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 .
Application Status
This action is written in response to applicant’s correspondence received 04/12/2024. Claims 1-2, 5-6, 8, 11, 13, 15, 26, 28, 31, 33, 35-36, 38-39, 41, 43, 47 and 59 are currently pending.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/12/2024 and 06/13/2025 were filed before the mailing date of any non-final first action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim interpretation:
Certain claim terms are interpreted as follows.
Applicant regards the term “epigenetic modulator” as meaning, “an agent that alters the transcriptional activity of a gene” (p. 11 ln 16-17). The broadest reasonable interpretation of the term encompasses any agent that alters transcription activity of a gene in any way, including both activation and repression. Species within this genus include but not limited to, “siRNAs (small interfering RNA), miRNAs (microRNA), piRNAs (Piwi-interacting RNA), lncRNAs (long non-coding RNA) or antisense non-coding transcripts”, as disclosed by Barman (Barman et al. Mechanisms of Antisense Transcription Initiation with Implications in Gene Expression, Genomic Integrity and Disease Pathogenesis. Non-coding RNA 2019, 5, 11.), transcriptional activators or repressors such as transcription factors, and CRISPR interference systems, which repress transcription by sterically blocking transcript elongation by RNA polymerase (see Larson et al. CRISPR interference (CRISPRi) for sequence-specific control of gene expression. Nat Protoc 8, 2180–2196 (2013).).
Applicant regards the term “vector” as meaning, “any genetic element, such as a plasmid, phage, transposon, cosmid, chromosome, artificial chromosome, virus, virion, etc., which is capable of replication when associated with the proper control elements and which can transfer gene sequences between cells.” (p. 26 ln 28-31). The term is interpreted accordingly herein.
Claim Objection
Claim 11 is objected to because of the following informalities: the claim recites “an amino acid sequence at least 80% identical to amino acid sequence of SEQ ID NO: 1”. This is grammatically incorrect. Amending the claim to recite, “an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 1” would correct the error. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6, 8 and 11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 6 and 8 both recite the term “the DNA binding domain”. There is insufficient antecedent basis for this term because claim 1, from which they both depend, does not recite a DNA binding domain. A “protein” is interpreted as distinct from a protein “domain”: a protein is interpreted to mean a whole protein with all of its domains, while a domain is interpreted as meaning a structurally and functionally defined subunit of a protein but not the whole protein.
Amending claim 1 to recite “a DNA binding domain
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the lack of antecedent basis.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 6, 8, 13, 15, 31 and 39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pollock (Pollock et al. Regulation of endogenous gene expression with a small-molecule dimerizer. Nature Biotechnology volume 20, pages729–733 (2002).), as evidenced by Qin (Qin et al. Systematic Comparison of Constitutive Promoters and the Doxycycline-Inducible Promoter. PLoS ONE 5(5): e10611.).
Regarding claim 1, Pollock teaches an isolated nucleic acid (plasmid) comprising an expression cassette comprising a promoter (CMV in Figure 1) operably linked to a transgene wherein the transgene encodes a FKBP-rapamycin binding protein (FRAP, Id.), an epigenetic modulator (transcriptional activator S3H, Id.), a rapamycin-binding protein (FKBP, Id.), and a DNA binding protein (ZFHD1, Id.) that specifically binds to an endogenous gene promoter (human VEGF gene, p. 729, quoted below, most relevant passages underlined):
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In this system, outlined in Figure 1A, small-molecule heterodimerizers based on the natural product rapamycin are used to reconstitute an active transcription factor by bringing together a DBD fused to FK506-binding protein (FKBP) and an activation domain fused to the rapamycin-binding domain of FRAP (FKBP rapamycin–associated protein). (p. 729)
To bring the endogenous VEGF gene under dimerizer control, we incorporated a recently described artificial zinc-finger DBD targeting the human VEGF gene promoter into a dimerizer-regulated transcriptional activator construct. The VZ-8 ZFP was designed to bind within a region of accessible chromatin adjacent to the transcription start site of the VEGF gene. VZ-8 activates the endogenous VEGF gene in HEK293 cells, a cell line that normally expresses negligible amounts of VEGF in the absence of hypoxic induction7. The construct RS3H-VZ-8F3 expresses a bicistronic transcript encoding two fusion proteins (Fig. 1B). The activator fusion comprises a domain of FRAP linked to a potent composite activation domain termed S3H (ref. 16). The DBD fusion consists of the VZ-8 ZFP joined to three copies of FKBP. (p. 729 § Results)
The S3H domain, as a transcriptional activator, is an agent that alters the transcriptional activity of a gene and therefore meets the definition of an “epigenetic modulator”, as described above in Claim Interpretation.
Regarding claim 2, Pollock teaches that the promoter is a CMV promoter. As evidenced by Qin, the CMV promoter is a commonly used constitutive promoter (“we decided to examine six constitutive promoters commonly used in mammalian systems, including the...cytomegalovirus immediate-early promoter (CMV)”).
Regarding claim 6, Pollock teaches wherein the DNA binding domain is a zinc finger domain (see above).
Regarding claim 8, Pollock teaches wherein the FKBP is directly fused to the DNA binding domain (see above).
Regarding claim 13, Pollock teaches wherein the FRB domain is a FRAP domain (see above).
Regarding claim 15, Pollock teaches wherein the FRB (FRAP) domain is fused to the epigenetic modulator (S3H, see above).
Regarding claim 31, Pollock teaches a vector (pCGNN-derived plasmid) comprising the nucleic acid (§ Plasmid construction).
Regarding claim 39, Pollock teaches a host cell comprising the nucleic acid and rapamycin (p. 730):
Addition of rapamycin or non immunosuppressive rapamycin analogs to cells expressing these fusion proteins reconstitutes a transcriptional activator targeted to the endogenous VEGF promoter….Transfected cells were incubated for 48 h in the presence or absence of AP21967, a rapamycin-analog dimerizer (see Experimental Protocol), and amounts of VEGF protein secreted into the culture medium were measured
Claim Rejections - 35 USC § 103
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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 41 is rejected under 35 U.S.C. 103 as being unpatentable over Pollock (Pollock et al. Regulation of endogenous gene expression with a small-molecule dimerizer. Nature Biotechnology volume 20, pages729–733 (2002)), as evidenced by the U.S. Food and Drug Administration (Rapamune Prescribing Information. Reference ID: 4087386. 2017.; hereinafter ‘FDA’).
Pollock teaches the invention of claims 1 and 39, from which the instantly rejected claims depend, as described above.
Pollock does not teach wherein the rapalog is Sirolimus. Instead, Pollock teaches, “AP21967, a rapamycin-analog dimerizer”.
However, Pollock does teach that addition of rapamycin or rapamycin analogs to cells expressing the fusion proteins encoded by the nucleic acid reconstitutes the transcriptional activator targeted to the endogenous VEGF promoter (p. 730).
As evidenced by the FDA, Sirolimus is also known as rapamycin (p. 23 § DESCRIPTION).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have substituted the rapamycin analog, AP21967, as taught by Pollock, with any rapamycin or rapamycin analog such as Sirolimus (a.k.a. rapamycin). Pollock suggests that rapamycin is a suitable inducer for the transcriptional activator. Rapamycin and its analogs, and their functions, were known in the art. One of ordinary skill could have substituted one known element for another, and the results of the substitution would have been predictable, based on Pollock’s statement that rapamycin would be an effective alternative to AP21967 for use with their nucleic acid construct.
Claims 5, 11, 28, 33, 35-36, 38, 43, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Pollock as applied to claims 1-2, 6, 8, 13, 15, 31 and 39, further in view of Rivera (Blood 2005; 105 (4): 1424–1430.; of record, applicant’s submission).
Pollock teaches the invention of claims 1 and 8, from which the instantly rejected claims depend, as described above.
Pollock does not teach that the FKBP is FKBP12 (relevant to claims 5, 11), or that the nucleic acid has flanking ITR sequences and is comprised in an rAAV capsid as part of an rAAV vector (relevant to claims 28, 33, 35-36, 38). Pollock further does not teach the nucleic acid in a pharmaceutical composition for in vivo use (relevant to claim 43). Rather, Pollock teaches the nucleic acid in a plasmid vector for in vitro use (Abstract). However, Pollock notes that the targeted endogenous VEGF gene is therapeutically valuable (p. 732), and suggests that the “dimerizer-responsive ZFP transcription factor” system “may be particularly advantageous in a gene therapy setting” due to its “tight, inducible expression” after administration of a “single regulatory cassette” (p. 732). Therefore, Pollock provides a teaching, suggestion or motivation to pursue strategies and modifications that would render the nucleic acid suitable for in vivo, therapeutic applications.
Rivera teaches a similar construct to Pollock’s, comprising a sequence encoding a fusion protein of a FRAP domain and epigenetic modulator (transcriptional activator), a fusion protein comprising a zinc finger domain and FKBP, the fusion proteins separated by an IRES and both operably linked to a CMV promoter, depicted in Figure 2B-C:
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. Rivera further teaches that the FKBP domain was, “3 copies of human FKBP12” (Figure 2 caption).
Rivera further teaches the nucleic acid in an rAAV1/2 vector, in a pharmaceutical composition (see § Vector and drug administration) for in vivo gene therapy (Abstract and p. 1429 § Improved potency of an AAV1 pseudotyped single vector). Rivera also notes that the vector produced, “safe and persistent regulated expression” after administration to subjects (p. 1429 § Discussion).
Rivera further teaches a method of modulating the transgene expression in a subject, comprising administering the nucleic acid, measuring expression of transgene in the subject relative to a control level, and adjusting the dose of rapalog-based expression wherein if the expression level is increased relative to control, the same or less concentration of the rapalog is administered, and wherein the expression level is lower than control, administering a higher concentration of the rapalog (relevant to claim 59):
In our later studies we were able to avoid excessive inductions of Epo by administering low doses of AP22594 and then escalating the dose (Figure 5). In general, incorporating tight regulation into gene therapy applications allows variations in expression associated with the vector or target tissue (Figure 1) to be addressed by adjustments in the dose of inducing drug.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the retroviral vector comprising the nucleic acid, as taught by Pollock, by inserting the nucleic acid into a rAAV vector, using FKBP12 as the FKBP protein, as taught by Rivera. The primary difference between Pollock and Rivera is that Pollock uses a retroviral vector for delivery of the nucleic acid, does not specify the type of FKBP, and uses a S3H transcriptional activator, while Rivera uses an rAAV and teaches a specific FKBP and p65 activator. However, as discussed above, Pollock contemplates a therapeutic use for their construct, which would have motivated the ordinary artisan to search for an alternative delivery vector suitable for in vivo applications. This would have led them to Rivera, which teaches that delivery of an equivalent cassette in an AAV vector would have predictably yielded safe and persistent regulated expression of the transgene.
Claims 26 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Pollock as applied to claims 1-2, 6, 8, 13, 15, 31 and 39, further in view of Kemaladewi (Nature. 2019 Aug;572(7767):125-130.; of record, applicant’s submission).
Pollock teaches the invention of claim 1, from which the instantly rejected claims depend, as described above.
Pollock does not teach wherein the endogenous gene is LAMA1.
However, Pollock does teach that the nucleic acid construct is modular and can be modified to include, “a wide variety of natural transcription factor DBDs and designed ZFPs” targeting, “entire panels of endogenous genes,” allowing “highly effective gene therapies” (p. 732).
Kemaladewi teaches modulating, “expression of Lama1 in the dy2j/dy2j mouse model of MDC1A using an adeno-associated virus (AAV9) carrying a catalytically inactive Cas9 (dCas9), VP64 transactivators and single-guide RNAs that target the Lama1 promoter. When pre-symptomatic mice were treated, Lama1 was upregulated in skeletal muscles and peripheral nerves, which prevented muscle fibrosis and paralysis.” (Abstract). They further note that, “Previous studies have demonstrated that transgenic Lama1 overexpression rescued myopathy and peripheral neuropathy” (p. 125).
Kemaladewi’s teachings are analogous to the instantly claimed invention in that Kemaladewi uses a nucleic acid dCas9 protein (i.e., a DNA binding domain) fused to a transcriptional activator (i.e., epigenetic modulator) and guide RNA targeting the promoter of an endogenous gene to regulate the transcription of the endogenous gene. Kemaladewi further teaches that upregulation of LAMA1 via a transactivating fusion protein was effective at treating MDC1A.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have substituted the generic DNA binding domain in the isolated nucleic acid, as taught by Pollock, with a binding domain specific to LAMA1 to upregulate LAMA1 and treat MDC1A, as taught by Kemaladewi. Pollock teaches a nucleic acid construct which is effective at inducibly upregulating the expression of a transgene via a fusion protein comprising DNA binding domains specific to a given promoter, in tandem with transcriptional activators. Pollock also teaches that this construct is modular and can be adapted to a wide variety of target genes. Kemaladewi provides a specific target gene as well as a reasonable expectation of success by showing that MCD1A can be successfully treated by upregulating LAMA1.
Claim 11 is rejected under 35 U.S.C. 102(a)(1) as being unpatentable over Pollock (Pollock et al. Regulation of endogenous gene expression with a small-molecule dimerizer. Nature Biotechnology volume 20, pages729–733 (2002)) in view of U.S. PGPUB 20080020377 to Hillen (hereinafter ‘Hillen’).
Pollock teaches the invention of claims 1 and 8, from which the instantly rejected claims depend, as described above.
Pollock does not teach wherein the FKBP12-zinc finger domain fusion protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 1.
Hillen’s disclosures concern methods of, “modulating the activity of a regulatory biomolecule” (Abstract), and one of their preferred embodiments to practice this method includes, “Dimerizer systems from ARIAD consisting of (1) a ZFHD1 DNA-binding domain fused to FKBP 12, (2) a modified form of FRAP, termed FRB, fused to the NF.kappa.B-derived p65 activation domain and (3) rapamycin, AP22565 or AP12967 as heterodimer-forming agents” (¶ [0064]).
Hillen teaches a ZHFD1-FKB fusion sequence for use in that embodiment, SEQ ID NO: 30, which has 100% identity to SEQ ID NO: 1, as shown in the below alignment:
RESULT 1
US-10-594-262B-30
(NOTE: this sequence has 4 duplicates in the database searched)
Sequence 30, US/10594262B
GENERAL INFORMATION
APPLICANT: Friedrich-Alexander-University Erlangen-Nuremberg
TITLE OF INVENTION: Peptide-based method for monitoring gene expression in a host
TITLE OF INVENTION: cell
FILE REFERENCE: H1776 US
CURRENT APPLICATION NUMBER: US/10/594,262B
CURRENT FILING DATE: 2010-11-15
PRIOR APPLICATION NUMBER: EP 04 00 7278.7
PRIOR FILING DATE: 2004-03-26
PRIOR APPLICATION NUMBER: US 60/570,497
PRIOR FILING DATE: 2004-05-13
NUMBER OF SEQ ID NOS: 33
SEQ ID NO 30
LENGTH: 465
TYPE: PRT
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: /note="Description of artificial sequence: ZHFD1-FKBP fusion"
Query Match 100.0%; Score 2465; Length 465;
Best Local Similarity 100.0%;
Matches 465; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MDYPAAKRVKLDSRERPYACPVESCDRRFSRSDELTRHIRIHTGQKPFQCRICMRNFSRS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MDYPAAKRVKLDSRERPYACPVESCDRRFSRSDELTRHIRIHTGQKPFQCRICMRNFSRS 60
Qy 61 DHLTTHIRTHTGGGRRRKKRTSIETNIRVALEKSFLENQKPTSEEITMIADQLNMEKEVI 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DHLTTHIRTHTGGGRRRKKRTSIETNIRVALEKSFLENQKPTSEEITMIADQLNMEKEVI 120
Qy 121 RVWFCNRRQKEKRINTRGVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRN 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RVWFCNRRQKEKRINTRGVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRN 180
Qy 181 KPFKFMLGKQEVIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVEL 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 KPFKFMLGKQEVIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVEL 240
Qy 241 LKLEVEGVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LKLEVEGVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQE 300
Qy 301 VIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLETRGVQVE 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 VIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLETRGVQVE 360
Qy 361 TISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQEVIRGWEEGVAQ 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 TISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQEVIRGWEEGVAQ 420
Qy 421 MSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLETSY 465
|||||||||||||||||||||||||||||||||||||||||||||
Db 421 MSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLETSY 465
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have substituted the generic FKBP-ZF fusion sequence in the dimerizer system, as taught by Pollock, with a specific, known sequence for that fusion protein in the same dimerizer system, as taught by Hillen. Pollock teaches all of the generic elements of the system and demonstrates its effectiveness, while Hillen teaches the same system and merely provides specific sequences which may be used, with a reasonable expectation of success.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
Claim 47 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The specification is enabling for a method for treating MDC1A in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the isolated nucleic acid of claim 1, wherein the isolated nucleic acid comprises an expression cassette for transgene encoding:
a FKBP12-ZFH1 fusion protein,
a fusion protein comprising a FKBP-rapamycin binding protein (FRB) and a transcriptional activator,
wherein the two fusion proteins are separated by an IRES,
wherein the epigenetic modulator is a transcriptional activator, and,
wherein the endogenous gene is LAMA1 (see claim 26).
However, the specification does not reasonably provide enablement for treating MDC1A for the full generic scope of those elements in other configurations (i.e., a FKBP12-FRB fusion protein and a ZFH1-transcriptional activator fusion), targeting the full scope of any endogenous gene, using the full scope of any epigenetic modulator (which may activate or repress transcription). as currently recited in claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In comparing the claims to the prior art, it is noted that while the claims were previously rejected in this Office Action insofar as the prior art teaches at least some of the embodiments encompassed by the claims, the application as filed is not particularly enabling for, nor does it specifically describe, the methods taught by the prior art where the application does not principally contemplate or describe those elements as provided in the prior art. Additionally, it is noted that the particular embodiments of the prior art are not enabling for the generic breadth of the methods as claimed.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention
Breadth of the Claims
Guidance of the Specification
State of the Art
Experimentation Required
Claim 1, from which claim 47 depends, encompasses any isolated nucleic acid (i.e., a linear nucleic acid, a circular plasmid, a viral vector, etc.) comprising a transgene encoding a FRB, a FKBP, a generic epigenetic modulator, and a generic DNA binding protein that specifically binds to a generic endogenous promoter. The claim does not specify any particular configuration for these elements. It does not specify in what order, from 5’ to 3’, they are encoded. It does not specify whether the elements are expressed as a single fusion protein, multiple fusion proteins, or if the expression cassette is simply multicistronic and expresses each element as a separate protein. Neither claim 1 nor claim 47 specifies what endogenous promoter should be targeted, the type of epigenetic modulator, and/or what function the epigenetic modulator needs to perform to achieve the recited treatment outcome (i.e., whether the modulator activates or represses transcription of the target gene).
The specification provides little guidance regarding how to achieve the recited treatment outcome by administering the generically recited nucleic acid. It discloses no working examples of a treatment, either in vitro or in vivo. It does disclose that, “MDC1a is a genetic disease associated with a mutation in LAMA2 gene, and epigenetic activation of expression of its analog gene LAMA1, which is normally expressed only during embryonic state, can be used to treat MDC1A”, and references the same Kemaladewi prior art cited above in the rejection of the claims under 35 U.S.C. § 103 (p. 36 ln 2-6). However, this is only one embodiment among the many encompassed by the claims.
In contrast to the breadth of the claims and the limited guidance in the specification, the prior art discloses that, as of 2020, “There are currently no treatments for MDC1A, and there is an incomplete understanding of disease pathogenesis.” (Fabian et al. Zebrafish Models of LAMA2-Related Congenital Muscular Dystrophy (MDC1A). Front. Mol. Neurosci., 08 July 2020.). The art also indicates that the efficacy of treatment varies unpredictably depending on the underlying genetic defect in MDC1A. For example, Körner found that although, “the proteasome inhibitor bortezomib partially improves muscle morphology and increases lifespan in dy3k/dy3k mice…bortezomib neither improved histological hallmarks of disease nor increased muscle strength and locomotive activity in dy2J/dy2J mice.” (Abstract. Körner et al. Bortezomib Does Not Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy. PLoS One. 2016 Jan 5;11(1):e0146471.). Altogether, the state of the art indicates that the pathophysiology of the disease was poorly understood, treatment outcomes vary unpredictably, and the art had not yet yielded an effective disease-modifying treatment.
As discussed in the above rejection of the claims under 35 U.S.C. § 103, customizable FKBP12/FRAP dimerizer systems for activating gene expression by expressing and forming heterodimers with a DNA binding domain to target a promoter and a transcriptional activation domain to activate transcription at that promoter were known in the art, with Pollock’s disclosure being published in 2002. Zinc finger proteins and the means to engineer their target specificity were also known in the art, as indicated by Pollock. Therefore, adapting the dimerizer system by substituting an appropriate zinc finger protein to target a chosen promoter would have been within the reach of the ordinary artisan. However, claim 1 recites a generic system of which the known dimerizer system is only a species, and which may vary significantly in function and outcome depending on what epigenetic modulator is used and what promoter is targeted. Additionally, claim 47 recites a broad method of treating MDC1A, but likewise does not state what promoter is to be targeted and does not state whether transcription is to be activated or repressed to treat MDC1A.
In order to practice the claimed invention, an undue amount of experimentation would be required. For example, it would be necessary for one of ordinary skill in the art to design a DNA binding domain and epigenetic modulator for every gene which may be involved in MDC1A pathophysiology and may be a viable therapeutic target, then administer the treatment. Additionally, given the teachings of the prior art, it appears likely that an epigenetic modulator which represses transcription of LAMA1 would not lead to the claimed treatment outcome, since the prior art shows that it is activation of LAMA1 which compensates for the LAMA2 deficiency in MDC1A.
The invention is the class of invention that the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art (MPEP 2164.03). Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue amount experimentation would be required to make and use the invention as claimed.
Conclusion
No claims are allowed at this time.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636