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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/21/26 has been entered.
Applicant’s election without traverse of group I and the species Huntington’s disease, SEQ ID NO: 6, AAV9, SEQ ID NO: 110, chemical, and modified tyrosine residue modified to comprise a covalently linked monosaccharide moiety in the reply filed on 9/25/24 is acknowledged.
Applicant’s election without traverse of Syn1 promoter SEQ ID NO: 152 in the reply filed on 4/3/26 is acknowledged.
Claims 42, 47, 82, and 84 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 9/25/24.
Improper Markush Rejection
Claims 2, 10, 11, 14, 17, 19, 23, 27, 29, 31, 32, 36, 100, 102, 104, 105, 114, and 115 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the claims is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the claim recites a multitude of miRNA seed sequences, each sequence having a different order of nucleotides and different activity.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
As set forth in MPEP2117, “Note that where a Markush group includes only materials from a recognized scientific class of equivalent materials or from an art-recognized class, "the mere existence of such a group in an application tend[s] to prove the equivalence of its members and when one of them [is] anticipated the group [is] therefore rendered unpatentable, in the absence of some convincing evidence of some degree of non-equivalency of one or more of the remaining members." In re Ruff, 256 F.2d 590, 598-99, 118 USPQ 340, 348 (CCPA 1958)("[A]ctual equivalence is not enough to justify refusal of a patent on one member of a group when another member is in the prior art. The equivalence must be disclosed in the prior art or be obvious within the terms of Section 103." Id. at 599, 118 USPQ at 348).”
In the instant case, art against any one miRNA seed sequence would not be evidence against any of the remaining members that have completely different sequences and do not have identical activity.
The instant claims are directed to the miRNA having at least one (or more) seed sequences selected from any seed sequence that has complementarity to SEQ ID NO: 4, any of SEQ ID NOs: 6-17, 40-44, or 50-66; or any of these sequences flanked by any miRNA backbone sequence. Each of these including any possible combination of the recited sequences have a different sequence and activity. The enormous possible genus of miRNAs are not a proper Markush grouping.
Additionally, each of the promoter sequences of claim 115 have a different sequence and activity. One cannot be substituted for another with expectation of identical activity because each has a different sequence, wherein the sequence dictates binding affinity and rate of initiation.
Response to Arguments
Applicant’s arguments are specific to claim 6, which has been cancelled.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 2, 10, 11, 14, 17, 19, 23, 27, 29, 31, 32, 36, 100, 102, 104, 105, 114, and 115 is/are rejected under 35 U.S.C. 103 as being unpatentable over of Deverman et al. (US 2017/0166926 A1), in view of Boussicault et al. (Brain, 2016, 139, 953-970), Aubourg et al. (US 2011/0034540 A1), Seyhan (Mol. BioSyst., 2016, 12, 295-312), Collard et al. (WO 2010/093906 A2)Valles-Sanchez et al. (WO 2020/104469 A1), Mauro et al. (Trends in Molecular Medicine November 2014, Vol. 20, No. 11, 604-613), and Sena-Esteves et al. (US 2018/0311290 A1).
Deverman et al. teach: [0203] In some embodiments, the rAAV having a capsid protein comprising one or more targeting peptides disclosed herein can be used to effectively transduce nervous systems. This makes the rAAV useful for delivery of therapeutics to treat, for example Huntington's disease (HD), Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, spinal muscular atrophy, types I and II, Friedreich's Ataxia, Spinocerebellar ataxia and any of the lysosomal storage disorders that involve cells with CNS.
Deverman et al. teach: [0179] The AAV vectors disclosed herein can be effectively transduced to a target environment (e.g., the CNS, the PNS, the heart, any combination thereof, and other desired system(s)) of a subject, for example, for delivering nucleic acids. In some embodiments, a method of delivering a nucleic acid sequence to the nervous system is provided. The method can include providing a protein comprising any one or more of the targeting sequences provided herein. The protein can be part of a capsid of an AAV. The AAV can comprise a nucleic acid sequence to be delivered to a nervous system. One can then administer the AAV to the subject.
Deverman et al. teach: [0148] AAV vectors that comprise coding regions of one or more proteins of interest are provided. The AAV vector can include a 5′ inverted terminal repeat (ITR) of AAV, a 3′ AAV ITR, a promoter, and a restriction site downstream of the promoter to allow insertion of a polynucleotide encoding one or more proteins of interest, wherein the promoter and the restriction site are located downstream of the 5′ AAV ITR and upstream of the 3′ AAV ITR. In some embodiments, the AAV vector includes a posttranscriptional regulatory element downstream of the restriction site and upstream of the 3′ AAV ITR. In some embodiments, the AAV vectors disclosed herein can be used as AAV transfer vectors carrying a transgene encoding a protein of interest for producing recombinant AAV viruses that can express the protein of interest in a host cell.
Deverman et al. teach that the viral vector is AAV9 [0068]. Deverman et al. teach: [0180] In some embodiments, the nucleic acid sequence to be delivered to a target environment (e.g., nervous system) comprises one or more sequences that would be of some use or benefit to the nervous system and/or the local of delivery or surrounding tissue or environment. In some embodiments, it can be a nucleic acid that encodes a protein of interest. In some embodiments, it can be a DNA sequence encoding a therapeutic RNA. In some embodiments, it can be a shRNA or an artificial miRNA delivery system.
Deverman et al. teach: [0189] In some embodiments, the therapeutic item to be administered to the subject comprises a short hairpin RNA (shRNA) or microRNA (miRNA) that knocks down Huntingtin expression by inducing the selective degradation of, or inhibiting translation from, RNA molecules transcribed from the disease causing HTT allele by binding to the CAG repeat. In some embodiments a method to treat patients with Huntington's Disease comprises incorporating Huntingtin-specific micro RNA expression cassette within an rAAV genome. This could then be packaged into one of the sequence variants disclosed for delivery through the vasculature (instant claim 10).
Deverman et al. teach: [0197] Dosages of a viral vector can depend primarily on factors such as the condition being treated, the age, weight and health of the patient, and may thus vary among patients. The dosage will be adjusted to balance the therapeutic benefit against any side effects and such dosages may vary depending upon the therapeutic application for which the recombinant vector is employed. The levels of expression of the transgene can be monitored to determine the frequency of dosage resulting from the vector.
Deverman et al. teach: [0198] In some embodiments, the vector can also comprise regulatory control elements known to one of skill in the art to influence the expression of the RNA and/or protein products encoded by the polynucleotide within desired cells of the subject.
Deverman et al. teach: [0199] In some embodiments, functionally, expression of the polynucleotide is at least in part controllable by the operably linked regulatory elements such that the element(s) modulates transcription of the polynucleotide, transport, processing and stability of the RNA encoded by the polynucleotide and, as appropriate, translation of the transcript. A specific example of an expression control element is a promoter, which is usually located 5′ of the transcribed sequence (instant claim 27). Another example of an expression control element is an enhancer, which can be located 5′ or 3′ of the transcribed sequence, or within the transcribed sequence. Another example of a regulatory element is a recognition sequence for a microRNA. Another example of a regulatory element is a transcription termination signal and/or a polyadenylation sequences.
Deverman et al. teach: [0230] The rAAV-Cap-in-cis-lox genome plasmid contains three main elements flanked by AAV2 ITRs (instant claim 36).
Therefore, it was known to treat Huntington’s disease via delivery of a recombinant viral vector comprising AAV ITRs and a transgene encoding a miRNA (instant claim 2).
Deverman et al. does not teach incorporation of a viral vector comprising a sequence encoding the CYP46A1 protein. However, it would have been obvious to include a recombinant viral vector comprising a nucleic acid encoding the CYP46A1 protein because Boussicault et al. teach that CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease (title). Boussicault et al. teach that restoring CYP46A1 activity in the striatum promises a new therapeutic approach in Huntington’s disease (abstract). Boussicault et al. teach that the target Huntington’s disease gene contains 160 CAG repeats (page 955) (instant claim 11).
It would have been obvious for the sequence to be in the same or a different vector; at the same or different time; and various time points; as a matter of design choice because each are being delivered for the same intended purpose and within the same treatment method. Administration at the same time or at different points, as well as administration of multiple regions comprising AAV ITRs and/or miRNAs being delivered for the same intended purpose, is considered to be a routine matter of design choice (instant claims 14, 17, 19, and 23).
Boussicault et al. teach that CYP46A1 expression is reduced in Huntington’s disease (page 957) and that delivery of CYP46A1 resulted in neuroprotection (page 959) and restored normal cholesterol levels (page 965). Therefore, it would have been obvious to deliver CYP46A1 in combination with the miRNAs with an expectation of each having a treatment effect on Huntington’s disease in a subject in need thereof because each were known to be used for the same intended use (instant claims 2 and 114).
Aubourg et al. teach: The inventors demonstrated that delivering an adeno-associated vector expressing a CYP46A1 gene into the brain of APP23 mice, a mouse model of Alzheimer's disease, resulted in a marked decrease of neuropathology and an improvement of cognitive deficits. On this basis, the inventors provide a viral vector for the treatment of Alzheimer's disease, wherein the vector expresses CYP46A1 in cells of the central nervous system [0007].
Aubourg et al. teach: [0018] By an "AAV vector" is meant a vector derived from an adeno-associated virus serotype, including without limitation, AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV6, AAV9, AAV10 etc. AAV vectors can have one or more of the AAV wild-type genes deleted in whole or part, preferably the rep and/or cap genes, but retain functional flanking ITR sequences. Functional ITR sequences are necessary for the rescue, replication and packaging of the AAV virion. Thus, an AAV vector is defined herein to include at least those sequences required in cis for replication and packaging (e.g., functional ITRs) of the virus (instant claim 36).
Aubourg et al. is evidence that it was known to deliver a nucleic acid encoding the CYP46A1 protein via an AAV vector with ITRs.
Seyhan teaches a multiplexed miRNA and transgene expression platform for simultaneous repression of a protein and expression of a protein coding sequence (title). Seyhan teaches: The data suggest that, it is possible to simultaneously deliver multiple negative (miRNA or shRNA) and positive (transgene) regulatory elements. Because many cellular processes require simultaneous repression and activation of downstream pathways, this approach offers a platform technology to achieve that dual manipulation efficiently (abstract).
The construct of Seyhan is additional evidence that it would have been obvious to deliver the miRNA construct of Deverman et al. in combination with the sequence encoding CYP46A1 because both have the same intended use of treating HD.
It would have been obvious to chemically modify the viral capsid with galactose because Collard et al. teach that galactose results in osmotic blood brain barrier disruption for the delivery of viral vectors comprising nucleic acid therapy [00196]. One would have been motivated to incorporate galactose because the objective of the method of Deverman et al. is to treat HD. Treatment of HD requires for the vector to cross the blood-brain barrier. Therefore, one would have reasonably expected that modification of the viral capsid with galactose would result in successful delivery of the vector of Deverman et al (instant claims 100, 102, 104, and 105).
With regards to selection of miRNAs, various miRNAs were known to be implicated in Huntington’s disease pathogenesis. With regards to SEQ ID NO: 6, the elected miRNA sequence, Valles-Sanchez et al. teach that SEQ ID NO: 6 is a human HTT gene targeting miRNA sequence (SEQ ID NO: 13). See sequence search result #3 in the PE2E file titled “ 20240930_105556_us-18-027-293-6.align450.rng” as follows:
RESULT 3
BHV05142
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
ID BHV05142 standard; DNA; 19 BP.
XX
AC BHV05142;
XX
DT 09-JUL-2020 (first entry)
XX
DE Human HTT gene targeting miRNA, SEQ ID:13.
XX
KW HTT gene; Huntington gene; alzheimers disease; delivery mechanism;
KW drug delivery; frontotemporal dementia; gene expression; gene silencing;
KW gene therapy; hepatotropic; huntingtons chorea; liver disease;
KW metabolic disorder; metabolic-gen.; miRNA; micro RNA;
KW motor neurone disease; neurodegenerative disease; neuroprotective;
KW parkinsons disease; rna interference; spinocerebellar ataxia; ss;
KW therapeutic; virus-like particle.
XX
OS Homo sapiens.
XX
CC PN WO2020104469-A1.
XX
CC PD 28-MAY-2020.
XX
CC PF 19-NOV-2019; 2019WO-EP081822.
XX
PR 19-NOV-2018; 2018EP-00206970.
PR 19-NOV-2018; 2018US-0769111P.
XX
CC PA (UNIQ-) UNIQURE IP BV.
XX
CC PI Valles-Sanchez A, Konstantinova PS, Van Deventer SJH, Gonzalez MS;
XX
DR WPI; 2020-45593J/047.
XX
CC PT Use of gene delivery vehicle for medical treatment for delivery of miRNA
CC PT to target cell for silencing of desired gene in transduced target cell,
CC PT where spread of miRNA to other non-transduced target cells results in
CC PT silencing of desired gene.
XX
CC PS Example 1; SEQ ID NO 13; 71pp; English.
XX
CC The present invention relates to use of gene delivery vehicle for medical
CC treatment for delivery of miRNA to target cell for silencing of desired
CC gene in transduced target cell. The miRNA is spread to other target cells
CC for silencing of desired gene, where gene delivery vehicle comprises a
CC miRNA scaffold. The gene delivery vehicle is an AAV based particle. The
CC gene delivery vehicle of the invention is useful for medical treatment
CC for delivery of a miRNA to a target cell resulting in silencing of a
CC desired gene in transduced target cell, for treating neurodegenerative
CC diseases such as Huntington's disease, amyotrophic lateral sclerosis,
CC spinocerebellar ataxia, Parkinson's disease, Alzheimer's disease, and
CC frontotemporal dementia (FTD), liver disease and metabolic disease. Note:
CC This sequence is described in the specification as a micro RNA (miRNA)
CC but is shown as a DNA sequence.
XX
SQ Sequence 19 BP; 6 A; 3 C; 7 G; 3 T; 0 U; 0 Other;
Query Match 100.0%; Score 19; Length 19;
Best Local Similarity 84.2%;
Matches 16; Conservative 3; Mismatches 0; Indels 0; Gaps 0;
Qy 1 AAGGACUUGAGGGACUCGA 19
||||||::|||||||:|||
Db 1 AAGGACTTGAGGGACTCGA 19
Therefore, this would have been an obvious selection of a miRNA for the delivery complex intended to treat Huntington’s disease.
Given that Deverman et al. teach: [0284] A subject having Huntington's disease is identified. The subject is then administered a first amount of an AAV vector that includes a polynucleotide that encodes for a small non-coding RNA (small hairpin RNA (shRNA) or microRNA (miRNA)) configured to reduce expression of the Huntingtin protein by its sequence); it would have been obvious for the miRNA sequence to be in an untranslated region of the transgene as a matter of design choice because this is a known configuration to control expression of the transgene product (instant claims 29 and 31).
The sequence of CYP46A1 was known and it would have been obvious to deliver it to treat HD. With regards to instant SEQ ID NO: 110 (claim 114), it was known and routine in the art to utilize codon optimization in human therapeutics, as evidenced by Mauro et al. It would have been obvious with a reasonable expectation of success to utilize known codon optimization parameters to arrive at the instantly recited sequence. Mauro et al. teach that codon optimization describes gene engineering approaches that use synonymous codon changes to increase protein production. Applications for codon optimization include recombinant protein drugs and nucleic acid therapies, including gene therapy, mRNA therapy, and DNA/RNA vaccines.
Mauro et al. teaches that the attempt to produce more protein by altering codon assignments has led to the broad use of codon-optimized mRNAs for the bioproduction of protein pharmaceuticals and nucleic acid therapies (page 604).
It would have been obvious for the promoter to comprise a Syn1 promoter (instant SEQ ID NO: 152) because Sena-Esteves et al. teach rAAVs comprising a Syn1 promoter comprising instant SEQ ID NO: 152 for modulation of transgene expression that is specific for CNS tissue (see abstract, [0019], and SEQ ID NO: 13). Given that the construct of Deverman et al. is for the treatment of HD, it would have been obvious to select a known promoter that is specific for CNS tissue with a reasonable expectation of successful delivery of the transgene (instant claim 115).
Response to Arguments
Applicant argues that Deverman et al. (US 2017/0166926 A1 and US 11,499,165) teaches engineered AAV capsids for broad CNS tropism, not disease-specific therapy. Applicant argues that Deverman et al. identify capsid variants (e.g., AAV-PHP.B) capable of improved CNS transduction, but they are limited to capsid engineering and biodistribution studies, without teaching any specific therapeutic transgene or indication such as HD.
Contrary to applicant’s assertions that Deverman et al. do not teach any indication such as HD, Deverman et al. specifically teach: “[0203] In some embodiments, the rAAV having a capsid protein comprising one or more targeting peptides disclosed herein can be used to effectively transduce nervous systems. This makes the rAAV useful for delivery of therapeutics to treat, for example Huntington's disease (HD)”.
Applicant argues that Deverman neither discloses nor suggests incorporating miRNA payloads for gene knockdown. The basis of this argument is unclear because the instant claims are not directed to any specific payload and Deverman explicitly teaches: [0189] In some embodiments, the therapeutic item to be administered to the subject comprises a short hairpin RNA (shRNA) or microRNA (miRNA) that knocks down Huntingtin expression by inducing the selective degradation of, or inhibiting translation from, RNA molecules transcribed from the disease causing HTT allele by binding to the CAG repeat. In some embodiments a method to treat patients with Huntington's Disease comprises incorporating Huntingtin-specific micro RNA expression cassette within an rAAV genome.
Applicant argues that moreover, the blood-brain barrier penetration of AAV-PHP.B observed in mice does not predict efficacy in human CNS due to known species-specific receptor dependency, a limitation later confirmed in the field. This is an interesting assertion by applicant given that the instant specification does not demonstrate in vivo delivery across the blood-brain barrier in the human CNS of the instant breath of constructs and raises the issue of enablement of the instant claim scope. Deverman et al. clearly teaches that the rAAV having a capsid protein comprising one or more targeting peptides disclosed herein can be used to effectively transduce nervous systems and that the rAAV can be used for delivery of therapeutics to treat, for example Huntington's disease (HD).
Applicant argues that Deverman teaches a skilled person that wildtype AAV9 vectors exhibited markedly reduced expression in nerves as compared to AAVs comprising the targeting peptides. (See, e.g., paragraph [0158] and FIGs 6F). It is noted that paragraph [0158] does not appear to be relevant and is dir3ected to capsid protein sequence. Applicant argues that accordingly, a skilled person would not be motivated to use a viral vector that lacks these peptides to arrive at the pending claims herein. The claims do not exclude the targeting peptides of Deverman et al. Additionally, the wildtype AAV9 did result in successful expression, particularly in the motor cortex and visual cortex, just not as high of an expression level as AAV-PHP.B.
Contrary to applicant’s arguments, Deverman clearly offers motivation to deliver the vector to treat HD and motivation to incorporate a microRNA (miRNA) that knocks down Huntingtin expression. Deverman explicitly teaches these elements.
Deverman et al. is relied upon for teaching a method of treating HD comprising delivery of an AAV comprising an isolated nucleic acid comprising a region comprising a AAV ITR and miRNA. Deverman et al. teach that the AAV vector can be used to deliver a transgene and to deliver miRNAs.
Applicant argues that Boussicault et al. (Brain, 2016, 139:953-970) teaches CYP46A1 restoration, not miRNA delivery or gene silencing.
This is a rejection under 35 USC 103 rather than 102 and therefore it is the combination of references that renders the instant claims obvious. Boussicault nor Aubourg are relied upon for miRNA delivery and gene silencing.
Applicant argues that Boussicault focuses solely on the role of CYP46A1 in cholesterol metabolism and neuroprotection in Huntington's disease and speculates that expression of CYP46A1 would have therapeutic effects in a subject having Huntington's Disease. This is precisely what Boussicault was relied upon for.
Applicant argues that Boussicault's therapeutic mechanism relies on gene augmentation-restoring a missing enzyme-not the RNA interference or miRNA- mediated suppression claimed here. Thus, while Boussicault involves AAV and HD, it teaches the opposite of the claimed miRNA-based knockdown approach and would not have motivated one of ordinary skill to replace gene augmentation with gene silencing. Substituting a cholesterol-metabolism enzyme for a miRNA construct that targets mutant HTT expression requires entirely different design and regulatory considerations.
The basis of this argument is not clear because the instant claims are directed to a combination of a transgene encoding a miRNA in combination with a sequence encoding CYP46A1. Although applicant argues that the instant mechanism is solely miRNA based, the instant claims require a sequence encoding CYP46A1. Boussicault et al. and Aubourg et al. are relied upon for motivation to incorporate a sequence encoding CYP46A1, which is recited in the instant claims.
Applicant argues that Mevel et al. (Chem Sci, 2020, 11:1122-1131) teaches surface chemical modification of AAV capsids; not CNS or HD-specific. The rejection has been amended and Mevel et al. is no longer required. The assertion regarding non-analogous technology has been addressed in the newly applied rejection under 35 USC 112, 1st paragraph because the instant specification does not demonstrate CNS delivery with the recited N-acetylgalactosamine and applicant points out that delivery with the modification is liver specific.
Applicant argues that the Examiner asserts that it was "known to treat Huntington's disease via delivery of a recombinant viral vector comprising AAV ITRs and a transgene encoding a miRNA." That conclusion is unsupported by any of the cited references. The only document demonstrating in vivo AAV therapy for HD (Boussicault) uses gene augmentation, while the only document discussing miRNAs (Hoss) identifies correlative biomarkers, not a therapeutic approach.
Contrary to applicant’s arguments, Deverman et al. offer motivation to treat Huntington’s disease via delivery of a recombinant viral vector comprising AAV ITRs and a transgene encoding a miRNA, whereas Boussicault et al. and Aubourg et al. offer motivation to incorporate a sequence encoding CYP46A1.
Applicant argus that none of the cited references provide:
- a motivation to select miRNA as a therapeutic modality for Huntington's disease (HD) (contrary to applicant’s argument, this is taught by Deverman et al.),
- a motivation to combine miRNA-based silencing with AAV-mediated CNS delivery (contrary to applicant’s argument, this is taught by Deverman et al.), or
- a reasonable expectation of success in using such miRNA constructs to treat HD (contrary to applicant’s argument, this is taught by Deverman et al.).
Although applicant argues picking and choosing, these three elements are all taught by the same reference.
Deverman et al. offer motivation to treat Huntington’s disease via delivery of a recombinant viral vector comprising AAV ITRs and a transgene encoding a miRNA, whereas Boussicault et al. and Aubourg et al. offer motivation to incorporate a sequence encoding CYP46A1. Aubourg is relied upon as evidence that it was known to utilize viral vectors to delivery CYP46A1, wherein Boussicault offers motivation to deliver CYP46A1 to treat HD.
The rationale to combine is the art recognized equivalence that both Deverman et al. and Boussicault et al. teach a compound to treat the same disease, HD. The compositions are each known in the art for the same purpose as each other. Therefore, it would have been obvious to combine the two with an expectation of treatment of the same disease.
One would have certainly been motivated to incorporate CYP46A1 delivery into the method of Deverman et al. because Deverman et al. teaches delivery of AAV comprising transgene encoding a miRNA for the treatment of HD and Boussicault offers motivation to deliver CYP46A1 for the same intended use.
Additionally, the instantly elected sequence (SEQ ID NO: 6) was known to be a human HTT gene targeting miRNA sequence, as taught by Valles-Sanchez et al. The claims are directed to a combination of structural elements that were each known to be useful for HD treatment. Any HD targeting miRNA of the prior art would have been an obvious selection. Importantly, claim 6 recites that the miRNA has any possible seed sequence that is complementary at any level to SEQ ID NO: 4, which is a broad limitation met by virtually any miRNA having minimal specificity.
New Rejections
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 2, 10, 11, 14, 17, 19, 23, 27, 29, 31, 32, 36, 100, 102, 104, 105, 114, and 115 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 HD via direct delivery of the instantly recited vector comprising a specific miRNA sequence that has demonstrated treatment of HD, wherein the complex is not targeted to the liver via GalNAC, does not reasonably provide enablement for a method for treating HD in a subject that does not have HD; and for a method of treating HD via broad systemic delivery of the instantly recited construct comprising any miRNA meeting any of the instantly recited structural limitations; and for treatment of HD when the construct is delivered to the liver via a GalNac. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The claims are directed to a method for treating HD in a subject that does not have HD but is at risk of developing HD; and a method of treating HD via broad systemic delivery of the instantly recited construct comprising any miRNA meeting any of the instantly recited structural limitations; and treatment of HD when the construct is delivered to the liver via a GalNac.
The specification does not draw an adequate nexus between delivery of the instant construct and treatment of HD in an individual that does not have HD, but is rather at risk of developing HD. The specification has not demonstrated even a single species of construct that resulted in treatment of HD in an individual that does not have HD.
Additionally, the specification is not enabling for a method of treating HD via broad systemic delivery of the instantly recited construct comprising any miRNA sequence meeting any of the instantly recited structural limitations (a seed sequence of any length that is complementary to any length of SEQ ID NO: 4, a sequence selected from SEQ iD NOs: 6-17, 40-44, or 40-66, and/or one of the sequences flanked by any miRNA backbone sequence). The claims encompass any single species of these sequences or any combination of them.
The specification discloses transfection in vitro of neuroblastoma derived SH-SY5Y cells with a specific expression construct comprising SP0013, SP0014, SP0030, SP0031, SP0032, SP0019, SP0020, SP0021, SP0022, SP0011, SP0034, SP0035, or SP0036, wherein the construct comprises a specific promoter with resultant transfection efficiency comparable to the neuronal-specific Syn-1 promoter.
Instant claim 2 does not require the presence of a promoter. The specification is not commensurate in scope with the claims.
Sayeg et al. (ACS Synth. Biol. 2015, 4, 788−795) teach that targeting transgene expression to specific cell types in vivo has proven instrumental in characterizing the functional role of defined cell populations. Genetic classifiers, synthetic transgene constructs designed to restrict expression to particular classes of cells, commonly rely on transcriptional promoters to define cellular specificity. However, the large size of many natural promoters complicates their use in viral vectors, an important mode of transgene delivery in the brain and in human gene therapy (page 788). The instant claims encompass systems without any promoter or with any promoter, which clearly is not enabled.
Sayeg et al. teach: NA packaging capacity characteristic of the most reliable and widely used gene therapy vectors, lentivirus and adeno-associated virus (AAV). Consequently, there are usually complications effectively packaging large cell-type-specific promoters in these viruses. Some shortened promoters have achieved remarkable specificity in lentiviral or AAV vectors; however, for many cell types it is difficult to identify a short promoter element with sufficient specificity (page 788).
Additionally, the specification does not draw an adequate nexus between delivery of the instant construct with a modification to the viral capsid (i.e. N-acetylgalactosamine or bridge GalNac) and the predictable outcome of treating HD (instant claims 104 and 105). The specification is not enabling for any possible modification species within the instantly recited genus and predictable treatment of HD.
For example, with respect to GalNAc, Tompach et al. (NUCLEIC ACID THERAPEUTICS Volume 00, Number 00, 2026, 1-10) teach that following subcutaneous administration, GalNAc rapidly accumulates in hepatocytes via asialoglycoprotein receptor (ASGPR) mediated endocytosis and are sequestered within endolysosomal compartments, creating an intracellular depot that sustains therapeutic effects for weeks to months. The specification does not demonstrate that the instant modifications result in treatment effects in the brain including the predictable treatment of HD.
Although the specification has demonstrated cell transfection in vitro via specific constructs, the specification is not enabled for mediating treatment of HD in vivo by the broadly recited methods, as delivery and effective action therein is known in the art to be unpredictable with regards to delivery constructs. Activity in vitro is not predictable of the in vivo therapeutic effect in the in vivo complex environment. This is supported by applicants own argument that the blood-brain barrier penetration of AAV-PHP.B of the prior art observed in mice does not predict efficacy in human CNS due to known species-specific receptor dependency, a limitation later confirmed in the field.
This is an interesting assertion by applicant given that the instant specification does not demonstrate in vivo delivery across the blood-brain barrier in the human CNS of the instant breath of constructs and raises the issue of enablement of the instant claim scope.
The in vivo disclosure of the specification is strictly prophetic and the in vitro data is not commensurate in scope with the instant claims.
As outlined above, it is well known that there is a high level of unpredictability in the art for therapeutic in vivo applications and design. The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating HD via broad systemic delivery of a broad genus of possible constructs encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any construct of the instant claims in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treatment of HD. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
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 2, 10, 11, 14, 17, 19, 23, 27, 29, 31, 32, 36, 100, 102, 104, 105, 114, and 115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 11, 13, 15, 17, 23, 24, 27-29, 31, 34, 36, and 84 of copending Application No. 18/833,081 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of application ‘081 are directed to a method of treating HD (claim 5) comprising administering a transgene encoding a miRNA and a sequence encoding a CYP46A1 protein, the same limitations as instantly claimed. Claim 6 of application ‘081 recites the same miRNA sequences as instant claim 2. Claim 11 of application ‘081 recites the same repeat limitations as instant claim 11. Claim 15 of application ‘081 recites the same vector requirements as instant claim 14. Claim 17 of application ‘081 recites the same administration requirements as instant claim 17. The claims coincide as follows:
Application ‘293 Current claim
2
4, 5 2
6 2
11 11
13 2
15 14
17 17
23 23
27 27
28 115
29 29
31 31
36 36
84 2
The claims are obvious variations of each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Art of Interest
Mueller et al. (WO 2018/057855 A1) teaches AAV treatment of HD (title). Mueller et al. teach: Aspects of the disclosure relate to compositions and methods useful for treating Huntington' s disease. In some embodiments, the disclosure provides interfering nucleic acids (e.g., artificial miRNAs) targeting the huntingtin gene (HTT) and methods of treating Huntington's disease using the same (abstract).
Mueller et al. teach: The disclosure provides an isolated nucleic acid comprising: a first region comprising a first adeno-associated virus (AAV) inverted terminal repeat (ITR), or a variant thereof; and, a second region comprising a transgene encoding one or more miRNAs (page 2).
Conclusion
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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