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 II and the species Alzheimer’s and vasculogenic factor Etv2 in the reply filed on 3/11/25 is acknowledged.
Claims 19-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 3/11/25.
It is noted that as instantly drafted, claim 13 requires for the neurodegenerative disease to comprise (have) all of the recited conditions. Given that applicant elected Alzheimer’s, the claims have been considered to the extent to which they read upon Alzheimer’s disease.
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 11, 13, 17, and 18 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 delivering polynucleotides encoding nucleic acid sequences that encode genes to skin cells, does not reasonably provide enablement for a method of delivering any polynucleotides encoding any cargo intracellularly into skin cells via any means with the predictable outcome of delivering the cargo to the brain. 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 instant claims are directed to a method for delivering intracellularly into skin cells of the human subject with a neurodegenerative disease any polynucleotide comprising nucleic acid sequences encoding any cargo via any means with the predictable outcome of delivering the cargo to the brain.
The instant claims are directed to delivering intracellularly into skin cells of the human subject a polynucleotide comprising nucleic acid sequences encoding any cargo with predictable delivery to the brain. Delivery of cargo into skin cells intracellularly would not necessarily result in delivery to the brain.
Although applicant argues that the skin cells would necessarily travel to the brain, applicant’s example is not representative of delivery of any possible cargo to any skin cell on the human body and a predictable outcome of delivery to the brain.
The specification does not draw an adequate nexus between delivery of any cargo to the skin intracellularly and the predictable outcome of delivery to the brain.
Therefore, the specification is not enabling for the entire claimed scope.
Additionally, the specification is not enabling for delivery of any cargo intracellularly into skin cells of a subject via any means with the predictable outcome of producing a skin-derived exosome, which is not recited but appears to be necessary for the instant method. Delivery of any cargo intracellularly to skin does not necessarily and predictably a) produce a skin-derived exosome or b) predictably result in brain delivery.
The specification demonstrates a gene expression profile of specific genes that are upregulated or downregulated in Alzheimer’s disease; and demonstrate that mRNA can be transferred from exosomes in culture in vitro in murine primary neuron cultures. However, the specification does not demonstrate delivery of any possible polynucleotide encoding any possible cargo intracellularly into skin cells with the predictable outcome of delivery to the brain.
Chen et al. (Cellular and Molecular Bioengineering, Vol. 9, No. 4, 2016, 509–529) teach that cell-derived exosomes can cross the blood-brain barrier model under stroke-like conditions in vitro, but not under normal conditions. Chen et al. teach that this study encourages further development of engineered exosomes as drug delivery vehicles or tracking tools for treating or monitoring neurological diseases. Chen et al. teach that it is likely that a fraction of the exosomes fuse with lysosomes resulting in their digestion (page 526). Chen et al. teach that a different possible fate of internalized exosomes is the fusion of multivesicular bodies with lysosomes to degrade the exosomes/intraluminal vesicles. Furthermore, different pathways of exosome secretion can differ between different cell types (page 526). Therefore, exosomes are known to be able to cross the blood-brain barrier under certain conditions and not others, supporting the unpredictability of any possible skin-derived exosome necessarily and predictably migrating to the brain, crossing the blood-brain barrier, and treating any possible brain disease, disorder, or injury.
Additionally, Duran-Mota et al. (ACS Biomater.Sci.Eng., 2021,7,4347−4361) teach: gene therapy (such as mRNA therapies) has emerged as a viable option to promote wound healing through modulation of gene expression. However, protecting the genetic cargo from degradation and efficient transfection into primary cells remain significant challenges in the push to clinical translation. Another limiting aspect of current therapies is the lack of sustained release of drugs to match the therapeutic window. Herein, we have developed an injectable, biodegradable and cytocompatible hydrogel-based wound dressing that delivers poly(β-aminoester)s (pBAEs) nanoparticles in a sustained manner over a range of therapeutic windows. We also demonstrate that pBAE nanoparticles, successfully used in previous in vivo studies, protect the mRNA load and efficiently transfect human dermal fibroblasts upon sustained release from the hydrogel wound dressing. This prototype wound dressing technology can enable the development of novel gene therapies for the treatment of chronic wounds (abstract).
Duran-Mota et al. is evidence that cargo can be delivered intracellularly into skin cells in the dermis layer of the skin and have action therein rather than necessarily migrating to the brain.
Chong et al. (Journal of Controlled Release1, 66, (2013), 211-219) teach: To be efficacious and widely accepted by physicians and patients, therapeutic siRNAs must access the viable skin layers in a stable and functional form, preferably without painful administration. In this study we explore the use of minimally-invasive steel microneedle devices to effectively deliver siRNA into skin. A simple, yet precise microneedle coating method permitted reproducible loading of siRNA onto individual microneedles. Following recovery from the microneedle surface, lamin A/C siRNA retained full activity, as demonstrated by significant reduction in lamin A/C mRNA levels and reduced lamin A/C protein in HaCaT keratinocyte cells (abstract).
Chong et al. is evidence that cargo can be delivered intracellularly into skin cells and have action therein rather than necessarily migrating to the brain.
Even with regards to the elected species of gene, Etv2, the specification is not enabling for delivery of Etv2 intracellularly into skin cells via any means predictably resulting in delivery to the brain. Applicant has not demonstrated that intracellular delivery to any possible skin cell of Etv2 predictably results in Etv2 delivery to the brain.
The specification is not enabling for delivery of any cargo to any skin cell of an individual with any possible neurodegenerative disease with the predictable outcome of delivering the cargo to the brain.
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 intracellularly delivering to skin cells any polynucleotide encoding any cargo and resulting in delivery to the brain 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 polynucleotide encoding any cargo delivered intracellularly to skin cells in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful delivery to the brain. 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)).
Response to Arguments
Applicant argues that the Examiner has alleged that the specification does not enable delivery of cargo to the brain via intracellular delivery into skin cells because the outcome is unpredictable. Applicants respectfully disagree. The specification and the evidence of record demonstrate that agents expressed in the skin result in gene products and a biological response in brain tissue-a previously unknown skin-brain axis-and, without being bound by theory, this “may” be mediated by skin-derived exosomes or other components of the skin secretome. Because the skin-to- brain route is a property of the route itself, not of any particular transgene, a person of ordinary skill in the art would have a reasonable expectation of success across the claimed scope.
Contrary to applicant’s arguments, the specification does not draw an adequate nexus between delivery of any naked polynucleotide comprising nucleic acid sequences encoding any possible cargo intracellularly via any means in vivo into skin cells and the predictable outcome of delivering the cargo to the brain. It is noted that the specification is enabling for the actual recited method step of delivering intracellularly in vivo into skin cells a polynucleotide encoding a cargo, but the instant rejection is based upon the intended use of the preamble.
Applicant argues that the specification provides direct in vivo evidence that skin-derived signals reach the brain. FIG. 2A shows that tissue nanotransfection (TNT) was used to deliver CD63-GFP plasmids to the skin of healthy mice to label the exosomes. FIG. 2B shows that the GFP signal was detected in the brain 24 hours post-TNT on the skin, "suggesting that skin-derived exosomes appeared to be able to enter circulation and lodge in the brain." As-Filed Specification, paragraph [0013]. The Declaration under 37 C.F.R. § 1.132 by Dr. Daniel Gallego-Perez ("Gallego-Perez Declaration") provides additional evidence that human transgenes expressed in grafted skin appear in the brain. Taken together, this data supports the discovery that agents expressed in the skin can result in gene products in the brain-i.e., a skin- brain axis that was not previously known or predictable.
The data argued by applicant is not commensurate in scope with the instant claims. The limited experimental evidence does not enable the full scope of delivering any encoded cargo from skin cells to the brain. Regarding Figures 2A and 2B, the specification itself characterizes these findings as “suggesting” that skin-derived exosomes can enter circulation and lodge into the brain. The examples in healthy mice are not commensurate in scope with human subjects having any neurodegenerative disease; the CD63-GFP reporter construct is not commensurate in scope with polynucleotides encoding any possible cargo; the TNT delivery into the skin is not commensurate in scope with any means of intracellular delivery into the skin cells; and detection of GFP in brain tissue is not commensurate in scope with successful delivery of any encoded cargo to the brain.
Detection of GFP associated with a reporter construct does not predictably establish that arbitrary encoded cargo will be expressed, incorporated into exosomes, and transported successfully to the brain. Applicant has demonstrated a particular experimental system and drawn possible conclusions rather than establishing the general applicability of the system to any claimed cargo.
CD63 is an exosome-associated protein, making CD63-GFP particularly suitable for labeling exosomes. The results do not establish that unrelated proteins, therapeutic factors, or functional nucleic acids will predictably incorporated into skin-derived exosomes and delivered to the brain in the same manner.
Additionally, brain fluorescence does not establish functional cargo delivery. Figure 2B does not independently establish that an arbitrary cargo was successfully transported to the brain, including various cargo that lack the exosome-associated characteristics of CD63. The results are limited to a particular reporter construct delivered using a particular transfection technique in healthy mice.
Applicant argues that claim 11 as amended does not recite production of a skin-derived exosome; it recites delivering intracellularly in vivo into skin cells of a human subject with a neurodegenerative disease a polynucleotide encoding the cargo. The Examiner's objection that exosome production and migration are unpredictable is therefore directed to a limitation the claim no longer contains. It is noted that the exosome is present in the examples argued by applicant, which is not commensurate in scope with the amended claims. Applicant argues that what the claim requires is that the cargo reach the brain, and the specification's guidance at paragraphs [0067]-[0084] on transfecting the skin of the subject and the disclosed cargo classes means no undue experimentation is required to practice the claimed method.
Contrary to applicant’s arguments, the paragraphs cited by applicant address how to introduce and express polynucleotides in cells, not how to ensure that the encoded cargo subsequently reaches the brain. Even upon transfection as disclosed in the cited paragraphs, it is unpredictable if the encoded cardo will be expressed in the transfected cells, incorporated into an extracellular vesicle (although not claimed, appears necessary for the function), if the vesicles will leave the skin and enter circulation, reach the brain, and be delivered to the brain rather than distributed to other tissues. The passages cited by applicant do not enable a predictable method of delivering any possible cargo to the brain of a human subject with any neurodegenerative disease comprising delivering intracellularly via any means into skin cells of the human subject a polynucleotide encoding the cargo.
The specification does not provide sufficient guidance regarding which encoded cargos are capable of undergoing the necessary trafficking from skin cells to the brain, or which structural or functional characteristics of the encoded cargos facilitate such transport.
Applicant argues that the references cited by the Examiner do not establish unpredictability. Chong et al. and Duran-Mota et al. show only that delivered nucleic acid can act locally in skin. Local action and secretome-mediated export are not mutually exclusive, and neither reference tested for brain delivery. Chen et al. concerns exosome uptake in an in vitro blood-brain barrier model and does not address in vivo skin-derived secretome trafficking. None of these references undermines the specification's direct evidence that skin-expressed agents reach the brain.
The examiner acknowledges that the demonstration of local activity following delivery of a nucleic acid to skin cells does not necessarily exclude the possibility that the nucleic acid or its encoded product may also undergo systemic transport or reach the brain. The references are not cited to establish that skin-to-brain delivery is impossible, but rather that delivery to skin cells and subsequent local action does not predictably enable or establish delivery of the encoded product to a distant organ.
The issue is not whether delivery to the brain is a possibility, but rather whether the specification, together with what was known in the art at the time of filing, teaches the skilled artisan which combinations of cargo, polynucleotide, skin-cell type, delivering modality, expression/secretion characteristics, systemic transport properties, and blood-brain transport characteristics will actually deliver any possible encoded cargo to the brain without undue experimentation. The specification is required to enable the full scope of the claims.
The specification does not draw an adequate nexus between intracellular delivery of any nucleic acid encoding any possible cargo to a skin cell and the predictable outcome of brain delivery. The polynucleotide must enter the skin cell and remain sufficiently functional, the encoded cargo must be expressed, the cargo must exit the skin cell or enter systemic circulation, it must remain sufficiently stable in vivo, it must cross the blood-brain barrier, and successfully be delivered to the brain. It would involve undue experimentation to determine which nucleic acids encoding which cargo would result in brain delivery.
The breadth of the instant claims requires undue experimentation including which cargo reaches the brain, construct design, assessment of cargo loading into exosomes, biodistribution, and confirmation of brain delivery.
The claimed genus of cargo ranges from small peptides to large proteins/transcription factors, antibodies, enzymes, growth factors, etc., each having different cargo considerations for brain delivery. For example, Sterzenbach et al. (Molecular Therapy, 2017, 25, 6, 1269-1278) demonstrated that exosomal incorporation of Cre recombinase depended upon engineering the cargo with a WW domain that facilitated recognition by the exosomal sorting machinery. Sterzenbach et al. is evidence that specific structural features are needed for different types of cargo.
Accordingly, the CD63-GFP results in instant Figures 2A and 2B do not establish that structurally and functionally diverse encoded cargos would undergo comparable extracellular vesicle incorporation and subsequent delivery to the brain.
The instant specification, nor the declaration, are enabling for delivery of a polynucleotide encoding any possible cargo (i.e. any siRNA, any transcription factor, etc.) to the skin intracellularly via any means and the predictable outcome of delivery to the brain.
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 11 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rosenberg et al. (US 2007/0280953 A1).
Rosenberg et al. teach methods for treating Alzheimer’s disease comprising administration of an Aβ gene vaccine to a human that has been diagnosed with Alzheimer’s disease [0013] (instant claims 11 and 13).
Rosenberg et al. teach delivery of a nucleic acid encoding the Aβ gene vaccine [0016] and teach intradermal administration [0015]. Rosenberg et al. exemplify delivery to mice ear skin using a gene gun [0161] (instant claim 11).
Therefore, Rosenberg et al. teaches delivering intracellularly, in vivo, into skin cells of a human subject, a polynucleotide comprising a nucleic acid encoding a cargo for treatment of Alzheimer’s disease.
Recitation of “delivering a cargo to the brain” of the preamble of instant claim 11 does not require any additional method step. The method step of delivering intracellularly in vivo into skin cells of a human subject with a neurodegenerative disease a polynucleotide comprising nucleic acid sequences encoding the cargo is anticipated by Rosenberg et al. In absence of an additional method step, the intended outcome of the preamble would necessarily flow from the recited method step.
Since Rosenberg et al. teaches a method comprising each of the instant method steps, the method would necessarily achieve the recited outcome of delivering a cargo to the brain, absent evidence to the contrary. As stated in the MPEP (see MPEP 2112), something that is old does not become patentable upon the discovery of a new property.
Therefore, the claims are anticipated by Rosenberg et al.
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) 11 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Davtyan et al. (Neurodegenerative Dis 2012;10:261–264).
Davtyan et al. teach DNA-based vaccination for the treatment of Alzheimer’s disease using an Alzheimer’s disease DNA epitope vaccine. Davtyan et al. teach intradermal administration of the DNA vaccine by gene gun. Davtyan et al. teach that the gene gun administers plasmid DNA into the epidermal layer of the skin and provides effective intracellular delivery of DNA plasmids in vivo.
Therefore, Davtyan et al. teach a method of delivering intracellularly, in vivo, into skin cells a polynucleotide comprising a nucleic acid sequence encoding the vaccine cargo.
The recitation of the preamble of delivering a cargo to the brain does not recite a separate method step. The only method step required by the instant claims is delivering intracellularly in vivo into skin cells of a human subject with a neurodegenerative disease a polynucleotide comprising nucleic acid sequences encoding the cargo, which is anticipated by Davtyan et al.
Alternatively, even if “delivering a cargo to the brain” is construed as imposing a limiting result, the limitation does not require any additional act/step. To the extent that delivery of the encoded cargo to the brain necessarily results from practicing the recited method step, the result is inherent and would necessarily flow from the method step.
Although Davtyan et al. does not expressly teach that the subject is human and teaches the method in mice, Davtyan et al. teaches that the two major delivery methods used for enhancing DNA uptake and immune responses to DNA vaccines in humans are electroporation (EP) and gene gun (GG) (page 261) and teaches that both delivery methods are effective at promoting potent antibodies specific for Aβ and that induction of a humoral response against amyloid- peptide may be beneficial for Alzheimer’s disease (AD) patients and may alleviate the onset and progression of AD (page 261).
In fact, the reasoning taught by Davtyan et al. for utilizing the gene is that low immunogenicity of DNA vaccines has been a problem in humans (page 262, column 1) and to select a suitable device for delivering DNA vaccines to humans (page 262, column 2). Clearly the intended use of the method of Davtyan et al. is to treat a human with AD. Given that the gene gun method was known to be used to deliver DNA vaccines successfully in humans and Davtyan et al. demonstrates that the method results in effective promotion of potent antibodies specific for Aβ, one would have had a reasonable expectation of delivering the polynucleotide comprising a nucleic acid encoding the cargo of Davtyan et al. into skin cells with the gene gun of Davtyan et al. in vivo in humans.
Claim(s) 17 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rosenberg et al. (US 2007/0280953 A1) as applied to claims 11 and 13 above, and further in view of Gallego-Perez et al. (Nature Nanotechnologoy, 12, 2017, 974-979), Morita et al. (PNAS, 2015, 112, 1, 160-165), and Wang et al. (Biochemical and Biophysical Research Communications 411 (2011) 620–626).
Rosenberg et al. teach methods for treating Alzheimer’s disease comprising administration of an Aβ gene vaccine to a human that has been diagnosed with Alzheimer’s disease [0013] (instant claims 11 and 13).
Rosenberg et al. teach delivery of a nucleic acid encoding the Aβ gene vaccine [0016] and teach intradermal administration [0015]. Rosenberg et al. exemplify delivery to mice ear skin using a gene gun [0161] (instant claim 11).
Therefore, Rosenberg et al. teaches delivering intracellularly, in vivo, into skin cells of a human subject a polynucleotide comprising a nucleic acid encoding a cargo for treatment of Alzheimer’s disease.
Rosenberg et al. do not teach that the cargo is a vasculogenic factor (instant claim 17), more specifically Etv2 (instant claim 18).
It would have been obvious to utilize the delivery system of Rosenberg et al. to delivery Etv2 cargo because Gallego-Perez et al. teach that polynucleotides encoding reprogramming factors including Etv2 can be delivered intracellularly in vivo into skin cells and that expression of the factor reprograms resident skin cells toward an endothelial phenotype, increases vascularization, and restores perfusion (pages 976-978). Therefore, Etv2 was a known genetic cargo delivered directly to the skin in vivo.
One would have reasonably expected that selection of Etv2 as the cargo encoded by the polynucleotide of Rosenberg et al. would result in the benefits taught by Gallego-Perez et al. because Gallego-Perez et al. teaches that Etv2-containing genetic cargo delivered into skin cells produces a vasculogenic response and improves tissue perfusion and Rosenberg et al. teaches successful delivery of polynucleotides encoding cargo to skin cells.
One would have been motivated to select Etv2 as taught by Gallego-Perez et al. specifically for treatment of Alzheimer’s disease as taught by Rosenberg et al. because Gallego-Perez et al. teach that the cellular therapy represents a promising strategy for reprogramming neurons and Wang et al. teaches that in an APP transgenic mouse model of Alzheimer’s disease, administration of VEGF increased vascularization in the hippocampus, decreased Aβ deposition, and ameliorated memory impairment. Therefore, Wang et al. teaches that inducing angiogenesis and vascularization is a therapeutically useful strategy in Alzheimer’s disease.
Additionally, Morita et al. teach that ETV2 directly converts human fibroblasts into functional endothelial cells (title) and teaches: we demonstrate that ets variant 2 (ETV2) alone directly converts primary human adult skin fibroblasts into functional vascular endothelial cells (ETVECs). In coordination with endogenous FOXC2 in fibroblasts, transduced ETV2 elicits expression of multiple key endothelial development factors, including FLI1, ERG, and TAL1, and induces expression of endothelial functional molecules, including EGFL7 and von Wille brand factor. Consequently, ETVECs exhibits EC characteristics in vitro and forms mature functional vasculature in Matrigel plugs transplanted in NOD SCID mice. Furthermore, ETVECs significantly improve blood flow recovery in a hind limb ischemic model using BALB/c-nu mice. Our study indicates that the creation of ETVECs provides further understanding of human EC development induced by ETV2 (abstract). Morita et al. is additional evidence of the known benefits of ETV2 delivery, benefits that would be desired in an Alzheimer’s patient.
Therefore, Rosenberg et al. teaches methods for treating Alzheimer’s disease using a polynucleotide encoding a gene vaccine via intradermal delivery in vivo to human subjects. Wang et al. teaches that stimulation of angiogenesis provides a therapeutic benefit for Alzheimer’s disease. Since Gallego-Perez et al. teach in vivo delivery to the skin of plasmid DNA encoding vasculogenic/endothelial reprogramming factors, including Etv2, wherein the plasmid is driven directly into skin cells with resultant increased vascularization and rescue of ischemic tissue, it would have been obvious to deliver a polynucleotide encoding Etv2 in the method of Rosenberg et al. with the expectation of promotion of a therapeutic effect for Alzheimer’s disease because Wang et al. teaches that promotion of angiogenesis provides therapeutic benefit for Alzheimer’s disease. Etv2 would have been an obvious selection because it was known to be capable of promoting formation of functional vasculature following delivery into skin cells.
One would have had a reasonable expectation of success because Wang et al. demonstrates that enhanced angiogenesis can improve Alzheimer’s pathology and function and Gallego-Perez et al. demonstrates that delivery of Etv3 into skin cells produces increased vascularization. Therefore, selecting a vasculogenic factor, more specifically Etv2, as the encoded cargo would have constituted the predictable use of a known agent to obtain a therapeutic benefit of vascular regeneration in Alzheimer’s disease. Morita et al. is evidence that Etv2 alone is sufficient to directly convert primary human adult skin fibroblasts into functional vascular endothelial cells.
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
