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 .
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1-2, 5-13, 15, 23-26, 29-30, and 37-38; drawn to a method of treating a WWOX associated CNS disease) in the reply filed on September 22, 2025, is acknowledged.
Claims 39 and 41-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Group II), there being no allowable generic or linking claim.
Applicant further elected the following species:
a. Synapsin-1 promoter as the promoter
In light of the Applicant’s elected species, claims 6-7, 13, and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. McClean et al. (Neuroscience Letters 576: 73-78). 2014) evidences that the synapsin-1 promoter does not direct expression of a gene in oligodendrocytes nor astrocytes (Figure 1 and page 76, column 1, paragraph 2).
DETAILED ACTION
The amended claims filed on August 1, 2023, have been acknowledged. Claims 3-4, 14, 16-22, 27-28, 31-36, 40, and 46-48 were cancelled. Claims 5, 10, 12-13, 15, 23, 26, 29-30, and 41-43 were amended. In light of the Applicant’s elected invention and species, claims 6-7, 13, 15, 39, and 41-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-2, 5, 8-12, 23-26, 29-30, and 37-38 are pending and examined on the merits.
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 1-2, 5, 8-12, 23-26, 29-30, and 37-38 receive domestic benefit from U.S. provisional application No. 63/064,181, filed on August 11, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) filed on February 10, 2023, has been considered.
Claim Objections
Claims 9, 12, and 37 are objected to because of the following informalities:
Claims 9 and 12 recite “synapsin I promoter” while claim 37 recites “synapsin- 1 promoter”. Choose one option for identifying the synapsin I promoter.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 29-30, and 38 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.
The term “the nucleotide sequence substantially as set forth” in claims 29 and 38 is a relative term which renders the claim indefinite. The term “the nucleotide sequence substantially as set forth” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what level of sequence similarity falls within the limitations of this term. It is not clear whether 51% or more sequence similarity would fall within this limitation or if 100% sequence similarity is required.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or 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 30 recites the broad recitation intrathecal, and the claim also recites cisternal or lumbar 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. Furthermore, Claim 30 uses parentheses to identify examples of intrathecal delivery. However, this renders the claim indefinite because it is unclear whether the limitations within the parentheses are part of the claimed invention.
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.
Claims 1, 5, 8, 10-11, 23-24, 26, and 29 rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent No. 7060811 (Aldaz), as evidenced by Kosla et al. (Experimental Biology and Medicine 245: 1122-1129. 2020) and Seiriki et al. (Neuron 94: 1085-1100. 2017).
Regarding claim 1, 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).
Kosla evidences that reduced WWOX expression is associated with astrocytomas, glioblastomas, and neuroblastomas (page 1124, column 2, paragraph 4-page 1126, column 1, paragraph 2 and Table 1).
Regarding claims 5, 8, and 10-11, 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).
Seiriki evidences that VIP promoters target neurons and show significantly different expression patterns than an oligodendrocyte specific promoter (PLP) (Figure 2 and page1090, column 1, paragraph 2).
Therefore, the VIP promoter is considered to be a promoter that specifically targets neurons with lower expression in oligodendrocytes (a glial cell).
Regarding claims 23-24, Aldaz teaches that the expression vector can be an adeno-associated virus (column 1, line 18-column 4, line 51).
Regarding claims 26 and 29, Aldaz teaches that their expression vector can comprise the nucleic acid sequence of SEQ ID NO: 1 (which has 100% sequence identity to SEQ ID NOs: 1 and 3 of the instant application) and encodes the polypeptide sequence of SEQ ID NO: 2 (which has 100% sequence identity to SEQ ID NO: 2 of the instant application).
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 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 7060811 (Aldaz) as applied to claim 1 above, and further in view of Kosla et al. (Experimental Biology and Medicine 245: 1122-1129. 2020; Published July 2020) and Wang et al. (Cell Death and Differentiation 19: 1049-1059. 2012).
The teachings of Aldaz are as discussed above.
Aldaz does not teach administering their expression vector encoding WWOX to treat Alzheimer’s.
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).
However, Wang teaches that WWOX expression is downregulated and active glycogen synthase kinase 3β (GSK3β) is upregulated in Alzheimer’s disease patients which may be caused by the downregulation of WWOX. Furthermore, dysregulation of GSK3β is involved in Alzheimer’s disease as it hyper phosphorylates Tau, disrupting microtubule stability (abstract, page 1049, column 1, paragraph 1-column 2, paragraph 1, page 1057, column 1, paragraph 1, and Figure 6). Wang teaches that WWOX, GSK3β, and Tau interact to control microtubule formation and neurite outgrowth ()Figure 6 and page 1055, column 2, 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 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 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.
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).
Similarly, Wang teaches that WWOX expression is reduced in Alzheimer’s patients and that WWOX is involved in inhibiting GSK3β phosphorylation of Tau to promote microtubule formation. Furthermore, Wang hypothesizes that the upregulation in the levels of active GSK3β in Alzheimer’s patients is caused by the downregulation of WWOX expression.
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, Wang provides a potential model for how reduced expression of WWOX impacts GSK3β expression levels and Tau hyper phosphorylation, and Adlaz reduces to practice that increasing 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.
Claims 1, 5, 8-12, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent No. 7060811 (Aldaz) as applied to claims 1 and 23-24 above, and further in view of Kosla et al. (Experimental Biology and Medicine 245: 1122-1129. 2020) and McClean et al. (Neuroscience Letters 576: 73-78). 2014).
Regarding claims 5 and 8-12, the teachings of Aldaz are as discussed above. Aldaz teaches that one of the types of cancer that can be treated is neuroblastoma by delivering a vector encoding WWOX and a gene targeting N-MYC (associated with neuroblastomas) to have a combined anti-proliferative effect on the target cancer (column 52, lines 26-39 and Table 6).
Aldaz does not teach administering their expression vector encoding WWOX wherein the promoter is synapsin I.
However, Kosla teaches that reduced WWOX expression is associated with neuroblastomas (page 1124, column 1, paragraph 2-page 1126, column 1, paragraph 2 and Table 1).
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) 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 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.
Regarding claim 25, the teachings of Aldaz are as discussed above.
Aldaz is silent as to the serotype of the AAV vector.
However, 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 (abstract).
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 neuroblastoma 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 to treat cancer. 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 United States Patent No. 7060811 (Aldaz) as applied to claim 1 above, and further in view of Hacker et al. (Cancers 17: 1-30. 2020. Published July 2020).
The teachings of Aldaz are as discussed above. Aldaz teaches that the vector can be delivered intravenously (column 4, lines 13-37).
Aldaz does 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 and expands the choice of serotype (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 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 and expands the choice of serotype. As such, intrathecal administration represents a reasonable substitute for intravenous administration for treating CNS cancers.
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).
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.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631