory element and operatively linked to a promoter. Patented claim 8 further limits the AAV vector claimed therein to an AAV2 vector, as recited at instant claim 6.
Regarding the capsid of instant dependent claim 7, Powell discloses that the Olig001 capsid is a novel AAV capsid with oligodendrocyte-preferring tropism generated using capsid shuffling and directed evolution (abstract; Figure 1; page 807, column 1, paragraph 2-page 807, column 2, paragraph 1). Thus, Powell discloses that the novel Olig001 capsid generates an AAV vector serotype with tropism for oligodendrocytes, thereby teaching the claim elements not recited in the patented application.
Instant claim 8 further limits the claimed capsid to “an Olig001 capsid comprising a viral protein 1 (VP1) and wherein the VP1 comprises the amino acid sequence of SEQ ID NO: 14.” SEQ ID NO: 14 was known in the art prior to the effective filing date of the instant application. McCown discloses chimeric AAV capsid structures capable of preferentially transducing oligodendrocytes over neurons and other cells of the CNS, wherein said AAV capsid structures correspond to SEQ ID NO: 2 and comprise VP1 capsid proteins (paragraphs [0061] and [0063]). As shown in the alignment of the Appendix, instant SEQ ID NO: 14 and SEQ ID NO: 2 of McCown are 100% identical to each other. Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 11 recites “the vector genome [of the rAAV vector of claim 6] further comprises at least one element selected from the group consisting of at least one AAV inverted terminal repeat (ITR) sequence, an enhancer, a promoter, an exon, an intron, and a poly-adenylation (polyA) signal sequence.” While the copending application does not claim these elements, these are known to be components of rAAV constructs. McCown teaches that rAAV genomes comprise at least one inverted terminal repeat at either the 3’ or 5’ end (paragraph [0055]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 12 recites “the vector genome [of the rAAV vector of claim 6] comprises at least one element selected from the group consisting of at least one AAV2 ITR, a cytomegalovirus (CMV) enhancer, a hybrid form of the CBA promoter (CBh promoter), a chicken B-actin (CBA) exon, a CBA intron, a minute virus of mice (MVM) intron and a bovine growth hormone (BGH) polyA.” While the copending application does not claim these elements, these are known components of rAAV constructs. McCown teaches that rAAV genomes may further comprise polyadenylation signals to appropriately control the expression of the heterologous nucleic acids disclosed therein (paragraph [0104]). However, McCown does not teach that these polyadenylation signals are specifically bovine growth hormone polyadenylation signals. This deficiency is cured by Samulski, which also discloses therapeutic rAAV vectors, wherein said rAAV vectors comprise control elements such as a polyA signal sequence, specifically bovine growth hormone polyA signal sequence such that said polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic RNA (paragraphs [0039] and [0091]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 13 recites “the rAAV vector of claim 6, wherein the vector genome further comprises at least one element selected from the group consisting of…a polyA comprising the nucleic acid sequence of SEQ ID NO: 11.” While the copending application does not claim this element, this is a known polyA signal sequence in the prior art. As set forth above, Samulski discloses therapeutic rAAV vectors, wherein said rAAV vectors comprise control elements such as a polyA signal sequence, specifically bovine growth hormone polyA signal sequence such that said polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic RNA (paragraphs [0039] and [0091]). An exemplary bGH polyA signal sequence is disclosed to be SEQ ID NO: 27 of Samulski (see paragraph [0014]), which comprises 100% identity to instant SEQ ID NO: 11, as shown in the alignment of the Appendix. Thus, the prior art teaches the claim elements not recited in the patented application.
With regard to claim 14, which recites “an rAAV vector comprising a vector genome comprising from 5’ to 3’:
an AAV inverted terminal repeat (ITR) comprising the nucleic acid sequence of SEQ ID NO: 5…;
an enhancer comprising the nucleic acid sequence of SEQ ID NO: 6 or SEQ ID NO: 17;
a promoter comprising the nucleic acid sequence of SEQ ID NO: 7;
an exon comprising the nucleic acid sequence of SEQ ID NO: 8 or SEQ ID NO: 18;
an intron comprising the nucleic acid sequence of SEQ ID NO: 9;
an intron comprising the nucleic acid sequence of SEQ ID NO: 10;
a modified nucleic acid encoding aspartoacylase (ASPA) comprising the nucleic acid sequence of SEQ ID NO: 2;
a polyA comprising the nucleic acid sequence of SEQ ID NO: 11; and
an AAV ITR comprising the nucleic acid sequence of SEQ ID NO: 5…”,
as set forth above, instant SEQ ID NO: 2 is not patentably distinct from the patented application, as both encode identical protein products of ASPA. Regarding the remaining claimed rAAV sequences, the prior art teaches all of these sequences.
Regarding the instantly claimed ITR sequences, Li discloses that AAV inverted terminal repeats provide for efficient excision and rescue from, and integration of a nucleotide sequence interposed between two flanking ITRs into a mammalian cell genome (paragraphs [0042] and [0043]). Li further discloses that these ITRs are preferably mutated to comprise a deletion in the D sequence, which is represented by SEQ ID NO: 1 (paragraph [0093]). As shown in the alignment of the Appendix, SEQ ID NO: 1 of Li comprises 100% identity to instant SEQ ID NO: 5.
Regarding the instantly claimed enhancer sequence, McCown discloses that the rAAV vectors taught therein may comprise a variety of enhancer sequences depending on the level and tissue-specific expression desired (paragraphs [0104]-[0106]). However, McCown is silent as to the instantly claimed sequence thereof. This deficiency is cured by McDonald. McDonald discloses rAAV vectors comprising one or more enhancers (paragraphs [0068] and [0136]), wherein said enhancers include a chicken beta-actin fused early enhancer, wherein said enhancer is fused to a CMV promoter (referred to as SEQ ID NO: 44; paragraphs [0071] and [0072]). As shown in the alignment of the Appendix, SEQ ID NO: 44 of McDonald comprises 100% identity to instant SEQ ID NO: 17 and is disclosed to comprise the chicken beta-actin early enhancer.
Regarding the instantly claimed promoter sequence, McCown discloses that the rAAV vectors taught therein may comprise a variety of promoter sequences depending on the level and tissue-specific expression desired (paragraphs [0104]-[0106]). However, McCown is silent as to the instantly claimed sequence thereof. This deficiency is cured by Tretiakova, which discloses rAAV vectors comprising the chicken beta actin promoter corresponding to SEQ ID NO: 16 taught therein (paragraphs [0008] and [0060]). As shown in the alignment of the Appendix, SEQ ID NO: 16 of Tretiakova comprises 100% identity to instant SEQ ID NO: 7.
Regarding the instantly claimed exon sequence, Colloca discloses novel promoter sequences (abstract), wherein said promoter sequences comprise a fragment of the beta-actin sequence corresponding to SEQ ID NO: 9 taught therein. As shown in the alignment of the Appendix, SEQ ID NO: 9 of Colloca comprises 100% identity to instant SEQ ID NO: 8.
Regarding the instantly claimed intron sequence corresponding to SEQ ID NO: 9, Clark discloses polynucleotides and AAV vectors providing for the expression of a transgene in neuron or glial garget cells (abstract), wherein such constructs comprise a promoter, which is itself comprised of an enhancer, a promoter, an exon, and a chimeric intron from the 5’ to 3’ end (paragraph [0135]). This architecture broadly reads on the instantly claimed construct comprising an enhancer, a promoter, and an exon. Clark teaches that SEQ ID NO: 10009 taught therein corresponds to the chimeric intron disclosed therein (paragraph [0136]). As shown in the alignment of the Appendix, SEQ ID NO: 10009 of Clark comprises 100% identity to instant SEQ ID NO: 9.
Regarding the instantly claimed intron sequence corresponding to SEQ ID NO: 10, Vandendriessche teaches therapeutic AAV constructs, wherein said constructs comprise the minute virus of mouse (MVM) intron, wherein the MVM intron corresponds to SEQ ID NO: 54 (paragraph [0032]). As shown in the alignment of the Appendix, SEQ ID NO: 54 of Vandendriessche comprises 100% identity to instant SEQ ID NO: 10.
Regarding the instantly claimed polyA sequence, Samulski further discloses that the rAAV constructs taught therein further comprise a bovine growth hormone polyA signal sequence having the sequence of SEQ ID NO: 27 (paragraphs [0009], [0014], [0020], and [0026]) to drive efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic mRNA (paragraph [0091]). As shown in the alignment of the Appendix, SEQ ID NO: 27 of Samulski comprises 100% identity to instant SEQ ID NO: 11.
Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 18 recites “a pharmaceutical composition comprising the rAAV vector of claim 6.” Although the copending application does not claim a pharmaceutical composition comprising the rAAV vectors claimed therein, such compositions are known in the art. McCown teaches that rAAV vectors may be provided within a pharmaceutical composition (paragraphs [0187] and [0188]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 19 recites “a method of treating a disease, disorder, or condition associated with deficiency or dysfunction of ASPA, the method comprising administering a therapeutically effective amount of the rAAV vector of claim 6,” wherein the treated disease is Canavan disease per instant claim 20. While the methods of the patented application are drawn to the treatment of Alzheimer’s disease, both Alzheimer’s disease and Canavan disease are associated with deficient levels or activity of ASPA. Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 21 recites “the rAAV vector [of the method of claim 19] is administered directly to the brain and/or central nervous system.” As set forth above, Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Janson cites examples of such therapy in rats, wherein the AAV-ASPA vector was delivered intraparenchymally or intracerebroventricularly (i.e. directly to the brain) to said rats (page 1393, column 1, paragraph 4-page 1393, column 2, paragraph 1). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 22 recites “the rAAV vector [of the method of claim 19] is administered to a region of the central nervous system…or wherein the rAAV vector is administered by a method selected from the group consisting of intraparenchymal administration, intrathecal administration, intracerebroventricular administration, intracisternal magna administration, and a combination thereof.” As set forth above, Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Janson cites examples of such therapy in rats, wherein the AAV-ASPA vector was delivered intraparenchymally or intracerebroventricularly to said rats (page 1393, column 1, paragraph 4-page 1393, column 2, paragraph 1). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claims 24 and 25 respectively recite “an isolated host cell comprising the rAAV vector of claim 6” and “the isolated host cell of claim 24, wherein the cell is selected from the group consisting of VERO, WI38, MRC5, A549, HEK293, B-50 or any other HeLa cell, HepG2, Saos-2, HuH7, and HT1080.” Mendes discloses HEK293 cells transfected with an ASPA open reading frame (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 28 recites “the isolated host cell of claim 25, wherein the cell comprises at least one nucleic acid encoding at least one protein selected from the group consisting of an AAV rep protein, an AAV capsid (Cap) protein, an adenovirus (Ad) early region 1A (E1a) protein, an Ad E1b protein, an Ad E2a protein, an Ad E4 protein and a viral associated (VA) RNA,” as set forth above, Samulski discloses therapeutic rAAV vectors. Samulski further discloses packaging cells useful for viral vector replication and packaging, wherein said packaging cells comprise genes encoding AAV Rep and Cap proteins (paragraph [0118]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 29 recites “a kit for the treatment of Canavan disease (CD), comprising a therapeutically effective amount of the rAAV vector of claim 6,” while instant claim 41 further recites that the kit “comprises a label or insert including instructions for using one or more of the kit components.” As set forth above, the rAAV of instant claim 6 is not patentably distinct from the copending application. Furthermore, the recited preamble of “a kit” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Accordingly, while the copending application does not explicitly recite a kit comprising the claimed rAAV, the copending application does disclose the claimed rAAV, which is the only recited claim limitation with patentable weight at instant claim 29. Regarding the additional limitations of instant claim 41, Sah discloses therapeutic rAAV vectors encoding ASPA, wherein said rAAVs may be packaged into a kit comprising instructions for using the kit (paragraphs [0223], [0486], and [0489]). Thus, the prior art teaches the claim elements not recited in the copending application.
Given that patent ‘604 recites a nucleic acid encoding aspartoacylase (ASPA), wherein said nucleic acid is carried in an AAV vector, and that the cited art discloses all of the instantly claimed rAAV components, as set forth above, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the AAV recited in patent ‘604 per the teachings of the prior art to predictably arrive at the instant invention of a therapeutic rAAV vector encoding ASPA. One would have been motivated to make such a modification in order to receive the expected benefit of generating a therapeutic rAAV encoding ASPA for treatment of patients in need thereof.
Claims 6-8, 11-14, 18-22, 24-25, 28-29, and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-8, and 11 of U.S. Patent No.11,382,961 B2 in view of Powell et al., 2016 (hereinafter Powell; of record), US 2015/0238550 A1 (hereinafter McCown), US 2017/0128528 A1 (hereinafter Samulski), Janson et al., 2002 (hereinafter Janson), Leone et al., 2012 (hereinafter Leone), Mendes et al., 2017 (hereinafter Mendes), US 2002/0177222 A1 (hereinafter Li), US 2022/0280657 A1 (hereinafter McDonald; effectively filed 08/12/2019), US 2019/0144884 A1 (hereinafter Tretiakova), WO 2019/076892 A1 (hereinafter Colloca), US 2022/0175965 A1 (hereinafter Clark; effectively filed 12/31/2019), US 2017/0275649 A1 (hereinafter Vandendriessche), and WO 2020/028751 A2 (hereinafter Sah).
MPEP 804 II B 1 states:
The specification can be used as a dictionary to learn the meaning of a term in the patent claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999)… Further, those portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent. In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970).
The following rejections are in view of the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc, v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims.
Instant claim 6 recites “a recombinant adeno-associated virus (rAAV) vector comprising (i) a vector genome, wherein the vector genome comprises a modified nucleic acid encoding aspartoacylase (ASPA) and comprising the nucleic acid sequence of SEQ ID NO: 2 and (ii) a capsid selected from the group consisting of a capsid of Olig001, Olig002, Olig003, AAV1, AAV2, AAV3, AAV3A, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10…and AAV-LK03.” Dependent claim 7 further limits the capsid of said vector to “Olig001, an Olig002, or an Olig003 capsid.”
In comparison, claims 1 and 11 of patent ‘961 both recite “an isolated nucleic acid comprising a first sequence that encodes ASPA,” while patented claims 6 and 7 further recite that the isolated nucleic acid claimed therein is in an AAV vector comprising a regulatory element and operatively linked to a promoter. Patented claim 8 further limits the AAV vector claimed therein to an AAV2 vector, as recited at instant claim 6.
Regarding the capsid of instant dependent claim 7, Powell discloses that the Olig001 capsid is a novel AAV capsid with oligodendrocyte-preferring tropism generated using capsid shuffling and directed evolution (abstract; Figure 1; page 807, column 1, paragraph 2-page 807, column 2, paragraph 1). Thus, Powell discloses that the novel Olig001 capsid generates an AAV vector serotype with tropism for oligodendrocytes, thereby teaching the claim elements not recited in the patented application.
Instant claim 8 further limits the claimed capsid to “an Olig001 capsid comprising a viral protein 1 (VP1) and wherein the VP1 comprises the amino acid sequence of SEQ ID NO: 14.” SEQ ID NO: 14 was known in the art prior to the effective filing date of the instant application. McCown discloses chimeric AAV capsid structures capable of preferentially transducing oligodendrocytes over neurons and other cells of the CNS, wherein said AAV capsid structures correspond to SEQ ID NO: 2 and comprise VP1 capsid proteins (paragraphs [0061] and [0063]). As shown in the alignment of the Appendix, instant SEQ ID NO: 14 and SEQ ID NO: 2 of McCown are 100% identical to each other. Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 11 recites “the vector genome [of the rAAV vector of claim 6] further comprises at least one element selected from the group consisting of at least one AAV inverted terminal repeat (ITR) sequence, an enhancer, a promoter, an exon, an intron, and a poly-adenylation (polyA) signal sequence.” While the copending application does not claim these elements, these are known to be components of rAAV constructs. McCown teaches that rAAV genomes comprise at least one inverted terminal repeat at either the 3’ or 5’ end (paragraph [0055]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 12 recites “the vector genome [of the rAAV vector of claim 6] comprises at least one element selected from the group consisting of at least one AAV2 ITR, a cytomegalovirus (CMV) enhancer, a hybrid form of the CBA promoter (CBh promoter), a chicken B-actin (CBA) exon, a CBA intron, a minute virus of mice (MVM) intron and a bovine growth hormone (BGH) polyA.” While the copending application does not claim these elements, these are known components of rAAV constructs. McCown teaches that rAAV genomes may further comprise polyadenylation signals to appropriately control the expression of the heterologous nucleic acids disclosed therein (paragraph [0104]). However, McCown does not teach that these polyadenylation signals are specifically bovine growth hormone polyadenylation signals. This deficiency is cured by Samulski, which also discloses therapeutic rAAV vectors, wherein said rAAV vectors comprise control elements such as a polyA signal sequence, specifically bovine growth hormone polyA signal sequence such that said polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic RNA (paragraphs [0039] and [0091]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 13 recites “the rAAV vector of claim 6, wherein the vector genome further comprises at least one element selected from the group consisting of…a polyA comprising the nucleic acid sequence of SEQ ID NO: 11.” While the copending application does not claim this element, this is a known polyA signal sequence in the prior art. As set forth above, Samulski discloses therapeutic rAAV vectors, wherein said rAAV vectors comprise control elements such as a polyA signal sequence, specifically bovine growth hormone polyA signal sequence such that said polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic RNA (paragraphs [0039] and [0091]). An exemplary bGH polyA signal sequence is disclosed to be SEQ ID NO: 27 of Samulski (see paragraph [0014]), which comprises 100% identity to instant SEQ ID NO: 11, as shown in the alignment of the Appendix. Thus, the prior art teaches the claim elements not recited in the patented application.
With regard to claim 14, which recites “an rAAV vector comprising a vector genome comprising from 5’ to 3’:
an AAV inverted terminal repeat (ITR) comprising the nucleic acid sequence of SEQ ID NO: 5…;
an enhancer comprising the nucleic acid sequence of SEQ ID NO: 6 or SEQ ID NO: 17;
a promoter comprising the nucleic acid sequence of SEQ ID NO: 7;
an exon comprising the nucleic acid sequence of SEQ ID NO: 8 or SEQ ID NO: 18;
an intron comprising the nucleic acid sequence of SEQ ID NO: 9;
an intron comprising the nucleic acid sequence of SEQ ID NO: 10;
a modified nucleic acid encoding aspartoacylase (ASPA) comprising the nucleic acid sequence of SEQ ID NO: 2;
a polyA comprising the nucleic acid sequence of SEQ ID NO: 11; and
an AAV ITR comprising the nucleic acid sequence of SEQ ID NO: 5…”,
as set forth above, instant SEQ ID NO: 2 is not patentably distinct from the patented application, as both encode identical protein products of ASPA. Regarding the remaining claimed rAAV sequences, the prior art teaches all of these sequences.
Regarding the instantly claimed ITR sequences, Li discloses that AAV inverted terminal repeats provide for efficient excision and rescue from, and integration of a nucleotide sequence interposed between two flanking ITRs into a mammalian cell genome (paragraphs [0042] and [0043]). Li further discloses that these ITRs are preferably mutated to comprise a deletion in the D sequence, which is represented by SEQ ID NO: 1 (paragraph [0093]). As shown in the alignment of the Appendix, SEQ ID NO: 1 of Li comprises 100% identity to instant SEQ ID NO: 5.
Regarding the instantly claimed enhancer sequence, McCown discloses that the rAAV vectors taught therein may comprise a variety of enhancer sequences depending on the level and tissue-specific expression desired (paragraphs [0104]-[0106]). However, McCown is silent as to the instantly claimed sequence thereof. This deficiency is cured by McDonald. McDonald discloses rAAV vectors comprising one or more enhancers (paragraphs [0068] and [0136]), wherein said enhancers include a chicken beta-actin fused early enhancer, wherein said enhancer is fused to a CMV promoter (referred to as SEQ ID NO: 44; paragraphs [0071] and [0072]). As shown in the alignment of the Appendix, SEQ ID NO: 44 of McDonald comprises 100% identity to instant SEQ ID NO: 17 and is disclosed to comprise the chicken beta-actin early enhancer.
Regarding the instantly claimed promoter sequence, McCown discloses that the rAAV vectors taught therein may comprise a variety of promoter sequences depending on the level and tissue-specific expression desired (paragraphs [0104]-[0106]). However, McCown is silent as to the instantly claimed sequence thereof. This deficiency is cured by Tretiakova, which discloses rAAV vectors comprising the chicken beta actin promoter corresponding to SEQ ID NO: 16 taught therein (paragraphs [0008] and [0060]). As shown in the alignment of the Appendix, SEQ ID NO: 16 of Tretiakova comprises 100% identity to instant SEQ ID NO: 7.
Regarding the instantly claimed exon sequence, Colloca discloses novel promoter sequences (abstract), wherein said promoter sequences comprise a fragment of the beta-actin sequence corresponding to SEQ ID NO: 9 taught therein. As shown in the alignment of the Appendix, SEQ ID NO: 9 of Colloca comprises 100% identity to instant SEQ ID NO: 8.
Regarding the instantly claimed intron sequence corresponding to SEQ ID NO: 9, Clark discloses polynucleotides and AAV vectors providing for the expression of a transgene in neuron or glial garget cells (abstract), wherein such constructs comprise a promoter, which is itself comprised of an enhancer, a promoter, an exon, and a chimeric intron from the 5’ to 3’ end (paragraph [0135]). This architecture broadly reads on the instantly claimed construct comprising an enhancer, a promoter, and an exon. Clark teaches that SEQ ID NO: 10009 taught therein corresponds to the chimeric intron disclosed therein (paragraph [0136]). As shown in the alignment of the Appendix, SEQ ID NO: 10009 of Clark comprises 100% identity to instant SEQ ID NO: 9.
Regarding the instantly claimed intron sequence corresponding to SEQ ID NO: 10, Vandendriessche teaches therapeutic AAV constructs, wherein said constructs comprise the minute virus of mouse (MVM) intron, wherein the MVM intron corresponds to SEQ ID NO: 54 (paragraph [0032]). As shown in the alignment of the Appendix, SEQ ID NO: 54 of Vandendriessche comprises 100% identity to instant SEQ ID NO: 10.
Regarding the instantly claimed polyA sequence, Samulski further discloses that the rAAV constructs taught therein further comprise a bovine growth hormone polyA signal sequence having the sequence of SEQ ID NO: 27 (paragraphs [0009], [0014], [0020], and [0026]) to drive efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic mRNA (paragraph [0091]). As shown in the alignment of the Appendix, SEQ ID NO: 27 of Samulski comprises 100% identity to instant SEQ ID NO: 11.
Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 18 recites “a pharmaceutical composition comprising the rAAV vector of claim 6.” Although the copending application does not claim a pharmaceutical composition comprising the rAAV vectors claimed therein, such compositions are known in the art. McCown teaches that rAAV vectors may be provided within a pharmaceutical composition (paragraphs [0187] and [0188]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 19 recites “a method of treating a disease, disorder, or condition associated with deficiency or dysfunction of ASPA, the method comprising administering a therapeutically effective amount of the rAAV vector of claim 6,” wherein the treated disease is Canavan disease per instant claim 20. While the methods of the patented application are drawn to the treatment of Parkinson’s disease, both Parkinson’s disease and Canavan disease are associated with deficient levels or activity of ASPA. Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 21 recites “the rAAV vector [of the method of claim 19] is administered directly to the brain and/or central nervous system.” As set forth above, Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Janson cites examples of such therapy in rats, wherein the AAV-ASPA vector was delivered intraparenchymally or intracerebroventricularly (i.e. directly to the brain) to said rats (page 1393, column 1, paragraph 4-page 1393, column 2, paragraph 1). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 22 recites “the rAAV vector [of the method of claim 19] is administered to a region of the central nervous system…or wherein the rAAV vector is administered by a method selected from the group consisting of intraparenchymal administration, intrathecal administration, intracerebroventricular administration, intracisternal magna administration, and a combination thereof.” As set forth above, Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Janson cites examples of such therapy in rats, wherein the AAV-ASPA vector was delivered intraparenchymally or intracerebroventricularly to said rats (page 1393, column 1, paragraph 4-page 1393, column 2, paragraph 1). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claims 24 and 25 respectively recite “an isolated host cell comprising the rAAV vector of claim 6” and “the isolated host cell of claim 24, wherein the cell is selected from the group consisting of VERO, WI38, MRC5, A549, HEK293, B-50 or any other HeLa cell, HepG2, Saos-2, HuH7, and HT1080.” Mendes discloses HEK293 cells transfected with an ASPA open reading frame (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 28 recites “the isolated host cell of claim 25, wherein the cell comprises at least one nucleic acid encoding at least one protein selected from the group consisting of an AAV rep protein, an AAV capsid (Cap) protein, an adenovirus (Ad) early region 1A (E1a) protein, an Ad E1b protein, an Ad E2a protein, an Ad E4 protein and a viral associated (VA) RNA,” as set forth above, Samulski discloses therapeutic rAAV vectors. Samulski further discloses packaging cells useful for viral vector replication and packaging, wherein said packaging cells comprise genes encoding AAV Rep and Cap proteins (paragraph [0118]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 29 recites “a kit for the treatment of Canavan disease (CD), comprising a therapeutically effective amount of the rAAV vector of claim 6,” while instant claim 41 further recites that the kit “comprises a label or insert including instructions for using one or more of the kit components.” As set forth above, the rAAV of instant claim 6 is not patentably distinct from the copending application. Furthermore, the recited preamble of “a kit” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Accordingly, while the copending application does not explicitly recite a kit comprising the claimed rAAV, the copending application does disclose the claimed rAAV, which is the only recited claim limitation with patentable weight at instant claim 29. Regarding the additional limitations of instant claim 41, Sah discloses therapeutic rAAV vectors encoding ASPA, wherein said rAAVs may be packaged into a kit comprising instructions for using the kit (paragraphs [0223], [0486], and [0489]). Thus, the prior art teaches the claim elements not recited in the copending application.
Given that patent ‘961 recites a nucleic acid encoding aspartoacylase (ASPA), wherein said nucleic acid is carried in an AAV vector, and that the cited art discloses all of the instantly claimed rAAV components, as set forth above, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the AAV recited in patent ‘961 per the teachings of the prior art to predictably arrive at the instant invention of a therapeutic rAAV vector encoding ASPA. One would have been motivated to make such a modification in order to receive the expected benefit of generating a therapeutic rAAV encoding ASPA for treatment of patients in need thereof.
Claims 6-8, 11-14, 18-22, 24-25, 28-29, and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-8, 11, 12, and 18-20 of U.S. Patent No.12,514,911 B2 in view of Powell et al., 2016 (hereinafter Powell; of record), US 2015/0238550 A1 (hereinafter McCown), US 2017/0128528 A1 (hereinafter Samulski), Janson et al., 2002 (hereinafter Janson), Leone et al., 2012 (hereinafter Leone), Mendes et al., 2017 (hereinafter Mendes), US 2002/0177222 A1 (hereinafter Li), US 2022/0280657 A1 (hereinafter McDonald; effectively filed 08/12/2019), US 2019/0144884 A1 (hereinafter Tretiakova), WO 2019/076892 A1 (hereinafter Colloca), US 2022/0175965 A1 (hereinafter Clark; effectively filed 12/31/2019), US 2017/0275649 A1 (hereinafter Vandendriessche), and WO 2020/028751 A2 (hereinafter Sah).
MPEP 804 II B 1 states:
The specification can be used as a dictionary to learn the meaning of a term in the patent claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999)… Further, those portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent. In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970).
The following rejections are in view of the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc, v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims.
Instant claim 6 recites “a recombinant adeno-associated virus (rAAV) vector comprising (i) a vector genome, wherein the vector genome comprises a modified nucleic acid encoding aspartoacylase (ASPA) and comprising the nucleic acid sequence of SEQ ID NO: 2 and (ii) a capsid selected from the group consisting of a capsid of Olig001, Olig002, Olig003, AAV1, AAV2, AAV3, AAV3A, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10…and AAV-LK03.” Dependent claim 7 further limits the capsid of said vector to “Olig001, an Olig002, or an Olig003 capsid.”
In comparison, claims 1 and 11 of patent ‘961 both recite “an isolated nucleic acid comprising a first sequence that encodes ASPA,” while patented claims 6, 7, 18, and 19 further recite that the isolated nucleic acid claimed therein is in an AAV vector comprising a regulatory element and operatively linked to a promoter. Patented claims 8 and 20 further limit the AAV vector claimed therein to an AAV2 vector, as recited at instant claim 6.
Regarding the capsid of instant dependent claim 7, Powell discloses that the Olig001 capsid is a novel AAV capsid with oligodendrocyte-preferring tropism generated using capsid shuffling and directed evolution (abstract; Figure 1; page 807, column 1, paragraph 2-page 807, column 2, paragraph 1). Thus, Powell discloses that the novel Olig001 capsid generates an AAV vector serotype with tropism for oligodendrocytes, thereby teaching the claim elements not recited in the patented application.
Instant claim 8 further limits the claimed capsid to “an Olig001 capsid comprising a viral protein 1 (VP1) and wherein the VP1 comprises the amino acid sequence of SEQ ID NO: 14.” SEQ ID NO: 14 was known in the art prior to the effective filing date of the instant application. McCown discloses chimeric AAV capsid structures capable of preferentially transducing oligodendrocytes over neurons and other cells of the CNS, wherein said AAV capsid structures correspond to SEQ ID NO: 2 and comprise VP1 capsid proteins (paragraphs [0061] and [0063]). As shown in the alignment of the Appendix, instant SEQ ID NO: 14 and SEQ ID NO: 2 of McCown are 100% identical to each other. Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 11 recites “the vector genome [of the rAAV vector of claim 6] further comprises at least one element selected from the group consisting of at least one AAV inverted terminal repeat (ITR) sequence, an enhancer, a promoter, an exon, an intron, and a poly-adenylation (polyA) signal sequence.” While the copending application does not claim these elements, these are known to be components of rAAV constructs. McCown teaches that rAAV genomes comprise at least one inverted terminal repeat at either the 3’ or 5’ end (paragraph [0055]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 12 recites “the vector genome [of the rAAV vector of claim 6] comprises at least one element selected from the group consisting of at least one AAV2 ITR, a cytomegalovirus (CMV) enhancer, a hybrid form of the CBA promoter (CBh promoter), a chicken B-actin (CBA) exon, a CBA intron, a minute virus of mice (MVM) intron and a bovine growth hormone (BGH) polyA.” While the copending application does not claim these elements, these are known components of rAAV constructs. McCown teaches that rAAV genomes may further comprise polyadenylation signals to appropriately control the expression of the heterologous nucleic acids disclosed therein (paragraph [0104]). However, McCown does not teach that these polyadenylation signals are specifically bovine growth hormone polyadenylation signals. This deficiency is cured by Samulski, which also discloses therapeutic rAAV vectors, wherein said rAAV vectors comprise control elements such as a polyA signal sequence, specifically bovine growth hormone polyA signal sequence such that said polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic RNA (paragraphs [0039] and [0091]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 13 recites “the rAAV vector of claim 6, wherein the vector genome further comprises at least one element selected from the group consisting of…a polyA comprising the nucleic acid sequence of SEQ ID NO: 11.” While the copending application does not claim this element, this is a known polyA signal sequence in the prior art. As set forth above, Samulski discloses therapeutic rAAV vectors, wherein said rAAV vectors comprise control elements such as a polyA signal sequence, specifically bovine growth hormone polyA signal sequence such that said polyA signal sequence drives efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic RNA (paragraphs [0039] and [0091]). An exemplary bGH polyA signal sequence is disclosed to be SEQ ID NO: 27 of Samulski (see paragraph [0014]), which comprises 100% identity to instant SEQ ID NO: 11, as shown in the alignment of the Appendix. Thus, the prior art teaches the claim elements not recited in the patented application.
With regard to claim 14, which recites “an rAAV vector comprising a vector genome comprising from 5’ to 3’:
an AAV inverted terminal repeat (ITR) comprising the nucleic acid sequence of SEQ ID NO: 5…;
an enhancer comprising the nucleic acid sequence of SEQ ID NO: 6 or SEQ ID NO: 17;
a promoter comprising the nucleic acid sequence of SEQ ID NO: 7;
an exon comprising the nucleic acid sequence of SEQ ID NO: 8 or SEQ ID NO: 18;
an intron comprising the nucleic acid sequence of SEQ ID NO: 9;
an intron comprising the nucleic acid sequence of SEQ ID NO: 10;
a modified nucleic acid encoding aspartoacylase (ASPA) comprising the nucleic acid sequence of SEQ ID NO: 2;
a polyA comprising the nucleic acid sequence of SEQ ID NO: 11; and
an AAV ITR comprising the nucleic acid sequence of SEQ ID NO: 5…”,
as set forth above, instant SEQ ID NO: 2 is not patentably distinct from the patented application, as both encode identical protein products of ASPA. Regarding the remaining claimed rAAV sequences, the prior art teaches all of these sequences.
Regarding the instantly claimed ITR sequences, Li discloses that AAV inverted terminal repeats provide for efficient excision and rescue from, and integration of a nucleotide sequence interposed between two flanking ITRs into a mammalian cell genome (paragraphs [0042] and [0043]). Li further discloses that these ITRs are preferably mutated to comprise a deletion in the D sequence, which is represented by SEQ ID NO: 1 (paragraph [0093]). As shown in the alignment of the Appendix, SEQ ID NO: 1 of Li comprises 100% identity to instant SEQ ID NO: 5.
Regarding the instantly claimed enhancer sequence, McCown discloses that the rAAV vectors taught therein may comprise a variety of enhancer sequences depending on the level and tissue-specific expression desired (paragraphs [0104]-[0106]). However, McCown is silent as to the instantly claimed sequence thereof. This deficiency is cured by McDonald. McDonald discloses rAAV vectors comprising one or more enhancers (paragraphs [0068] and [0136]), wherein said enhancers include a chicken beta-actin fused early enhancer, wherein said enhancer is fused to a CMV promoter (referred to as SEQ ID NO: 44; paragraphs [0071] and [0072]). As shown in the alignment of the Appendix, SEQ ID NO: 44 of McDonald comprises 100% identity to instant SEQ ID NO: 17 and is disclosed to comprise the chicken beta-actin early enhancer.
Regarding the instantly claimed promoter sequence, McCown discloses that the rAAV vectors taught therein may comprise a variety of promoter sequences depending on the level and tissue-specific expression desired (paragraphs [0104]-[0106]). However, McCown is silent as to the instantly claimed sequence thereof. This deficiency is cured by Tretiakova, which discloses rAAV vectors comprising the chicken beta actin promoter corresponding to SEQ ID NO: 16 taught therein (paragraphs [0008] and [0060]). As shown in the alignment of the Appendix, SEQ ID NO: 16 of Tretiakova comprises 100% identity to instant SEQ ID NO: 7.
Regarding the instantly claimed exon sequence, Colloca discloses novel promoter sequences (abstract), wherein said promoter sequences comprise a fragment of the beta-actin sequence corresponding to SEQ ID NO: 9 taught therein. As shown in the alignment of the Appendix, SEQ ID NO: 9 of Colloca comprises 100% identity to instant SEQ ID NO: 8.
Regarding the instantly claimed intron sequence corresponding to SEQ ID NO: 9, Clark discloses polynucleotides and AAV vectors providing for the expression of a transgene in neuron or glial garget cells (abstract), wherein such constructs comprise a promoter, which is itself comprised of an enhancer, a promoter, an exon, and a chimeric intron from the 5’ to 3’ end (paragraph [0135]). This architecture broadly reads on the instantly claimed construct comprising an enhancer, a promoter, and an exon. Clark teaches that SEQ ID NO: 10009 taught therein corresponds to the chimeric intron disclosed therein (paragraph [0136]). As shown in the alignment of the Appendix, SEQ ID NO: 10009 of Clark comprises 100% identity to instant SEQ ID NO: 9.
Regarding the instantly claimed intron sequence corresponding to SEQ ID NO: 10, Vandendriessche teaches therapeutic AAV constructs, wherein said constructs comprise the minute virus of mouse (MVM) intron, wherein the MVM intron corresponds to SEQ ID NO: 54 (paragraph [0032]). As shown in the alignment of the Appendix, SEQ ID NO: 54 of Vandendriessche comprises 100% identity to instant SEQ ID NO: 10.
Regarding the instantly claimed polyA sequence, Samulski further discloses that the rAAV constructs taught therein further comprise a bovine growth hormone polyA signal sequence having the sequence of SEQ ID NO: 27 (paragraphs [0009], [0014], [0020], and [0026]) to drive efficient addition of a poly-adenosine “tail” at the 3’ end of a eukaryotic mRNA (paragraph [0091]). As shown in the alignment of the Appendix, SEQ ID NO: 27 of Samulski comprises 100% identity to instant SEQ ID NO: 11.
Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 18 recites “a pharmaceutical composition comprising the rAAV vector of claim 6.” Although the copending application does not claim a pharmaceutical composition comprising the rAAV vectors claimed therein, such compositions are known in the art. McCown teaches that rAAV vectors may be provided within a pharmaceutical composition (paragraphs [0187] and [0188]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 19 recites “a method of treating a disease, disorder, or condition associated with deficiency or dysfunction of ASPA, the method comprising administering a therapeutically effective amount of the rAAV vector of claim 6,” wherein the treated disease is Canavan disease per instant claim 20. While the methods of the patented application are drawn to the treatment of Huntington’s disease, both Huntington’s disease and Canavan disease are associated with deficient levels or activity of ASPA. Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Additionally, patented claim 12 recites administration directly to the cerebral cortex, intracranial white matter, basal ganglia, thalamus, hypothalamus, brain stem, and cerebellum.
Instant claim 21 recites “the rAAV vector [of the method of claim 19] is administered directly to the brain and/or central nervous system.” As set forth above, Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Janson cites examples of such therapy in rats, wherein the AAV-ASPA vector was delivered intraparenchymally or intracerebroventricularly (i.e. directly to the brain) to said rats (page 1393, column 1, paragraph 4-page 1393, column 2, paragraph 1). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 22 recites “the rAAV vector [of the method of claim 19] is administered to a region of the central nervous system…or wherein the rAAV vector is administered by a method selected from the group consisting of intraparenchymal administration, intrathecal administration, intracerebroventricular administration, intracisternal magna administration, and a combination thereof.” As set forth above, Janson discloses that Canavan disease is a monogenetic, autosomal recessive disease in which the gene coding for ASPA is defective, thereby leading to an increase in N-acetyl-aspartate, which impairs normal myelination and results in spongiform degermation of the brain. Janson further discloses that administration of an rAAV comprising the ASPA gene is capable of treating Canavan disease in the human brain (abstract). Janson cites examples of such therapy in rats, wherein the AAV-ASPA vector was delivered intraparenchymally or intracerebroventricularly to said rats (page 1393, column 1, paragraph 4-page 1393, column 2, paragraph 1). Leone discloses that the human therapy disclosed in Janson also showed success at long-term follow up (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claims 24 and 25 respectively recite “an isolated host cell comprising the rAAV vector of claim 6” and “the isolated host cell of claim 24, wherein the cell is selected from the group consisting of VERO, WI38, MRC5, A549, HEK293, B-50 or any other HeLa cell, HepG2, Saos-2, HuH7, and HT1080.” Mendes discloses HEK293 cells transfected with an ASPA open reading frame (abstract). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 28 recites “the isolated host cell of claim 25, wherein the cell comprises at least one nucleic acid encoding at least one protein selected from the group consisting of an AAV rep protein, an AAV capsid (Cap) protein, an adenovirus (Ad) early region 1A (E1a) protein, an Ad E1b protein, an Ad E2a protein, an Ad E4 protein and a viral associated (VA) RNA,” as set forth above, Samulski discloses therapeutic rAAV vectors. Samulski further discloses packaging cells useful for viral vector replication and packaging, wherein said packaging cells comprise genes encoding AAV Rep and Cap proteins (paragraph [0118]). Thus, the prior art teaches the claim elements not recited in the patented application.
Instant claim 29 recites “a kit for the treatment of Canavan disease (CD), comprising a therapeutically effective amount of the rAAV vector of claim 6,” while instant claim 41 further recites that the kit “comprises a label or insert including instructions for using one or more of the kit components.” As set forth above, the rAAV of instant claim 6 is not patentably distinct from the copending application. Furthermore, the recited preamble of “a kit” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Accordingly, while the copending application does not explicitly recite a kit comprising the claimed rAAV, the copending application does disclose the claimed rAAV, which is the only recited claim limitation with patentable weight at instant claim 29. Regarding the additional limitations of instant claim 41, Sah discloses therapeutic rAAV vectors encoding ASPA, wherein said rAAVs may be packaged into a kit comprising instructions for using the kit (paragraphs [0223], [0486], and [0489]). Thus, the prior art teaches the claim elements not recited in the copending application.
Given that patent ‘911 recites a nucleic acid encoding aspartoacylase (ASPA), wherein said nucleic acid is carried in an AAV vector, and that the cited art discloses all of the instantly claimed rAAV components, as set forth above, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the AAV recited in patent ‘911 per the teachings of the prior art to predictably arrive at the instant invention of a therapeutic rAAV vector encoding ASPA. One would have been motivated to make such a modification in order to receive the expected benefit of generating a therapeutic rAAV encoding ASPA for treatment of patients in need thereof.
Allowable Subject Matter
As previously set forth, the prior art does not disclose or otherwise fairly teach or suggest the sequence of instant SEQ ID NO: 2. The double patenting rejections set forth above are the only remaining rejections of record and overcoming the double patenting rejection, such as by filing a proper terminal disclaimer(s), would result in allowability of the claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-F 8-5.
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/SARAH E ALLEN/Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
