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 .
Claim Status
As of the Non-Final Office Action mailed 7/1/2025, claims 1, 3, 15-17, 20-22, 33-34, 41, 43, 46, 48, 51, 54, and 86 were pending.
In Applicant's Response filed on 12/31/2025, claims 1, 24, 28-29, 31-32, and 51 were amended and claims 100-107 were newly added.
As such, claims 1, 3, 15-17, 20-22, 33-34, 41, 43, 46, 48, 51, 54, 86 and 100-107 are pending and have been examined herein.
THIS ACTION IS NON-FINAL.
Withdrawn Objections/Rejections
The rejection of record of claims 1, 3, 15-17, 20-22, 33-34, 41, 43, 46, 48, 51, 54, and 86 under 35 USC § 101 for lacking patentable utility has been withdrawn in view of Applicant’s amendments to the instant claims.
Maintained/Modified Rejections
Applicant’s arguments regarding the rejections of claims 1, 3, 15-17, 20-22, 24-25, 27-29, 31-34, 39-41, 43, 46, 48, 51, 54, and 86 under 35 U.S.C. 112(a) have been fully considered but are not persuasive. Thus, the rejection has been recast below and modified to include Applicant’s claim amendments. Response to arguments will follow the rejection.
The rejection of record of claims 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, and 86 under 35 U.S.C. 102 as anticipated by Dodge et al has been recast below and modified to reflect amendments to the instant claims. Response to arguments will follow the rejection.
The rejection of record of claims 21, 34, 46, 48, 54 under 35 USC § 103 as being unpatentable over Dodge et al as applied to claims 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, 86, and 101 above, and further in view of Dirren et al (Hum Gene Ther. 15 Jan 2014;25(2):109-20; previously cited) has been recast below and modified to reflect amendments to the instant claims. Response to arguments will follow the rejection.
The rejection of record of claims 22, 29, and 31-32 under 35 USC § 103 as being unpatentable over Dodge et al as applied to claims 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, 86 above, and further in view of Thorne et al (US 10,123969 B2, 14 Oct 2016; Published 13 Nov 2018; previously cited) and Davidson et al (US 9,487,779 B2, 5 June 2014; Published 8 Nov 2016; previously cited) has been recast below and modified to reflect amendments to the instant claims. Response to arguments will follow the rejection.
The rejection of record of claim 25 under 35 USC § 103 as being unpatentable over Dodge et al as applied to claims 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, 86 above, and further in view of Ellis et al (Gene Therapy, 19 Jan 2012; previously cited) has been recast below and modified to reflect amendments to the instant claims. Response to arguments will follow the rejection.
The rejection of record of claim 27 under 35 USC § 103 as being unpatentable over Dodge et al as applied to claims 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, 86 above, and further in view of Inouye et al (Protein Expr Purif. 7 Feb 2015;109:47-54; previously cited) has been recast below and modified to reflect amendments to the instant claims. Response to arguments will follow the rejection.
Claim Rejections - 35 USC § 112(a)
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, 15-17, 20-22, 24-25, 27-29, 31-34, 39-41, 43, 46, 48, 51, 54, 86, 100-105, and 107 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of administering a vector to a primate, comprising unilateral intracerebroventricular injection of an AAV9 vector to the primate wherein the vector comprises eTFSCN1A under the control of GABA-selective regulatory element, does not reasonably provide enablement for a method of administering a vector to a primate where the vector comprises any cell-type selective regulatory element to target any cell in any primate as broadly embraced by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considered whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirement, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d at 737, 8 USPQ2d 1400, 1404 (Fed. Cir.1988)).
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore, skepticism raised in the enablement rejection are those raised in the art by artisans of expertise.
Nature of the invention:
A method of administering a vector to a primate, comprising intracerebroventricular (ICV) administration of a vector to the primate, wherein the vector comprises a cell-type selective regulatory element.
The state of the prior art:
The state of the prior art for administering to a primate any vector containing a cell selective regulatory element via intracerebroventricular administration was unpredictable before the effective filing date of the claimed invention.
The breadth of the claims:
The claims encompass administering to any primate a vector containing any cell selective regulatory element. Cell selective regulatory element encompasses promoters, UTRs, introns, exons, etc., so long as it targets neuronal cells.
The level of skill in the art:
The level of skill is high that requires a researcher with a PhD degree.
The working examples and guidance provided:
The specification discloses working examples in which Cynomolgus monkeys (non-human primate) were transduced with AAV9-CBA-eGFP-Kash via multiple administration routes (working example 1), different AAV serotypes were assessed using AAV1, 5, and 9 with CBA-eGFP-KASH (example 2), and the biodistribution of eTFSCN1A in cynomolgus monkey via unilateral intracerebroventricular injection of an AAV9 vector containing eTFSCN1A under the control of a GABA selective regulatory element (working example 3-5). This is the only example in which a cell selective regulatory element was used (required by the instant claims).
The specification fails to provide any working examples in which any other vectors containing any other cell selective regulatory element were delivered to any other primate.
The unpredictable nature of the art:
The claims read on gene transfer or gene therapy by administering a vector (AAV, lentiviral, retroviral, etc.) comprising a nucleic acid sequence comprising various types of cell selective regulatory elements (promoters, UTRs, WPRE, etc.) via intracerebroventricular injection to any primate. The state of the prior art of gene transfer and gene therapy was not well developed and was highly unpredictable at the time of filing. While progress has been made in recent years for gene transfer in vivo, vector targeting to desired tissues in vivo continues to be unpredictable and inefficient as supported by numerous teachings available in the art. There are many factors that contribute to the unpredictability of gene transfer or gene therapy in vivo.
Chen et al (Nucleic Acids Resear, 41(20):9230-9242) teaches that CSREs are defined as genomic regions exhibiting distinctive modification patterns, relative to those in other cell types. CSREs were significantly enriched at well-known regulatory regions, such as promoters, 5′ and 3′ UTRs ( formula , Fisher’s exact tests) ( Figure 2 B). Exon and intron regions were also enriched in CSREs, suggesting that part of a gene body may serve as regulatory elements, such as enhancers, for its own expression (“CREs relate to various genomic features” para 1). The strong enrichments of CSREs in promoter regions ( formula , Fisher’s exact tests) demonstrates underlying modifications acting in promoter regions play critical roles in regulating gene expression (same para). It also teaches that there are 34,721 distinct CSREs in the human genome (collectively spanning 4.62%), most of which (94.1%) were specific to a single cell type with only 5.9% being found in two or more cell types.
Kotterman et al., 2014 (Nature Reviews, Vol. 15, p. 445-451) reports that AAV still has significant challenges regarding successful use in treatment regimens (pg. 450 col. 2). Specifically Kotterman points out “widespread natural exposure to AAVs has resulted in a large portion of the population with neutralizing antibodies specific to capsids in the blood and other body fluids, which markedly limit gene delivery by many natural vectors... following cellular transduction, AAV capsid epitopes can become cross-presented on major histocompatibility complex (MHC) class I molecules, which leads to the elimination of transduced cells by capsid-specific cytotoxic T lymphocytes and the corresponding loss of gene expression”. “For systemically administered viruses, the liver is often the default destination, which can represent a barrier when other organs are the intended targets. In addition, endothelial cell layers, especially those within the blood-brain barrier, pose a physical barrier for entry into a tissue. A vector that gains access to an organ, or that is directly administered to that organ, can then encounter numerous transport barriers to efficient transduction of the often large tissue volumes involved in disease, including cell bodies and intervening extracellular matrix to which many AAV variants bind”. “The surface of a target cell may lack the primary and/or secondary receptors that are necessary for vector binding and internalization. Furthermore, endosomal escape, proteasomal escape, nuclear entry and vector unpackaging all represent barriers to transduction” (e.g. p. 447, under BOX 1).
Shim et al., 2017 (Current Gene Therapy, Vol. 17, No. 5, p. 1-18) reports that in all gene therapy applications, delivery issues are essential, and nucleic acids are highly polar macromolecules and cannot diffuse through cell membranes. For the delivery of nucleic acids into target cells, viral and nonviral methods have been used. Despite success, viral vectors still suffer from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems (e.g. p. 1, right column, 2nd paragraph). “Although nonviral methods have many advantages, including safety, the reasons these methods are falling behind viral methods with regard to outcomes might still be a matter of “delivery”, including passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release… Behavior in the physiological environment is the most important hurdle for vectors” (e.g. p. 13, left column, 4th full paragraph). Thus, viral vector delivery of nucleic acid still suffer from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems. Nonviral delivery of nucleic acid still face the hurdle of passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release.
Lenzi et al., 2014 (NCBI Bookshelf, A Service of the National Library of Medicine, National Institute of Health, Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington (DC): National Academies Press (US), pages 1-16) discuss scientific hurdles of gene transfer in vivo. Some scientific hurdles, such as the absence of efficient delivery systems, difficulty with sustained expression, insertional mutagenesis and host immune reactions, remain formidable challenges to the field of gene transfer. Many of the hurdles have to do with providing efficient gene delivery. For examples, the vector uptake and distribution must be tightly controlled so that expression of the vector-encoded gene remains within the therapeutic range-if the expression is too low, the functional protein product may not be produced at a high enough concentration to effectively restore the intended biochemical pathway. Transcription of the new genetic material must remain stable so that the transgene is expressed as long as necessary to treat the disease. The degree to which the vector containing the transgene is taken up in a sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the efficiency of interactions between vector and host cell receptors. The ideal vector would be cell-type specific, but the design of either non-viral or viral vectors that successfully target a specific cellular receptor has been elusive despite a great deal of effort. To date, re-engineered viral vectors are often too large, too unstable, or otherwise unable to reach the nucleus of some cell types. Non-viral gene delivery remains prohibitively inefficient for most therapeutic applications (e.g. p. 10, under “Scientific Hurdles”). For viral vectors, especially adenoviral and adeno-associated viral vectors, the exposed individuals have circulating antibodies that can interfere with transduction of closely related recombinant vectors. The control of an unanticipated immune response can be complicated by the challenge of “turning off” expression of transgene driven by constitutive, non-conditioned promoter sequence specifically designed to always be “on” (e.g. p. 11, 1st paragraph).
In addition, post-dated Bulcha et al., 2021 (Signal Transduction and Targeted Therapy, 6:53, p. 1-24) discusses “Viral vector platforms within the gene therapy landscape” (e.g. Title). Bulcha reports the challenges of rAAV vector for gene therapy include immunogenicity towards the vector remains the largest challenge for AAV-based gene therapies. In fact, the immune system will always be a major barrier for any gene therapy approach. The adaptive immunity to the capsid and the foreign transgene represents major factors for decreased efficacies (e.g. p. 14, bridging left column and right column). “Mechanisms for innate immunity have been well-described in response to viruses, but exploration of innate immune response towards AAV vectors is understudied… In addition, evidence is accumulating for the possibility that the AAV vector genome can elicit an innate immune response, necessitating an area of research that is critically needed” (e.g. p. 14, right column, 2nd full paragraph). “Finally, a challenge that must be confronted is managing the right treatment doses, which may be at the heart of the strong immunological responses and subsequent toxicities seen in recent trials… These studies and others indicate that further evaluation of the appropriate routes of administration, capsid choice, and vector genome designs are still needed, even for approved drugs” (e.g. Bridging, p. 14, right column and p. 15, left column).
The degree to which the vector containing the transgene is taken up in a sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the efficiency of interactions between vector and host cell receptors. The challenges of rAAV vector for gene therapy include immunogenicity towards the vector remains the largest challenge for AAV-based gene therapies. The adaptive immunity to the capsid and the foreign transgene represents major factors for decreased efficacies. The AAV vector genome can elicit an innate immune response, necessitating an area of research that is critically needed. This makes it unpredictable for one of ordinary skill in the art. Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would not know how to practice the claimed invention and would require undue experimentation to practice over the full scope of the invention claimed.
The amount of experimentation necessary:
One skilled in the art before the effective filing date of the claimed invention would require to identify various genes of interests derived from various primates as well as cell selective regulatory elements, preparation of rAAV vector expressing the various proteins and regulatory elements derived from various animals, administration of the rAAV vectors to a primate via intracerebroventricular administration, trial and error experimentation to determine whether sufficient rAAV vector can be delivered to the target site in said primate, and trial and error experimentation to determine whether sufficient protein of interest are expressed at the target cell/site of the primate.
For the reasons set forth above, one skilled in the art before the effective filing date of the claimed invention would not be able to make and/or use the invention as claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of the art.
Response to Arguments
Applicant’s arguments have been fully considered but are not persuasive.
On p. 8 of Remarks, Applicant argues that the claim has been amended to include specific features of the vector administered to the primate such as a polypeptide, guide RNA, RNAi, or an antisense oligonucleotide, operably linked to a regulatory element selective for unipolar, bipolar, multipolar, pseudounipolar, or GABAergic neuron. Applicant states that the examiner has reduced the scope of enablement to narrow parameters based on the working examples and argues that the application as filed provides “numerous” working examples supporting a class encompassing the claimed invention and enabling a person of ordinary skill in the art to perform the claimed method without undue experimentation. Applicant points to example 1 and 2 of the instant specification as support. Applicant also argues that the examiner has not provided a rationale to why a clinically accepted animal model in the art requires additional studies in humans to satisfy the enablement requirement.
In response, the examiner disagrees. The examiner agrees with Applicant regarding the “primate” as claimed. However, as per MPEP 2164.02, one of the major inquiries of enablement is whether the specification discloses "some general quality running through" the broad genus of nucleotide sequences administered in the broad genus of vectors embraced by the claims to the broad genus of primates embraced by the claims that gives the genus of vectors “a peculiar fitness for the particular purpose"? The specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality . . . running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, the Supreme Court found that Amgen failed to enable all that it claimed, even if allowing for a reasonable degree of experimentation. Id. at 613; see also Baxalta Inc. v Genentech, Inc., 81 F.4th 1362, 1367, 2023 USPQ2d 1103 (Fed. Cir. 2023). In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. (see MPEP 2164.01). In a similar manner, the claims are drawn to a broad genus of administering nucleotide sequences (polypeptides, RNAi, gRNA) with the function of targeting subsets of neurons. Applicant has defined the genus by its function (targeting neurons) but has not recited any specific, structural features required by the instant claims needed for the method of administration. The vector components (polypeptide, RNAi, gRNA) do not have any “peculiar fitness” for the particular purpose (targeting and being expressed in neuronal cells) required by the claim. Thus, Applicant’s arguments are not persuasive.
Claim Interpretation
Claim 1 recites the phrase, inter alia, “cell-type selective regulatory element.” Under BRI, anything that helps control gene expression in a specific cell type, such as promoters, UTR, cis regulatory elements, introns, exons, etc., would constitute a cell-type selective regulatory element. The examiner is utilizing this interpretation for the purposes of rejections below.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, 86, and 101 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Dodge et al (US 9,034,836 B2, 4 Dec 2008; Published 19 May 2015; previously cited).
Dodge teaches a method to deliver a transgene product to the spinal cord in a subject having spinal muscular atrophy, comprising administering via intracerebroventricular injection a recombinant adeno-associated virus (AAV) vector comprising said transgene to at least one ventricle of the brain, whereby said transgene is expressed and the expressed protein product is delivered to the spinal cord, wherein the transgene is survival motor neuron gene 1 (SMN-1) where the subject is a mammal and the mammal is a human (see claim 1 and 6-7 of Dodge) (“a method of administering a vector to a primate, comprising intracerebroventricular (ICV) administration of a vector to the primate wherein the vector comprises a nucleotide sequence operably linked to a cell-type regulatory element, wherein the nucleotide sequence encodes a polypeptide” as in instant claim 1; “wherein the vector is administered to more than one ventricle of the brain” as in instant claim 15; “wherein the vector is administered to one ventricle of the brain” as in instant claim 20; “wherein the vector comprises a nucleotide sequence encoding a polypeptide” as in instant claim 24; “wherein the vector is an adeno-associated viral (AAV) vector” as in instant claim 33; “wherein the administration is by route of injection” as in instant claim 43; “wherein the primate is a human” as in instant claim 46). The invention provides a method of delivering a therapeutic transgene product to a target cell of the CNS, which is a neuron, glial cell, motor neuron, etc. (“wherein the cell-type regulatory element is selectively expressed in a neuronal cell, wherein the neuronal cell is selected from the group consisting of . . . multipolar . . . neuron” as in instant claim 1). The transgene encodes a biologically active molecule, expression of which in the CNS results in at least partial correction of neuropathology and/or stabilization of disease progression. The transgene may be insulin growth factor-1 (IGF-1), calbindin D28, parvalbumin, HIF1-alpha, SIRT-2, VEGF, SMN-1, SMN-2, CNTF (Ciliary neurotrophic factor), sonic hedgehog (shh), erythropoietin (EPO), lysyl oxidase (LOX), progranulin, prolactin, ghrelin, neuroserpin, angiogenin, and placenta lactogen. The reference teaches that the AAV vector is AAV4, however the AAV can be selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, and AAV8 (see claim 2 of Dodge; col 7 lines 63-66) (“wherein the AAV is . . . (3) any one of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8” as in instant claim 34). The reference teaches that the injections of the viral vector can be single or multiple, unilateral or bilateral (col 15, lines 30) (“wherein the vector is administered unilaterally” as in instant claim 3; “wherein the vector is administered bilaterally” as in instant claim 16). The reference also teaches pharmacological regulation of gene expression with viral vectors can been obtained by including various regulatory elements and drug-responsive promoters such as cytomegalovirus (CMV) promoter, CMV/human β3-globin promoter, GFAP promoter, the 1.8-kb neuron-specific enolase (NSE) promoter, chicken beta actin (CBA) promoter, the β-glucuronidase (GUSB) promoter, and ubiquitin promoters such as those isolated from human ubiquitin A, human ubiquitin B, and human ubiquitin C (col 12 lines 25-46). To prolong expression, other regulatory elements may additionally be operably linked to the transgene, such as, e.g., the Woodchuck Hepatitis Virus Post-Regulatory Element (WPRE) (“cell-type selective regulatory element” as in the instant specification Example 2) or the bovine growth hormone (BGH) polyadenylation site. This anticipates “wherein the vector comprises a cell-type selective regulatory element” as in instant claim 1. The reference also teaches that recombinant AAV-based vectors have the rep and cap viral genes that account for 96% of the viral genome removed, leaving the two flanking 145-basepair (bp) inverted terminal repeats (ITRs), which are used to initiate viral DNA replication, packaging and integration (col 8 lines 10-20) (“wherein the vector comprises a 5’ AAV ITR sequence and a 3’ AAV ITR sequence” as in instant claim 39). The composition can include pharmaceutically acceptable carriers such as phosphate buffered saline, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents (col 5, lines 60-64) (“wherein the vector is administered in a pharmaceutically acceptable carrier” as in instant claim 40). Dodge does not state that the vector is administered in combination with a contrast agent, anticipating “wherein the vector is not administered in combination with a contrast agent” as in instant claim 41. Working example 1 of Dodge shows that vectors were injected into both the lateral and 4th ventricle at the same time (“wherein the vector is administered simultaneously” as in instant claim 17).
Claim 86 recites language that intends to express the intended result of a process step positively recited in claim 1 (see MPEP 2111.04). Absent evidence to the contrary, the examiner is interpreting the limitations of claim 86 to flow from the method step of claim 1.
Thus, Dodge anticipates the invention of instant claims 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, 86, and 101.
Response to Arguments
Applicant's arguments filed regarding the Dodge reference have been fully considered but they are not persuasive.
Applicant argues on p. 10 of Remarks that the incorporation of subject matter from claim 51 (not previously rejected under 102 or 103) makes independent claim 1 novel.
In response, the examiner disagrees. A clerical error was made in which claim 51 was left out of the 102 rejection as anticipated over Dodge (as it teaches glial cells, which are multipolar cells and reads on previous claim 51) or, in the alternative, under 103 as obvious over the previously cited Dirren reference, which discusses AAV9 targeting of astrocytes (which are known multipolar, GABAergic/GABAceptive neurons; also reading on “multipolar . . . GABAergic neurons” as in previously presented claim 51). Furthermore, newly cited reference Miller discusses the targeting of GABAergic inhibitory neurons via vector containing transcription factors targeting SCN1A. Thus, Applicant’s arguments are not persuasive.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 21, 34, 46, 48, 51, 54, and 101 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dodge et al as applied to claims 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, 86, and 101 above, and further in view of Dirren et al (Hum Gene Ther. 15 Jan 2014;25(2):109-20; previously cited).
Dirren teaches ICV injection of recombinant AAV6 with the cytomegalovirus (cmv) promoter preferentially targets motoneurons, whereas AAV9 particles combined with the astrocyte-specific gfaABC1D promoter lead to significant transgene expression selectively targeted to astrocytes (abstract) (“wherein the regulatory element is selectively expressed in glial cells, wherein the glial cells are selected from the group consisting of astrocytes” as in instant claim 54; “wherein the neuronal cell is a GABAergic neuron” as in instant claim 51). Importantly, ICV co-injection of both AAV6-cmv and AAV9-gfaABC1D results in segregated expression of two different transgenes in motoneurons and astrocytes, respectively (same para). The reference teaches targeting of astrocytes is of particular interest for non-cell-autonomous diseases such as ALS (Discussion para 3). The reference teaches that most AAV serotypes display a preferential neuronal tropism (same para). For instance, only a limited number of astrocytes were observed to express GFP using serotype 6 AAV particles. However, capsid engineering has allowed to shift AAV tropism toward glial cells and the rh43 AAV has been shown to infect astrocytes after direct intracerebral injections (same para). Extensive transduction of astrocytes has also been demonstrated with AAV9 in particular when delivered intravenously (same para) (“wherein the AAV is . . . AAV9” as in instant claim 34; “wherein the AAV is AAV9” as in instant claim 101). This shows that for astrocyte targeted delivery, one of ordinary skill would use AAV9 and that the AAV9 vector would maintain its targeting capabilities when delivered intravenously, reading on “wherein the primate further receives an intravenous administration of the vector” as in instant claim 21. The reference also teaches that the vector was also delivered to African green monkeys of St. Kitts origin (i.e., old world monkey), reading on “wherein the primate is a non-human primate” as in instant claim 46 and “wherein the non-human primate is an old world monkey” as in instant claim 48.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a vector to a primate as taught by Dodge, where the primate receives intravenous administration of the vector as taught by Dirren, to arrive at the instantly claimed invention. Dirren shows that astrocytes can be effectively transduced with AAV9 vectors when delivered intravenously, one of ordinary skill would have been motivated to modify the vector of Dodge to include an AAV9 vector with a reasonable expectation of advantageously targeting astrocytes both through ICV and intravenous injection as taught by the prior art.
Claim(s) 22, 29, 31-32, and 100 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dodge et al as applied to claims 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, 86 and 101 above, and further in view of Thorne et al (US 10,123969 B2, 14 Oct 2016; Published 13 Nov 2018; previously cited) and Davidson et al (US 9,487,779 B2, 5 June 2014; Published 8 Nov 2016; previously cited).
Thorne teaches a method of enhancing therapeutic/drug transport to perivascular spaces of a patient's brain, the method comprising the step of: injecting or infusing a therapeutic/drug and an osmolyte into a patient's cerebrospinal fluid (CSF), wherein the osmolyte is introduced to the CSF at a concentration between 0.5 M and 12.9 M (dependent on the solubility upper limit of the osmolyte), and wherein the therapeutic/drug delivery to the perivascular spaces of cerebral blood vessels and parenchyma in the patient's brain includes passing the therapeutic/drug through lining cells positioned on an external surface of the cerebral blood vessels, and wherein passing the therapeutic/drug through the lining cells is facilitated by the presence of the osmolyte, and wherein the injecting or infusing step is by way of intracerebroventricular injection or infusion, intrathecal intracisternal injection or infusion, or intrathecal lumbar injection or infusion (see claim 1 of Thorne) (“wherein the primate further receives an intrathecal administration of the vector, wherein the intrathecal administration comprises intrathecal cisternal administration or intrathecal lumbar administration” as in instant claim 22). The reference also teaches that the therapeutic/drug is a macromolecule or biopharmaceutical selected from siRNA (i.e., interfering RNA) as well as antisense oligonucleotides (see claim 11 of Thorne; col 8, line 15-16) (“wherein the vector comprises a nucleotide sequence encoding an interfering RNA” as in instant claim 29 in-part; “wherein the vector comprises a nucleotide sequence encoding an antisense oligonucleotide that reduces the expression of a target gene” as in instant claim 31).
Davidson teaches of small interfering RNA molecules targeted against an allele of interest and methods of using these siRNA molecules. The reference teaches that the siRNA can be used to target a gene that is amenable to siRNA therapy such as Tau (col 2, lines 29-31) and that by reducing tau expression, it can be used to treat tau-related diseases (col 12 lines 24-27) (“an interfering RNA that reduces expression of a target gene” as in instant claim 29; “wherein the RNAi reduces expression of a target gene selected from the group consisting of . . Tau” as in instant claim 100). Finally, the reference also teaches that the siRNA be in a vector that contains a CMV promoter and an appropriate viral vector may be an adenoviral, lentiviral, adeno-associated viral (AAV), poliovirus, herpes simplex virus (HSV) or murine Maloney-based viral vector (col 2, lines 53-57) (“wherein the vector is selected from the group consisting of a lentivirus . . . or herpes simplex virus” as in instant claim 32).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a vector to a primate as taught by Dodge, where the primate receives intrathecal administration and that the vector can contain an siRNA as taught by Thorne, to arrive at the instantly claimed invention. Thorne shows that a vector containing an siRNA can successfully be delivered via intracerebroventricular or intrathecal administration. One of ordinary skill would have been motivated to modify the method of delivery of Dodge to include intrathecal administration as taught by Thorne with a reasonable expectation of advantageously being able to continue to target specific genes of interest as taught by the prior art.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a vector to a primate as taught by Dodge and Thorne in combination, where the siRNA targets tau as taught by Davidson, to arrive at the instantly claimed invention. As Davidson shows siRNAs can be delivered in various vector types to target tau, one of ordinary skill would have been motivated to modify the vector of Dodge and Thorne in combination to include a tau-targeting siRNA with a reasonable expectation of advantageously being able to reduce the expression of tau and treat tau-related diseases as taught by the prior art.
Claim(s) 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dodge et al as applied to claims 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, 86, and 101 above, and further in view of Ellis et al (Gene Therapy, 19 Jan 2012; previously cited).
Ellis teaches that an emerging strategy is to correct the mutant gene at the endogenous locus via homologous recombination, which preserves the integrity/regulation imparted by the native locus (herein referred to as gene targeting) (abstract). The spontaneous frequency of gene targeting using plasmid vectors is on the order of 10−6, a frequency too low to translate to clinical use (Introduction para 2). However, reports demonstrate that sequence-specific endonucleases can increase the efficiency of gene targeting by 100–50 000-fold, a frequency that has clinical relevance to a variety of diseases (Same para). The reference teaches that there are three major classes of nucleases that can be used to create sequence-specific DNA double-strand breaks (DSBs): homing endonucleases, TALE nucleases and zinc-finger nucleases (ZFNs) (same para). In particular, ZFNs are engineered proteins that fuse zinc finger DNA-binding domains to a C-terminal nuclease domain derived from the type IIS FokI restriction endonuclease. A pair of ZFNs bind their cognate recognition sites in a specific orientation thereby allowing the nuclease domain to dimerize and enzymatically create the DNA DSB (same para). It also teaches that a pair of ZFNs can be designed to bind and cleave nearly any site in the human genome including sites of mutated genes that cause disease and that ZFNs have been engineered to a wide range of gene targets and have been shown to stimulate specific gene modification in a wide range of cell type (same para). The reference also teaches that high frequencies of gene targeting (~1%) can be achieved in a human cell line and in mouse model derived fibroblasts using a single AAV6 vector for delivery of both ZFNs and a repair substrate (Introduction, para 5). The reference concludes that monomeric ZFNs are functional for gene targeting using the provided repair substrate and guarantees that every cell receiving ZFNs also receives the desired repair molecule and avoids concerns associated with multiple particle transduction, especially when relatively high particle numbers are necessary for efficient gene targeting (Discussion, para 1). This shows why one of ordinary skill would include TALENs and, particularly, ZFNs to induce double stranded breaks at the DNA site of concern to ensure repair molecule delivery and transduction, reading on “wherein the polypeptide is a DNA binding protein, wherein the DNA binding protein is selected from the groups consisting of a zinc finger protein (ZFP), zinc finger nuclease (ZFN), or a transcription activator-like effector nuclease (TALEN)” as in instant claim 25.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a vector to a primate as taught by Dodge, where the vector contains ZFNs as taught by Ellis, to arrive at the instantly claimed invention. As Ellis shows ZFNs can be used to correct the mutant gene at the endogenous locus via homologous recombination, one of ordinary skill would have been motivated to modify the vector of Dodge to include ZFNs with a reasonable expectation of advantageously guarantees that every cell receiving ZFNs also receives the desired repair molecule and avoids concerns associated with multiple particle transduction, especially when relatively high particle numbers are necessary for efficient gene targeting as taught by the prior art.
Claim(s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dodge et al as applied to claims 1, 3, 15-17, 20, 24, 33, 34, 39-41, 43, 46, 86, and 101 above, and further in view of Inouye et al (Protein Expr Purif. 7 Feb 2015;109:47-54; previously cited).
Inouye teaches genetic codes comprise 64 nucleotide triplets (codons) encoding 20 amino acids and 3 stop codons (see pg. 47, col 1, paragraph 1). The frequencies of codon usage among organisms differ markedly and at present, codon optimization of heterologous protein genes has been applied to achieve optimum expression of proteins in specific host cells such as bacteria, fungi, yeasts, plants, and mammals (see pg. 47, col 1, paragraph 1). The codon optimized genes for proteins can be chemically synthesized using the suitable codons for the host cells without altering the amino acid sequences (see pg. 47, col 1, paragraph 1). Codon optimization for proteins has been proposed using several software applications and to express a heterologous protein in mammalian cells, the overall proportions of usage of each codon were altered to closely match human codon usage (http://www.kazusa.or.jp/codon/) (see pg. 47, col 1, paragraph 1). This shows that codon optimization of a protein can be performed to achieve optimum expression in a host and reads on “wherein the nucleotide sequence is a codon-optimized variant and/or fragment thereof” as in instant claim 27.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a vector to a primate as taught by Dodge, where the nucleotide sequence in the vector is codon optimized as taught by Inouye, to arrive at the instantly claimed invention. One of ordinary skill would have been motivated to modify the protein with a reasonable expectation of success because Inouye teaches that codon optimization of heterologous protein genes can be used advantageously to create coding sequences can be applied to achieve optimum expression of proteins in specific host cells, such as in mammalian cells. Furthermore, codon optimization for protein expression in selected cells has been routine since at least 2015 (see date of Inouye reference). Multiple tools, including various software programs (such as the one utilized by Inouye), had been designed and were available to researchers for generating codon-optimized sequences for any gene based on knowledge of highly expressed genes in the host of interest. Thus, one of ordinary skill would have found it obvious to optimize the codons of proteins because Inouye suggests optimization via selection of preferred codons for use in a specific host cell of interest. Therefore, it would have been obvious to one of ordinary skill at the time of filing to codon optimize the coding sequence of Dodge and arrive at instantly claimed codon optimized variant of the therapeutic protein.
Response to Arguments – Previously Presented References of Record (Dirren, Thorne, Davidson, Ellis, and Inouye)
Applicant's arguments filed regarding the Dirren, Thorne, Davidson, Ellis, and Inouye have been fully considered but they are not persuasive.
On p. 11 of Remarks, Applicant argues that, because the amendment to claim 1 to include subject matter from claim 51 (not previously rejected on the record) and the dependent claims directly or indirectly depend on instant claim 1, the claims are not obvious over the prior art.
In response, the examiner disagrees. As previously stated, a clerical error was made in which claim 51 was left out of the 102 rejection as anticipated over Dodge (as it teaches glial cells, which are multipolar cells and reads on previous claim 51) or, in the alternative, under 103 as obvious over the previously cited Dirren reference, which discusses AAV9 targeting of astrocytes (which are known multipolar, GABAergic/GABAceptive neurons; also reading on “multipolar . . . GABAergic neurons” as in previously presented claim 51). Furthermore, newly cited reference Miller discusses the targeting of GABAergic inhibitory neurons via vector containing transcription factors targeting SCN1A. Thus, Applicant’s arguments are not persuasive. Applicant has not provided any substantive arguments regarding the specific teachings of any of the cited reference discussed above.
New Grounds of Rejections – Obviousness
Claim(s) 102-107 is/are rejected under 35 U.S.C. 103 as being unpatentable over as Dodge et al in view of Dirren et al as applied to claims 21, 34, 46, 48, 54, and 101 above, and further in view of Miller et al (US20150353917A1, 6/5/2015; published 12/10/2015).
Regarding instant claim 102, Dirren teaches targeting astrocytes with AV9 vectors (see above 103 rejection).
Regarding instant claim 103, Dodge teaches that the nucleic acid encodes a polypeptide (see above 102 rejections).
Regarding instant claim 107, Dodge teaches unilateral administration of vectors (see above 102 rejection).
The difference between the combined teachings of Dodge and Dirren and the instant invention is that they do not teach that the polypeptide is a DNA binding protein such as a zinc finger protein (instant claims 104 and 105). It also does not teach that the ZFP is eTFSCN1A.
Miller teaches that Dravet syndrome is associated with mutations in the SCN1A gene resulting in mutant protein with decreased function which results in decreased activity of GABAergic inhibitory neurons (para 97). It teaches that DS can be treated by introducing into the brain an engineered nuclease designed to cleave the mutant SCN1A alleles and knockout expression and introduce a wild type cDNA encoding the SCN1A gene in order to replace the mutant allele with the wild type gene (same para). The reference further teaches the engineered nuclease designed to cleave a mutant SCN1A nucleic acid sequence includes engineered zinc finger fusion proteins or engineered Crispr/Cas with targeted nuclease activity (para 123-133). The zinc finger fusion can be introduced using various viral vectors including lentiviral vectors, including AAV9 and variant thereof (para 236-247), which can be operably linked to a promoter or other regulatory sequence and, specifically, a tissue specific regulatory element (para 230).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer a vector to a primate as taught by Dodge and Dirren in combination, where the polypeptide is a SCN1A transcription factor as taught by Miller, to arrive at the instantly claimed invention. Miller shows zinc finger proteins can be used to target GABAergic neurons within AAV9 vectors. One of ordinary skill would have been motivated to simply substitute the polypeptide as taught by Dodge and Dirren in combination with the SCN1A-targeting transcription factor with a reasonable expectation of advantageously to preferentially express the transgene within the vector in GABAergic inhibitory neurons with a reasonable expectation as taught by the prior art.
Conclusion
No claim is allowed.
THIS ACTION IS NON-FINAL.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632