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 .
DETAILED ACTION
The amended claims filed on April 7, 2026, have been acknowledged. Claims 2-22, 27-28, 31-36, and 39-48 were cancelled. Claims 1, 29-30, and 37-38 were amended. Claims 49-52 are new. Claims 1, 23-26, 29-30, 37-38, and 49-52 are pending and examined on the merits.
Rejections and/or objections not reiterated from the previous office action mailed December 8, 2025, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The applicant claims domestic priority from U.S. provisional application No. 63/064,181, filed on August 11, 2020. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 23-26, 29-30, 37-38, and 49-52 receive domestic benefit from U.S. provisional application No. 63/064,181, filed on August 11, 2020.
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.
Claims 1, 23-26, 29, and 49-51 are rejected under 35 U.S.C. 103 as being unpatentable over Sze et al. (Cell Death and Disease 6: 1-2. 2015) and further in view of Kosla et al. (Experimental Biology and Medicine 245: 1122-1129. 2020; Published July 2020), United States Patent No. 7060811 (Aldaz), and Fol et al. (Acta Neuropathol 131:247–266. 2016). This is a new rejection made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been considered but is mott in response to the new rejection of record.
Regarding claims 1, 23-26, 29, and 51, Sze teaches that substantial evidence reveals that tumor suppressor WW domain-containing oxidoreductase (WWOX) controls protein aggregation in the human brain. Downregulation of WWOX appears to start in the middle ages that leads to the slow progression of neurodegeneration. When WWOX protein is totally lost due to alteration of WWOX/Wwox gene such as missense or nonsense mutation and deletion, neural disorders, and metabolic diseases occur in vivo, including neurodegeneration. WWOX blocks neurodegeneration by binding tau and tau-hyper phosphorylating enzymes GSK3β, ERK, and JNK1, and promotes neuronal differentiation. WWOX is frequently downregulated in the Alzheimer’s Disease hippocampi. When WWOX is knocked down by siRNA, aggregation of TPC6AΔ and TIAF1 occurs in the mitochondria to induce apoptosis. WWOX is required for the survival of organisms. It regulates many pathophysiological processes for blocking neurodegeneration, and functions as a multi-tasked molecule among protein interaction networks. Restoration of WWOX is expected to help survival of neural cells by preventing accumulation of protein aggregates in neurons (whole document).
Sze does not teach administering to the brain of a patient a WWOX wild type gene to treat Alzheimer’s disease.
However, Kosla teaches that reduced WWOX expression is associated with astrocytomas, glioblastomas, neuroblastomas, and neurodegeneration, such as Alzheimer’s disease (page 1124, column 1, paragraph 2-page 1126, column 1, paragraph 2 and Table 1). Furthermore, Kosla identifies that WWOX has a pleiotropic role that impacts brain cancer and neurodegenerative development and that reduced WWOX expression is associated with development of these diseases (Figures 1-2).
Aldaz teaches a method of treating a subject having brain cancer comprising contacting a cancerous brain cell within the subject with an expression vector comprising a polynucleotide encoding an WWOX polypeptide under the transcriptional control of a promoter, wherein expression of the WWOX polypeptide confers a therapeutic benefit on the subject. Aldaz teaches that WWOX is known to be a tumor suppressor gene that is mutated in several cancers (column 1, line 18-column 4, line 51). Aldaz teaches that their expression vector can comprise the nucleic acid sequence of SEQ ID NO: 1 (which is the wild type nucleic acid sequence) which has 100% sequence identity to SEQ ID NOs: 1 and 3 of the instant application and encodes the wild type polypeptide sequence of WWOX. As the wild type sequence is known to function properly, it would have been obvious to use the wild type sequence of SEQ ID NO: 1 of Aldaz to treat Alzheimer’s disease.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the expression vector encoding WWOX to treat Alzheimer’s to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the expression vector of Aldaz to treat Alzheimer’s with a reasonable expectation of success because Sze has identified the importance of WWOX expression in the development of Alzheimer’s disease and specifically identifies that restoration of WWOX is expected to help survival of neural cells by preventing accumulation of protein aggregates in neurons. Furthermore, Kosla has identified a connection between the reduced expression of WWOX and development of brain cancers and neurodegenerative diseases caused by alterations in the differentiation and maintenance of neurons and glial cells from the reduced expression. Additionally, Aldaz teaches that reduced expression of WWOX is associated with cancer and successfully reduced to practice that increasing wildtype WWOX expression suppressed tumor growth (Example 4).
Therefore, as Kosla connects reduced WWOX expression levels to alterations in neuronal and glial cell differentiation and maintenance that increase the likelihood of neurodegenerative diseases and brain cancers, Sze provides a potential model for how reduced expression of WWOX impacts Alzheimer’s disease development and identifies restoring WWOX expression (i.e. increasing WWOX expression) as a possible treatment option for Alzheimer’s disease, and Adlaz reduces to practice that increasing wildtype WWOX expression through an expression vector can treat cancer, it would have been obvious to one of ordinary skill that using the expression vector of Aldaz to increase the expression of WWOX would represent a viable option for treating Alzheimer’s disease. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of Sze, Kosla, and Aldaz do not teach using a synapsin I promoter to drive expression of the WWOX gene.
However, Fol teaches a method of treating Alzheimer’s disease comprising a gene therapy approach to directly overexpress APPsα in the brain using AAV-mediated gene transfer and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1ΔE9 AD model mice. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and partially rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze and a significant reduction of soluble Aβ species and plaque load. Fol teaches that they used AAV9 vectors with a Synapsin promoter to express the APPsα in the brain (abstract, page 248, column 1, paragraph 1-page 261, column 2, paragraph 1, and Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used an AAV9 vector comprising a synapsin I promoter to deliver the WWOX gene to neurons to treat Alzheimer’s disease to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use an AAV9 vector comprising a synapsin I promoter to deliver the WWOX gene with a reasonable expectation of success because Sze and Fol are focused on treating Alzheimer’s disease by restoring expression of a gene/protein that exhibits reduced expression in Alzheimer’s disease (WWOX and APPsα, respectively) and is associated with the development of increased protein aggregation and plague formation when downregulated. Furthermore, Fol successfully reduces to practice that AAV9 vectors comprising a synapsin promoter can drive expression of a gene in neurons to treat Alzheimer’s disease. Although Fol doesn’t specific that the synapsin promoter is synapsin I, it is well understood in the field that this is the primary synapsin promoter used for driving expression of genes in neurons and would be abundantly obvious to one of ordinary skill in the art to use a synapsin I promoter. As the prior art teaches that AAV9 vectors comprising synapsin promoters are suitable for driving expression of a downregulated gene in Alzheimer’s disease to treat Alzheimer’s disease, it would have been obvious that a similar vector construct could be used to drive expression of WWOX to treat Alzheimer’s disease.
Regarding claims 49-50, Kosla teaches that reduced WWOX expression is associated with astrocytomas, glioblastomas, neuroblastomas, neurodegeneration, and epileptic syndromes WOREE and SCAR12 (page 1123, column 1, paragraph 7-page 1126, column 1, paragraph 2 and Table 1). Furthermore, Kosla identifies that WWOX has a pleiotropic role that impacts brain cancer, neurodegenerative development, and regulation of neurodevelopment and differentiation and that reduced WWOX expression is associated with development of cancers and epileptic syndromes. Kosla teaches that WWOX deficiency is associated with neurodifferentiation and neuron migration issues that result in result in foliation impairment and brain malformation (Figures 1-2 and page 1123, column 1, paragraph 7-page 1126, column 1, paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the AAV vector encoding WWOX of the combined teachings of Sze, Kosla, Aldaz, and Fol to target neurons and treat WOREE or SCAR12 to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the AAV vector of the combined teachings of Sze, Kosla, Aldaz, and Fol to target neurons and treat WOREE or SCAR12 with a reasonable expectation of success because Kosla has identified a connection between the reduced expression of WWOX and development of brain cancers, neurodegeneration, and epileptic disorders. Kosla identifies that alterations in the differentiation and maintenance of neurons are associated with reduced expression of WWOX, leading to the development of brain cancer and epileptic disorders, such as WOREE and SCAR12 (see Figure 2). Furthermore, Kosla has identified specific neuronal phenotypes associated with WWOX deficiency that lead to foliation impairment and brain malformation. As Kosla has drawn a connection between reduced WWOX expression and a multitude of different disorders, including brain cancer, neurodegeneration, and epileptic disorders and Aldaz has shown that an expression vector comprising a polynucleotide encoding an WWOX polypeptide under the transcriptional control of a promoter can be administered to a patient to treat brain cancer, one of ordinary skill in the art would understand the connection between these diseases and reasonably consider that what treatment works for one disorder within this system (i.e. brain cancer of Aldaz) could also work with other related disorders within the system (i.e. WOREE and SCAR12). Therefore, it would have been obvious to one of ordinary skill that using the AAV vector of Sze, Kosla, Aldaz, and Fol to increase the expression of WWOX in neurons would represent a viable option for treating WWOX or SCAR12. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Sze et al. (Cell Death and Disease 6: 1-2. 2015) and further in view of Kosla et al. (Experimental Biology and Medicine 245: 1122-1129. 2020; Published July 2020), United States Patent No. 7060811 (Aldaz), and Fol et al. (Acta Neuropathol 131:247–266. 2016) as applied to claim 1 above, and further in view of Hacker et al. (Cancers 17: 1-30. 2020. Published July 2020). This is a new rejection made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been considered but is mott in response to the new rejection of record.
The teachings of Sze, Kosla, Aldaz, and Fol are as discussed above. Aldaz teaches that the vector can be delivered intravenously (column 4, lines 13-37) and Fol teaches direct injection into the hippocampus (page 249, column 2, paragraph 1).
The combined teachings of Sze, Kosla, Aldaz, and Fol do not teach wherein the injections are intrathecal.
However, Hacker teaches that intrathecal injection is a known method for CNS directed gene therapy and allows for the vector doses to be substantially lower (page 4, paragraph 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the intravenous route of administration of Aldaz or the direct hippocampus injection of Fol with the intrathecal administration of Hacker to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Hacker teaches that intrathecal administration is a known method for CNS directed gene therapy and allows for the vector doses to be substantially lower. Furthermore, intrathecal administration ensures that a higher dose reaches the CNS compared to intravenous injections and represents a safer and simpler injection protocol compared to direct injection into the hippocampus. As such, intrathecal administration represents a reasonable substitute for intravenous and direct hippocampus administration for treating CNS diseases. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Sze et al. (Cell Death and Disease 6: 1-2. 2015) and further in view of Kosla et al. (Experimental Biology and Medicine 245: 1122-1129. 2020; Published July 2020), United States Patent No. 7060811 (Aldaz), and Fol et al. (Acta Neuropathol 131:247–266. 2016) as applied to claim 1 above, and further in view of Chang et al. (Brain 131, 2366-2375. 2008).
The teachings of Sze, Kosla, Aldaz, and Fol are as discussed above. Kosla teaches that WWOX has a considerable influence of the development of the CNS. To date, WWOX has been shown to contribute to the signaling pathways regulating CNS development and neural differentiation such as WNT, Hedgehog, TGFb, and Hippo. Studies on a WWOX knockout mouse model found the number of hippocampal GABA-ergic interneurons to be reduced accompanied by reduced GABA synthesis and the appearance of neuroinflammation markers. This finding was confirmed in previous research on human neural progenitor cells (hNPC), in which major changes in the transcription of genes related to neurotransmitter synthesis and management were observed after WWOX silencing. WWOX also demonstrated a profound influence on adhesion, cytoskeleton organization, and cellular signaling in hNPC, thus probably contributing to proper neurodifferentiation and neuron migration (page 1123, column 1, paragraph 5- page 1124, column 1, paragraph 1 and Figures 1-2)
The combined teachings of Sze, Kosla, Aldaz, and Fol do not teach wherein the CNS disease being treated is multiple sclerosis.
However, Change teaches that subcortical white matter interneurons are destroyed during the inflammatory demyelination that occurs in the brains of individuals with multiple sclerosis. In response to this neuronal loss, some chronically demyelinated brain regions contained neurons at densities that, on average, exceeded those in normal-appearing white matter by 72%. These neurons express immunophenotypic markers of fully differentiated interneurons (neurons that are not myelinated), have the shape of mature neurons and receive ultrastructurally confirmed synapses. Demyelinated brain regions with increased neuronal densities also contain a morphologically distinct population of activated microglial cells and a significant increase in cells with characteristics of immature neurons that may originate, in part, from adjacent SVZs. These findings support the possibility that white matter interneurons can be replaced following their destruction, likely from neurogenesis. This study demonstrates an increase in the absolute number of cells with unambiguous neuronal phenotype based upon morphology, antigen expression and ultrastructural evidence of synaptic connections. These phenotypes are similar to the interneurons normally found in subcortical white matter and support functional replacement of previously destroyed neurons (page 2372, column 2, paragraph 2-page 2374, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the AAV vector of the combined teachings of Sze, Kosla, Aldaz, and Fol to treat multiple sclerosis to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the AAV vector of the combined teachings of Sze, Kosla, Aldaz, and Fol to treat multiple sclerosis with a reasonable expectation of success because Kosla identifies a role for WWOX in CNS development and neural differentiation, especially differentiation of interneurons and expression of genes associated with adhesion, cytoskeleton organization, and cellular signaling in neural progenitor cells. Chang identifies that multiple sclerosis is associated with neuronal loss and a subset of multiple sclerosis patients were considered to be undergoing functional replacement of previously destroyed neurons as some chronic lesions had a population of fully differentiated interneurons and immature neurons at densities that, on average, exceeded those in normal-appearing white matter by 72%. As Chang identifies that functional replacement of interneurons can occur in multiple sclerosis in patients, it would have been obvious to administer an AAV vector targeted to these developing neurons to protect them and ensure proper differentiation into fully differentiated interneurons as Kosla has already identified a role for WWOX expression in CNS development and neural differentiation, including in interneurons. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over Kosla et al. (Experimental Biology and Medicine 245: 1122-1129. 2020; Published July 2020), and further in view of United States Patent No. 7060811 (Aldaz) and McClean et al. (Neuroscience Letters 576: 73-78). 2014). This rejection is repeated with regards to the rejection of record cited in the Non-final Office action mailed on December 8, 2025. Applicant’s traversal is addressed below.
Kosla teaches that reduced WWOX expression is associated with astrocytomas, glioblastomas, neuroblastomas, neurodegeneration, and epileptic syndromes WOREE and SCAR12 (page 1123, column 1, paragraph 7-page 1126, column 1, paragraph 2 and Table 1). Furthermore, Kosla identifies that WWOX has a pleiotropic role that impacts brain cancer, neurodegenerative development, and regulation of neurodevelopment and differentiation and that reduced WWOX expression is associated with development of cancers and epileptic syndromes (Figures 1-2 and page 1123, column 1, paragraph 7-page 1126, column 1, paragraph 2).
Kosla does not teach administering to the brain of a patient suffering from WOREE or SCAR12 a vector comprising a WWOX wild type gene under the control of a promoter.
Aldaz teaches a method of treating a subject having brain cancer comprising contacting a cancerous brain cell within the subject with an expression vector comprising a polynucleotide encoding an WWOX polypeptide under the transcriptional control of a promoter, wherein expression of the WWOX polypeptide confers a therapeutic benefit on the subject. Aldaz teaches that WWOX is known to be a tumor suppressor gene that is mutated in several cancers (column 1, line 18-column 4, line 51). Furthermore, Aldaz teaches that reduced expression of WWOX is associated with cancer and successfully reduced to practice that increasing WWOX expression suppressed tumor growth (i.e. treated the cancer) (Example 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the expression vector encoding WWOX to treat WOREE or SCAR12 to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the expression vector of Aldaz to treat WOREE or SCAR12 with a reasonable expectation of success because Kosla has identified a connection between the reduced expression of WWOX and development of brain cancers and epileptic disorders. Kosla identifies that alterations in the differentiation and maintenance of neurons and glial cells are associated with reduced expression of WWOX, leading to the development of brain cancer and epileptic disorders, such as WOREE and SCAR12 (see Figure 2). As Kosla has drawn a connection between reduced WWOX expression and a multitude of different disorders, including brain cancer and epileptic disorders and Aldaz has shown that an expression vector comprising a polynucleotide encoding an WWOX polypeptide under the transcriptional control of a promoter can be administered to a patient to treat brain cancer, one of ordinary skill in the art would understand the connection between these diseases and reasonably consider that what works for one disorder within this system (i.e. brain cancer of Aldaz) could also work with other related disorders within the system (i.e. WOREE and SCAR12). Therefore, it would have been obvious to one of ordinary skill that using the expression vector of Aldaz to increase the expression of WWOX would represent a viable option for treating WWOX or SCAR12 based on the disclosures of Kosla and Aldaz. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the synapsin I promoter and the AAV9 vector, the teachings of Kosla and Aldaz are as discussed above. Aldaz teaches that tissue-specific promoters can be used for cancer gene therapy, including VIP which targets neurons (column 24, lines 36-54 and Table 3). Aldaz teaches that the expression vector can be an adeno-associated virus (column 1, line 18-column 4, line 51). Aldaz is silent as to the serotype of the AAV vector.
The combined teachings of Kosla and Aldaz do not teach administering their expression vector encoding WWOX wherein the promoter is synapsin I and is silent as to the serotype of the AAV vector.
However, McClean teaches that the synapsin-I promoter directs expression to neurons and does not direct expression of a gene in oligodendrocytes nor astrocytes as GFP expression was observed only in NeuN or NF-H-positive cells (two neuron markers). McLean teaches that AAV9 crosses the blood–brain barrier and shows enhanced transduction efficiency compared to other serotypes and successfully reduces to practice that an AAV9 vector with a human synapsin-I promoter drives robust neuron-specific transgene expression (Figure 1 and page 76, column 1, paragraph 2 and abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the VIP tissue-specific promoter of Aldaz with the synapsin I neuron specific promoter of McLean to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because McLean teaches that synapsin-I shows neuron specific expression with no expression in astrocytes or oligodendrocytes. Therefore, it was known that the synapsin-I promoter was a viable tissue-specific promoter for targeting neuronal cells while excluding glial cells. As such, synapsin-I represents a reasonable substitute for the VIP tissue specific promoter for targeting neurons.
Furthermore, the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
It would have been obvious to a person skilled in the art to use an AAV9 serotype vector since one skilled in the art would recognize that there are a finite number of AAV serotypes and that AAV9 is known to cross the blood-brain barrier, a critical component for targeting CNS cells and expanding the delivery options to include systemic administration. Furthermore, McLean has successfully reduced to practice that an AAV9 vector with a human synapsin-I promoter drives robust neuron-specific transgene expression. Therefore, AAV9 would be immediately envisioned as a viable AAV serotype to use to deliver WWOX to the brain. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 38, Aldaz teaches that their expression vector can comprise the nucleic acid sequence of SEQ ID NO: 1 (which is the wild type nucleic acid sequence) which has 100% sequence identity to SEQ ID NOs: 1 and 3 of the instant application and encodes the wild type polypeptide sequence of WWOX. As the wild type sequence is known to function properly, it would have been obvious to use the wild type sequence of SEQ ID NO: 1 of Aldaz to treat WOREE or SCAR12.
Response to Arguments
Applicant's arguments filed April 7, 2026, are acknowledged.
Applicant argues that the VIP promoter as described by Aldaz and synapsin I promoter (a neuron specific promoter) are clearly not described in the art as interchangeable as asserted in the Office Action. For example, Table 3 of Aldaz describes VIP promoter as one of many promoters for expression of transgenes in various types of cancer cells, where VIP promoter is indicated to be active in non-small cell lung cancers, neurons, lymphocytes, mast cells, and eosinophils. Clearly, VIP promoter is not a "neuron-specific" promoter (like synapsin I promoter) and is not an art-recognized equivalent to synapsin I promoter (page 7, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
In order to complete the art of record and rebut Applicant’s arguments, United States Patent Application No. 20220112519 (which has an earlier effective filing date of February 19, 2019) identifies multiple possible neuronal specific promoters, including synapsin promoters and the VIP promoter (paragraph 0013). Therefore, these were art recognized equivalents for targeting neuronal cells. Furthermore, although VIP targets other cells, as well, it does targets neurons, as identified by Aldaz. One of ordinary skill in the art would recognize that although VIP promoters can target other cells, there are CNS specific administration routes that would ensure that expression is limited to neurons.
Applicant further argues that neither Kosla, nor Aldaz, nor McLean, whether taken individually or together, teach which cells are required for WWOX transgene expression for treating WOREE or SCAR12, especially since, and as acknowledged by the Office Action, Kosla teaches that WWOX expression is associated with dysfunction in glial cells as well as neurons. See Kosla at FIG. 2. For example, as illustrated in FIG. 2 of Kosla, WWOX deficiency is shown to reduce myelination and reduce oligodendrocyte and astrocyte numbers due to loss of WWOX expression in these cells. See Kosla FIG. 2, middle column. In view of the disclosures of Kosla, a person of ordinary skill in the art would not have selected a neuron-specific promoter, such as synapsin I, for expression of a WWOX transgene for treatment of WOREE or SCAR12 (page 7, paragraphs 3-4).
Applicant's arguments have been fully considered but they are not persuasive.
Although Kosla identifies multiple effects associated with WWOX deficiency that are associated with WOREE and SCAR12, Kosla identifies multiple neuron specific phenotypes from WWOX deficiency (page 1123, column 1, paragraph 7-page 1124, column 1, paragraph 1). Therefore, it would be well understood to one of ordinary skill in the art that they could try treating WOREE or SCAR12 by specifically targeting neurons. Although other options are also available (targeting neurons and glia or just glia), it would still be no less obvious to use a synapsin I promoter to target neurons as they show a distinct phenotype that could be treated.
Furthermore, the Applicant argues that the Application demonstrates that, while WWOX is expressed in neurons and glial cells (oligodendrocytes and astrocytes), loss of functional WWOX expression specifically in neurons leads to the defects seen in WOREE syndrome and SCAR12 (including hypomyelination, reduced oligodendrocyte maturation, and impaired axonal conductivity). See pages 37-42 of the Application. These results are unexpected, especially in view of the disclosures of Kosla (page 7, paragraphs 5-6).
Applicant's arguments have been fully considered but they are not persuasive.
Although Applicant argues unexpected results, the claims are not commensurate in scope with the experimental results cited by the Applicant. MPEP 716.02(d) discloses that whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
Regarding the claims at issue in the instant application, claim 37 encompasses a method for the treatment of WOREE syndrome or SCAR12, the method comprising: administering to the brain of a patient in need of such treatment, an AAV9 gene delivery system comprising a WWOX wild type gene under control of a synapsin I promoter. None of the cited results refer to a treatment method. Instead, the results identify loss of functional WWOX expression specifically in neurons leads to the defects seen in WOREE syndrome and SCAR12. Although this data shows that WWOX expression in neurons is important in the development of WOREE syndrome and SCAR12, there is no data regarding treating these neurons with a vector encoding WWOX.
As such, the claims as written are not commensurate in scope with alleged unexpected results.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KEENAN A BATES/Examiner, Art Unit 1631
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