DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to an amendment filed 3/30/2026.
Claims 1, 2, 4, 6, 10, 20, 32-38, 98, 99. 101-103 and 107-117 are pending.
The instant application is a 371 filing of PCT/US2019/049793 filed 9/5/2019 which claims priority to U.S. provisional application 62/727,500 filed 9/5/2018.
Information Disclosure Statement
An information disclosure statement filed 6/30/2026 has been identified and the documents considered. The corresponding signed and initialed PTO Form 1449 has been mailed with this action. considered. The signed and initialed PTO Form 1449 has been mailed with this action. Applicants have asserted in the statement filed under 37 CFR 1.56, 1.97 and 1.98.
Response to Amendments
The previous objections to the claims have been overcome by amendment. The following new observations are presented below.
Claim Objections
Claim 1 is objected to because of the following informalities: because of the amendment, claim 1, line 11 should recites --wherein the napDNAbp bound to the gRNA directs--. Appropriate correction is required.
Claim 99 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 98. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). By amendment the adenosine base editor is delivered by one or more AAV vectors hence both claim 98 and 99 recite the same limitations.
Claim Rejections - 35 USC § 112
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.
Claim 1 is 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. This is a new rejection necessitated by applicants’ amendment.
Claim 1 by amendment recites that the adenosine base editor and gRNA are “delivered to the heart by one or more AAV. At the same time, the claim states that the method requires contacting the LMNA gene with these components. The step of contacting is a hand of man step wherein the practitioner does the contacting. The step of delivering the AAV to the heart suggests injection or intraarterial administration of some sort. But it cannot be both and hence it is unclear if the adenosine base editor and gRNA are contacted by the practitioner or injected.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4, 6, 10, 20, 32-38, 98, 99. 101-103 and 107-117 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method for correcting a C1824T mutation in an lamin A/C (LMNA) gene, the method comprising intraarterial administration of one or more AAV encoding an adenosine base editor comprising an napDNAbp with at least 95% identity to the amino acid sequence of SEQ ID NO:73 and at least one adenosine deaminase with at least 95% identity to the amino acid sequence of SEQ ID NO:10 and, wherein the guide RNA (gRNA) comprises a guide sequence that binds with at least 10 contiguous nucleotides with 100% complementarity to the LMNA gene mutation, wherein the gRNA binds to the adenosine base editor thereby converting the T:A base pair at residue position 1824 to a C:G base pair wherein the adenosine base editor coding sequences are operably linked to an expression control sequences , does not reasonably provide enablement for any other embodiment. 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 use the invention commensurate in scope with these claims. The basis of the rejection has not been overcome. The issues remaining are underlined above.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to a method of correcting a mutant LMNA gene. It entails introducing into a cell comprising the mutant LMNA gene gRNA sequences bound to an adenosine base editor that thereafter converts the T to a C in C1824T
2) Scope of the invention. The scope of the invention is extremely broad in that the method as performed does not designate the location of the cell and a read through of the claims indicates that the method is performed in vivo as well as in vitro. Secondly, the method of contacting lacks specificity. Finally, a number of molecules are claimed in terms of sequence identity to adenosine deaminase, Cas9, adenosine base editor.
3) Number of working examples and guidance. The specification discloses in vitro data that demonstrates that ABEmax corrects a C1824T point mutation in LMNA gene. ABEmax is a A base editor in that it modifies to an A. Fibroblasts from two different HPGS patients were infected with lentivirus expressing ABEmax and sgRNA targeting c.1824 to generate a T to C point mutation in LMNA gene. 10 days post-infection, 38% and 61% correction of LMNA c.1824, respectively, was observed (e.g., ¶ 0317). Figure 3 provides in vivo mouse experimental demonstrating the use of base editor to correct a C1824T point mutation in LMNA. AAV- mediated in vivo somatic cell base editing of LMNA corrects the T1824 mutation, restores lamin A mRNA and protein. An optimized dual split-ABEmax AAV9 construct was used to inject homozygous human LMNA C1824T knock-in mice to determine whether the T1824 point mutation could be corrected. Panel C of Figure 2 shows T to C correction at c.1824 in the DNA of four different tissues (heart, liver, skeletal muscle and aorta). Panel D of Figure 3 shows an increase in full length LMNA mRNA in the liver and heart of treated mice, while panel E of Figure 3 shows an increase in wild-type Lamin A protein in the liver and heart of treated mice. The data demonstrate that ABEmax AAV9 is capable of correcting a C1824T mutation in mouse heart, liver, skeletal muscle and aorta (e.g., ¶ 0318). Intraperitoneal injection of the split-intein AAV containing the ABE and the sgRNA corrects the C1824T mutation in a mouse model of HGPS and has an efficiency of >30% editing in the heart and >50% editing in the liver (e.g., ¶ 0325).
4) State of the art. The art as claimed embraces two disciplines. The first is correction of LMNA gene mutations that contribute to Hutchinson-Gilford progeria syndrome (HGPS) and therapeutic interventions. And the second is use of napDNAbp and adenosine deaminase with gRNAs to correct a mutant phenotype.
HGPS is known as premature aging syndrome caused by a spontaneous point mutation (c.1824C>T) in the LMNA gene which results in the synthesis of progerin, a mutant version of lamin A. It is a dominant de novo mutation wherein complications in health are caused by the buildup of progerin as this protein does not undergo the usual lamin A processing (see page 2, col 2 of Cisneros). To treat this, the art teaches there are two approaches (Cisneros, page 4, col 2).
The spectrum of therapies that have been addressed can be divided into two groups: a) progerin-targeting strategies ; and b) strategies aimed at alleviating the harmful effects driven by progerin
Discussion of genome editing details the need for specificity but also the inability to translate from in vitro and mouse models to humans (Cisneros, bridging paragraph, pages 4-5). As to the second approach, Zokinvy has been approved to reduce the effects of progerin accumulation with some success (See Suzuki, 2023, page 4, col 1).
5) Unpredictability of the art. The use of ABE for correction of HGPS has run into the same issues demonstrating a level of unpredictability found in the art of genome editing. Primarily, delivery is the beginning and the end of all obstacles. The state of the art of delivery of biomolecule delivery at the time of filing had established the following. First, animal models did not correlate with humans when looking at modes of delivery. This is an established fact. The physiology and the size of the mouse do not correlate with human anatomy. As well, endpoints in mice studies do not comport well with the need not to overwhelm the human system with biomolecules. In other words, increasing doses in NHP and humans have led to death. Hence, mice models have allowed proof of principle issues to be established. In patent prosecution, this is relevant wherein the ability to establish a correlation is necessary.
The issue of ‘correlation’ is related to the issue of the presence or absence of working examples. ‘Correlation’ as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a ‘working example’ if that example ‘correlates’ with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute ‘working examples’.
As reviewed by Lin et al, page 1, col 2, therapeutic editing requires an effective and targeted delivery method for humans. This has not been found wherein trials with AAV8 and AAV9 as well as LNP and electroporation have been proposed, none have been found to adequately serve the purposes of treatment (Line et al, page 2, col 2).
In addition, the delivery efficiency and specificity of gene editing for the pathogenic human LMNA c.1824 C > T allele need to be tested in clinical application, which is challenging and often involves years of try and error practice. Moreover, what is the optimal distribution of ABEmax-VRQR, and which organs can be targeted by distinct delivery methods (AAV, LNP, EP or others)? Although in vivo delivery for therapies remains many challenges, we anticipate that further testing could determine the suitable delivery for gene therapy to control diseases and improve human health.
This is also impacted by immunogenic effects which also requires consideration of delivery mechanisms complicated by the impact of the immunity against the delivery agent. These were reviewed in the previous action. It is provided here for completeness.
“Kotterman et al., 2014 (Nature Reviews, Vol. 15, p. 445-451) reports that AAV still has significant challenges regarding successful use in treatment regimens (pg. 450 col. 2). Specifically Kotterman points out “widespread natural exposure to AAVs has resulted in a large portion of the population with neutralizing antibodies specific to capsids in the blood and other body fluids, which markedly limit gene delivery by many natural vectors... following cellular transduction, AAV capsid epitopes can become cross-presented on major histocompatibility complex (MHC) class I molecules, which leads to the elimination of transduced cells by capsid- specific cytotoxic T lymphocytes and the corresponding loss of gene expression". “For systemically administered viruses, the liver is often the default destination, which can represent a barrier when other organs are the intended targets. In addition, endothelial cell layers, especially those within the blood-brain barrier, pose a physical barrier for entry into a tissue. A vector that gains access to an organ, or that is directly administered to that organ, can then encounter numerous transport barriers to efficient transduction of the often large tissue volumes involved in disease, including cell bodies and intervening extracellular matrix to which many AAV variants bind". “The surface of a target cell may lack the primary and/or secondary receptors that are necessary for vector binding and internalization. Furthermore, endosomal escape, proteasomal escape, nuclear entry and vector unpackaging all represent barriers to transduction" (e.g. p. 447, under BOX 1).
Shim et al., 2017 (Current Gene Therapy, Vol. 17, No. 5, p. 1-18) reports that in all gene therapy applications, delivery issues are essential, and nucleic acids are highly polar macromolecules and cannot diffuse through cell membranes. For the delivery of nucleic acids into target cells, viral and nonviral methods have been used. Despite success, viral vectors still suffer from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems (e.g. p. 1, right column, 2™ paragraph). “Although nonviral methods have many advantages, including safety, the reasons these methods are falling behind viral methods with regard to outcomes might still be a matter of “delivery”, including passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release... Behavior in the physiological environment is the most important hurdle for vectors” (e.g. p. 13, left column, 4 full paragraph). Thus, viral vector delivery of nucleic acid still suffers from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems. Nonviral delivery of nucleic acid still face the hurdle of passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release.
Lenzi et al., 2014 (NCBI Bookshelf, A Service of the National Library of Medicine, National Institute of Health, Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington (DC): National Academies Press (US), pages 1-16) discuss scientific hurdles of gene transfer in vivo. Some scientific hurdles, such as the absence of efficient delivery systems, difficulty with sustained expression, insertional mutagenesis and host immune reactions, remain formidable challenges to the field of gene transfer. Many of the hurdles have to do with providing efficient gene delivery. For examples, the vector uptake and distribution must be tightly controlled so that expression of the vector-encoded gene remains within the therapeutic range-if the expression is too low, the functional protein product may not be produced at a high enough concentration to effectively restore the intended biochemical pathway. Transcription of the new genetic material must remain stable so that the transgene is expressed as long as necessary to treat the disease. The degree to which the vector containing the transgene is taken up in a sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the capacity and production problems (e.g. p. 1, right column, 2™ paragraph). “Although nonviral methods have many advantages, including safety, the reasons these methods are falling behind viral methods with regard to outcomes might still be a matter of “delivery”, including passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release... Behavior in the physiological environment is the most important hurdle for vectors” (e.g. p. 13, left column, 4 full paragraph). Thus, viral vector delivery of nucleic acid still suffers from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems. Nonviral delivery of nucleic acid still face the hurdle of passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release.
Lenzi et al., 2014 (NCBI Bookshelf, A Service of the National Library of Medicine, National Institute of Health, Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington (DC): National Academies Press (US), pages 1-16) discuss scientific hurdles of gene transfer in vivo. Some scientific hurdles, such as the absence of efficient delivery systems, difficulty with sustained expression, insertional mutagenesis and host immune reactions, remain formidable challenges to the field of gene transfer. Many of the hurdles have to do with providing efficient gene delivery. For examples, the vector uptake and distribution must be tightly controlled so that expression of the vector-encoded gene remains within the therapeutic range-if the expression is too low, the functional protein product may not be produced at a high enough concentration to effectively restore the intended biochemical pathway. Transcription of the new genetic material must remain stable so that the transgene is expressed as long as necessary to treat the disease. The degree to which the vector containing the transgene is taken up in a sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the efficiency of interactions between vector and host cell receptors. Administration routes also play an important role to determine whether sufficient DNA or vector can be obtained at target sites in a subject. Different administration route of the nucleic acid can result in different efficiency of gene expression and can influence whether sufficient expressed gene product can be obtained at the target cells so as to perform its purpose in vivo. The type of promoter used also can affect the efficiency of desired nucleic acid and gene product expressed at the target cells and whether sufficient nucleic acid and gene product is expressed so as to provide desired effect for treating a disease or condition or for altering physiological or disease trait in vivo.”
Third, the claims noted in the double patenting rejection above recite functional outcomes which are according to the specification inherent to the steps as recited. Hence, the description of the method encompasses those steps and no other steps or structures are required to mediate these effects.
The following are incorporated from the response to the previous office action
Applicants refer to a number of preclinical and clinical results as evidence that the art is predictable. While the various preclinical models and clinical trials are valid demonstrations of the promise and interest in developing gene editing techniques, the references in totality demonstrate that even post filing the unpredictability of use of a complex as recited was known (Cisneros bridging ¶ page 4-5).
Altogether these results demonstrate the potential of gene-editing technology for the treatment of patients with HGPS; however, the limitations of these therapies, including out of target effects at the chromosomal level, and side effects associated to the viral delivery system (gene integration, immune system induction) should be carefully considered before their translation to clinics.
Gutman teaches, page 847, col 1, ¶1.
While straightforward in principle, executing preclinical studies in mice that allow for meaningful and immediate application to the treatment of human cancer is difficult. Moreover, the potential use of GEM cancer models to accelerate the process of bringing effective new treatments to patients is largely theoretical, as few examples exist in which mouse preclinical data has been successfully translated to clinical practice.
Sharma (Molecular Therapy, 2021), page 578, col 2, states
Although both preclinical work and clinical trials focusing on curative therapies are proceeding globally, the clinical translation of CRISPRCas9-mediated gene correction is associated with unpredictable outcomes.186 Factors affecting the success rate of CRISPR-Cas9- mediated gene editing in humans includes off-target effects and cargo delivery methods. It has been observed that off-target effects are principally guided by sgRNAs, and thus rational designs of sgRNAs are necessary to ensure the efficiency of CRISPR-Cas9 gene-editing technology. It was observed that off-target effects were common in human cell culture with persistent Cas9 expression.187,188 while these effects were less common in in vivo models.189 It might be plausible that the occurrence of off-target effects in cell cultures are due to the influence of various factors, such as cell type, expression level, transfection method, cell culture maintenance, consecutive nuclease expression, guide sequence, and repair events.18
Zhang cited by applicants recognizes this
In summary, the A50;h51KI humanized DMD mice described in this study, combined with the optimized SpCas9-VRQR-mediated single-cut gene editing, should facilitate clinical translation of CRISPR-Cas gene editing as a means of permanent correction of DMD in humans.
Hence, the preclinical models demonstrate POTENTIAL application in humans.
What does stop the direct translation of the preclinical models and what is sought in the clinical trials is overcoming the barriers to achieve efficient and adequate gene delivery. These trials seek to determine vector/delivery mode that is necessary to understand for each of the disorders. The trials are set up to determine this. Sharma, page 580, col 1,
As the treatment of human diseases needs to be tissue-specific, it is essential to efficiently deliver the CRISPR-Cas9 cargo into target tissue. Therefore, additional consideration should be given to the suitable delivery system that is based on the charge, size, and content of the CRISPR-Cas9 cargo. CRISPR-Cas9 cargo may be of three types, i.e., plasmid DNA encoding sgRNA and Cas9, a combination of sgRNA and Cas9 mRNA, and a combination of sgRNA and Cas9 protein. Various physical, viral, and non-viral systems have been used as vectors for the delivery of CRISPR-Cas9
Relevant to this method, Sharma also teaches the obstacles associated with DNA repair methods (see page 579, last ¶ to page 580, first ¶). As set forth by Hirakawa et al, 2020, Bioscience Report, page 10, ¶5),
The trials to date have focused on easily accessible tissues, such as the cervix, eye, and liver. The latter being the most likely place for the delivered editing agent to accumulate.
Systemic administration increases the risk of off-target effects. And these are found with editor function, Hirakawa et al, page 15,
An ideal gene editor would exhibit perfect specificity for the target sequence and cause no mutations to any other region of the genome. Unfortunately, CRISPR/Cas-based editors (and other editors, such as ZFNs and TALENs) rarely achieve such a high standard. Off-target effects primarily arise from the sgRNA seed sequence or PAM sequences binding with sequence mismatches (1–5 bps have been shown to be tolerated) but can also be influenced by cell type and the DNA repair pathways in a particular cell type. The reader is referred to Zhang et al. [166] for a more thorough review of the mechanisms of CRISPR off-target effects. Off-target effects were postulated early in the development of gene editors and recent advances have increased the sensitivity for detection of these effects. As a result, off-target effects have been shown in virtually all systems studied.
This has led to the need to find delivery routes that are effective for the particular in vivo target. This is the teachings of Raguram which applicants cite.
With current in vivo delivery modalities, gene editing agents can be readily delivered to cells in the liver via intravenous injection and to cells in the eye via intraocular injection. For this reason, in vivo gene editing therapies in the near future will likely treat diseases that can be addressed through editing the liver or eye. Efficient delivery to non-liver tissues following intravenous administration remains a major challenge for most delivery vehicles. The use of naturally occurring and newly engineered AAV capsids is a promising strategy for targeting non-liver tissues, including the CNS (Goerisen et al., 2022), skeletal muscle (Tabebordbar 2021), and heart (Koblan al., 20215). Analogous strategies could prove useful for retargeting VLPs to target new cell types by using different envelope glycoproteins.
This supports Jo et al which is an eye related disorder. Given the closed and accessibility of that organ However, delivery vehicles often accumulate in the liver when systemically delivered.
The development of LNPs that enable efficient non-liver delivery remains a critical goal for the therapeutic gene editing field. Understanding the mechanisms by which different LNP formulations enable different tissue-targeting properties might enable better methodologies for engineering new LNPs with desired targeting capabilities (Dilliard 2021).
Applicants have not indicated a target organ or means to successfully deliver to this organ. Considering the heart which is a main target of LMNA therapy, Legere and Hinson teach,
(page 1236, col 1) Since the discovery of CRISPR-Cas9 technology, many delivery strategies have been employed to target the heart, yet important gaps in knowledge and capabilities remain.
(page 1237, col 2) The use of LNPs targeting the heart has been restricted to date due to poor tropism. LNP’s surface structure favors passive accumulation in the liver, which is problematic for therapeutic development aimed at correcting damaged cardiac muscle
6) Undue experimentation. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. The MPEP teaches, "However, claims reading on significant numbers of inoperative embodiments would render claims non- enabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative. Atlas Powder Co. v. E.I. duPont de Nemours & Co., 750 F.2d 1569, 1577, 224 USPQ409, 414 (Fed. Cir. 1984); In re Cook, 439 F.2d 730, 735, 169 USPQ 298,302 (CCPA 1971). (see MPEP 2164.08(b). In this case, the following issues add up to a significant number of inoperative embodiments such that undue experimentation would have been required. Because the art is nascent as to delivery of genome editing structures to humans for targeted therapy and because the claims rely as a critical factor on an underdeveloped aspect of the art, the claims lack enablement. These means to use genome editing components as recited are to be developed, they did not exist at the time of filing.
Response to Arguments
Applicants’ arguments as relates to the instant claims are the following. First, it is noted that the lack of promoter directing expression as required of sequences for expression is not corrected in the claims. However, the main issue is whether one can reach the target sufficiently with the claim as recited. Delivery does not comport to administering to the heart. As well, the system does not allow one to determine who is suspected of having HGPS (claim 38) and hence it is not enabled as recited.
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.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634
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