DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/25/2026 has been entered.
Claim Status
Claims 5-6, 10-12, 15-16, 19-20 are cancelled. Claims 1, 13 are amended. Claims 22-23 are new.
Claims 1-4, 7-9, 13-14, 17-18, 21-23 are examined on the merits.
Priority
The application is a continuation of International Patent Application No. PCT/EP2020/075871, filed September 16, 2020, which claims priority to European Patent Application No. 19197533.3 filed September 16, 2019.
Withdrawn Rejections
The rejection of claims 1-4, 7-9, 13-14, 17-18, 21 under 35 U.S.C. 103, are withdraw in view of Applicant’s arguments and amendments of the claims in the reply filed 02/25/2026.
The rejection of claims 5-6, 11, 15-16, 19-20 under 35 U.S.C 103, is moot in view of the cancellation of the claims in the reply filed 02/25/2026.
The rejection of claims 1-3, 7, 9, 13, 17, 21 under the nonstatutory double patenting rejection are withdrawn in view of Applicant’s amendments of the claims in the reply filed 02/25/2026.
The rejection of claims 5-6, 15-16, 19-20 under the nonstatutory double patenting rejection is moot in view of the cancellation of the claims in the reply filed 02/25/2026.
New Rejections necessitated by Claim Amendments
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 7-8, 13-14, 17-18, 21-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a repeat expansion disorder, wherein the repeat expansion disorder is Huntington’s disease, and wherein the repeat expansion disorder produces a transcript containing an exon 1 having a CAG repeat and a missplicing 3’ from the repeat expansion, the method comprising administering a recombinant adeno-associated virus (AAV) vector comprising i) an AAV capsid protein, and ii) a vector genome comprising a polynucleotide comprising SEQ ID NO: 9, wherein the polynucleotide targets the exon 1, is complementary to a target sequence in the exon 1 that is 5’ from the repeat expansion, and induces a reduction of the misspliced transcript and full length transcript, and wherein the polynucleotide is comprised in a pri-mi-RNA scaffold, does not reasonably provide enablement for treating any other repeat expansion disorder or for methods with vector genomes comprising SEQ ID NO: 10. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404: Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The instant claim 1 is drawn to a method of treating a repeat expansion disorder, wherein the repeat expansion disorder produces a transcript containing an exon 1 having a CAG repeat and a missplicing 3' from the repeat expansion, the method comprising administering a recombinant adeno-associated virus (AAV) vector comprising i) an AAV5 capsid protein, and ii) a vector genome comprising a polynucleotide comprising SEQ ID NO: 10, wherein the polynucleotide targets the exon 1, is complementary to a target sequence in the exon 1 that is 5' from the repeat expansion, and induces a reduction of the misspliced transcript and full length transcript, and wherein the polynucleotide is comprised in a pri-mi-RNA scaffold. The nature of the claim is complicated, because the claim requires the outcome of treating a repeat expansion disorder targeting exon 1 having CAG repeat, yet the claim is drawn to administering a genetic construct encoding SEQ ID NO 10 that targets CAG repeat expansion in huntingtin gene (no other CAG repeat expansion disorder). The instant claim 13 is drawn to a method for reducing a repeat expansion disorder transcript resulting in a missplicing 3' from a repeat expansion in a subject in need thereof; the method comprising administering to the subject a recombinant adeno-associated virus (AAV) vector comprising i) an AAV5 capsid protein, and ii) a vector genome comprising a polynucleotide comprising SEQ ID NO: 10, wherein the polynucleotide targets an exon 1 having a repeat expansion, is complementary to a target sequence in the exon 1 that is 5' from the repeat expansion, and induces a reduction of the misspliced transcript and full length transcript, and wherein the polynucleotide is comprised in a pri-mi-RNA scaffold. The nature of the claim is complicated, because the claim requires the outcome of reducing a repeat expansion disorder transcript, yet the claim is drawn to administering a genetic construct encoding SEQ ID NO 10 that targets CAG repeat expansion in huntingtin gene (no other repeat expansion disorder).
Breadth of the claims: The claims encompass a method for treating repeat expansion disorder comprising administering to the subject a recombinant AAV5 vector comprising a polynucleotide SEQ ID NO 10 that targets exon 1 of the huntingtin gene, that induces the reduction of the misspliced transcript and the full length transcript. The claims are broad with respect to the treatment of a CAG repeat expansion disorder or any repeat expansion disorder including, but not limited to disease recited in dependent claim 9.
The claims are broad with respect to the treatment of a CAG repeat expansion disorder present in exon 1 and to any repeat expansion disorder. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification envisions a polynucleotide for use in the treatment of a repeat expansion disorder is provided, wherein said repeat expansion is a CAG repeat, wherein said repeat expansion disorder results in missplicing 3' from said repeat expansion, producing a misspliced transcript, and wherein said polynucleotide is capable of inducing a reduction of said misspliced transcript. Preferably, such a CAG repeat is comprised in an exon. More preferably, said polynucleotide provided for use in the treatment of a repeat expansion disorder in accordance with the invention, comprises a use wherein said misspliced transcripts contain an exon comprising the CAG repeat and containing an intron sequence which is 3' and adjacent from said exon with the CAG repeat. Most preferably, said CAG repeat is in-frame with the reading frame of the encoded protein. As described above, repeat expansions, such as a CAG repeat, when e.g. contained in an exon sequence, can cause missplicing, i.e. cause splice donor site to not be utilized. For example, when a CAG repeat is comprised in exon 1 (as is the case in Huntington's disease), the splice donor of a subsequent (e.g., line 22, page 8). The specification envisions a polynucleotide for use in accordance with the invention is provided, being for use in the treatment of a CAG repeat expansion disorder, and wherein
said misspliced transcript that is reduced comprises an exon comprising the CAG repeat and containing an intron sequence which is 3' and adjacent from said exon with the CAG repeat, said misspliced transcripts further comprise a poly A 3' adjacent to said intron sequence. As described above, it is understood that because of a repeat expansion, transcription, splicing
and/or polyadenylation may be affected due to an expanded repeat sequence (e.g., line 5, page 9). The specification envisions reduction of misspliced transcripts preferably comprises the use of a polynucleotide that is complementary to said misspliced transcript. With regard to complementarity of a polynucleotide to the misspliced transcripts it is understood that complementarity means that nucleotides of the polynucleotide form base pairs with a target sequence comprised within said misspliced transcript. Hence, a polynucleotide is designed such that it targets a sequence within said misspliced transcript. In this context, reference can also be made to sequence-specifically targeting misspliced transcripts (e.g., line 7, page 10). The specification envisions the complementarity can also be substantial, i.e. it may not be required to have the polynucleotide and target sequence to be fully complementary. In a further embodiment, the complementarity between the polynucleotide and the target sequence consists of having no mismatches, one mismatched
nucleotide, or two mismatched nucleotides. It is understood that one mismatched nucleotide means that over the entire length of the polynucleotide that base pairs with the target sequence one nucleotide does not base pair with the target nucleotide. The length of the target nucleotide comprised within the misspliced transcript may be in the range of 13-25 nucleotides. Accordingly, the length of the polynucleotide in accordance with the invention may have the same length as the target nucleotide. In a further embodiment, the polynucleotide for use in the treatment of a repeat expansion disorder in accordance with the invention is complementary to said misspliced transcripts and said complementarity is 5' from the repeat expansion. Targeting a sequence 5' from the expanded repeat sequence may ensure that whatever missplicing occurs downstream from the expanded repeat sequence, the misspliced transcripts produced are efficiently reduced. Concomitantly, any transcripts which have not underwent missplicing may be reduced as well (e.g., line 10, page 10). The specification envisions the polynucleotide in accordance with the invention may be an antisense oligonucleotide or comprised in a double stranded RNA capable of inducing RNA interference. In one embodiment, the polynucleotide in accordance with the invention is an
anti sense oligonucleotide. Anti sense oligonucleotides are well known in the art ( e.g. inotersen and volanesorsen (Ionis) are antisense oligonucleotides that have been approved for human use), likewise, target sequences can be selected and polynucleotides designed in accordance
with the invention to target misspliced transcripts. Such antisense oligonucleotides can include RNA and/or DNA nucleotides. Such antisense nucleotides can include synthetic nucleotides. Such polynucleotides may have modifications that provide stability to the polynucleotide (e.g. extend half-life), can increase affinity to its target sequence and/or enhance delivery. In one embodiment, the polynucleotide in accordance with the invention is comprised in a double stranded RNA capable of inducing RNA interference. Double stranded RNA capable of inducing RNA interference can also be utilized and a polynucleotide in accordance with the invention can be designed to target misspliced transcripts. RNA interference may be
preferred as it can easily be employed using a gene therapy approach that can provide for a durable reduction of misspliced transcripts e.g., lines 5-22). The specification envisions a polynucleotide for use in the treatment of an expanded repeat disorder in accordance with the invention is provided, wherein said misspliced transcript encodes a polyQ protein and wherein said polynucleotide induces a reduction of said polyQ protein encoded by said misspliced transcript. For example, CAG repeat expansions contained in frame within a misspliced transcript, e.g. within an exon sequence,
when targeted, reduce the levels of said polyQ protein. Such a polyQ protein may also be a truncated polyQ protein, i.e. meaning that the amino acid sequence length is shorter as compared with a non-misspliced transcript (e.g., line 21, page 17). The specification envisions Examples of expanded repeat disorders that can produce a polyQ protein from a
misspliced transcript include e.g. Huntington disease or Spinocerebellar Ataxia Type 3 (SCA3) (schematically depicted in Figures 1, 2 and Figure 10). Genes having expanded repeats that cause disease may be referred to as mutant genes, producing mutant transcripts and mutant protein, e.g. in case of Huntington disease, one may refer to a mutant HTT gene,
mutant HTT transcripts, and mutant HTT protein, likewise, in case of an expansion in ataxin-3 causing SCA3, one may refer to a mutant ataxin-3 gene, transcript or protein. Hence, reducing a transcript produced from a gene with a repeat expansion, i.e. causing a disease or disorder, may also be referred to as reducing a mutant transcript. In Huntington disease, the
expanded repeat sequence allows for the utilization of a cryptic polyadenylation site within intron 1, resulting in alternative transcripts which are misspliced, i.e. splicing is incomplete and intron 1 splicing does not occur. Truncated transcripts are formed which have terminated in a cryptic poly A signal within the intron sequence adjacent to the exon 1 containing the expanded repeat. The truncated transcript is translated into a truncated poly Q protein, comprising the sequence of the exon with the expanded polyQ followed by the sequence encoded by the sequence of the adjacent intron (e.g., lines 34, page 17, line 1, page 18). The specification envision the most preferably said polynucleotide targeting said target sequence 5'GGCCUUCGAGUCCCUCAAGUCCUU-3' (SEQ ID NO. 8) (ensembl.org transcript HTT-201 (Human Transcript) ENST00000355072.10 Exon 1 mRNA position 172-195) comprises or consists of 5'- AAGGACUUGAGGGACUCGAAGA-3' (SEQ ID NO. 9) or 5'- AAGGACUUGAGGGACUCGAAG-3' (SEQ ID NO. 10). It is understood that said sequences represent RNA The corresponding DNA comprises the same sequence but instead of a U (uracil) list a T (thymine). Said polynucleotide preferably being comprised in a miRNA scaffold, such as a miRNA scaffold derived from miR451, and as described in WO2016102664 (incorporated herein by reference) and as described in the examples. Preferably said miRNA scaffold comprises 5' AAGGACUUGAGGGACUCGAAGA-3'
(SEQ ID NO. 9). The specification envisions the polynucleotide for use in the treatment of a repeat expansion disorder in accordance with the invention, includes the use in the treatment of Huntington Disease, said polynucleotide inducing a reduction of misspliced mutant HTT transcripts, wherein the exon with the CAG repeat expansion is exon I of mutant HTT and the intron sequence which is 3' and adjacent therefrom is from intron 1 of mutant HTT. It is understood that said misspliced mutant HTT transcripts (or aberrant mutant HTT transcripts) have terminated in intron 1. The transcript that is thus produced from a mutant HTT gene does not comprise exon 2 sequences or further HTT exon or intron sequences that are encoded by the HTT gene and are 3' to the intron 1 encoding sequence. Such a misspliced mutant HTT transcript (or aberrant mutant HTT transcript) comprises an exon 1 sequence with the expanded repeat and a part of intron 1 until a cryptic poly A site (e.g., line 17, page 24). The specifications envisions a gene delivery vector for use in accordance to the invention, wherein said gene delivery vector is a virus derived particle, most preferably wherein said gene delivery vehicle is an AA V based particle. AAV-based gene delivery of polynucleotides of the invention comprised in the miR45 l scaffold are denoted as AAV miQURE. For example, AAV-based gene delivery of a polynucleotide targeting the huntingtin gene that is associated with Huntington Disease and comprised in the miR45 l scaffold is denoted as AAV-miHTT (e.g., line 3, page 31).
The working examples, does teach treatment of Huntington’s disease, the working example disclose the use of AAV vectors based on the AAV5 serotype carrying the RNA sequence that is complementary to HTT, comprised in a miRNA scaffold, corresponds respectively with 5'- AAGGACUUGAGGGACUCGAAGA-3' (SEQ ID NO. 9) (SEQ ID NO 9 has an additional “A” at the 3’ end of SEQ ID NO 10) (e.g., lines 11-21, page 36). Mouse models used in these experiments include wildtype (WT), Ql 75KI (QI 75 HET KI) and Ql 75FDN (Ql 75 HOM KI). Both models have inserted the human exon 1 sequence with 175 CAG repeats (e.g., line 34, page 36 to 37; Fig. 3A). Ql 75 HET KI mice were bilaterally injected into the striatum at 3 months of age and followed until sacrifice after 12 months post-injection (Q 175 HET KI study 1) or at 5 months of age and sacrificed 2 months post-injection (Ql 75 HET KI study 3). The non- treated mice were injected with formulation buffer (PBS+ 5% Sucrose), treated mice were injected with AAV-miHTT with low dose (5.2x109 genome copies/mouse) or high dose (1.3x1011 genomes copies/mouse) (e.g., line 2, page 37; Fig. 2).
The working examples disclose dose-dependent lowering of both full-length HTT and mis-spliced Exon 1 HTT mRNAs in the striatum and cortex in QI 75 HOM KI mice. In other words, we confirmed that AAV-delivered miHTT can target and significantly lower the mis-spliced Exon 1 HTT mRNA in vivo, providing an important therapeutic advantage. (e.g., line 17; Fig. 9). Similarly, the working example disclose the lowering of exon 1 HTT mRNA and protein in frontal cortex of Ql 75 KI HET mice at 2 months after intrastriatal treatment of AAV-miHTT (e.g., line 33, page 51; Fig. 11).
Predictability and state of the art: The state of the art with respect to treating repeat expansion disorders is under developed and unpredictable. Zain et al. (Neurotherapeutics, 2019) teaches that Nucleotide repeat disorders encompass more than 30 diseases, most of which show dominant inheritance, such as Huntington’s disease, spinocerebellar ataxias, and myotonic dystrophies. Yet others, including Friedreich’s ataxia, are recessively inherited. A common feature is the presence of a DNA tandem repeat in the disease-associated gene and the propensity of the repeats to expand in germ and in somatic cells, with ensuing neurological and frequently also neuromuscular defects (e.g., abstract). Zain teaches that the most studied are trinucleotide repeat (TNRs) sequences; however, larger repeats also exist in the human genome, such as tetra-, penta-, and hexanucleotide repeats. Expanded repeat sequences are found in both coding and non-coding gene regions, and some examples are shown in Table 1 (e.g., right column, paragraph 1st).
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Zain teaches that expansion of CAG•CTG repeats is the hallmark of a number of different NRDs. The location of these sequences within the open reading frame of the corresponding disease genes varies and the biological pathways leading to phenotypes are different. However, CAG•CTG repeat expansion results in most cases in the production of toxic RNA and/or protein containing polyglutamine tracts. We have limited the scope of this review to include only the following CAG-related diseases: Huntington’s disease (HD), myotonic dystrophy type 1 and 2 (DM1 and DM2), and spinocerebellar ataxias 1, 2, and 3 (SCA 1, 2, and 3). Huntington’s disease is an autosomal dominant disorder characterized by progressive degeneration of nerve cells in the brain leading to movement, cognitive, and psychological impairment. CAG expansion in exon 1 of the Huntingtin (HTT) gene results in toxic mutant (mutHTT) RNA and protein (e.g., left column, paragraph 1st). Tabrizi et al. (The Lancet, 2022) teaches the potential interventions for Huntington’s disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement (e.g., abstract). Tabrizi teaches clinical trials of AAV-mediated RNAi therapy in Huntington’s disease are already underway. The AMT-130 trial (NCT04120493) is evaluating the safety, tolerability, and efficacy of bilateral intrastriatal injections of AAV5-miHTT on CSF biomarkers in patients with early-stage Huntington’s disease. AAV5-miHTT is an engineered AAV5 vector-expressing miRNA that targets total huntingtin. AAV5-miHTT is injected using MRI guided convection-enhanced delivery. Another program for AAV-delivered anti-huntingtin RNAi therapy (VY-HTT01). This program is currently on hold, pending development of more efficient viral delivery. A third AAV clinical trial in Huntington’s disease is currently being planned to evaluate an AAV1-delivered anti-HTT miRNA that has shown promising results in non-human primate models (e.g., right column, paragraph 3rd, page 650). Tabrizi teaches that animal studies and case reports suggest that partial lowering of wild-type huntingtin (up to 50%) in the healthy adult brain is likely to be safe.1 However, the long-term effects of decreasing total amounts of huntingtin (both wild-type huntingtin and mutant huntingtin) in the brains of patients with Huntington’s disease are unknown. By contrast, allele-selective approaches do not lead to the potential side-effects caused by impairing the physiological function of the wild-type protein. However, the current allele-selective approaches have some limitations, such as their inability to target all individuals with Huntington’s disease by using single nucleotide polymorphism (SNP)-related approaches3 and the potential for some CAG-targeting therapies to decrease the transcription of other genes sharing similar sequences (e.g., left column, paragraph 2nd, page 647).
Thus, the teachings of the post-filing art are consistent with the prior art demonstrating the underdeveloped and unpredictable nature of the invention.
Amount of experimentation necessary: Repeat expansion disorders are highly complex, involving different genes with different etiologies and gene-based therapies are still in developmental stages. It would require a large amount of experimentation to make use of AAV5 carrying SEQ ID NO 10 for treatment of all repeat expansion disorders.
For a specific gene therapy to be efficacious, it would require to address: (1) the specific means of AAV5-SEQ ID NO 10 for treatment of repeat expansion disorders: delivery, expression, activity, (2) to define the specific dosage of therapeutic molecules delivered to the cells or to the subjects in time course, (3) the potential deleterious effect of decreasing total amounts of huntingtin (both wild-type huntingtin and mutant huntingtin) in the brains of patients with Huntington’s disease or other repeat expansion disorders.
In view as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1-4, 7-8, 13-14, 17-18, 21-23 are not considered to be enabled by the instant disclosure.
In view of the breadth of the claims, the lack of guidance provided by the specification, the lack of the predictability of the art to which the invention pertains, undue amount of experimentation would be required to make and use the claimed invention to treat repeat expansion disorders in a subject, with a reasonable expectation of success. Because the specification does not contain a detailed description of how to make and use the method based on administration of pharmaceutical composition comprising the claimed AAV5 vector encoding the SEQ ID NO 10, according to the invention, and absent working examples that provide evidence that is reasonably predictive of the ability of treating repeat expansion disorders, the claim is not enabled commensurate in scope with the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 7-9, 13-14, 17-18, 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Konstantinova et al (“Konstantinova”, US 2017/0355989 A1) in view of Neueder et al. (“Neueder”, Scientific Report, 2017, 7:1307, cited as reference A13 in IDS filed 03/15/2022 ) and Sah et al. (“Sah”, WO 2017 /201258 A1).
This rejection is made to address the amendment to the claims in the reply filed 02/25/2026.
Regarding claims 1, 7, 13, 17, 21-23, Konstantinova teaches a double stranded RNA is for use in inducing RNAi against Huntingtin exon 1 sequences. The double stranded RNA of to the invention was capable of reducing neuronal cell death and huntingtin aggregates in an animal model (e.g., abstract). Konstantinova teaches that Huntington's disease is a genetic neurodegenerative disorder caused by a genetic mutation in the huntingtin gene. The genetic mutation involves a DNA segment of the huntingtin gene known as the CAG trinucleotide repeat. Normally, the CAG segment in the huntingtin gene of humans is repeated multiple times, i.e. about 10-35 times. People that develop Huntington's disease have an expansion of the number of CAG repeats in at least one allele (e.g., paragraph 001; Fig. 1 [see below]).
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Konstantinova teaches the selected double stranded RNA of the current invention was found to be effective in reducing huntingtin gene expression. The double stranded RNA when provided in a cell, either directly via transfection or indirectly via delivery of DNA (e.g. transfection) or via vector-mediated expression upon which the said double stranded RNA can be expressed, is capable of reducing expression of both a mutated huntingtin gene and a normal huntingtin gene (e.g., paragraph 0004). Konstantinova teaches for the medical use of a double stranded RNA according to the invention, such as the treatment or Huntington's disease, wherein such medical use may also comprise an expression cassette or a viral vector, such as AAV5, capable of expressing the said double stranded RNA of the invention (e.g., paragraph 0005). Konstantinova teaches Examples of pri/pre-miRNA scaffold for miH12 pre-miH12-155 (SEQ ID NO.44) and premiH12-451 scaffold (e.g., paragraph 0007; Fig. 2).
Konstantinova does not teach a repeat expansion resulting in missplicing 3’ from the repeat expansion, as is required by instant claims 1-3, 9, 14, 18. Konstantinova does not teach SEQ ID NO 9, as required by the instant claims. However, this is cured by Neueder and Sah.
Regarding claims 1-2, 9, 18, Neueder teaches a messenger RNA of huntingtin that is incompletely spliced (misspliced transcript), generating a short huntingtin exon1 mRNA in fibroblast and brain regions of Huntington’s disease patients, comprising huntingtin exon 1, including CAG repeat expansion and the 5′ sequence of intron 1 leading to the production of the highly pathogenic exon 1 huntingtin protein (e.g., abstract; paragraph 2nd, page 2; Fig. 1A-D [see below]; Fig. 2A-D).
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Regarding claim 3, Neueder teaches a huntingtin exon 1 mRNA (misspliced transcript) that utilize the cryptic polyA site located at 7327 bp into HTT intron 1 (7327 site) (e.g., paragraph 1st, page 3; Fig. 1A-D).
Regarding claim 8, Neueder conclude that the extremely pathogenic exon 1 HTT fragment is generated by incomplete splicing in a polyglutamine-length dependent manner in HD patients. This finding will have important implications for strategies to lower mutant HTT levels in patients (e.g., paragraph 1st, page 2).
Sah teaches methods for treating neurodegenerative diseases
such as Huntington's Disease are also included in the present invention. The siRNAs included in the compositions featured herein encompass a dsRNA having an ,antisense strand (that is 30 nucleotides or less, generally 19-24 nucleotides in length), that is substantially complementary to at least part of an mRNA transcript of the mutated HTT gene (e.g., paragraph 0008). Sah teaches SEQ ID NO 42 that has 100% identity with SEQ ID NO 9, of the instant claims (e.g., Table 1, see alignment below]).
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Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Konstantinova an AVV5 vector carrying a dsRNA for reducing expression of both a mutated huntingtin gene and a normal huntingtin gene in a subject, with the teachings of Neueder the extremely pathogenic exon 1 HTT fragment is generated by incomplete splicing in a polyglutamine-length dependent manner in HD patients and the teachings of Sah the SEQ ID NO 42 for targeting the huntingtin gene; for someone skilled in the art would have been obvious to use both teachings to achieve the predictable result of obtaining a composition suitable for treating Huntington’s disease with an AAV5 vector carrying a dsRNA capable of inhibiting wild type and pathogenic huntingtin transcripts.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to treat Huntington’s disease patients, by lowering the mRNA transcript of the mutated huntingtin gene.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-4, 7-9, 13-14, 17-18, 21-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9, 11-17, 20, of U.S. Patent No. 11,371,044 (“044”) in view of Neueder et al. (“Neueder”, Scientific Report, 2017, 7:1307, cited as reference A13 in IDS filed 03/15/2022 ), Konstantinova et al (“Konstantinova”, US 2017/0355989 A1) and Sah et al. (“Sah”, WO 2017 /201258 A1).
This rejection is made to address the amendment to the claims in the reply filed 02/25/2026.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are a variation of “044”, the patent claims are drawn to a method of reducing or delaying symptoms of Huntington's disease in a human subject carrying at least one Huntingtin allele with an abnormal number of CAG repeats, the method comprising administering to the subject a viral 5 vector encoding a double stranded RNA comprising a first RNA sequence and a second RNA sequence. The difference is that the some of the dependent claims include repeat expansion resulting in missplicing 3’ from the repeat expansion, encoding a truncated poly-glutamine protein. However, one of ordinary skill in the art would recognize that he/she could use SEQ ID NO 9 for reduction of both a misspliced transcript and the full length transcript, then it is obvious that the instant method of treating a CAG repeat disorder was known at the time of the filing.
Regarding claims 1, 7, 9, 13, 17, 21, 22-23, “044” teaches a method of reducing or delaying symptoms of Huntington's disease in a human subject carrying at least one Huntingtin allele with an abnormal number of CAG repeats, the method comprising administering to the subject a viral 5 vector encoding a double stranded RNA comprising a first RNA sequence and a second RNA sequence wherein the first and second RNA sequence are substantially complementary wherein the first RNA sequence has a sequence length of at least 19 nucleotides and is complementary to SEQ ID NO: 1, 10 wherein the first strand of the double stranded RNA is selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7 (claim 1). The method of claim 1, wherein the Huntingtin allele comprises more than 35 CAG repeats (claim 2). The method of claim 1, wherein the Huntingtin allele comprises more than 39 CAG repeats (claim 3). The method of claim 1, wherein the viral vector is an adeno associated viral (AAV) vector (claim 4). The method of claim 1, wherein the AAV vector is a serotype 5 vector (claim 5). The method of claim 1, wherein the double stranded RNA is comprised in a pre-miRNA scaffold, a pri-miRNA scaffold, a shRNA, or an siRNA (claim 6). The method of claim 1, wherein the double stranded 30 RNA is encoded by an expression cassette in the viral vector (claim 9). The method of claim 9, wherein the viral vector is an AAV serotype 5 vector (claim 11). 12. A method of treating a human subject carrying at least one Huntingtin allele with an abnormal number of CAG repeats, comprising administering to the subject a viral vector encoding a double stranded RNA comprising a first RNA sequence and a second RNA sequence wherein the first and second RNA sequence are substantially complementary, wherein the first RNA sequence has a sequence length of at least 19 nucleotides and is complementary to SEQ ID NO: 1, wherein the first strand of the double stranded RNA is selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7 (claim 12). The method of claim 12, wherein the Huntingtin allele comprises more than 35 CAG repeats (claim 13). The method of claim 12, wherein the Huntingtin allele comprises more than 39 CAG repeats (claim 14). The method of claim 12, wherein the viral vector is an adeno associated viral (AAV) vector (claim 15). The method of claim 12, wherein the AAV vector is a serotype 5 vector (claim 16). The method of claim 12, wherein the double stranded RNA is comprised in a pre-miRNA scaffold, a pri-miRNA scaffold, a shRNA, or an siRNA (claim 17). The method of claim 12, wherein the double stranded RNA is encoded by an expression cassette in the viral vector (claim 20).
“044” does not teach a repeat expansion resulting in missplicing 3’ from the repeat expansion, as is required by instant claims 1-3, 9, 14, 18. “044” does not teach reduction of the misspliced transcript and full length transcript, as required by the instant claims 1, 4, 13-14. “044 does not teach SEQ ID NO 9, as required by the instant claims. “044” does not teach the pri-mi451 scaffold. However, this is cured by Konstantinova, Neueder and Sah.
Konstantinova teaches a double stranded RNA is for use in inducing RNAi against Huntingtin exon 1 sequences. The double stranded RNA of to the invention was capable of reducing neuronal cell death and huntingtin aggregates in an animal model (e.g., abstract). Konstantinova teaches that Huntington's disease is a genetic neurodegenerative disorder caused by a genetic mutation in the huntingtin gene. The genetic mutation involves a DNA segment of the huntingtin gene known as the CAG trinucleotide repeat. Normally, the CAG segment in the huntingtin gene of humans is repeated multiple times, i.e. about 10-35 times. People that develop Huntington's disease have an expansion of the number of CAG repeats in at least one allele (e.g., paragraph 001). Konstantinova teaches the selected double stranded RNA of the current invention was found to be effective in reducing huntingtin gene expression. The double stranded RNA when provided in a cell, either directly via transfection or indirectly via delivery of DNA (e.g. transfection) or via vector-mediated expression upon which the said double stranded RNA can be expressed, is capable of reducing expression of both a mutated huntingtin gene and a normal huntingtin gene (e.g., paragraph 0004). Konstantinova teaches for the medical use of a double stranded RNA according to the invention, such as the treatment or Huntington's disease, wherein such medical use may also comprise an expression cassette or a viral vector, such as AAV5, capable of expressing the said double stranded RNA of the invention (e.g., paragraph 0005). Konstantinova teaches Examples of pri/pre-miRNA scaffold for miH12 pre-miH12-155 (SEQ ID NO.44) and premiH12-451 scaffold (e.g., paragraph 0007; Fig. 2).
Neueder teaches a messenger RNA of huntingtin that is incompletely spliced (misspliced transcript), generating a short huntingtin exon1 mRNA in fibroblast and brain regions of Huntington’s disease patients, comprising huntingtin exon 1, including CAG repeat expansion and the 5′ sequence of intron 1 leading to the production of the highly pathogenic exon 1 huntingtin protein (e.g., abstract; paragraph 2nd, page 2; Fig. 1A-D [see below]; Fig. 2A-D).
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Neueder teaches a huntingtin exon 1 mRNA (misspliced transcript) that utilize the cryptic polyA site located at 7327 bp into HTT intron 1 (7327 site) (e.g., paragraph 1st, page 3; Fig. 1A-D). Neueder conclude that the extremely pathogenic exon 1 HTT fragment is generated by incomplete splicing in a polyglutamine-length dependent manner in HD patients. This finding will have important implications for strategies to lower mutant HTT levels in patients (e.g., paragraph 1st, page 2).
Sah teaches methods for treating neurodegenerative diseases
such as Huntington's Disease are also included in the present invention. The siRNAs included in the compositions featured herein encompass a dsRNA having an ,antisense strand (that is 30 nucleotides or less, generally 19-24 nucleotides in length), that is substantially complementary to at least part of an mRNA transcript of the mutated HTT gene (e.g., paragraph 0008). Sah teaches SEQ ID NO 42 that has 100% identity with SEQ ID NO 9, of the instant claims (e.g., Table 1, see alignment below]).
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Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of “044” -a method of reducing or delaying symptoms of Huntington's disease in a human subject carrying at least one Huntingtin allele with an abnormal number of CAG repeats, the method comprising administering to the subject a viral 5 vector encoding a double stranded RNA, with the teachings of Konstantinova –a method for reducing expression of both a mutated huntingtin gene and a normal huntingtin gene in a subject with the vector AAV5, capable of expressing the said double stranded RNA in a pri-miRNA scaffold with the teachings of Neueder -the extremely pathogenic exon 1 HTT fragment is generated by incomplete splicing in a polyglutamine-length dependent manner in HD patients and the teachings of Sah the SEQ ID NO 42 for targeting the huntingtin gene; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method for treating Huntington’s disease with an AAV5 vector carrying a dsRNA capable of inhibiting wild type and pathogenic huntingtin transcripts.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to treat Huntington’s disease patients, by lowering the mRNA transcript of the mutated huntingtin gene.
Claims 1-4, 7-9, 13-14, 17-18, 21-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-14 of U.S. Patent No. 10,767,180 (“180”) in view of Neueder et al. (“Neueder”, Scientific Report, 2017, 7:1307, cited as reference A13 in IDS filed 03/15/2022 ), Konstantinova et al (“Konstantinova”, US 2017/0355989 A1) and Sah et al. (“Sah”, WO 2017 /201258 A1).
This rejection is made to address the amendment to the claims in the reply filed 02/25/2026.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are a variation of “180”, the patent claims are drawn to a method of treating a subject with Huntington's disease or a subject that is genetically predisposed for Huntington's disease who does not yet show symptoms of Huntington's disease, comprising administering to a subject with Huntington's disease an effective amount of a viral vector encoding a double stranded RNA. The difference is that the some of the dependent claims include repeat expansion resulting in missplicing 3’ from the repeat expansion, encoding a truncated poly-glutamine protein. However, one of ordinary skill in the art would recognize that he/she could use SEQ ID NO 9 for reduction of both a misspliced transcript and the full length transcript, then it is obvious that the instant method of treating a CAG repeat disorder was known at the time of the filing.
Regarding claims 1, 7, 9, 13, 17, 21, 22-23, “180” teaches a method of treating a subject with Huntington's disease or a subject that is genetically predisposed for Huntington's disease who does not yet show symptoms of Huntington's disease, comprising administering to a subject
with Huntington's disease an effective amount of a viral vector encoding a double stranded RNA comprising a first RNA sequence and a second RNA sequence wherein the first and second RNA sequence are substantially complementary, wherein the first RNA sequence comprises SEQ ID NO:3,
SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7 (claim 11). The method of claim 11, wherein the viral vector is an adeno associated viral (AAV) vector (claim 12). The method of claim 11, wherein the AAV vector is a serotype 5 vector (claim 13). The method of claim 11, wherein the double stranded RNA is comprised in a pre-miRNA scaffold, a pri-miRNA scaffold, a shRNA, or an siRNA (claim 14).
“180” does not teach a repeat expansion resulting in missplicing 3’ from the repeat expansion, as is required by instant claims 1-3, 9, 14, 18. “180” does not teach reduction of the misspliced transcript and full length transcript, as required by the instant claims 1, 4, 13-14. “180 does not teach SEQ ID NO 9, as required by the instant claims. “180” does not teach the pri-mi451 scaffold. However, this is cured by Neueder, Konstantinova and Sah.
The teachings of Neueder, Konstantinova and Sah are discussed above under U.S.C 103 rejections.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of “180” -a method of reducing expression of an RNA transcript comprising SEQ ID NO 1 in a neuron the method comprising administering to the subject a viral 5 vector encoding a double stranded RNA, with the teachings of Konstantinova –a method for reducing expression of both a mutated huntingtin gene and a normal huntingtin gene in a subject with the vector AAV5, capable of expressing the said double stranded RNA in a pri-miRNA scaffold with the teachings of Neueder -the extremely pathogenic exon 1 HTT fragment is generated by incomplete splicing in a polyglutamine-length dependent manner in HD patients and the teachings of Sah the SEQ ID NO 42 for targeting the huntingtin gene; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method for treating Huntington’s disease with an AAV5 vector carrying a dsRNA capable of inhibiting wild type and pathogenic huntingtin transcripts.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to treat Huntington’s disease patients, by lowering the mRNA transcript of the mutated huntingtin gene.
Claims 1-4, 7-9, 13-14, 17-18, 21-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-9, 11-12, 14-15 of U.S. Patent No. 10,174,321 (“321”) in view of Neueder et al. (“Neueder”, Scientific Report, 2017, 7:1307, cited as reference A13 in IDS filed 03/15/2022 ) Konstantinova et al (“Konstantinova”, US 2017/0355989 A1) and Sah et al. (“Sah”, WO 2017 /201258 A1).
This rejection is made to address the amendment to the claims in the reply filed 02/25/2026.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are a variation of “321”, the patent claims are drawn to a method of treating a subject with Huntington's disease or a subject that is genetically predisposed for Huntington's disease who does not yet show symptoms of Huntington's disease, comprising administering to a subject with Huntington's disease an effective amount of a viral vector encoding a double stranded RNA. The difference is that the some of the dependent claims include repeat expansion resulting in missplicing 3’ from the repeat expansion, encoding a truncated poly-glutamine protein. However, one of ordinary skill in the art would recognize that he/she could use SEQ ID NO 9 for reduction of both a misspliced transcript and the full length transcript, then it is obvious that the instant method of treating a CAG repeat disorder was known at the time of the filing.
Regarding claims 1, 7, 9, 13, 17, 21, “321” teaches a double stranded RNA comprising a first RNA sequence and a second RNA sequence wherein the first and second RNA sequence are substantially complementary, wherein the first RNA sequence has a sequence length of at least 19 nucleotides and is fully complementarity to SEQ ID NO. 1 (claim 1). A double stranded RNA according to claim 1, wherein said double stranded RNA is capable of reducing huntingtin gene expression (claim 2).
A double stranded RNA according to claim 1, wherein the double stranded RNA is comprised in a pre-miRNA scaffold, a pri-miRNA scaffold, a shRNA, or an siRNA, preferably a pre-miRNA scaffold (claim 3). A double stranded RNA according to claim 1, wherein the first strand is selected from the group consisting of SEQ ID NO.3, SEQ ID NO.4, SEQ ID NO.5, SEQ ID NO.6, and SEQ ID NO.7 (claim 5). An expression cassette encoding the double stranded RNA according to claim 1 (claim 9). A gene therapy vector comprising the expression cassette according to claim 9 (claim 11). A gene therapy vector according to claim 11, wherein the gene therapy vector is an AAV vector, preferably an AAV vector of serotype 5 (claim 12). A method of treating Huntington's disease comprising, administering to an individual with Huntington's disease the double stranded RNA according to claim 1 (claim 14). A method of treating Huntington's disease comprising,
administering to an individual with Huntington's disease the expression cassette according to claim 9 (claim 15).
Regarding claims 22-23, “321” teaches a double stranded RNA according to claim 1, wherein the double stranded RNA is comprised in a pre-miRNA scaffold derived from miR-451a or miR-155 (claim 7).
“321” does not teach a repeat expansion resulting in missplicing 3’ from the repeat expansion, as is required by instant claims 1-3, 9, 14, 18. “321” does not teach reduction of the misspliced transcript and full length transcript, as required by the instant claims 1, 4, 13-14. “321” does not teach SEQ ID NO 9, as required by the instant claims. However, this is cured by Neueder, Konstantinova and Sah.
The teachings of Neueder, Konstantinova and Sah are discussed above under U.S.C 103 rejections.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of “321” -a method of treating Huntington’s disease comprising administering to the subject a AAV 5 vector encoding a double stranded RNA where the double stranded RNA is comprised in a pre-miRNA scaffold, with the teachings of Konstantinova –a method for reducing expression of both a mutated huntingtin gene and a normal huntingtin gene in a subject with the vector AAV5, capable of expressing the said double stranded RNA in a pri-miRNA scaffold with the teachings of Neueder -the extremely pathogenic exon 1 HTT fragment is generated by incomplete splicing in a polyglutamine-length dependent manner in HD patients and the teachings of Sah the SEQ ID NO 42 for targeting the huntingtin gene; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method for treating Huntington’s disease with an AAV5 vector carrying a dsRNA capable of inhibiting wild type and pathogenic huntingtin transcripts.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to treat Huntington’s disease patients, by lowering the mRNA transcript of the mutated huntingtin gene.
Conclusion
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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