DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s 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.
Claims 42, 47, 55, 82, and 84 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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
Claim 6 is 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 claim is 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 have a different sequence and activity. The enormous possible genus of miRNAs are not a proper Markush grouping.
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, 6, 10, 11, 14, 17, 19, 23, 27, 29, 31, 32, 36, 100, 102, 104, 105, and 114 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), Hoss et al. (PLOS Genetics, 2014, 10, 2, e1004188, 1-14), and Mevel et al. (Chem Sci, 2020, 11, 1122-1131), Aubourg et al. (US 2011/0034540 A1), Valles-Sanchez et al. (WO 2020/104469 A1), and Mauro et al. (Trends in Molecular Medicine November 2014, Vol. 20, No. 11, 604-613).
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.
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. 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.
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.
It would have been obvious to include a recombinant viral vector comprising a nucleic acid encoding the CYP46A1 gene 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). 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.
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.
With regards to selection of miRNAs, various miRNAs were known to be implicated in Huntington’s disease pathogenesis. For example, Hoss et al. teach that various miRNAs located in the Hox gene clusters are implicated in Huntington’s disease pathogenesis and that the seed region binds to the 3’UTR of the target.
Additionally, since Mevel et al. teach chemical modification of the AAV capsid with N-acetylgalactosamine to improve gene delivery (title and abstract), this would have been an obvious selection with an expectation of improved delivery.
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.
Aubourg et al. is evidence that it was known to deliver a nucleic acid encoding the CYP46A1 protein via an AAV vector with ITRs.
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.
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).
Response to Arguments
Applicant argues: Deverman fails to teach specific methods of treating central nervous system diseases or disorders. Instead, the primary focus of Deverman is directed to modified AAVs that can be useful in delivering cargo to the central nervous system. At most, Deverman describes potential uses for these modified AAVs in broad strokes.
Contrary to applicant’s argument, Deverman specifically teaches that the AAVs can be used to treat HD and is not required to teach that the AAVs can only be used to treat HD.
Applicant argues that Deverman is silent on the use of a combination of CYP46A1 and at least on miRNA that targets the HTT gene, as required by the claims as pending herein.
Importantly, Deverman et al. is not relied upon for teaching this combination. 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.
Additionally, contrary to applicant’s argument, the instant claims in fact do not require a miRNA that targets the HTT gene. Claim 2 requires a second region that comprises a transgene encoding any possible miRNA.
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 notes that neither Boussicault nor Aubourg teach or suggest using CYP46A1 in combination with an miRNA, let alone any other inhibitor. As set forth above, 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 such a combination.
Applicant argues that at most, 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 Aubourg does not mention nor reference Huntington's disease. Aubourg was not relied upon for teachings of HD. 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.
Applicant argues that a skilled person would not have been motivated with an expectation of success to arrive at the pending claims herein in view of any combination of Deverman, Boussicault, and Aubourg. Contrary to applicant’s argument, 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.
Turning to Valles-Sanchez, Applicant submits that the specification of Valles-Sanchez teaches that the disclosed miRNA sequences are to be comprised in a miR-451 scaffold. These teachings are supported by the Applicant's arguments on the record.
Valles-Sanchez et al. teach that an RNA molecule such as present in nature, i.e. a pri-miRNA, a pre-miRNA or a miRNA duplex, may be used as a scaffold for producing an artificial miRNA that specifically targets a gene of choice and teaches that instant SEQ ID NO: 6 (miR-451) is a human HTT gene targeting miRNA sequence.
Valles-Sanchez et al. teach: The invention relates to the field of gene therapy. In addition the invention relates to the field of interfering RNA and/or microRNA (mi RNA). In particular the invention relates to gene therapy involving such mi RNA's and more in particular to methods and means to improve delivery of said mi RNAs to target cells of a patient. The invention provides for a gene delivery vehicle for use in delivery of a mi RNA to a cell resulting in silencing of a desired gene and whereby spread of said mi RNA to other non-transduced cells results in silencing of said desired gene in said non-transduced cells (abstract).
Given the teachings of Valles-Sanchez et al., one would have certainly selected miR-451 as HD targeting as a matter of design choice. Any HD targeting miRNA of the prior art would have been an obvious selection. With regards to applicants arguments regarding a scaffold, the instant claims do not exclude additional elements. Valles-Sanchez et al. does not teach away from delivering miR-451 in the system of Deverman et al. Additionally, one would have certainly expected that incorporation of a HD targeting miRNA would in fact target HD in the system of Deverman et al. with the delivery benefits taught by Deverman et al.
Applicant argues that Hoss et al. fails to overcome the deficiencies of Valles-Sanchez, as it fails to teach or suggest the miRNA sequence in the pending claims herein. That is, Hoss does not disclose any sequences that are referenced in the claims as amended herein. Instant claim 6 is the only claim that recites specific miRNA sequences. Additionally, Hoss et al. teach that various miRNAs located in the Hox gene clusters are implicated in Huntington’s disease pathogenesis and that the seed region binds to the 3’UTR of the target; and is therefore evidence of various miRNAs that would have also been obvious selections. 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.
Applicant argues that Mevel fails to overcome any of the deficiencies of Deverman, Boussicault, Aubourg, Valles- Sanchez, and Hoss described above. That is, Mevel is silent on the combination of miRNAs and CYP46A1 for the treatment of Huntington's disease. Mevel is not relied upon for such a teaching and is specific to chemical modification of the AAV capsid with N-acetylgalactosamine to improve gene delivery as set forth in the rejection.
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
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636