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 .
This action is in response to the papers filed on 06/12/2026. Claims 1-22 are currently pending as per claims filed on 06/12/2026. Claims 4 and 7 are amended per applicant’s claim amendment filed 06/12/2026. Applicant’s election of Group II, claims 3-7 in the reply filed on 06/12/2026 is acknowledged. Because Applicants did not distinctly and specifically point out supposed errors in the restriction requirement, the election has been treated as an election without traverse. See MPEP § 818.03(a).
Applicant further elected in vivo application and elected the following species: the small molecule sunitinib and the polypeptide Snrk in the reply filed on 06/12/2026 which is acknowledged.
Therefore, claims 1, 2, and 8-22 are withdrawn from further consideration
pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
The requirement is still deemed proper and is therefore made FINAL.
Therefore, claims 3-7 are subject to examination to which the following grounds of rejection are applicable. Claim 3 is an independent claim.
Priority
The instant application is a 371 of PCT/ US2022/012311 filed 01/13/2022 which claims benefit to US Provisional application no. 63/138,091 filed 01/15/2021.
Thus, the earliest possible priority for the instant application is 01/15/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/14/2023 and 06/16/2026 was filed after the mailing date of the current office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112 (b)
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 6 and 7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 cites the term “or” and “and/or” in line 5 and 6, respectively. It is unclear if the applicant is intending to claim traumatic brain injury and alternatives, in which the alternative is the combination of spinal cord injury, traumatic brain injury, spinal cord crush, and optic nerve injury, or, the applicant is intending to claim the species of injuries all as alternatives. Additionally, spinal cord injury is recited twice in the claim. Appropriate correction is required.
Claims 7 is indefinite in that it fails to point out what is included or excluded by the claim language due to improper use of Table 1. "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table 'is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s)). As such, the metes and bounds of the claims cannot be determined.
Claim Rejections - 35 USC § 112 (a)
Scope of Enablement
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 3-7 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:
An in vivo method for increasing regeneration of a damaged or degenerating retinal ganglion cell (RGC), the method comprising contacting the damaged or degenerating RGC with an AAV2-Cree virus and AAV2 virus manufactured with single guide RNA to target the gene encoding the gene Snrk that reduces the expression or activity of the polypeptide Snrk via intravitreal injection in a CRISPR/Cas9 mouse model and wherein the damage to the RGC is caused by optic nerve crush,
does not reasonably provide enablement for:
An in vivo method for increasing regeneration of any damaged or degenerating neuron, the method comprising contacting the damaged or degenerating neuron with sunitinib (elected species), let alone any agent, that reduces the expression or activity of the polypeptide Snrk in any subject including a human subject and through any means of contact, thereby increasing regeneration of the damaged or degenerating neuron.
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 or use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is
required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the
state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in
the art; (f) the amount of direction provided by the inventor; (g) the existence of working
examples; and (h) the quantity of experimentation needed to make or use the invention
based on the content of the disclosure.
While all of these factors are considered, a sufficient number are discussed
below so as to create a prima facie case.
the breadth of the claims; the nature of the invention:
Claim 3 is directed to an in vivo method for increasing regeneration of any damaged or degenerating neuron, the method comprising contacting the damaged or degenerating neuron with a vast genus of agents that reduces the expression or activity of the polypeptide Snrk in a human subject and through any means of contact. Claim 4 further limits claim 3 wherein the damage to the neuron is associated with an injury or a neurodegenerative disease. Claim 5 further limits claim 4 to a species from a group of neurodegenerative diseases. Claim 6 further limits claim 4 to a species from a group of injuries. Claim 7 further limits claim 3 to the agent being the small molecule sunitinib as recited in Table 1 of the specification.
the amount of direction provided by the inventor; the existence of working
examples:
As recited above, claim 3 is broadly but reasonable interpreted as an in vivo method for increasing regeneration of any damaged or degenerating neuron, the method comprising contacting the damaged or degenerating neuron any agent, wherein the agent can be sunitinib, that reduces the expression or activity of the polypeptide Snrk in any subject and through any means of contact, thereby increasing regeneration of the damaged or degenerating neuron.
The specification does not provide support for the genus of agents that reduce the expression or activity of Snrk polypeptide, as elected, and the damage to any neuron is associated with any injury or neurodegenerative disease. The specification does not provide support for the agent to be the small molecule sunitinib, as elected, as there are no working examples of use of sunitinib in the claimed method.
The specification describes a method for increasing regeneration of a damaged or degenerating retinal ganglion cell (RGC) comprising intravitreal injection in a mouse model and wherein the damage to the RGC is caused by optic nerve crush (para 0390, Example 1). Furthermore, the only agents shown to cause increasing regeneration of damaged or degenerating neurons is co-injection with AAV2-Cre and AAV2 single guide RNA (targeting genes of interest including Snrk) through a CRISPR/Cas9 system mouse model (Example 1, para 0390, FIGS. 6A-D). Therefore, the specification only provides details for an in vivo method of increasing regeneration of a damaged or degenerating neuron associated with optic nerve injury, the method comprising contacting the damaged or degenerating neuron with an AAV-Cre and single guide RNA AAV targeting genes of interest including Snrk causing disruption in expression of the genes in a CRISPR/Cas9 mouse model and the contact occurring via intravitreal injection.
the state of the prior art; the level of predictability in the art:
Methods for increasing regeneration of neurons that have been damaged or are degenerating have been explored based on prior art, however the use of various agents for increasing regeneration in neurons based on reducing expression of various genes and their ability to treat neuron injuries and neurogenerative diseases remains an area of research as these technologies are still in their infancy stage of development.
In the context of damage to retinal ganglion cells (RGCs), which are a type of neuron found in the eye, Zhang et al (Trends in Pharmacological Sciences, 2025, pages 45-61), teaches that regeneration of RGCs likely requires targeting of multiple factors and multiple combinations of factors as different subtypes of RGCs exist, each shown to respond differently to treatments aimed to increase regeneration of damaged neurons (page 56, Single-cell sequencing deciphers RGC subtype-specific responses after injury). Chen et al (Neural Regeneration Research, 2026, pages 989-999) teaches that, while optic nerve crush injury is a standard approach for researching optic disease mechanisms, the approach does not fully replicate the persistent, asynchronous cell death observed in diseases such as acute or chronic glaucoma (page 990, third col, page 990), therefore indicating that optic nerve crush injury, as shown to be in the injury used in the instant application, does not necessarily translate to modeling other neurodegenerative diseases.
In regards to the use of sunitinib as an agent to increasing regeneration of neurons that have been damaged or are degenerating, the specification does not demonstrate any working examples of employing sunitinib for the claimed method and the prior does not indicate predictable success in its use as for increasing regeneration of damaged neurons through reduction of expression of genes of interest in vivo. Barbosa-Azevedo et al (molecules, 2025, pages 1-26) teaches that sunitinib is a tyrosine kinase inhibitor known to selectively inhibit several growth factor receptors including vascular endothelial growth factor receptor 1 (VEGFR1), 2 (VEGFR2) and 3 (VEGFR3), platelet-derived growth factor receptor alpha (PDGFRα) (page 2, para 3) and that, in other studies, Sunitinib caused significant neurodegeneration in the hippocampus and cerebral cortex and also led to alterations in chromatin condensation, mitochondrial damage, and accumulated autophagosomes in the neurons of sunitnib-treated mice (page 3, para 1), thus indicating detrimental outcomes to neurons. Indeed Barbosa-Azevedo further teaches, in their study, that sunitnib caused cytotoxic effects in human neuronal cells (abstract, page 1). Furthermore, there is no prior art indicating that sunitinib is capable of reducing expression of Snrk as claimed.
Therefore, the prior art highlights the unpredictability in the methods to increasing regeneration of damaged neurons as neurons exist as various subtypes exhibiting unique phenotypes that would not guarantee any agent could reduce expression of any of the genes of interest and even that any of the genes of interest would elicit the effect of increasing regeneration. Moreover, the prior art highlights that using various agents such as AAVs and small molecules such as sunitinib can cause deleterious outcomes, thus failing to effectively increase regeneration of a damages or degenerating neuron.
the quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The skilled artisan would be required to perform under levels of experimentation
in order to practice the claimed invention. The instant specification does not reduce to
practice the claimed invention; the instant specification does not provide guidance on an in vivo method for increasing regeneration of any damaged or degenerating neuron by using sunitinib, let alone any agent, such that the agent reduces the expression of Snrk and the damage is associated with an injury or neurodegenerative disease except: the agent is an AAV with single guide RNA to Snrk, the subject in a CRISPR/Cas9 model mouse suffering from optic nerve injury, and the contacting occurs via intravitreal injection of the agent. Moreover, the prior art highlights the unpredictability of treating neurons as their phenotypes differ between subtypes, optic nerve injury models do not recapitulate all neurodegenerative diseases, and sunitinib is not indicated to reduce Snrk expression.
Thus, the skilled artisan would be forced to 1) determine which agent to use and determine if the agent decreases expression of Snrk 2) how to administer the agent such that it is able to contact the damaged neuron in vivo and 3) determine if that agent and its administration for contact is able to increase regeneration of the damaged or degenerating neuron cause by the injury or neurogenerative disease.
the level of one of ordinary skill:
The level of one of ordinary skill is a PhD holder.
Conclusion:
When all of the Wands factors are considered together, they establish a prima
facie case that the specification is not enabling for the claims. The Specification only
provides details for a method for increasing regeneration of a damaged or degenerating RGC, the method comprising: contacting the damaged or degenerating RGC with an AAV2-Cree virus and AAV2 virus manufactured with single guide RNA that targets the and reduces the expression or activity of the polypeptide Snrk via intravitreal injection in a CRISPR/Cas9 mouse model and wherein the damage to the RGC is caused by optic nerve crush.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over Atlasi et al (PloS Genetics, 2013, pages 1-16) and further in view of Zou (US 20050049195 A1).
To the extent that claim 3 has not been amended to explicitly read on the elected species (Snrk), the following rejection applies:
Regarding claim 3, Zou teaches a method of modulating growth of a neuron in a subject by contacting the neuron with a Wnt, Wnt-like, or chemical affecting Wnt pathway (i.e. an agent) to promote regeneration of damaged neurons (para 0040, 0049, 0067).
However, Zou does not teach the agent reduces the expression or activity of a polynucleotide selected from the group recited in claim 3.
Atlasi teaches that Wnt signaling is capable of downregulating the expression of Tcf3 (abstract, page 1), which listed as a species in the group recited in instant claim 3.
Thus, It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of Zou of using a chemical affecting the Wnt pathway (that is Wnt or Wnt-like) to promote regeneration of damaged neurons, with the teachings of Wnt being capable of downregulating Tcf3 expression as taught by Atlasi, to arrive at a method for increasing regeneration of a damaged or degenerating neuron by contacting the neuron with an agent that reduces expression of Tcf3 such as a Wnt, Wnt-like, or chemical affecting Wnt pathway. One would be motivated to do so as Atlasi teaches that Wnt is capable of downregulating Tcf3 and since methods of modulating growth of a neuron in a subject by contacting the neuron with a Wnt, Wnt-like, or chemical affecting Wnt pathway is known in the art, one would have a reasonable expectation of success.
Regarding claim 4 and 6, the teachings of Zou and Atlasi render obvious claim 3. Moreover, Zou teaches that the method for modulating growth of a neuron is a neuron of a spinal cord that has been damaged by a neurogenerative disease or traumatic spinal cord injury (para 0041, claims 1-3), anticipating wherein damage to the neuron is associated with an injury or a neurodegenerative disease (claim 4) and wherein the injury is spinal cord injury (claim 6).
Regarding claim 5, the teachings of Zou and Atlasi render obvious claim 3. Moreover, Zou teaches that the method can be used for any disease or condition wherein neuronal dysfunction is contemplated including Parkinson's disease (para 0125), anticipating wherein the neurodegenerative disease is Parkinson's disease.
Claim(s) 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al (Nature Communications, 2019, pages 1-14) and further in view of Yoshida et al (Brain Research, 2000, pages 274-282) and Zou (US 20050049195 A1).
To the extent that claim 3 reads on the elected species (Snrk) and in vivo, the following rejection applies:
Regarding claim 3, Lu teaches that Snrk is a target of miR-103a-3p as the Snrk mRNA has two binding sites for miR-103a-3p and that overexpression of miR-103a-3p significantly reduced Snrk expression in glomerular endothelial cells (page 3, right col, para 1).
Lu does not teach an in vivo method for increasing regeneration of a damaged or degenerating neuron, the method comprising contacting the damaged or degenerating neuron with an agent that reduces expression or activity of a polypeptide Snrk.
However, one of ordinary skill in the art would have considered the teachings of
Yoshida and Zou as these references are analogous prior art pertaining to the role of Snrk in apoptosis of neurons and methods related to modulating growth of a neuron in a subject by contacting the neuron with an agent.
Yoshida teaches that cerebellar granule neurons undergo apoptotic cell death when cultured in low K+ and this apoptotic phenomenon is associated with increased low-K+ induced expression of Snrt (abstract page 274; page 275, para 2-3).
Zou teaches an in vivo method of modulating growth of a neuron in a subject by contacting the neuron with a Wnt, Wnt-like, or chemical affecting Wnt pathway (i.e. an agent) to promote regeneration of damaged neurons and the agent can be administered intravenously, directly into the cerebrospinal fluid, or by another mechanism that is specific to the disease that is being treated (para 0040, 0049, 0067, para 0276).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to combine the teachings of Lu and Yoshida to reduce apoptotic cell death in cerebellar granule neurons by using a miR-103a-3p that targets increased low-K+ induced expression of Snrt, particularly because Yoshida teaches that low K+ induces cerebellar granule neurons apoptosis by increasing expression of Snrt. Furthermore, it would be obvious to target cerebellar granule neurons in a subject by contacting said cerebellar granule neurons with an agent because Zou teaches how to contact a neuron in a subject with a Wnt,. A skilled artisan would have had a reasonable expectation of success as contacting a neuron in a subject in vivo to promote regeneration of damaged neurons was known in the art before the effective filing date of the claimed invention as taught by Zhou.
Regarding claim 4 and 6, the teachings of Yoshida, Lu and Zou, render obvious claim 3. Moreover, Zou teaches that the method for modulating growth of a neuron is a neuron of a spinal cord that has been damaged by a neurogenerative disease or traumatic spinal cord injury (para 0041, claims 1-3), rendering obvious wherein damage to the neuron is associated with an injury or a neurodegenerative disease (claim 4) and wherein the injury is spinal cord injury (claim 6).
Regarding claim 5, the teachings of Yoshida, and Lu and Zou, render obvious claim 3 and 4. Moreover, Zou teaches that the method can be used for any disease or condition wherein there is neuronal dysfunction is contemplated including Parkinson's disease (para 0125), rendering obvious wherein the neurodegenerative disease is Parkinson's disease.
Claim(s) 3 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Hirotsune (US 20190314320 A1) in view of Zou (US 20050049195 A1), as evidenced by Atlasi et al (PloS Genetics, 2013, pages 1-16).
To the extent that claim 3 and 7 have not been amended to explicitly read on the selected species (Snrk and in vivo application in claim 3 and sunitinib in claim 7), the following rejection applies in relation to reducing expression of Ctcf:
Regarding claim 3 and 7, Hirotsune teaches knockdown (i.e. reduced expression) of Ctcf using an siRNA (e.g, inhibitory nucleic acid molecule comprising siRNA) leads to promoting axon elongation and regeneration of dorsal root ganglion neurons (para 0336, 0353-0355).
Hirotsune does not teach an in vivo method comprising contacting the damaged or degenerating neuron with the siRNA.
However, one of ordinary skill in the art would have considered the teachings of
Zou as this reference is analogous prior art pertaining to methods related to modulating growth of a neuron in a subject in vivo by contacting the neuron with an agent.
Zou teaches a method of modulating growth of a neuron in a subject by contacting the neuron with a Wnt, Wnt-like, or chemical affecting Wnt pathway (i.e. an agent) to promote regeneration of damaged neurons (para 0040, 0049, 0067).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to knockdown (i.e. reduced expression) of Ctcf in a subject in vivo using an siRNA by contacting dorsal root ganglion neurons of a subject, particularly because Hirotsune reduced expression of Ctcf using an siRNA leads to promoting axon elongation and regeneration of dorsal root ganglion neurons. A skilled artisan would have had a reasonable expectation of success as contacting a neuron in a subject in vivo to promote regeneration of damaged neurons was known in the art before the effective filing date of the claimed invention as taught by Zhou.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliana Candelaria whose telephone number is (571)272-5488. The examiner can normally be reached Monday - Friday 8am - 5pm.
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/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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