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 .
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are pending.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01 April 2026 has been entered.
Status of the Application
Applicant’s response and amendment filed 11 March 2026 are acknowledged and entered.
Applicant has amended Claim 1 and cancelled Claims 5-6, 22-23.
Response to Amendment
The 112(a) Written Description rejection is maintained.
The 112(a) Scope of Enablement rejection is withdrawn.
Some 112(b) rejections are maintained; others are withdrawn.
The 103 rejections are maintained and updated in response to the claim amendments.
NSDP rejections are maintained and updated in response to the claim amendments.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Information Disclosure Statement
The IDS has been considered.
Claim Interpretation
The claims recite applying focused ultrasound to “one or more regions” of the CNS, delivering the recombinant virus or recombinant plasmid to “one or more regions” of the brain or spinal cord, and expressing a microRNA in “an organ or tissue region”. The Spec. and claims do not define what is considered a “region”. Therefore, “region” is interpreted as any portion of the CNS, the brain or spinal cord, or an organ or tissue.
Claim 1 recites …a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord… applying to the one or more regions of the central nervous system…. A person of ordinary skill in the art understands that the CNS consists of the brain and spinal cord and that the brain and spinal cord comprise the CNS.
Claim 15 recites “a retrograde virus” which is not a term common in the art and is not defined by the Spec. or claims. The term is interpreted as any virus that shows retrograde transport, meaning upstream from the axon terminals to the soma (retrograde tracer), including AAV. That interpretation is based on Haery (and Nasse. 2023. Viral Vectors 101: The AAV Retrograde Serotype. Available online at blog.addgene.org. Accessed on 08 April 2025, “Haery, of record”).
Claim 15 is interpreted as the following:
The method of claim 13 wherein:
the transgene is a recombinase gene and the non-oncolytic virus is a retrograde virus or
the transgene that is delivered is inactivated
by subsequent delivery of the recombinase enzyme or
by a gene encoding the recombinase enzyme which prevents expression of the transgene.
Claim Objections
Claims 1 and 4 are objected to for minor informalities: Claim 1 recites … on magnetic resonance imaging and Claim 4 recites …a magnetic resonance imaging (MRI) contrast agent to the mammal. Claim 1 should be amended to show the abbreviation MRI: …on magnetic resonance imaging (MRI). Claim 4 should then recite: …administering a or an MRI contrast agent…
Appropriate correction is required.
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 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection. This rejection is maintained and updated in response to the claim amendments.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 recite a method of delivering therapeutic transgene to … a brain or spinal cord of a mammal, said method comprising administering to a mammal in need thereof… microbubbles comprising mammalian serum albumin protein and… a non-oncolytic recombinant virus comprising the transgene... (Claim 1); …wherein the transgene encodes a protein, a glycoprotein, a miRNA, or siRNA… (Claim 11); and …wherein a target sequence for a microRNA is inserted into the transgene… (Claim 18). These broad claims encompass the following large genera:
The non-oncolytic recombinant virus (that is AAV, adenovirus, lentivirus, or HSV) comprising any therapeutic transgene that is delivered to a mammal in need thereof,
The therapeutic transgene encoding any protein, any glycoprotein, any miRNA, or any siRNA,
The therapeutic transgene encoding any miRNA target, and
Any therapeutic transgene delivered to a mammal who has PD and need the therapeutic transgene.
Any kind of therapeutic transgene that possesses any potentially therapeutic use, and any transgene encoding any therapeutic protein, any therapeutic glycoprotein, any therapeutic miRNA or any therapeutic miRNA target, or any therapeutic siRNA would be encompassed by the claims as instantly presented. Therapeutic transgenes, therapeutic proteins/therapeutic glycoproteins/therapeutic miRNA/therapeutic siRNA/therapeutic miRNA targets are broad genera/subgenera with diverse members and different structures that underly their functions.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
The Spec. does not provide a definition of therapeutic transgene or therapeutic proteins/therapeutic glycoproteins/therapeutic miRNA/therapeutic siRNA/therapeutic miRNA targets. The Spec. discusses (p. 3 L25-32) the transgene can encode a therapeutic protein and Cre/Lox; (p. 5 L1-8) the transgene can encode a miRNA or siRNA and/or can be related to Parkinson’s disease, Alzheimer’s disease, depression, dementia, a cardiovascular disease, or a cerebrovascular disease. The Spec. discusses (pp. 11-12 L20-34) delivering the gene for tyrosine hydroxylase (TH, for Parkinson’s disease), p11 (for depression), low-density lipoprotein receptor (LDL-R, for Alzheimer’s disease), or nerve growth factor (NGF, for Alzheimer’s disease). Those therapeutic genes do not share a structural commonality that underlies their function as a therapeutic gene.
Regarding the therapeutic transgene encoding siRNA, miRNA, or a glycoprotein, glycoprotein and siRNA each get one mention in the entire Spec. (pp. 4-5 L24 and 1). The Spec. mentions (p. 11 L28-34) a vector that delivers miRNA or shRNA targeting IDOL. The Spec. discusses (pp. 13-14 L25-23) including a target sequence for an endogenous miRNA with the transgene so the transgene can be turned off in a cell wherein the miRNA is expressed and lists miR122, miR124, and a list of other miRNAs.
The Spec. teaches some Examples (start on p. 17) of using their method of delivery. The examples show only a recombinant plasmid or virus (i.e., AAV2) encoding GFP. There are no examples showing delivery of any other transgene besides GFP. While GFP may be generously considered a therapeutic transgene in some instances (i.e., it can be used to distinguish tissues), it doesn’t have any structure responsible for that function. No examples show possession of a method of delivering any other therapeutic transgenes, wherein the therapeutic transgene encodes any protein (aside from GFP), any glycoprotein, any miRNA or miRNA target, or any siRNA. The Spec. doesn’t disclose any structure responsible for the function of being “a therapeutic transgene that a mammal who has PD would be in need of”; yet, that is encompassed/recited by the claims.
However, despite the broad claims and lack of discussion of such structures in the Spec., there exist in the world a great many transgenes that can be considered therapeutic, a huge number of proteins, a huge number of glycoproteins, a huge number of miRNAs and miRNA target sequences, and a huge number of siRNAs. Each species of therapeutic transgene encompassed by those genera or sub-genera has a different structure (i.e., sequence of nucleic acids) that underlies its unique function as a sequence of nucleotides that encodes a specific sequence of amino acids that form a specific protein or encoding a specific sequence of nucleotides that target a specific gene. Due to the absence of discussion in the Spec., an artisan wouldn’t know what therapeutic transgene(s) perform the function of being therapeutic for PD.
Applicant has demonstrated possession of a method of delivering only the transgene GFP.
The Spec. does not show exemplary members of the broad sub-genera of claimed therapeutic transgenes (besides for GFP), therapeutic transgenes encoding any protein (besides for GFP), therapeutic transgenes encoding any glycoprotein, therapeutic transgenes encoding any miRNA/miRNA target, or therapeutic transgenes encoding any siRNA. Applicant has claimed methods of delivering all of the members of those genera but shows data for only transgenes encoding GFP. Possession of the single species does not demonstrate possession of any therapeutic transgene, therapeutic transgenes encoding any protein, glycoprotein, miRNA, siRNA, or therapeutic transgenes encoding any miRNA target. The examples shown do not support possession of a method to deliver the entire category of any therapeutic transgene, any protein, glycoprotein, etc. The Specification does not provide specific guidance for determining which species of therapeutic transgenes, proteins, glycoproteins, siRNA, miRNA, or therapeutic transgenes encoding a miRNA target within the broad genera would or would not be acceptable to use in their methods. Although the claims claim a functional characteristic (i.e., the transgene is therapeutic or can be used to treat PD), the functional characteristic is not coupled with a known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for being a therapeutic transgene encoding a protein/glycoprotein/miRNA/miRNA target/siRNA. The Spec. has identified no core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for being a therapeutic transgene encoding a protein/glycoprotein/miRNA/miRNA target/siRNA that is disclosed in such a way to demonstrate possession of the full invention as claimed at time of filing. The therapeutic transgenes encoding a protein/glycoprotein/miRNA/miRNA target/siRNA lack a common structure. A shared sequence common to therapeutic transgenes encoding proteins, siRNAs, miRNAs, and/or miRNA targets is not identified. A protein domain common to the encoded therapeutic proteins or glycoproteins is not identified. Sufficient data are not shown to substantiate claiming the broad genera of any therapeutic transgenes encoding any protein/glycoprotein/miRNA/miRNA target/siRNA. Finally, there are many ways a transgene can possess or provide therapeutic properties, and the Specification does not teach any defining characteristics of such features.
The specification teaches only a couple members from some of the genera or sub-genera. The Spec. provides an example of delivering the transgene GFP. The Spec. discloses miRNAs listed on p. 14, for which no data are shown. However the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genera of therapeutic transgenes encoding a protein/glycoprotein/miRNA/miRNA target/siRNA claimed.
While none of these elements is specifically required to demonstrate possession, in combination their absence means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of an invention a method of delivering any therapeutic transgene encoding a protein/glycoprotein/miRNA/miRNA target/siRNA. Claims 1, 11, and 18 are rejected for failing to demonstrate possession of the claimed invention. Claims 3-4, 7, 11, 13, 15, 18, 20, and 25 are rejected because they depend from Claim 1 and do not remedy the issues.
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 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 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. This rejection is maintained and updated in response to the claim amendments.
A claim may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.
Claim 1 recites administering to a mammal… an amount of microbubbles… and an amount of a non-oncolytic recombinant virus… and applying to the one or more regions of the central nervous system of the mammal focused ultrasound in an amount effective to transiently disrupt the blood brain barrier and deliver…. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. What comprises an acceptable amount of microbubbles, non-oncolytic recombinant virus, and focused ultrasound is not clear. The claims and Spec. do not define what amounts of microbubbles, amounts of non-oncolytic recombinant virus, and amounts of focused ultrasound to effectively transiently disrupt the BBB and deliver the virus are or are not acceptable to use in the method. The claims and Spec. do not define what amount of ultrasound provides for delivery of the virus. Because those terms are unclear, an artisan would not know how to carry out the method steps.
Claim 1 is rejected for those reasons. Claims 3-4, 7, 11, 13, 15, 18, 20, and 25 are rejected because they depend from Claim 1 and do not remedy the issues. In the interest of compact prosecution the claims are interpreted as: administering any amount of microbubbles comprising the virus, and applying any amount of ultrasound that results in delivery of the virus.
Applicant should note that removing both instances of “an amount of” and “in an amount” will obviate this rejection without narrowing the claims.
A broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 11 recites the broad recitation a protein, and the claim also recites a glycoprotein and wherein the protein is optionally a recombinase which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the interest of compact prosecution the “optional” limitation is interpreted as fully optional.
Similarly, Claim 13 recites the “optional” recitation optionally the mammal is administered the recombinase. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by optionally is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 15 is rejected because it depends from Claim 13 and doesn’t remedy the issues.
In the interest of compact prosecution the “optional” limitation is interpreted as fully optional.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 4 recites the method of Claim 1 further comprising administering an MRI contrast agent to the mammal. Claim 4 depends from and fails to further limit Claim 1 which recites that delivery of the recombinant virus is evidenced by contrast extravasation on magnetic resonance imaging (MRI). Evidencing delivery by contrast extravasation on MRI requires that the mammal be administered a contrast agent; otherwise it would not be possible to detect delivery using contrast extravasation imaging. Therefore Claim 4 does not further limit Claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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:
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.
Claims 1, 3-4, 7, 11, 20, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Mead (et al. 2017. Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson’s Disease Model. Nano Lett. 17[6]:3533–3542, “Mead”, of record) in view of Howard (et al. 2006. Ultrasound Guided Site Specific Gene Delivery System Using Adenoviral Vectors and Commercial Ultrasound Contrast Agents. J. Cell. Physiol. 209:413-421, “Howard”) and Aryal (et al. 2015. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model. Phys. Med. Biol. 60:2511, “Aryal”).
Mead is directed to a focused ultrasound gene therapy approach for restoring dopaminergic neuron function in a rat Parkinson’s disease (PD) model. Mead teaches (§Abstract) a two-pronged treatment strategy, composed of MR image-guided focused ultrasound (FUS) and brain-penetrating nanoparticles (BPN), that provides widespread but targeted GDNF [glial cell-line derived neurotrophic factor] transgene expression in the brain. Mead teaches (same §) MRI-guided FUS allows circulating gene vectors to partition into the brain tissue by noninvasive and transient opening of the blood−brain barrier (BBB) [in] the areas where FUS is applied [and] once beyond the BBB, BPN provide widespread and uniform GDNF expression throughout the targeted brain tissue.
Mead teaches (§Main text ¶2) neurotrophic factors like GDNF are attractive candidates for gene therapy because they protect neurons from continued degeneration, induce neuronal regeneration and sprouting, and enhance dopamine generation from the remaining neuronal population. Mead teaches (§Main text ¶4) FUS permits the targeted delivery of nanoparticles as large as 100 nm across the BBB via the activation of ultrasound contrast agent microbubbles (MBs).
Regarding Claim 1, Mead teaches (§Main text ¶5) they used a BPN formulation to deliver a GDNF gene-bearing plasmid (GDNF-BPN; the BPN is loaded with plasmid DNA) to the striatum of PD rats whose BBB was transiently opened in a targeted manner with MR image-guided FUS. That indicates Mead used a plasmid and FUS to deliver a therapeutic transgene to the brain of a mammal. Although Mead didn’t use viral vectors, they were well aware of and discuss (§Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) the use of viral vectors to express GDNF.
Regarding Claim 1, Mead teaches (§Materials and Methods-Microbubble Fabrication and Characterization) the microbubbles (MBs) used in their study comprise serum albumin. In addition to the teachings described above (about widespread delivery to the brain), that indicates Mead used microbubbles and FUS to deliver the plasmid comprising the GDNF transgene to the rats, and the microbubbles comprise serum albumin which is a mammalian serum protein. Therefore Mead teaches some limitations of Claim 1.
Regarding Claim 3, Mead teaches (§Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) animals in their study replicate the level of neurodegeneration seen in early stage human PD patients and (§Discussion-Relevance to Clinical Trials ¶2) FUS has many advantages for performing on human patients, including early stage human patients who are not considered eligible for more invasive treatments. Therefore it is clear that Mead contemplated using their strategy on human patients, thereby teaching some limitations of Claim 3.
Mead teaches (§Materials and Methods-FUS-Mediated DNA-BPN Delivery ¶1-2) rats were co-injected with GDNF-BPN and microbubbles. That indicates that the microbubbles and plasmid were concurrently administered. Mead’s “co-injection” (§Materials and Methods-FUS-Mediated DNA-BPN Delivery ¶1-2) followed by saline to clear the catheter indicates the components were in a composition.
Regarding Claim 7, Mead teaches (§Materials and Methods-FUS-Mediated DNA-BPN Delivery ¶1-2) sonication using FUS began immediately after clearance of the catheter. That indicates that the FUS was applied after the MBs and plasmid were administered. Therefore Mead teaches some limitations of Claim 7.
Regarding Claim 4, Mead teaches Mead teaches (§Materials and Methods-FUS-Mediated DNA-BPN Delivery ¶1-2) immediately following BBB opening, post-treatment T2*-weighted images were acquired followed by intravenous administration of MRI contrast agent. Therefore Mead teaches limitations of Claim 4.
Regarding Claim 11, Mead teaches (Fig. 2) FUS-mediated delivery of GDNF-BPN to the striatum of PD rats leads to a significant increase in GDNF protein levels in the striatum [emphasis added]. Therefore Mead teaches some limitations of Claim 11.
Regarding Claim 20, Mead teaches (§Abstract) their study used a rat model of PD and their strategy restored both dopamine levels and dopaminergic neuron density and reversed behavioral indicators of PD-associated motor dysfunction with no evidence of local or systemic toxicity and potentially provides a novel means to treat PD. Therefore Mead teaches some limitations of Claim 20.
Regarding Claim 25, Mead teaches (§Results-Characterization of GDNF-BPN ¶1) their nanoparticles rapidly penetrated brain tissue and provided uniform and efficient reporter gene expression in the rat striatum after delivery with FUS. Mead further teaches (§Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1) delivery of GDNF-BPN with FUS to the striatum led to an 11-fold increase in ipsilateral striatal GDNF protein when compared to control. That indicates that Mead used FUS applied to the striatum to deliver the GDNF plasmid. Therefore Mead teaches some limitations of Claim 25.
Altogether, Mead teaches a non-invasive method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, an amount of a population of microbubbles and an amount of a plasmid comprising the transgene; and applying to one or more regions of the central nervous system (CNS) of the mammal (including its striatum) focused ultrasound (FUS) in an amount that provides for delivery of the recombinant virus or the plasmid to the one or more regions of the brain or spinal cord.
As discussed, Mead well aware of and discusses (§Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) the use of viral vectors to express GDNF.
Mead also teaches (§Main text ¶1) projection neurons are involved in PD:
One of the primary hallmarks of PD is the degeneration of dopaminergic neurons with cell bodies in the substantia nigra pars compacta (SNpc) and axon projections extending into the striatum. The resulting dopamine deficiency leads to progressive and debilitating motor control deficits including bradykinesia, rigidity, and resting tremor.
Mead does not teach that they used a recombinant virus (i.e., recombinant adenovirus) to encode the transgene (Claim 1). Mead does not teach encapsulating the virus within the microbubbles (Claim 1). Mead does not teach using contrast extravasation on MRI to demonstrate the FUS effectively transiently disrupted the BBB and delivered the recombinant virus (Claim 1).
However, Howard teaches an ultrasound guided site-specific gene delivery system that uses adenoviral vectors and commercial ultrasound contrast agents to successfully deliver adenovirus particles encoding GFP, wherein the virus particles are encapsulated inside of microbubbles.
Howard teaches (§Abstract) they produced microbubbles enclosing and protecting adenovirus. Howard teaches (§Main text ¶1-2) viruses are attractive delivery vectors because they efficiently transfer genes with sustained expression, but that it’s important to deliver a gene of interest to only target tissues. Howard teaches (§Main text ¶4) in their system, the microbubbles protect the viruses from rapid degradation by the immune system, thus allowing for intravenous injection. Howard teaches (§Discussion ¶3) Imagent® effectively enclosed and protected adenoviral vectors from inactivation by the body’s complement system, which allowed targeted non-invasive systemic delivery. Howard teaches (same §) ultrasound-mediated microbubble destruction improved the efficacy and reduced the non-specific expression of gene therapy vectors and provided a useful tool for manipulating gene expression in the living animal.
Howard teaches (§Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3) a process whereby they produced microbubbles comprising adenovirus particle and neutralized the virus adsorbed to the surface while leaving virus particles inside the microbubbles:
This data indicates that the treatment with complement of the Ad-GFP bubbles inactivated the adenoviruses present on the bubble’s surface leaving instead intact and viable the adenoviruses encapsulated by the microbubbles without destroying the integrity of the Imagent bubble shell [emphasis added].
Howard also shows (Figs. 5-6) successful delivery of their microbubble-encapsulated recombinant adenovirus particles to target tissues.
Altogether, Howard teaches successfully producing microbubbles wherein a recombinant adenovirus encoding a protein is encapsulated, and using FUS to deliver them to target tissues.
Mead and Howard don’t teach using contrast extravasation on MRI to evidence BBB disruption and successful delivery to the brain.
However, Aryal teaches using MR-guided FUS to transiently open the BBB and using contrast extravasation to demonstrate having successfully done so.
Aryal teaches (§Abstract) using FUS to deliver doxorubicin to rat brains. Aryal teaches (§1. Introduction ¶2) FUS applied to microbubbles transiently disrupts tight junctions to induce transport. Aryal teaches (§2. Materials and Methods-2.4 Sonications) they intravenously administered the ultrasonic contrast agent Definity® to rats and applied FUS. Aryal teaches (same §) they aimed to permeabilize the BTB [blood tumor barrier] in the entire tumor and the BBB in a surrounding rim of at least 1 mm.
Regarding Claim 7: Aryal teaches (same §, ¶2) the encapsulated drug was administered intravenously just before sonication.
Aryal teaches (§Abstract) they determined efficacy (of doxorubicin delivery) by measuring extravasation of the MRI contrast agent before and after sonication, and that (same § and Figs. 2, 3a, and 5b) FUS significantly enhanced doxorubicin concentrations at tumors in the brain. Aryal teaches (§Abstract, §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption) the FUS technique successfully disrupted the BTB and BBB. Aryal teaches (§2. Materials and Methods-2.2 Experimental set up) accurate targeting in vivo was confirmed by sonicating a spot in the brain near the tumor and checking that the resulting MRI contrast extravasation was at the desired target. That indicates MRI contrast extravasation confirmed successful disruption of the BBB and successful delivery of microbubble cargo.
That indicates that it was routine and conventional to use administer an MRI contrast agent to a mammal and use contrast extravasation on MRI to confirm successful delivery.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the FUS-mediated delivery system for treating PD of Mead with the encapsulated recombinant adenoviral vector technique (wherein the recombinant virus is encapsulated within the microbubbles) of Howard and contrast extravasation technique of Aryal for the benefits of:
using recombinant adenovirus-mediated gene transfer to efficiently transfer a therapeutic gene with sustained expression,
protecting virus particles from the immune system but still allowing tissue-specific delivery, and
confirming delivery of the virus particles to target tissues of the CNS.
One would have been motivated to do so with a reasonable expectation of success because Mead demonstrates using FUS to deliver microbubbles comprising nanoparticles to the CNS, which demonstrates it was routine and conventional to use FUS delivered microbubbles to transfer genetic material. One would have been motivated to do so with a reasonable expectation of success because Howard teaches the benefits of using recombinant adenovirus particles to deliver a transgene to target tissues and teaches that encapsulating the virus particles within microbubbles protects them, including from the innate immune system. One would have been motivated to do so with a reasonable expectation of success because Aryal demonstrates it was routine and conventional to use contrast extravasation to demonstrate a delivery product was successfully delivered to a specific location in the brain (i.e., a tumor and the 1 mm surrounding it).
It would have been a simple matter to use Howard’s technique for encapsulating recombinant virus particles within microbubbles and then use the routine and conventional techniques of Mead and Aryal for administering such microbubble-encapsulated recombinant virus particles to the brain. It would have been obvious to encode Mead’s GDNF on Howard’s adenovirus for the benefit of sustained expression. Therefore the limitations of Claims 1, 3-4, 7, 11, 20, and 25 would have been obvious in view of Mead, Howard, and Aryal.
Claims 1, 3-4, 7, 11, 13, 15, 20, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Mead, Howard, and Aryal as applied to Claims 1, 3-4, 7, 11, 20, and 25 in the 103 rejection above, and further in view of Tervo (et al. 2016. A Designer AAV Variant Permits Efficient Retrograde Access to Projection Neurons. Neuron 92:372–382, “Tervo”, of record).
The teachings of Mead as applicable to Claim(s) 1, 3-4, 7, 11, 20, and 25 have been described in the 103 rejection above.
Mead, Howard, and Aryal make obvious a noninvasive method of delivering a therapeutic transgene to one or more regions of the brain of a mammal, the method comprising: administering to a mammal microbubbles comprising mammalian serum albumin and a nononcolytic recombinant adenovirus comprising the transgene, wherein the recombinant virus is encapsulated in the microbubbles; and applying to one or more regions of the brain FUS effective to transiently disrupt the BBB and deliver the recombinant adenovirus to the brain, which disruption and delivery is evidenced by contrast extravasation on MRI.
Mead, Howard, and Aryal do not teach that the transgene is flanked by recombinase sites for a recombinase (Claim 13), or a retrograde virus is employed to deliver a recombinase gene (Claim 15).
However, Tervo teaches limitations Mead, Howard, and Aryal do not teach. Tervo is drawn to an AAV vector that permits retrograde access to projection neurons.
Regarding the AAV virus of Claim 1, Tervo teaches (§Abstract) their newly evolved recombinant AAV variant, rAAV2-retro, permits robust retrograde access to projection neurons.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the FUS-mediated recombinant adenovirus delivery of Mead, Howard, and Aryal by packaging Mead’s GDNF transgene in the rAAV2-retro virus of Tervo. One would have done so for the benefit of permitting robust retrograde access to projection neurons.
One would have been motivated to swap the retrograde AAV2 of Tervo for the recombinant adenovirus delivery of Mead, Howard, and Aryal because Tervo shows their retrograde AAV2 provides better access and transformation of projection neurons than a non-retrograde AAV2 serotype, and an artisan would have wanted to prove the best coverage and transformation of the target as possible. One would have been motivated to target the GDNF transgene of Mead to projection neurons because Mead teaches (§ cited above) projection neurons are involved in PD. Those teachings would have motivated an artisan to package the GDNF transgene of Mead in the rAAV2 virus of Tervo and use Mead/Howard/Aryal’s FUS and microbubbles to deliver the rAAV2 virus carrying GDNF across the BBB for the benefit of enhancing transformation of projection neurons. One would have been motivated to do so with a reasonable expectation of success because Tervo teaches (§Using rAAV2-retro for Circuit Interrogation and Gene Manipulation ¶3) their work establishes rAAV2-retro as an effective reagent to genetically access projection neurons for interrogation of neural circuits and for possible therapeutics, because Mead teaches (§Main text ¶1) projection neurons are affected in PD, and because Howard teaches benefits of encapsulating virus particles within microbubbles for delivery. It would have been a simple matter to swap Tervo’s AAV2-retro vector for Mead and Howard’s recombinant adenovirus.
One would have been motivated to do so with a reasonable expectation of success because Tervo teaches (§Results-Directed Evolution of rAAV2-retro ¶1 and §Discussion ¶1-2) rAAV2-retro exhibits markedly increased efficacy of retrograde access compared to its parental serotype—up to two orders of magnitude enhancement compared to other AAV serotypes. One would have been motivated to do so with a reasonable expectation of success because Mead demonstrates that FUS-delivered microbubbles provide a noninvasive strategy to restore dopaminergic neuronal function in PD, because Howard teaches benefits of encapsulating virus particles within microbubbles for delivery, and because Tervo teaches benefits of using rAAV2 to transform projection neurons. Mead’s FUS-delivered microbubbles would have allowed an artisan to deliver the transgene via a minimally invasive procedure. Therefore all the limitations of Claims 1, 3-4, 7, 11, 20, and 25 would have been obvious in view of Mead, Howard, Aryal, and Tervo.
Regarding Claims 13 and 15: Tervo teaches (§Abstract) retrograde access to projection neurons for delivering sensors and effectors to neurons would be useful for gene therapeutic treatment of neurodegenerative disorders. Tervo teaches (§Abstract) their newly evolved variant, rAAV2-retro, permits robust retrograde access to projection neurons.
Tervo teaches (§Introduction, final ¶) the rAAV2-retro gene delivery system can be used on its own or in conjunction with Cre recombinase driver lines to achieve long-term, high-level transgene expression that is sufficient for effective functional interrogation of neural circuit function, as well as for genome editing in targeted neuronal populations. Tervo teaches (§Efficient Retrograde Access to Projection Neurons ¶2) using AAV to deliver Cre recombinase to Rosa26-Lox-STOP-Lox-H2B-EGFP. That teaches that it was common in the art to surround a gene with recombination sites (i.e., Lox) for a recombinase. Tervo teaches (Fig. 2; §Efficient Retrograde Access to Projection Neurons ¶2-3) the retrograde AAV2 resulted in a dense layer of EGFP-positive layer V projection neurons and rAAV2-retro exhibits up to two orders of magnitude enhancement over existing serotypes in retrograde access to projection neurons. Tervo also teaches (§Retrograde Access to Genetically Defined Neuronal Populations, entire §) using a Cre-dependent color flipping expression system which expresses tdTomato in the absence of Cre but inverts to drive expression of GFP in Cre-positive cells.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the delivery system comprising FUS, microbubbles, and rAAV2 carrying GDNF of Mead, Howard, Aryal, and Tervo with the retrograde rAAV2-retro gene delivery system comprising Cre recombinase of Tervo for the benefit of achieving long-term, high-level transgene expression in targeted neuronal populations and because that can be used, among other reasons for functional interrogation of neural circuit function, as well as for genome editing. It would have been obvious to modify the GDNF-based therapy and delivery system of Mead, Howard, and Aryal with the Cre-dependent color flipping system of Tervo for the benefit of being able to easily visualize which specific cells had received Cre and which hadn’t. One would have been motivated to do so with a reasonable expectation of success because incorporating the Cre recombinase system into the GDNF-based therapy of Mead, Howard, and Aryal would have allowed the artisan to determine if the cellular and systemic benefits of expressing GDNF (i.e., dopaminergic neuron density and function; and locomotor function) are reversible upon turning off GDNF by administering recombinase, or whether any of them persist. One would have been motivated to do so because they would want to know how long the benefits would persist once GDNF stopped being expressed. Modifying the GDNF-based therapy and delivery system of Mead, Howard, and Aryal with the teachings of Tervo would have produced the limitations of Claims 13 and 15 (in addition to the limitations of Claims 1, 3-4, 7, 11, 20, and 25).
Claims 1, 3-4, 7, 11, 18, 20, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Mead, Howard, and Aryal as applied to Claims 1, 3-4, 7, 11, 20, and 25 in the 103 rejection above, and further in view of Geisler (and Fechner. 2016. MicroRNA-regulated viral vectors for gene therapy. World J. Exp. Med. 6[2]:37-54 92:372–382, “Geisler”, of record) and Zeng (et al. 2008. The Relationship between Over-expression of Glial Cell-derived Neurotrophic Factor and Its RET Receptor with Progression and Prognosis of Human Pancreatic Cancer. J. Int. Med. Res. 36:656–664, “Zeng”, of record).
The teachings of Mead, Howard, and Aryal as applicable to Claim(s) 1, 3-4, 7, 11, 20, and 25 have been described in the 103 rejection above.
Mead, Howard, and Aryal make obvious a noninvasive method of delivering a therapeutic transgene to one or more regions of the brain of a mammal, the method comprising: administering to a mammal microbubbles comprising mammalian serum albumin and a nononcolytic recombinant adenovirus comprising the transgene, wherein the recombinant virus is encapsulated in the microbubbles; and applying to one or more regions of the brain FUS effective to transiently disrupt the BBB and deliver the recombinant adenovirus to the brain, which disruption and delivery is evidenced by contrast extravasation on MRI.
Mead, Howard, and Aryal do not teach inserting a target sequence for a miRNA into the transgene wherein the corresponding miRNA is expressed in an organ or tissue where the transgene may be expressed (Claim 18).
However, Geisler, drawn to miRNA-regulated vectors for gene therapy, teaches gene therapeutic approaches that include transcriptional suppression of transgene expression. Geisler teaches (§Introduction ¶1) tissue-specific targeting of viral vectors is a key requirement for safe and efficient gene therapy but that many viral vectors transduce a broad range of cell types. Geisler teaches (same §)using miRNA-dependent control of transgene expression to restrict transgene expression in gene therapeutic approaches.
Geisler teaches (§Box-Core tip) inserting a miRNA target sequence for a cell-specifically expressed miRNA into the transgene expression cassette because the miRNA-induced regulation can result in an up to 100-fold reduction of transgene expression in tissues where expression is not desired. Geisler teaches (same §) doing so is a highly efficient technology to restrict transgene expression to a specific tissue. Geisler teaches (§Discussion-Engineering, optimization and limits of artificial target sites for microRNA-mediated post-transcriptional transgene silencing ¶1) using endogenously expressed miRNAs to negatively regulate expression of an exogenous nucleic acid. An artisan would have readily recognized that this strategy can be applied to regulate expression location of any transgene delivered via any kind of vector or plasmid, including the GDNF transgene of Mead.
Zeng, drawn to the relationship between GDNF overexpression and progression of human pancreatic cancer, teaches (§Discussion ¶2) neurotrophic factors can activate pancreatic cancers and facilitate their extension along nerves, and GDNF in the celiac neural plexus can induce invasion by pancreatic cancer cells. Zeng also teaches (§Discussion ¶3) different rates of expression of GDNF in normal tissue and in benign and malignant pancreatic tumor suggest that GDNF may play a role in the malignant transformation of pancreatic epithelia.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the GDNF recombinant virus delivery system comprising FUS and microbubbles of Mead, Howard, and Aryal with the teachings of Geisler and Zeng for the benefit of producing a GDNF plasmid whose expression is specifically limited to target cells that are dopaminergic neurons. One would have been motivated to do so with a reasonable expectation of success because Geisler teaches tissue-specific targeting is necessary for a safe gene therapy and because the teachings of Zeng indicate that GDNF outside the brain can activate pancreatic cancers and induce their invasion along nerves. Given the teachings of Zeng about the negative effects of GDNF overexpression in the pancreas, including a pancreas-specific miRNA “kill switch” (an idea taught by Geisler) in the transgene encoding GDNF of Mead, Howard, and Aryal would have been advisable to reduce the possibility that the GDNF gene therapy would induce pancreatic cancer, especially because Mead’s system includes systemic administration via intravenous injection. An artisan wouldn’t want to risk the possibility of a PD treatment causing pancreatic cancer, so they would have wanted to include the kill switch. Modifying the GDNF retrovirus delivery system comprising FUS and microbubbles of Mead, Howard, and Aryal with the teachings of Geisler and Zeng would have produced the limitations of Claim 18 (and Claims 1, 3-4, 7, 11, 20, and 25).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 8642341 (issued 04 February 2014, “US341”, of record) in view of Mead (et al. 2017. Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson’s Disease Model. Nano Lett. 17[6]:3533–3542, “Mead”, of record), Howard (et al. 2006. Ultrasound Guided Site Specific Gene Delivery System Using Adenoviral Vectors and Commercial Ultrasound Contrast Agents. J. Cell. Physiol. 209:413-421, “Howard”), Aryal (et al. 2015. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model. Phys. Med. Biol. 60:2511, “Aryal”), Tervo (et al. 2016. A Designer AAV Variant Permits Efficient Retrograde Access to Projection Neurons. Neuron 92:372–382, “Tervo”, of record), Geisler (and Fechner. 2016. MicroRNA-regulated viral vectors for gene therapy. World J. Exp. Med. 6[2]:37-54 92:372–382, “Geisler”, of record) and Zeng (et al. 2008. The Relationship between Over-expression of Glial Cell-derived Neurotrophic Factor and Its RET Receptor with Progression and Prognosis of Human Pancreatic Cancer. J. Int. Med. Res. 36:656–664, “Zeng”, of record). This rejection is maintained and updated in response to the claim amendments.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the patented US341 claims are directed to a method of treating a mammal having depressive disorder by directly delivering to the nucleus accumbens of the mammal an AAV comprising a p11 nucleic acid that encodes a human p11 protein to treat the depressive disorder. Although the issued claims don’t explicitly recite that the AAV is a recombinant virus, an artisan would readily recognize that the various components mean the AAV is recombinant.
The instant claims are directed to a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, microbubbles comprising a mammalian serum albumin protein and a non-oncolytic recombinant virus comprising the transgene (wherein the virus can be AAV or adenovirus) and wherein the virus is encapsulated within the microbubbles; and applying to one or more regions of the mammal’s CNS focused ultrasound (FUS) to transiently disrupt the BBB and deliver the recombinant virus to the one or more regions of the brain or spinal cord (wherein the delivery is evidenced by contrast extravasation MRI), wherein the transgene can encode a protein, wherein the mammal is a human, wherein FUS is applied either concurrently with the microbubbles and recombinant virus or after administering the microbubbles and recombinant virus; wherein the FUS is applied to specific sites; wherein the transgene is flanked by recombination sites for a recombinase and wherein the transgene can be a recombinase gene and the nononcolytic virus can be a retrograde virus or wherein the transgene can be inactivated by subsequent delivery of recombinase enzyme or a gene encoding recombinase enzyme; or wherein a target sequence for a miRNA is inserted into the transgene and wherein the corresponding miRNA is expressed in an organ/tissue specific manner.
Both claim sets are directed to methods of administering a transgene expressing a protein to a mammal’s CNS. An artisan would have been aware that the nucleus accumbens forms part of the striatum (i.e., a partial limitation of Claim 25).
The patented US341 claims do not recite using FUS to deliver the AAV encoding p11 wherein the AAV is encapsulated within microbubbles, the mammalian serum albumin protein, the contrast extravasation MRI, or the order of microbubble and FUS administration, or the limitations about a recombinase, retrograde virus, or miRNA/miRNA target sequence.
However Mead teaches (§Main text ¶1-5; §Materials and Methods-Microbubble Fabrication and Characterization, §Materials and Methods-FUS-Mediated DNA-BPN Delivery; §Materials and Methods-FUS-Mediated DNA-BPN Delivery, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2, §Discussion-Relevance to Clinical Trials ¶2, Fig. 2, §Results-Characterization of GDNF-BPN ¶1, §Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) using FUS and microbubbles to noninvasively disrupt the BBB to aid drug delivery to the brain as well as other claim limitations.
Howard teaches (§Abstract, §Main text ¶1-2, ¶4; §Discussion ¶3, §Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3; Figs. 5-6) encapsulating a virus within microbubbles to protect the virus from the immune system and successfully delivering it to target tissues.
Aryal teaches (§Abstract, §1. Introduction ¶2, §2. Materials and Methods-2.4 Sonications; Figs. 2, 3a, and 5b; §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption, §2. Materials and Methods-2.2 Experimental set up) evidencing BBB disruption and cargo delivery on contrast extravasation on MRI.
Tervo teaches (§Abstract, §Using rAAV2-retro for Circuit Interrogation and Gene Manipulation ¶3, §Results-Directed Evolution of rAAV2-retro ¶1 and §Discussion ¶1-2; §Introduction, final ¶; §Efficient Retrograde Access to Projection Neurons ¶2, Fig. 2; §Efficient Retrograde Access to Projection Neurons ¶2-3; §Retrograde Access to Genetically Defined Neuronal Populations, entire §) Cre/recombinase system for (1) functional interrogation of neural circuits and (2) a color visualization system.
Geisler (§Introduction ¶1, §Box-Core tip, §Discussion-Engineering, optimization and limits of artificial target sites for microRNA-mediated post-transcriptional transgene silencing ¶1) and Zhang (§Discussion ¶2-3) teach the importance of being able to control transgene function to make gene therapy safer.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the invention of the patented US341 claims with the teachings of Mead, Howard, Aryal, Tervo, Geisler, and Zhang for the benefits of improving the delivery of the p11 plasmid of the US341 claims (including being able to easily visualize which specific cells had received Cre and which hadn’t and reducing nonspecific adhesion to nontarget cells) and including a gene therapy safety switch. Doing so would have produced the invention of the instant Claims.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-46 of U.S. Patent No. 10537725 (issued 21 January 2020, “US725”) in view of Mead, Howard, Aryal, Tervo, Geisler, and Zhang. This rejection is new.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the patented US725 claims are directed to an ultrasound device and methods of using ultrasound-assisted delivery of a compound to a targeted cell, tissue, organ, or region of the body.
The instant claims are directed to a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, microbubbles comprising a mammalian serum albumin protein and a non-oncolytic recombinant virus comprising the transgene (wherein the virus can be AAV or adenovirus) and wherein the virus is encapsulated within the microbubbles; and applying to one or more regions of the mammal’s CNS focused ultrasound (FUS) to transiently disrupt the BBB and deliver the recombinant virus to the one or more regions of the brain or spinal cord (wherein the delivery is evidenced by contrast extravasation MRI), wherein the transgene can encode a protein, wherein the mammal is a human, wherein FUS is applied either concurrently with the microbubbles and recombinant virus or after administering the microbubbles and recombinant virus; wherein the FUS is applied to specific sites; wherein the transgene is flanked by recombination sites for a recombinase and wherein the transgene can be a recombinase gene and the nononcolytic virus can be a retrograde virus or wherein the transgene can be inactivated by subsequent delivery of recombinase enzyme or a gene encoding recombinase enzyme; or wherein a target sequence for a miRNA is inserted into the transgene and wherein the corresponding miRNA is expressed in an organ/tissue specific manner.
Both claim sets are directed to methods of using ultrasound to deliver a compound to a cell/tissue/organ/region of the body
The patented US725 claims do not recite using FUS to deliver a recombinant virus encoding a therapeutic gene, wherein the virus is encapsulated within the microbubbles, the mammalian serum albumin protein, the contrast extravasation on MRI, the specific region of the brain that is the striatum, the order of microbubble and FUS administration, or the limitations about a recombinase, retrograde virus, or miRNA/miRNA target sequence.
However Mead teaches (§Main text ¶1-5; §Materials and Methods-Microbubble Fabrication and Characterization, §Materials and Methods-FUS-Mediated DNA-BPN Delivery; §Materials and Methods-FUS-Mediated DNA-BPN Delivery, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2, §Discussion-Relevance to Clinical Trials ¶2, Fig. 2, §Results-Characterization of GDNF-BPN ¶1, §Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) using FUS and microbubbles to noninvasively disrupt the BBB to aid drug delivery to the brain as well as other claim limitations.
Howard teaches (§Abstract, §Main text ¶1-2, ¶4; §Discussion ¶3, §Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3; Figs. 5-6) encapsulating a virus within microbubbles to protect the virus from the immune system and successfully delivering it to target tissues.
Aryal teaches (§Abstract, §1. Introduction ¶2, §2. Materials and Methods-2.4 Sonications; Figs. 2, 3a, and 5b; §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption, §2. Materials and Methods-2.2 Experimental set up) evidencing BBB disruption and cargo delivery on contrast extravasation on MRI.
Tervo teaches (§Abstract, §Using rAAV2-retro for Circuit Interrogation and Gene Manipulation ¶3, §Results-Directed Evolution of rAAV2-retro ¶1 and §Discussion ¶1-2; §Introduction, final ¶; §Efficient Retrograde Access to Projection Neurons ¶2, Fig. 2; §Efficient Retrograde Access to Projection Neurons ¶2-3; §Retrograde Access to Genetically Defined Neuronal Populations, entire §) Cre/recombinase system for (1) functional interrogation of neural circuits and (2) a color visualization system.
Geisler (§Introduction ¶1, §Box-Core tip, §Discussion-Engineering, optimization and limits of artificial target sites for microRNA-mediated post-transcriptional transgene silencing ¶1) and Zhang (§Discussion ¶2-3) teach the importance of being able to control transgene function to make gene therapy safer.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to use the ultrasound device and methods of using ultrasound to deliver a compound to an area of the body of the patented US725 claims with the teachings of Mead, Howard, Aryal, Tervo, Geisler, and Zhang for the benefit of providing noninvasive delivery of a transgene across the BBB and including a gene therapy safety switch. Doing so would have produced the invention of the instant Claims.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-78 of U.S. Patent No. 9024507 (issued 21 January 2020, “US507”) in view of Mead, Howard, Aryal, Tervo, Geisler, and Zhang. This rejection is new.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the patented US507claims are directed to an ultrasound device.
The instant claims are directed to a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, microbubbles comprising a mammalian serum albumin protein and a non-oncolytic recombinant virus comprising the transgene (wherein the virus can be AAV or adenovirus) and wherein the virus is encapsulated within the microbubbles; and applying to one or more regions of the mammal’s CNS focused ultrasound (FUS) to transiently disrupt the BBB and deliver the recombinant virus to the one or more regions of the brain or spinal cord (wherein the delivery is evidenced by contrast extravasation MRI), wherein the transgene can encode a protein, wherein the mammal is a human, wherein FUS is applied either concurrently with the microbubbles and recombinant virus or after administering the microbubbles and recombinant virus; wherein the FUS is applied to specific sites; wherein the transgene is flanked by recombination sites for a recombinase and wherein the transgene can be a recombinase gene and the nononcolytic virus can be a retrograde virus or wherein the transgene can be inactivated by subsequent delivery of recombinase enzyme or a gene encoding recombinase enzyme; or wherein a target sequence for a miRNA is inserted into the transgene and wherein the corresponding miRNA is expressed in an organ/tissue specific manner.
Both claim sets are directed to ultrasound device or methods that require using ultrasound device to deliver a compound to the brain.
The patented US507 claims do not recite using FUS to deliver a recombinant virus encoding a therapeutic gene, wherein the virus is encapsulated within the microbubbles, the mammalian serum albumin protein, the contrast extravasation on MRI, the specific region of the brain that is the striatum, the order of microbubble and FUS administration, or the limitations about a recombinase, retrograde virus, or miRNA/miRNA target sequence.
However Mead teaches (§Main text ¶1-5; §Materials and Methods-Microbubble Fabrication and Characterization, §Materials and Methods-FUS-Mediated DNA-BPN Delivery; §Materials and Methods-FUS-Mediated DNA-BPN Delivery, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2, §Discussion-Relevance to Clinical Trials ¶2, Fig. 2, §Results-Characterization of GDNF-BPN ¶1, §Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) using FUS and microbubbles to noninvasively disrupt the BBB to aid drug delivery to the brain as well as other claim limitations.
Howard teaches (§Abstract, §Main text ¶1-2, ¶4; §Discussion ¶3, §Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3; Figs. 5-6) encapsulating a virus within microbubbles to protect the virus from the immune system and successfully delivering it to target tissues.
Aryal teaches (§Abstract, §1. Introduction ¶2, §2. Materials and Methods-2.4 Sonications; Figs. 2, 3a, and 5b; §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption, §2. Materials and Methods-2.2 Experimental set up) evidencing BBB disruption and cargo delivery on contrast extravasation on MRI.
Tervo teaches (§Abstract, §Using rAAV2-retro for Circuit Interrogation and Gene Manipulation ¶3, §Results-Directed Evolution of rAAV2-retro ¶1 and §Discussion ¶1-2; §Introduction, final ¶; §Efficient Retrograde Access to Projection Neurons ¶2, Fig. 2; §Efficient Retrograde Access to Projection Neurons ¶2-3; §Retrograde Access to Genetically Defined Neuronal Populations, entire §) Cre/recombinase system for (1) functional interrogation of neural circuits and (2) a color visualization system.
Geisler (§Introduction ¶1, §Box-Core tip, §Discussion-Engineering, optimization and limits of artificial target sites for microRNA-mediated post-transcriptional transgene silencing ¶1) and Zhang (§Discussion ¶2-3) teach the importance of being able to control transgene function to make gene therapy safer.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to use the ultrasound device of the patented US507 claims with the teachings of Mead, Howard, Aryal, Tervo, Geisler, and Zhang for the benefit of providing noninvasive delivery of a transgene across the BBB and including a gene therapy safety switch. Doing so would have produced the invention of the instant Claims.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12122844 (issued 22 October 2024, “US844”) in view of Mead, Howard, Aryal, Tervo, Geisler, and Zhang. This rejection is maintained and updated in response to the claim amendments.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the patented US844 claims are directed to a method of inhibiting glioblastoma comprising intracranially or intracisternally administering to a human a recombinant AAV comprising an expression vector encoding an antibody against VEGF.
The instant claims are directed to a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, microbubbles comprising a mammalian serum albumin protein and a non-oncolytic recombinant virus comprising the transgene (wherein the virus can be AAV or adenovirus) and wherein the virus is encapsulated within the microbubbles; and applying to one or more regions of the mammal’s CNS focused ultrasound (FUS) to transiently disrupt the BBB and deliver the recombinant virus to the one or more regions of the brain or spinal cord (wherein the delivery is evidenced by contrast extravasation MRI), wherein the transgene can encode a protein, wherein the mammal is a human, wherein FUS is applied either concurrently with the microbubbles and recombinant virus or after administering the microbubbles and recombinant virus; wherein the FUS is applied to specific sites; wherein the transgene is flanked by recombination sites for a recombinase and wherein the transgene can be a recombinase gene and the nononcolytic virus can be a retrograde virus or wherein the transgene can be inactivated by subsequent delivery of recombinase enzyme or a gene encoding recombinase enzyme; or wherein a target sequence for a miRNA is inserted into the transgene and wherein the corresponding miRNA is expressed in an organ/tissue specific manner.
Both claim sets are directed to methods of administering a therapeutic transgene expressing a protein to a mammal’s CNS.
The patented US844 claims do not recite using FUS to deliver the AAV in microbubbles, the mammalian serum albumin protein, the contrast extravasation on MRI, the specific region of the brain that is the striatum, the order of microbubble and FUS administration, or encapsulating the AAV within the microbubbles, or the limitations about a recombinase, retrograde virus, or miRNA/miRNA target sequence.
However Mead teaches (§Main text ¶1-5; §Materials and Methods-Microbubble Fabrication and Characterization, §Materials and Methods-FUS-Mediated DNA-BPN Delivery; §Materials and Methods-FUS-Mediated DNA-BPN Delivery, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2, §Discussion-Relevance to Clinical Trials ¶2, Fig. 2, §Results-Characterization of GDNF-BPN ¶1, §Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) using FUS and microbubbles to noninvasively disrupt the BBB to aid drug delivery to the brain as well as other claim limitations.
Howard teaches (§Abstract, §Main text ¶1-2, ¶4; §Discussion ¶3, §Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3; Figs. 5-6) encapsulating a virus within microbubbles to protect the virus from the immune system and successfully delivering it to target tissues.
Aryal teaches (§Abstract, §1. Introduction ¶2, §2. Materials and Methods-2.4 Sonications; Figs. 2, 3a, and 5b; §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption, §2. Materials and Methods-2.2 Experimental set up) evidencing BBB disruption and cargo delivery on contrast extravasation on MRI.
Tervo teaches (§Abstract, §Using rAAV2-retro for Circuit Interrogation and Gene Manipulation ¶3, §Results-Directed Evolution of rAAV2-retro ¶1 and §Discussion ¶1-2; §Introduction, final ¶; §Efficient Retrograde Access to Projection Neurons ¶2, Fig. 2; §Efficient Retrograde Access to Projection Neurons ¶2-3; §Retrograde Access to Genetically Defined Neuronal Populations, entire §) Cre/recombinase system for (1) functional interrogation of neural circuits and (2) a color visualization system.
Geisler (§Introduction ¶1, §Box-Core tip, §Discussion-Engineering, optimization and limits of artificial target sites for microRNA-mediated post-transcriptional transgene silencing ¶1) and Zhang (§Discussion ¶2-3) teach the importance of being able to control transgene function to make gene therapy safer.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the invention of the patented US844 claims with the teachings of Mead, Howard, Aryal, Tervo, Geisler, and Zhang for the benefit of improving the delivery of the AAV encoding an anti-VEGF antibody of the US844 claims (including reducing nonspecific adhesion to nontarget cells) and including a gene therapy safety switch. Doing so would have produced the invention of the instant Claims.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7-8, 11, 13, 17, 36-40 of copending Application No. 17442732 (reference application, “App732”) in view of Mead, Tervo, and Rychak. This rejection is maintained and updated in response to the claim amendments.
Note: a notice of allowance has been mailed in this application. Once the patent issues this rejection will convert to a nonprovisional NSDP rejection. That will not be considered a new grounds of rejection.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the copending App732 claims are directed to a method of delivering an oncolytic virus to one or more regions of a brain or spinal cord of a mammal, comprising the exact same steps as the instant claims.
The instant claims are directed to a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, microbubbles comprising a mammalian serum albumin protein and a non-oncolytic recombinant virus comprising the transgene (wherein the virus can be AAV or adenovirus) and wherein the virus is encapsulated within the microbubbles; and applying to one or more regions of the mammal’s CNS focused ultrasound (FUS) to transiently disrupt the BBB and deliver the recombinant virus to the one or more regions of the brain or spinal cord (wherein the delivery is evidenced by contrast extravasation MRI), wherein the transgene can encode a protein, wherein the mammal is a human, wherein FUS is applied either concurrently with the microbubbles and recombinant virus or after administering the microbubbles and recombinant virus; wherein the FUS is applied to specific sites; wherein the transgene is flanked by recombination sites for a recombinase and wherein the transgene can be a recombinase gene and the nononcolytic virus can be a retrograde virus or wherein the transgene can be inactivated by subsequent delivery of recombinase enzyme or a gene encoding recombinase enzyme; or wherein a target sequence for a miRNA is inserted into the transgene and wherein the corresponding miRNA is expressed in an organ/tissue specific manner.
Both claim sets are directed to methods of administering genetic material to a mammal’s CNS and both claim sets recite the exact same steps and many of the same limitations.
The copending App732 claims don’t recite using the method to deliver a transgene encoding a protein, the contrast extravasation on MRI, the specific region of the brain that is the striatum, or encapsulating the AAV within the microbubbles, or the limitations about a recombinase, retrograde virus, or miRNA/miRNA target sequence.
However Mead teaches (§Main text ¶1-5; §Materials and Methods-Microbubble Fabrication and Characterization, §Materials and Methods-FUS-Mediated DNA-BPN Delivery; §Materials and Methods-FUS-Mediated DNA-BPN Delivery, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2, §Discussion-Relevance to Clinical Trials ¶2, Fig. 2, §Results-Characterization of GDNF-BPN ¶1, §Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) using FUS and microbubbles to noninvasively disrupt the BBB to aid drug delivery to the brain as well as other claim limitations.
Howard teaches (§Abstract, §Main text ¶1-2, ¶4; §Discussion ¶3, §Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3; Figs. 5-6) encapsulating a virus within microbubbles to protect the virus from the immune system and successfully delivering it to target tissues.
Aryal teaches (§Abstract, §1. Introduction ¶2, §2. Materials and Methods-2.4 Sonications; Figs. 2, 3a, and 5b; §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption, §2. Materials and Methods-2.2 Experimental set up) evidencing BBB disruption and cargo delivery on contrast extravasation on MRI.
Tervo teaches (§Abstract, §Using rAAV2-retro for Circuit Interrogation and Gene Manipulation ¶3, §Results-Directed Evolution of rAAV2-retro ¶1 and §Discussion ¶1-2; §Introduction, final ¶; §Efficient Retrograde Access to Projection Neurons ¶2, Fig. 2; §Efficient Retrograde Access to Projection Neurons ¶2-3; §Retrograde Access to Genetically Defined Neuronal Populations, entire §) Cre/recombinase system for (1) functional interrogation of neural circuits and (2) a color visualization system.
Geisler (§Introduction ¶1, §Box-Core tip, §Discussion-Engineering, optimization and limits of artificial target sites for microRNA-mediated post-transcriptional transgene silencing ¶1) and Zhang (§Discussion ¶2-3) teach the importance of being able to control transgene function to make gene therapy safer.
Therefore, it would have been obvious to modify the invention of the App732 claims with the teachings of Mead (by swapping Mead’s plasmid encoding GDNF for the App732 claims’ oncolytic virus), Howard (encapsulating the virus to protect it), Aryal (contrast extravasation on MRI, Tervo (specifically the rAAV2 for targeting specific neurons), Geisler, and Zhang (including a gene therapy safety switch) for the benefit of delivering GDNF to tread PD in a subject not suffering from cancer and including a gene therapy safety switch. Doing so would have produced the limitations of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 31, 53-68 of copending Application No. 17769255 (“App255”) in view of Mead, Howard, Aryal, Tervo, Geisler, and Zhang. This rejection is maintained and updated in response to the claim amendments.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the copending App255 claims are directed to a gene therapy vector comprising (Claim 62) a capsid protein and encoding APOE2 and for inhibiting APOE4, and a method of using the vector to treat an APOE4-related disease, including (Claim 68) formulating the vector for administration to the CNS. Although the copending claims don’t explicitly recite that the gene therapy includes a recombinant virus, an artisan would readily recognize that the various components mean the AAV vector + capsid are recombinant.
The instant claims are directed to a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, microbubbles comprising a mammalian serum albumin protein and a non-oncolytic recombinant virus comprising the transgene (wherein the virus can be AAV or adenovirus) and wherein the virus is encapsulated within the microbubbles; and applying to one or more regions of the mammal’s CNS focused ultrasound (FUS) to transiently disrupt the BBB and deliver the recombinant virus to the one or more regions of the brain or spinal cord (wherein the delivery is evidenced by contrast extravasation MRI), wherein the transgene can encode a protein, wherein the mammal is a human, wherein FUS is applied either concurrently with the microbubbles and recombinant virus or after administering the microbubbles and recombinant virus; wherein the FUS is applied to specific sites; wherein the transgene is flanked by recombination sites for a recombinase and wherein the transgene can be a recombinase gene and the nononcolytic virus can be a retrograde virus or wherein the transgene can be inactivated by subsequent delivery of recombinase enzyme or a gene encoding recombinase enzyme; or wherein a target sequence for a miRNA is inserted into the transgene and wherein the corresponding miRNA is expressed in an organ/tissue specific manner.
Both claim sets are directed to methods of administering a transgene, including a transgene expressing a protein, to a mammal’s CNS.
The copending App255 claims do not recite using FUS to deliver the AAV in microbubbles, the mammalian serum albumin protein, the contrast extravasation on MRI, the specific region of the brain that is the striatum, the order of microbubble and FUS administration, or encapsulating the AAV within the microbubbles, or the limitations about a recombinase, retrograde virus, or miRNA/miRNA target sequence.
However Mead teaches (§Main text ¶1-5; §Materials and Methods-Microbubble Fabrication and Characterization, §Materials and Methods-FUS-Mediated DNA-BPN Delivery; §Materials and Methods-FUS-Mediated DNA-BPN Delivery, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2, §Discussion-Relevance to Clinical Trials ¶2, Fig. 2, §Results-Characterization of GDNF-BPN ¶1, §Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) using FUS and microbubbles to noninvasively disrupt the BBB to aid drug delivery to the brain as well as other claim limitations.
Howard teaches (§Abstract, §Main text ¶1-2, ¶4; §Discussion ¶3, §Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3; Figs. 5-6) encapsulating a virus within microbubbles to protect the virus from the immune system and successfully delivering it to target tissues.
Aryal teaches (§Abstract, §1. Introduction ¶2, §2. Materials and Methods-2.4 Sonications; Figs. 2, 3a, and 5b; §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption, §2. Materials and Methods-2.2 Experimental set up) evidencing BBB disruption and cargo delivery on contrast extravasation on MRI.
Tervo teaches (§Abstract, §Using rAAV2-retro for Circuit Interrogation and Gene Manipulation ¶3, §Results-Directed Evolution of rAAV2-retro ¶1 and §Discussion ¶1-2; §Introduction, final ¶; §Efficient Retrograde Access to Projection Neurons ¶2, Fig. 2; §Efficient Retrograde Access to Projection Neurons ¶2-3; §Retrograde Access to Genetically Defined Neuronal Populations, entire §) Cre/recombinase system for (1) functional interrogation of neural circuits and (2) a color visualization system.
Geisler (§Introduction ¶1, §Box-Core tip, §Discussion-Engineering, optimization and limits of artificial target sites for microRNA-mediated post-transcriptional transgene silencing ¶1) and Zhang (§Discussion ¶2-3) teach the importance of being able to control transgene function to make gene therapy safer.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the invention of the copending App255 claims with the teachings of Mead, Howard, Aryal, Tervo, Geisler, and Zhang for the benefit of improving the delivery of the vector of the App255 claims to the CNS as required by App255’s Claim 68 and including a gene therapy safety switch. Doing so would have produced the invention of the instant Claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 50-52, 59 of copending Application No. 17779812 (“App812”, now issued as US Pat. No. 12611467) in view of Mead, Howard, Aryal, Tervo, Geisler, and Zhang. This rejection is maintained and updated in response to the claim amendments.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the copending App812 claims are directed to a gene therapy AAV comprising (Claims 51-52, 59) a capsid protein and encoding apoliprotein E. An artisan wouldn’t know what the vector is for but they would look at the Spec. and find (p. 2 L25-43) it’s for treating Alzheimer’s disease or other cognitive impairment. That would have motivated an artisan to want to deliver the composition specifically to the brain or CNS. Although the copending claims don’t explicitly recite that the gene therapy includes a recombinant vector + capsid protein is a virus, an artisan would readily recognize that the various components mean the vector + capsid protein is a virus that is recombinant.
The instant claims are directed to a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, microbubbles comprising a mammalian serum albumin protein and a non-oncolytic recombinant virus comprising the transgene (wherein the virus can be AAV or adenovirus) and wherein the virus is encapsulated within the microbubbles; and applying to one or more regions of the mammal’s CNS focused ultrasound (FUS) to transiently disrupt the BBB and deliver the recombinant virus to the one or more regions of the brain or spinal cord (wherein the delivery is evidenced by contrast extravasation MRI), wherein the transgene can encode a protein, wherein the mammal is a human, wherein FUS is applied either concurrently with the microbubbles and recombinant virus or after administering the microbubbles and recombinant virus; wherein the FUS is applied to specific sites; wherein the transgene is flanked by recombination sites for a recombinase and wherein the transgene can be a recombinase gene and the nononcolytic virus can be a retrograde virus or wherein the transgene can be inactivated by subsequent delivery of recombinase enzyme or a gene encoding recombinase enzyme; or wherein a target sequence for a miRNA is inserted into the transgene and wherein the corresponding miRNA is expressed in an organ/tissue specific manner.
Both claim sets are directed to a transgene (a product or method of administering it), including a transgene expressing a protein, that is delivered to a mammal’s CNS.
The copending App812 claims do not recite using FUS to deliver the AAV in microbubbles, the mammalian serum albumin protein, the contrast extravasation on MRI, the specific region of the brain that is the striatum, the order of microbubble and FUS administration, or encapsulating the AAV within the microbubbles, or the limitations about a recombinase, retrograde virus, or miRNA/miRNA target sequence.
However Mead teaches (§Main text ¶1-5; §Materials and Methods-Microbubble Fabrication and Characterization, §Materials and Methods-FUS-Mediated DNA-BPN Delivery; §Materials and Methods-FUS-Mediated DNA-BPN Delivery, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2, §Discussion-Relevance to Clinical Trials ¶2, Fig. 2, §Results-Characterization of GDNF-BPN ¶1, §Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) using FUS and microbubbles to noninvasively disrupt the BBB to aid drug delivery to the brain as well as other claim limitations.
Howard teaches (§Abstract, §Main text ¶1-2, ¶4; §Discussion ¶3, §Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3; Figs. 5-6) encapsulating a virus within microbubbles to protect the virus from the immune system and successfully delivering it to target tissues.
Aryal teaches (§Abstract, §1. Introduction ¶2, §2. Materials and Methods-2.4 Sonications; Figs. 2, 3a, and 5b; §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption, §2. Materials and Methods-2.2 Experimental set up) evidencing BBB disruption and cargo delivery on contrast extravasation on MRI.
Tervo teaches (§Abstract, §Using rAAV2-retro for Circuit Interrogation and Gene Manipulation ¶3, §Results-Directed Evolution of rAAV2-retro ¶1 and §Discussion ¶1-2; §Introduction, final ¶; §Efficient Retrograde Access to Projection Neurons ¶2, Fig. 2; §Efficient Retrograde Access to Projection Neurons ¶2-3; §Retrograde Access to Genetically Defined Neuronal Populations, entire §) Cre/recombinase system for (1) functional interrogation of neural circuits and (2) a color visualization system.
Geisler (§Introduction ¶1, §Box-Core tip, §Discussion-Engineering, optimization and limits of artificial target sites for microRNA-mediated post-transcriptional transgene silencing ¶1) and Zhang (§Discussion ¶2-3) teach the importance of being able to control transgene function to make gene therapy safer.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the invention of the copending App812 claims with the teachings of Mead, Howard, Aryal, Tervo, Geisler, and Zhang for the benefit of improving the delivery of the vector of the App812 claims to the brain/CNS (which an artisan would have wanted to do since the product is for treating Alzheimer’s disease) and including a gene therapy safety switch. Doing so would have produced the invention of the instant Claims.
Claims 1, 3-4, 7, 11, 20, and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 12-14, 16, and 24-27 of copending Application No. 17794109 (“App 109”) in view of MeiraGTx (2018. MeiraGTx Announces Publication of New Research Identifying Underlying Mechanism of Functional Improvement Seen with AAV-GAD Gene Therapy in Parkinson’s Disease. Press Release. Available online at investors.meiragtx.com/news-releases/news-release-details/meiragtx-announces-publication-new-research-identifying. Accessed on 09 January 2026, “Meira”, of record), Mead, Howard, and Aryal. This rejection is maintained and updated in response to the claim amendments.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the copending App109 claims are directed to a method for improving a wakeful function in a subject suffering from an acquired cognitive deficiency, comprising administering to the subject an effective amount of an upregulator of GABAB signaling, including combining the upregulator with anterior-forebrain stimulating therapy including (Claim 16) focused ultrasound (FUS).
The instant claims are directed to a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, microbubbles comprising a mammalian serum albumin protein and a non-oncolytic recombinant virus comprising the transgene (wherein the virus can be AAV or adenovirus) and wherein the virus is encapsulated within the microbubbles; and applying to one or more regions of the mammal’s CNS focused ultrasound (FUS) to transiently disrupt the BBB and deliver the recombinant virus to the one or more regions of the brain or spinal cord (wherein the delivery is evidenced by contrast extravasation MRI), wherein the transgene can encode a protein, wherein the mammal is a human, wherein FUS is applied either concurrently with the microbubbles and recombinant virus or after administering the microbubbles and recombinant virus; and wherein the FUS is applied to specific sites.
An artisan would readily recognize that GABAB signaling may be upregulated in various way, including by administering a recombinant AAV comprising a transgene encoding the GABAB receptor or a transgene that upregulates GABA. Meira teaches such an AAV:
(§About AAV-GAD) AAV-GAD is an investigational gene therapy medicine designed to deliver the GAD gene to the STN in order to increase production of GABA, the primary inhibitory neurotransmitter in the human brain. GAD is the rate-limiting enzyme in the synthesis of GABA.
Although Meira doesn’t explicitly teach that the gene therapy includes a recombinant vector, an artisan would readily recognize that the various components mean the AAV is recombinant. Therefore, both claim sets may be considered to be directed to methods that can comprise administering a transgene, including a transgene expressing a protein, to a mammal’s CNS, and to administering FUS to the forebrain.
The copending App109 claims do not recite using FUS to deliver the AAV in microbubbles, the mammalian serum albumin protein, the contrast extravasation on MRI, the specific region of the brain that is the striatum, the order of microbubble and FUS administration, or encapsulating the AAV within the microbubbles.
However Mead teaches (§Main text ¶1-5; §Materials and Methods-Microbubble Fabrication and Characterization, §Materials and Methods-FUS-Mediated DNA-BPN Delivery; §Materials and Methods-FUS-Mediated DNA-BPN Delivery, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2, §Discussion-Relevance to Clinical Trials ¶2, Fig. 2, §Results-Characterization of GDNF-BPN ¶1, §Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) using FUS and microbubbles to noninvasively disrupt the BBB to aid drug delivery to the brain as well as other claim limitations.
Howard teaches (§Abstract, §Main text ¶1-2, ¶4; §Discussion ¶3, §Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3; Figs. 5-6) encapsulating a virus within microbubbles to protect the virus from the immune system and successfully delivering it to target tissues.
Aryal teaches (§Abstract, §1. Introduction ¶2, §2. Materials and Methods-2.4 Sonications; Figs. 2, 3a, and 5b; §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption, §2. Materials and Methods-2.2 Experimental set up) evidencing BBB disruption and cargo delivery on contrast extravasation on MRI.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the invention of the copending App109 claims with the teachings of Meira, Mead, Howard, and Aryal for the benefit of improving delivery of the upregulator of GABAB signaling to the brain/CNS. Doing so would have produced the invention of Claims 1, 3-4, 7, 11, 20, and 25.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 8, 11, 13, 16, 18-21, 24-25, 28-29, and 32 of copending Application No. 17632063 (“App063”) in view of Mead, Howard, Aryal, Tervo, Geisler, and Zhang. This rejection is maintained and updated in response to the claim amendments.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the copending App063 claims are directed to a method for targeting a specific population of mammalian neurons by administering a vector comprising a conditionally activatable gene or gene product and a second composition comprising a second vector comprising an ORF that activates the gene in the first viral vector, wherein focused ultrasound (FUS) is employed, wherein the vector can be a retrograde viral vector, and wherein the neurons are in the brain. Although the copending claims don’t explicitly recite that the AAV is a recombinant virus, an artisan would readily recognize that the various components mean the AAV is recombinant.
The instant claims are directed to a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, microbubbles comprising a mammalian serum albumin protein and a non-oncolytic recombinant virus comprising the transgene (wherein the virus can be AAV or adenovirus) and wherein the virus is encapsulated within the microbubbles; and applying to one or more regions of the mammal’s CNS focused ultrasound (FUS) to transiently disrupt the BBB and deliver the recombinant virus to the one or more regions of the brain or spinal cord (wherein the delivery is evidenced by contrast extravasation MRI), wherein the transgene can encode a protein, wherein the mammal is a human, wherein FUS is applied either concurrently with the microbubbles and recombinant virus or after administering the microbubbles and recombinant virus; wherein the FUS is applied to specific sites; wherein the transgene is flanked by recombination sites for a recombinase and wherein the transgene can be a recombinase gene and the nononcolytic virus can be a retrograde virus or wherein the transgene can be inactivated by subsequent delivery of recombinase enzyme or a gene encoding recombinase enzyme; or wherein a target sequence for a miRNA is inserted into the transgene and wherein the corresponding miRNA is expressed in an organ/tissue specific manner.
An artisan would readily recognize that the App063 claims are directed to expressing a transgene. Therefore, both claim sets may be considered to be directed to methods that can comprise administering a transgene, including a transgene expressing a protein, to a mammal’s CNS, and wherein the transgene includes recombination.
The copending App063 claims do not recite using microbubbles, the mammalian serum albumin protein, the contrast extravasation on MRI, the specific region of the brain that is the striatum, the order of microbubble and FUS administration, or encapsulating the AAV within the microbubbles, or the limitations about a recombinase, retrograde virus, or miRNA/miRNA target sequence .
However Mead teaches (§Main text ¶1-5; §Materials and Methods-Microbubble Fabrication and Characterization, §Materials and Methods-FUS-Mediated DNA-BPN Delivery; §Materials and Methods-FUS-Mediated DNA-BPN Delivery, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2, §Discussion-Relevance to Clinical Trials ¶2, Fig. 2, §Results-Characterization of GDNF-BPN ¶1, §Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) using FUS and microbubbles to noninvasively disrupt the BBB to aid drug delivery to the brain as well as other claim limitations.
Howard teaches (§Abstract, §Main text ¶1-2, ¶4; §Discussion ¶3, §Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3; Figs. 5-6) encapsulating a virus within microbubbles to protect the virus from the immune system and successfully delivering it to target tissues.
Aryal teaches (§Abstract, §1. Introduction ¶2, §2. Materials and Methods-2.4 Sonications; Figs. 2, 3a, and 5b; §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption, §2. Materials and Methods-2.2 Experimental set up) evidencing BBB disruption and cargo delivery on contrast extravasation on MRI.
Tervo teaches (§Abstract, §Using rAAV2-retro for Circuit Interrogation and Gene Manipulation ¶3, §Results-Directed Evolution of rAAV2-retro ¶1 and §Discussion ¶1-2; §Introduction, final ¶; §Efficient Retrograde Access to Projection Neurons ¶2, Fig. 2; §Efficient Retrograde Access to Projection Neurons ¶2-3; §Retrograde Access to Genetically Defined Neuronal Populations, entire §) Cre/recombinase system for (1) functional interrogation of neural circuits and (2) a color visualization system.
Geisler (§Introduction ¶1, §Box-Core tip, §Discussion-Engineering, optimization and limits of artificial target sites for microRNA-mediated post-transcriptional transgene silencing ¶1) and Zhang (§Discussion ¶2-3) teach the importance of being able to control transgene function to make gene therapy safer.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the invention of the copending App063 claims with the teachings of Mead, Howard, Aryal, Tervo, Geisler, and Zhang for the benefit of improving delivery of the vector to the brain/CNS and including a gene therapy kill switch. Doing so would have produced the invention of the instant Claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of copending Application No. 18575597 (“App597”) in view of Mead, Howard, Aryal, Tervo, Geisler, and Zhang. This rejection is maintained and updated in response to the claim amendments.
Although the claims at issue are not identical, they are directed to overlapping subject matter because the copending App597 claims are directed to a method of treating PD by increasing expression of AADC in the brain in a subject with PD, wherein the agent comprises a nucleic acid encoding the AADC polypeptide and administration causes expression of the AADC polypeptide, wherein the agent comprises a vector including AAV. Although the copending claims don’t explicitly recite that the AAV is a recombinant virus, an artisan would readily recognize that the various components mean the AAV is recombinant.
The instant claims are directed to a method to deliver a therapeutic transgene to one or more regions of a brain or spinal cord of a mammal, comprising: administering to a mammal in need thereof, microbubbles comprising a mammalian serum albumin protein and a non-oncolytic recombinant virus comprising the transgene (wherein the virus can be AAV or adenovirus) and wherein the virus is encapsulated within the microbubbles; and applying to one or more regions of the mammal’s CNS focused ultrasound (FUS) to transiently disrupt the BBB and deliver the recombinant virus to the one or more regions of the brain or spinal cord (wherein the delivery is evidenced by contrast extravasation MRI), wherein the transgene can encode a protein, wherein the mammal is a human, wherein FUS is applied either concurrently with the microbubbles and recombinant virus or after administering the microbubbles and recombinant virus; wherein the FUS is applied to specific sites; wherein the transgene is flanked by recombination sites for a recombinase and wherein the transgene can be a recombinase gene and the nononcolytic virus can be a retrograde virus or wherein the transgene can be inactivated by subsequent delivery of recombinase enzyme or a gene encoding recombinase enzyme; or wherein a target sequence for a miRNA is inserted into the transgene and wherein the corresponding miRNA is expressed in an organ/tissue specific manner.
An artisan would readily recognize that the App597 claims are directed to expressing a transgene. Therefore, both claim sets may be considered to be directed to methods that can comprise administering a transgene encoded on an AAV vector, including a transgene expressing a protein, to a mammal’s CNS.
The copending App597 claims do not recite using FUS or microbubbles, the mammalian serum albumin protein, the contrast extravasation on MRI, the specific region of the brain that is the striatum, the order of microbubble and FUS administration, or encapsulating the AAV within the microbubbles, or the limitations about a recombinase, retrograde virus, or miRNA/miRNA target sequence.
However Mead teaches (§Main text ¶1-5; §Materials and Methods-Microbubble Fabrication and Characterization, §Materials and Methods-FUS-Mediated DNA-BPN Delivery; §Materials and Methods-FUS-Mediated DNA-BPN Delivery, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2, §Discussion-Relevance to Clinical Trials ¶2, Fig. 2, §Results-Characterization of GDNF-BPN ¶1, §Results-Localized Delivery of GDNF-BPN with FUS Elicits Robust GDNF Protein Expression in the Striatum ¶1, §Discussion-Comparison to Previous Preclinical Studies with GDNF ¶2) using FUS and microbubbles to noninvasively disrupt the BBB to aid drug delivery to the brain as well as other claim limitations.
Howard teaches (§Abstract, §Main text ¶1-2, ¶4; §Discussion ¶3, §Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3; Figs. 5-6) encapsulating a virus within microbubbles to protect the virus from the immune system and successfully delivering it to target tissues.
Aryal teaches (§Abstract, §1. Introduction ¶2, §2. Materials and Methods-2.4 Sonications; Figs. 2, 3a, and 5b; §3Results-3.1. Bilateral tumor progression and BBB/BTB disruption, §2. Materials and Methods-2.2 Experimental set up) evidencing BBB disruption and cargo delivery on contrast extravasation on MRI.
Tervo teaches (§Abstract, §Using rAAV2-retro for Circuit Interrogation and Gene Manipulation ¶3, §Results-Directed Evolution of rAAV2-retro ¶1 and §Discussion ¶1-2; §Introduction, final ¶; §Efficient Retrograde Access to Projection Neurons ¶2, Fig. 2; §Efficient Retrograde Access to Projection Neurons ¶2-3; §Retrograde Access to Genetically Defined Neuronal Populations, entire §) Cre/recombinase system for (1) functional interrogation of neural circuits and (2) a color visualization system.
Geisler (§Introduction ¶1, §Box-Core tip, §Discussion-Engineering, optimization and limits of artificial target sites for microRNA-mediated post-transcriptional transgene silencing ¶1) and Zhang (§Discussion ¶2-3) teach the importance of being able to control transgene function to make gene therapy safer.
Therefore it would have been obvious to an artisan before the effective filing date of the claimed invention to modify the invention of the copending App597 claims with the teachings of Mead, Howard, Aryal, Tervo, Geisler, and Zhang for the benefit of improving delivery of the vector to the brain/CNS and including a gene therapy kill switch. Doing so would have produced the invention of Claims 1, 3-4, 7, 11, 13, 15, 18, 20, and 25.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 11 March 2026 have been fully considered but they are not persuasive. Arguments are addressed below. Arguments that are no longer relevant are not addressed.
112a Written Description (WD)
Applicant argues that (§D) the claim amendments address the WD problem because the Spec. identifies representative therapeutic transgenes which reasonably conveys that they were in possession.
That is not persuasive because the claims recite a broad genus of transgenes that are identified solely by their function of being therapeutic (Claim 1) and treating PD (Claim 20). Although the claims don’t explicitly recite the exact term treating, the claims encompass treatment because the claims recite deliver[ing] a therapeutic transgene… to a mammal in need thereof. But neither the Claims nor the Spec. disclose what structure is required for the function of being therapeutic or treating PD. As discussed previously, the statutory requirement is that inventors were in possession of the claimed invention. As Applicant acknowledges, the claim recites functional characteristics (i.e., in their terms, the claimed therapeutic use embodiments). The Spec. does not support full possession—or possession of a representative number of species—of an invention comprising the claimed functional characteristics. Furthermore, the Spec. does not adequately describe any structure(s) that underlie the claimed functional characteristics in a way that demonstrates possession. Therefore the WD rejection is maintained.
112b
Applicant argues that Claim 1 has been amended to clarify the claimed subject matter but those arguments aren’t persuasive because the claims and Spec. still do not clarify what is “an amount” and because those terms are unclear, an artisan would not know how to carry out the method steps. The claim recites three different amounts: microbubbles, virus, and FUS and an artisan wouldn’t know how much of each one to administer. For example, is a single MB encapsulating a single virus particle sufficient to show up on an MRI documenting contrast extravasation?
Regarding Claim 11, it isn’t clear whether the limitation about the protein being a glycoprotein or the optional limitation about the protein being a recombinase are fully optional or if those limitations further limit the claim.
112d
Claim 4 doesn’t further limit Claim 1 because Claim 1 already requires that the BBB disruption and delivery is evidenced by contrast extravasation on MRI which requires contrast be administered to the mammal.
103
Applicant argues against the 103 rejection on pp. 7-9. Arguments over Rychak and Long are not persuasive because those references are no longer applied and have been replaced with Howard. Those arguments aren’t found persuasive in view of Howard because Howard discloses encapsulating the recombinant virus within microbubbles:
Howard teaches an ultrasound guided site-specific gene delivery system wherein the virus particles are encapsulated inside of microbubbles. Howard’s system describes they produced microbubbles enclosing and protecting adenovirus and (§Main text ¶4) in their system, the microbubbles protect the viruses from rapid degradation by the immune system, thus allowing for intravenous injection. Howard very clearly teaches a process whereby they produced microbubbles comprising adenovirus particle and neutralized the virus adsorbed to the surface while leaving virus particles inside the microbubbles:
(§Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3) This data indicates that the treatment with complement of the Ad-GFP bubbles inactivated the adenoviruses present on the bubble’s surface leaving instead intact and viable the adenoviruses encapsulated by the microbubbles without destroying the integrity of the Imagent bubble shell [emphasis added].
Howard also shows (Figs. 5-6) successful delivery of their microbubble-encapsulated recombinant adenovirus particles to target tissues.
Howard discusses that placing the virus within the microbubble protects it from the immune system. Howard also discusses that using a recombinant adenovirus is beneficial because it allows for sustained transgene expression. Therefore Howard demonstrates successfully encapsulating a complex particulate biological agent (capsid/envelope) within the microbubbles which “suppl[ies] the missing teaching [and] sufficient rationale” Applicant’s arguments discuss. Then, Mead and Aryal teach the other claim elements, including that using FUS/MB to disrupt the BBB and deliver a transgene to the brain is routine in the art.
Therefore the 103 rejection is maintained.
NSDP
Applicant argues that the issued patents are directed to different subject matter than the instant claims and argues against Rychak. Those arguments are not found persuasive because the instant claims would have been obvious in view of the issued claims and the prior art. As discussed about in the responses to arguments over the 103 rejections, arguments over Rychak are not persuasive because that reference is no longer applied and has been replaced with Howard. Howard discloses encapsulating the recombinant virus within microbubbles:
Howard teaches an ultrasound guided site-specific gene delivery system wherein the virus particles are encapsulated inside of microbubbles. Howard’s system describes they produced microbubbles enclosing and protecting adenovirus and (§Main text ¶4) in their system, the microbubbles protect the viruses from rapid degradation by the immune system, thus allowing for intravenous injection. Howard very clearly teaches a process whereby they produced microbubbles comprising adenovirus particle and neutralized the virus adsorbed to the surface while leaving virus particles inside the microbubbles:
(§Results-Complement inactivates adenoviruses adsorbed on the microbubbles’ surface in vitro ¶3) This data indicates that the treatment with complement of the Ad-GFP bubbles inactivated the adenoviruses present on the bubble’s surface leaving instead intact and viable the adenoviruses encapsulated by the microbubbles without destroying the integrity of the Imagent bubble shell [emphasis added].
Howard also shows (Figs. 5-6) successful delivery of their microbubble-encapsulated recombinant adenovirus particles to target tissues.
Howard discusses that placing the virus within the microbubble protects it from the immune system. Howard also discusses that using a recombinant adenovirus is beneficial because it allows for sustained transgene expression. Therefore Howard demonstrates successfully encapsulating a complex particulate biological agent (capsid/envelope) within the microbubbles which “suppl[ies] the missing teaching [and] sufficient rationale” Applicant’s arguments discuss. Then, Mead and Aryal teach the other claim elements, including that using FUS/MB to disrupt the BBB and deliver a transgene to the brain is routine in the art.
Applicant’s remarks state that since any of the copending claims are not yet allowed, it is premature to consider the NSDP rejections over them. Therefore the NSDP rejections over the copending claims (as updated) are maintained.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Saunders (et al. 2012. Novel recombinant adeno-associated viruses for Cre activated and inactivated transgene expression in neurons. Frontiers Neural Circuit. 6:47).
Saunders teaches benefits of using Cre recombinase system in gene therapy.
Lipsman (et al. 2018. Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat. Comm. 9:2336).
Lipsman teaches contrast extravasation MRI to evidence BBB disruption and microbubble delivery to the brain.
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RUTHIE S ARIETI
Examiner
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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