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
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 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.
Response to Amendments
Applicant’s amendments, corrected specification, and response filed Dec. 1, 2025 have been received and entered into the case.
Status of the Claims
Claims 1-8 and 12-23 are currently pending.
Claims 1, 7, 8, 12 and 13 are amended.
Claims 14-20 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.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 9-11 are cancelled.
Claims 21-23 are new.
Claims 1-8, 12, 13, and 21-23 have been considered on the merits.
Specification Objections
Specification objections are withdrawn due to amendment.
Claim Objections
The claim objections are withdrawn due to amendment.
Claim Rejections - 35 USC § 112(b)
The claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ), are withdrawn due to amendment.
Claim Rejections - 35 USC § 112(a)
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), written description are withdrawn due to amendment.
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), scope of enablement are withdrawn due to amendment. New claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ) have been added to address the claim amendments.
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 1-8, 12, 13 and 21-23 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 treating amyotrophic lateral sclerosis by direct delivery to upper motor neurons of an AAV viral vector with the serotype AAV2 containing a sequence encoding for UCHL1 protein with 100% homology with SEQ ID NO. 1 operably connected to a CMV or UCHL1 promoter, does not reasonably provide enablement for the treating of all neurological diseases, disorders or injuries associated with upper motor neuron activity by administering an AAV2 vector expressing all amino acid sequences and variants thereof comprising SEQ ID NO. 1, and does not provide enable for all promoters other than CMV and UCHL1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, the enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to treating neurological diseases, disorders or injuries associated with upper motor neuron activity by administering an AAV2 vector expressing any amino acid sequences and variants thereof comprising SEQ ID NO. 1, which increases the concentration of UCHL1 in the upper motor neurons of the subject relative to the concentration of UCHL1 in the motor neurons prior to treatment. Thus, the claims taken together with the specification imply that any kind of neurological diseases, disorders or injuries associated with upper motor neuron activity, can be treated with any AAV2 vector expressing any amino acid sequences and variants thereof comprising SEQ ID NO. 1, and with any promoter which increases the concentration of UCHL1 in the upper motor neurons of the subject.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
Inventions targeted for treatment of diseases bear a heavy responsibility to provide supporting evidence because of the unpredictability in biological responses to therapeutic treatments. The standard of enablement is high for such inventions because as the state of the art stands, treatments and gene therapies for treating neurological diseases, disorders and injuries associated with motor neuron activity are unpredictable and the causes vary for the different neurological diseases, disorders and injuries.
For instance, with respect to central nervous diseases including AML, Alarcan et al. (Journal of Personalized Medicine, 2022) reports that amyotrophic lateral sclerosis (AML) lacks an efficient therapy in part due to the blood-brain barrier for the diffusion of candidate drugs (abstract). Alarcan states that despite advances in drug discovery, the development of therapies targeting central nervous system diseases is complicated and limited by the blood-brain barrier and the blood-spinal cord barrier(pg. 1-2 bridging para.). In addition, Feldman et al. (The Lancet, 2022) reports that AML is incurable and that AML is a heterogeneity disease with many causes (pg. 1373 Col. 1 last para. and pg. 1374 Col. 1 para. 2). Feldman reports that gene therapies are being developed to treat AML, however, there is no approved therapy yet (pg. 1374-1375 bridging para.). With respect to the unpredictability of gene therapy, Morris et al. (Neuroscience, 2022) reports that the permanent nature of most gene therapies is a drawback for using the therapy for a wide-range of diseases, since it presents the risk of irreversible adverse effects (abstract and pg. 313 last para.). Morris states that “gene therapy has the potential to transform treatment for a wide range of neurological disease but, in its current form, has inherent risks which limit its clinical use” (pg. 313 last para.).
Thus, as the state of the art stands, treatment of neurological diseases, disorders and injuries associated with motor neuron activity is highly unpredictable.
(5) The relative skill of those in the art:
The relative skill of those in the art is high.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The instant specification provides working examples and guidance for the gene therapy of amyotrophic lateral sclerosis by direct delivery to upper motor neurons of an AAV viral vector with the serotype AAV2 containing a sequence encoding for UCHL1 protein operably connected to a CMV or UCHL1 promoter.
For an instance, in Example 1 of the specification, it is shown that there is direct delivery to upper motor neurons in Macaque monkeys of AAV2-hUCHL1-IresmCherry is injected into the motor cortex and that the serotype AAV2 transduces mostly to neurons after testing AAV serotypes 1-9 (0132, 0140 and 0142). The nucleic acid sequence for this plasmid is SEQ ID NO. 7 (0044). In addition, the promoters, CMV, CBA and UCHL1 promoters, were tested for effectiveness (0136 and 0138). Additionally, in Example 1, it was demonstrated that by introducing the UCHL1 gene using retrograde transduction, into the motor cortex of hSODG93A mice (a ALS mouse model) and TDP-43 mouse model (a mouse model with the A315T mutation detected in ALS patients) that there is improved cytoarchitectural integrity, stability and health of CSMN (corticospinal motor neuron) (0152-0159). For the mice experiments pAAV.CBA.UCHL1-IRES-eGFP.WPRE plasmid was packaged into AAV2 virus particles and where the mouse UCHL1 cDNA ORF was subcloned into a AAV plasmid with CBA promoter and injected into motor cortex (0173 and 0176). The nucleic acid sequence for this plasmid is SEQ ID NO. 8 (0044).
In Example 2, it is demonstrated that UCHL1 is necessary and sufficient for maintaining cytoarchitectural integrity of upper motor neurons showing in UCHL1-/- mice (mice where UCHL1 is knocked out in the corticospinal motor neurons) that upper motor neuron integrity is restored with AAV mediated gene delivery of UCHL1 (0186). Additionally, it was demonstrated that targeted AAV2-mediated delivery of UCHL1 only to CSMN was sufficient to improve the cells cytoarchitectural integrity when UCHL1 is introduced to just CSMNs where UCHL1 selectively knock out in the large SCPN in layer 5 or in SMN in the spinal cord of mice (0194). For these experiments a CBA.UCHLl-IRES-eGFP.WPRE plasmid that was packaged into AAV2 virus particles was used (0220).
However, the specification does not provide any guidance for additional vectors that express UCHL1 with an amino acid or variant of SEQ ID NO. 1 that increase the concentration of UCHL1 in motor neurons in a subject with other neurological diseases, disorders or injuries associated with upper motor neuron activity. Additionally, the specification is silent with respect to the amino acid sequence of the UCHL1 that is expressed in the examples. The applicants have not provided additional UCHL1 amino acid variants or data for additional neurological diseases, disorders or injuries to give the skilled artisan any reason to expect that any amino acid variant that increases UCHL1 concentration in motor neurons would be effective towards all potential neurological disease, disorders or injuries associated with upper motor neuron activity. There is no guidance or data showing variants of UCHL1 sequences other than that encoded by the nucleic acid sequences of SEQ ID NO. 7 and 8.
Claims drawn to pharmaceuticals and methods of treatment generally require supporting data because of the unpredictability in biological responses to therapeutic treatments. The efficacy of a drug treatment faces numerable unfavorable obstacles in vivo. As such, in vivo utility necessarily involves unpredictability with respect to physiological activity of an asserted process in humans and other animals. See discussion in Ex parte Kranz, 19 USPQ 2d 1216, 1218-1219 (6/90). For example, the delivery of a drug across necessary cell surfaces in amounts needed to be efficacious, but not lethal to the subject, necessitates sensitive testing in order to adequately determine the proper dosage.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to use the claimed invention within the broad scope as instantly claimed.
Claim Rejections - 35 USC § 102
The claim rejections under 35 USC § 102 are withdrawn due to amendment.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are withdrawn due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 7, 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Arancio et al. (US 2007/0071724 A1)(ref. of record) as evidenced by NCBI BLAST (Blastp suite alignment of instant SEQ ID NO. 1 with SEQ ID NO. 2, accessed Jul. 23, 2025) in view of Moullier et al. (US 2021/0162072 A1, priority to Nov. 8, 2019).
With respect to claim 1, Arancio teaches a method of treating a subject with a neuropathological condition including amyotrophic lateral sclerosis (a neurological disease or disorder associated with upper motor neuron activity by administering to the subject an effective amount of a adenovirus associated virus (AAV) vector that express UCHL1 capable of increasing ubiquitin carboxyl hydrolase ligase 1 (UCHL1) activity in the neural tissue of the subject (abstract, 0007, 0009-0011, 0063 and 0075). With respect to claims 1 and 7, Arancio teaches the UCHL1 expressed has the amino acid sequence of SEQ ID NO. 2 (0011 and 0059-0060). SEQ ID NO. 2 taught by Arancio shares 99% homology with SEQ ID NO. 1 of claims 1 and 7 as shown by a NCBI Blastp alignment and, therefore the vector of Arancio expresses a UCHL1 or a variant thereof comprising an amino acid sequence of SEQ ID NO. 1.
Although, Arancio is silent with respect to whether there is an increase in the concentration of UCHL1 in upper motor neurons of the subject relative to the concentration of UCHL1 in the upper motor neurons of the subject prior to administrating the therapeutic agent as recited in claim 1, Arancio teaches the claimed method of administering a therapeutic agent that is effective in increasing UCHL1 concentration. Therefore, once administered to the subject there would be an increase in the concentration of UCHL1 in upper motor neurons of the subject relative to the concentration of UCHL1 in the upper motor neurons of the subject prior to administrating the therapeutic agent. The claimed result must be inherent to the method taught by Arancio and a necessary effect of practicing the method.
With respect to claim 2, Arancio teaches a method where the condition is amyotrophic lateral sclerosis (0010).
Arancio does not teach the method where the vector is AAV2 as recited in claim 1. However, Moullier teach a similar method of treating a neurological disease or disorder by gene therapy with AAV vectors containing transgenes, where the transgene encodes a cDNA, and where the cDNA encodes for UCH-L1 (abstract, 0001, and 0040). Moullier further teaches the method where the vector is AAV and is the serotype 2 (0084, 0089-0091). At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of Arancio in such a way that the AAV vector is AAV2 for the purpose being able administer a gene therapy vector to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity. Furthermore, it would have been obvious to one skilled in the art to have further modified Arancio such that AAV vector is AAV2, since methods of treating neurological conditions were known to use the AAV2 serotype as taught by Moullier. Such a modification merely involves the substitution of one known serotype of AAV vector for another for the administering of a gene therapy vector to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity.
Arancio does not teach the method where the subject has hereditary spastic paraplegia (HSP) or primary lateral sclerosis (PLS) as recited in claims 3 and 4, respectively. However, Moullier teach a similar method of treating a neurological disease or disorder by gene therapy with AAV vectors containing transgenes, where the transgene encodes a cDNA, and where the cDNA encodes for UCH-L1 (abstract, 0001, and 0040). Moullier teaches the CNS diseases that are treated by the method include amyotrophic lateral sclerosis, hereditary spastic paraplegia and primary lateral sclerosis (0041 and 0213). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Arancio to include the treatment of hereditary spastic paraplegia and primary lateral sclerosis for the benefit of treating addition neurological diseases or disorders using gene therapy as taught by Moullier. It would have been obvious to one of ordinary skill in the to modify the method of Arancio to include the treatment of hereditary spastic paraplegia and primary lateral sclerosis, since Moullier teaches a similar method of treating neurological condition with gene therapy where the a vector encoding for UCH-L1 can be used and the conditions treated include amyotrophic lateral sclerosis, hereditary spastic paraplegia and primary lateral sclerosis. For these same reasons, one of ordinary skill in the art would have had reasonable expectation of success in making such a modification to the method taught by Arancio.
Although, Arancio teaches the method where the vector containing the UCHL1 sequence contains a promoter, Arancio does not teach any of the promoters listed in claim 12 or that the promoter is the human UCHL1 or CMV promoter as recited in claim 13. However, Moullier teach a similar method of treating a neurological disease or disorder by gene therapy with AAV vectors containing transgenes, where the transgene encodes a cDNA, and where the cDNA encodes for UCH-L1 (abstract, 0001, and 0040). Moullier further teaches the method where the promoter used to express the cDNA is human elongation factor la-subunit (EF1α), cytomegalovirus (CMV), immediate-early enhancer and/or promoter, chicken β-actin (CBA), phosphoglycerate kinase gene (PGK), and ubiquitin C (UBC) (0201 and 0207). At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of Arancio in such a way that the promoter is one of the claimed promoters for the purpose being able administer a gene therapy vector containing a cDNA with a promoter to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity. Furthermore, it would have been obvious to one skilled in the art to have further modified Arancio such that the promoter in the vector is one of the claimed promoters, since methods of treating neurological conditions were known to use these promoters to express cDNAs contained in AAV vectors as taught by Moullier. Such a modification merely involves the substitution of one known type of promoter for another for the administering of a gene therapy vector containing a cDNA with a promoter to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 8 is rejected under 35 U.S.C. 103(a) as being unpatentable over Arancio as evidenced by NCBI BLAST in view of Moullier (as applied to claims 1-4, 7, 12 and 13 above), and further in view of Jara et al. (Gene Therapy, 2016).
The teachings of Arancio and Moullier can be found in the previous rejection above.
Arancio does not teach the method where the therapeutic agent is administered by injection into the motor cortex of the subject as recited in claim 8. However, Jara teaches direct cortex injection of AAV has been proven to be more suitable for clinical studies of CSMN (corticospinal motor neurons) and teaches direct motor cortex injection of an AAV2 vector in a ALS mouse model (pg. 273 Col. 1 para. 2, pg. 274 para. 2 and Fig. 4). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Arancio so that the administration of the AAV vector that express UCHL1 is injected into the motor cortex of the subject for the benefit of directly treating motor neurons in the subject as taught by Jara. It would have been obvious to one of ordinary skill in the art to administer the vector to treat ALS by injection as taught by Arancio into the motor cortex, since Jara teaches a similar method of treating ALS by injecting a AAV2 vector expressing a therapeutic protein into the motor cortex. One of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Arancio to administer the AAV vector by injection into the motor neuron cortex, since Jara teaches the successful administration of a similar AAV2 vector into the motor cortex.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1, 2, 4-6, 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Arancio et al. (US 2007/0071724 A1)(ref. of record) as evidenced by NCBI BLAST (Blastp suite alignment of instant SEQ ID NO. 1 with SEQ ID NO. 2, accessed Jul. 23, 2025) in view of Passini et al. (WO 2010/129021 A1) (ref. of record).
With respect to claim 1, Arancio teaches a method of treating a subject with a neuropathological condition including amyotrophic lateral sclerosis (a neurological disease or disorder associated with upper motor neuron activity by administering to the subject an effective amount of a adenovirus associated virus (AAV) vector that express UCHL1 capable of increasing ubiquitin carboxyl hydrolase ligase 1 (UCHL1) activity in the neural tissue of the subject (abstract, 0007, 0009-0011, 0063 and 0075). With respect to claims 1 and 7, Arancio teaches the UCHL1 expressed has the amino acid sequence of SEQ ID NO. 2 (0011 and 0059-0060). SEQ ID NO. 2 taught by Arancio shares 99% homology with SEQ ID NO. 1 of claims 1 and 7 as shown by a NCBI Blastp alignment and, therefore the vector of Arancio expresses a UCHL1 or a variant thereof comprising an amino acid sequence of SEQ ID NO. 1.
Although, Arancio is silent with respect to whether there is an increase in the concentration of UCHL1 in upper motor neurons of the subject relative to the concentration of UCHL1 in the upper motor neurons of the subject prior to administrating the therapeutic agent as recited in claim 1, Arancio teaches the claimed method of administering a therapeutic agent that is effective in increasing UCHL1 concentration. Therefore, once administered to the subject there would be an increase in the concentration of UCHL1 in upper motor neurons of the subject relative to the concentration of UCHL1 in the upper motor neurons of the subject prior to administrating the therapeutic agent. The claimed result must be inherent to the method taught by Arancio and a necessary effect of practicing the method.
With respect to claim 2, Arancio teaches a method where the condition is amyotrophic lateral sclerosis (0010).
Arancio does not teach the method where the vector is AAV2 as recited in claim 1. However, Passini teaches a method for treating disorder affecting motor neuron function including disease or injury to the brain or spinal cord by delivering genes to the CNS by AAV vectors (abstract and pg. 3 lines 22-28). Passini teaches the method where AAV vector can be AAV2 (pg. 40 lines 4-10). At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of Arancio in such a way that the AAV vector is AAV2 for the purpose being able administer a gene therapy vector to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity. Furthermore, it would have been obvious to one skilled in the art to have further modified Arancio such that AAV vector is AAV2, since methods of treating neurological conditions were known to use the AAV2 serotype as taught by Passini. Such a modification merely involves the substitution of one known serotype of AAV vector for another for the administering of a gene therapy vector to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity.
Arancio does not teach the method where the subject has primary lateral sclerosis (PLS) or a spinal cord injury as recited in claims 4 and 5, respectively. However, Passini teaches a method for treating disorder affecting motor neuron function including disease or injury to the brain or spinal cord by delivering genes to the CNS by AAV vectors (abstract and pg. 3 lines 22-28). Passini teaches the motor neuron disorders treated include amyotrophic lateral sclerosis, primary lateral sclerosis and traumatic spina cord injury (abstract). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Arancio to include the treatment of primary lateral sclerosis and a spinal cord injury for the benefit of treating addition neurological diseases or disorders using gene therapy as taught by Passini. It would have been obvious to one of ordinary skill in the to modify the method of Arancio to include the treatment of hereditary spastic paraplegia and primary lateral sclerosis, since Passini teaches a similar method of treating neurological condition with gene therapy where the a vector encoding and the conditions treated include amyotrophic lateral sclerosis, primary lateral sclerosis and a spinal cord injury. For these same reasons, one of ordinary skill in the art would have had reasonable expectation of success in making such a modification to the method taught by Arancio.
Arancio does not teach the method where the therapeutic agent is administered to the motor neurons of the subject as recited in claim 6. However, Passini teaches a method for treating disorder affecting motor neuron function including disease or injury to the brain or spinal cord by delivering genes to the CNS by AAV vectors (abstract and pg. 3 lines 22-28). Passini further teaches the method where a therapeutically effective amount to the composition is administered to the motor neuron cells in vivo (pg. 4 lines 13-18 and 25-31). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Arancio to so that the therapeutic agent or AAV vector is administered to the motor neurons of the subject for the benefit administering the therapeutic agent directly to the cells affected in the neurological condition as taught by Passini. It would have been obvious to one of ordinary skill in the to modify the method of Arancio to deliver the therapeutic agent to the motor neurons of the subject, since Passini teaches a similar method of treating neurological conditions associated with upper motor neuron activity in a subject with gene therapy where the a vector is administered to the motor neurons. Additionally, one of ordinary skill in the art would have had reasonable expectation of success in making such a modification to the method taught by Arancio, since delivery of AAV vectors to motor neurons was known in the art for treating neurological conditions associated with motor neuron activity as taught by Passini.
Although, Arancio teaches the method where the vector containing the UCHL1 sequence contains a promoter, Arancio does not teach any of the promoters listed in claim 12, or that the promoter is the human UCHL1 or CMV promoter as recited in claim 13. However, Passini teaches a method for treating disorder affecting motor neuron function including disease or injury to the brain or spinal cord by delivering genes to the CNS by AAV vectors where the gene operably link to a promoter (abstract, pg. 3 lines 22-28 and pg. 15 lines 15-23). Passini further teaches the method where the promoter is cytomegalovirus (CMV) promoter, chicken beta actin (CBA) promoter, and human ubiquitin C (Ubc) promoter (pg. 29 lines 14-29). At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of Arancio in such a way that the promoter is one of the claimed promoters for the purpose being able administer a gene therapy vector containing a cDNA with a promoter to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity. Furthermore, it would have been obvious to one skilled in the art to have further modified Arancio such that the promoter in the vector is one of the claimed promoters, since methods of treating neurological conditions were known to use many of these promoters to express cDNAs contained in AAV vectors as taught by Passini. Such a modification merely involves the substitution of one known type of promoter for another for the administering of a gene therapy vector containing a cDNA with a promoter to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 8 is rejected under 35 U.S.C. 103(a) as being unpatentable over Arancio as evidenced by NCBI BLAST in view of Passini (as applied to claims 1, 2, 4-6, 12 and 13 above), and further in view of Jara et al. (Gene Therapy, 2016).
The teachings of Arancio and Passini can be found in the previous rejection above.
Arancio does not teach the method where the therapeutic agent is administered by injection into the motor cortex of the subject as recited in claim 8. However, Jara teaches direct cortex injection of AAV has been proven to be more suitable for clinical studies of CSMN (corticospinal motor neurons) and teaches direct motor cortex injection of an AAV2 vector in a ALS mouse model (pg. 273 Col. 1 para. 2, pg. 274 para. 2 and Fig. 4). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Arancio so that the administration of the AAV vector that express UCHL1 is injected into the motor cortex of the subject for the benefit of directly treating motor neurons in the subject as taught by Jara. It would have been obvious to one of ordinary skill in the art to administer the vector to treat ALS by injection as taught by Arancio into the motor cortex, since Jara teaches a similar method of treating ALS by injecting a AAV2 vector expressing a therapeutic protein into the motor cortex. One of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Arancio to administer the AAV vector by injection into the motor neuron cortex, since Jara teaches the successful administration of a similar AAV2 vector into the motor cortex.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1, 2, 7, 12, 13, 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Arancio et al. (US 2007/0071724 A1)(ref. of record) as evidenced by NCBI BLAST (Blastp suite alignment of instant SEQ ID NO. 1 with SEQ ID NO. 2, accessed Jul. 23, 2025) in view of Esteves et al. (US 2019/0038773 A1, published Feb. 7, 2019).
With respect to claim 1, Arancio teaches a method of treating a subject with a neuropathological condition including amyotrophic lateral sclerosis (a neurological disease or disorder associated with upper motor neuron activity by administering to the subject an effective amount of a adenovirus associated virus (AAV) vector that express UCHL1 capable of increasing ubiquitin carboxyl hydrolase ligase 1 (UCHL1) activity in the neural tissue of the subject (abstract, 0007, 0009-0011, 0063 and 0075). With respect to claims 1 and 7, Arancio teaches the UCHL1 expressed has the amino acid sequence of SEQ ID NO. 2 (0011 and 0059-0060). SEQ ID NO. 2 taught by Arancio shares 99% homology with SEQ ID NO. 1 of claims 1 and 7 as shown by a NCBI Blastp alignment and, therefore the vector of Arancio expresses a UCHL1 or a variant thereof comprising an amino acid sequence of SEQ ID NO. 1.
Although, Arancio is silent with respect to whether there is an increase in the concentration of UCHL1 in upper motor neurons of the subject relative to the concentration of UCHL1 in the upper motor neurons of the subject prior to administrating the therapeutic agent as recited in claim 1, Arancio teaches the claimed method of administering a therapeutic agent that is effective in increasing UCHL1 concentration. Therefore, once administered to the subject there would be an increase in the concentration of UCHL1 in upper motor neurons of the subject relative to the concentration of UCHL1 in the upper motor neurons of the subject prior to administrating the therapeutic agent. The claimed result must be inherent to the method taught by Arancio and a necessary effect of practicing the method.
With respect to claim 2, Arancio teaches a method where the condition is amyotrophic lateral sclerosis (0010).
Arancio does not teach the method where the vector is AAV2 as recited in claim 1. However, Esteves teaches a similar method of administering a nucleic acid to the central nervous system where the nucleic acid encodes a transgene operably linked to a transgene to treat a central nervous system disease including amyotrophic lateral sclerosis (ALS) (0002-0006). Esteves further teaches that the nucleic acid is in a vector and teaches the vector is adeno-associated virus (AAV) and can be of the serotype of AAV2 (0010-0011). At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of Arancio in such a way that the AAV vector is AAV2 for the purpose being able administer a gene therapy vector to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity. Furthermore, it would have been obvious to one skilled in the art to have further modified Arancio such that AAV vector is AAV2, since methods of treating neurological conditions were known to use the AAV2 serotype as taught by Esteves. Such a modification merely involves the substitution of one known serotype of AAV vector for another for the administering of a gene therapy vector to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity.
Although, Arancio teaches the method where the vector containing the UCHL1 sequence contains a promoter, Arancio does not teach any of the promoters listed in claim 12. However, Esteves teaches a similar method of administering a nucleic acid to the central nervous system where the nucleic acid encodes a transgene operably linked to a transgene to treat a central nervous system disease including amyotrophic lateral sclerosis (ALS) (0002-0006). Esteves further teaches that the promoter can be the cytomegalovirus (CMV) promoter, chicken beta actin (CBA) promoter, the SV40 promoter, EF1α promoter, the phosphoglycerol kinase (PGK) promoter (0070). At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of Arancio in such a way that the promoter is one of the claimed promoters for the purpose being able administer a gene therapy vector containing a cDNA with a promoter to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity. Furthermore, it would have been obvious to one skilled in the art to have further modified Arancio such that the promoter in the vector is one of the claimed promoters, since methods of treating neurological conditions were known to use many of these promoters to express cDNAs contained in AAV vectors as taught by Esteves. Such a modification merely involves the substitution of one known type of promoter for another for the administering of a gene therapy vector containing a cDNA with a promoter to a subject with a neurological disease, disorder or injury associated with upper motor neuron activity.
Although, Arancio teaches the method where the vector containing the UCHL1 sequence contains a promoter, Arancio does not teach the promoter is the UCHL1 promoter as claims 13 and 21 and where the UCHL1 promoter is the human UCHL1 promoter as recited in claim 22 is being interpreted to mean as explained in the rejection under U.S.C. 35 §112(b). However, Esteves teaches a similar method of administering a nucleic acid to the central nervous system where the nucleic acid encodes a transgene operably linked to a transgene to treat a central nervous system disease including amyotrophic lateral sclerosis (ALS) (0002-0006). Esteves further teaches the nucleic acid can encode a protein which gene is associated with a disease of the central nervous system a where the genes is UCH-L1 (0076). Esteves teaches the method where the native promoter of the transgene is used when the expression of the transgene is desired to mimic the native expression, when the expression of the transgene needs to be regulated temporally or developmentally, or in a tissue-specific manner, or in response to specific transcriptional stimuli (0072). Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method of Arancio so that the promoter used is the UCHL1 promoter and is the human UCHL1 promoter for the benefit controlling the location and timing of the expression of UCHL1 transgene and to mimic the native expression as taught by Esteves. It would have been obvious to one of ordinary skill in the art to make such a modification to Arancio, since Esteves teaches a similar gene therapy method for treating central nervous system conditions where the gene can be UCHL1 and the promoter is the native promoter of the desired gene to be expressed and Arancio teaches the human UCHL1 gene. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the method of Arancio, since Arancio and Esteves teach gene therapy using the gene for UCHL1, Arancio teaches gene therapy using the human gene for UCHL1, and Esteves teaches that the native promoter can be used for gene therapy.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 8 is rejected under 35 U.S.C. 103(a) as being unpatentable over Arancio as evidenced by NCBI BLAST in view of Esteves (as applied to claims 1, 2, 7, 12, 13, 21 and 22 above), and further in view of Jara et al. (Gene Therapy, 2016).
The teachings of Arancio and Esteves can be found in the previous rejection above.
Arancio does not teach the method where the therapeutic agent is administered by injection into the motor cortex of the subject as recited in claim 8. However, Jara teaches direct cortex injection of AAV has been proven to be more suitable for clinical studies of CSMN (corticospinal motor neurons) and teaches direct motor cortex injection of an AAV2 vector in a ALS mouse model (pg. 273 Col. 1 para. 2, pg. 274 para. 2 and Fig. 4). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Arancio so that the administration of the AAV vector that express UCHL1 is injected into the motor cortex of the subject for the benefit of directly treating motor neurons in the subject as taught by Jara. It would have been obvious to one of ordinary skill in the art to administer the vector to treat ALS by injection as taught by Arancio into the motor cortex, since Jara teaches a similar method of treating ALS by injecting a AAV2 vector expressing a therapeutic protein into the motor cortex. One of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Arancio to administer the AAV vector by injection into the motor neuron cortex, since Jara teaches the successful administration of a similar AAV2 vector into the motor cortex.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 23 is rejected under 35 U.S.C. 103(a) as being unpatentable over Arancio as evidenced by NCBI BLAST in view of Esteves (as applied to claims 1, 2, 7, 12, 13, 21 and 22 above), and further in view of Wang et al. (Journal of Neurochemistry, 2011).
The teachings of Arancio and Esteves can be found in the previous rejection above.
Neither Arancio or Esteves teach the method where the UCHL1 promoter comprises the SEQ ID NO:16 as recited in claim 23.
However, Wang teaches the native hUCHL1 promoter has 100% homology to SEQ ID NO. 16, see supplemental contents GenEmbl, Result 1 (Fig. 1). Accordingly, at the effective time of filing of the claim invention, one of ordinary skill in the art would have been motivated to modify the method taught by the combined teachings of Arancio and Esteves so that the native hUCHL1 promoter comprises SEQ ID NO. 16 for the benefit of using the native promoter sequence as taught by Wang. It would have been obvious to one of ordinary skill in the art to use the known hUCHL1 promoter in the method of taught by the combined teachings of Arancio and Esteves, since Esteves teaches using the native hUCHL1 promoter and Wang teaches the sequence comprises SEQ ID NO. 16. For these reasons one of ordinary skill in the art would have had a reasonable expectation of success in including the native sequence of SEQ ID NO. 16 in the method taught by the combined teachings of Arancio and Esteves.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Dec. 1, 2025 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 112 (a) enablement, Applicant argues that one of skill in art could select a promoter that drives the expression UCHL1 in the AAV2 vector without undue experimentation and that specification demonstrates that the claimed AAV2 vector expressing UCHL1 improves upper motor neuron health (Remarks pg. 10 para. 2). However, this argument was not found to be persuasive, since the specification does not provide any guidance for additional AAV2 vectors that express UCHL1 with an amino acid or variant of SEQ ID NO. 1 that increase the concentration of UCHL1 in motor neurons in a subject with other neurological diseases, disorders or injuries associated with upper motor neuron activity. The specification is silent with respect to the amino acid sequence of the UCHL1 that is expressed in the examples. The applicants have not provided additional UCHL1 amino acid variants or data for additional neurological diseases, disorders or injuries to give the skilled artisan any reason to expect that any amino acid variant that increases UCHL1 concentration in motor neurons would be effective towards all potential neurological disease, disorders or injuries associated with upper motor neuron activity. There is no guidance or data showing variants of UCHL1 sequences other than that encoded by the nucleic acid sequences of SEQ ID NO. 7 and 8.
With respect to the rejections under 35 U.S.C. § 102, Applicant argues that Arancio does not disclose a UCHL1 sequence or a variant containing an amino acid sequence with 100% homology to SEQ ID NO: 1 (Remarks pg. 10-11 bridging para.). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a UCHL1 sequence or a variant containing an amino acid sequence with 100% homology to SEQ ID NO: 1) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, the claims under 35 U.S.C. § 102 have been withdrawn due to amendment.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that neither Arancio nor Moullier disclose a UCHL1 sequence or a variant containing an amino acid sequence with 100% homology to SEQ ID NO: 1 (Remarks pg. 11 para. 3). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a UCHL1 sequence or a variant containing an amino acid sequence with 100% homology to SEQ ID NO: 1) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that neither Arancio nor Moullier teach administering a AAV2 vector expressing UCHL1 by injection into the motor cortex as recited in amended claim 8 (Remarks pg. 11 para. 3). In addition, Applicant argues that the AAV2 vector was particularly effective for selective upper motor neuron targeting by motor cortex injection (Remarks pg. 11 para. 3). The Applicant’s amendments limiting claim 8 to include injection into the motor cortex necessitated a new rejection. Applicant’s arguments are drawn to Arancio and Moullier failing to teach this new limitation. However, this new limitation is addressed in the new rejection.
Applicant argues that neither Arancio nor Passini disclose a UCHL1 sequence or a variant containing an amino acid sequence with 100 % homology to SEQ ID NO: 1 (Remarks pg. 11 para. 5). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a UCHL1 sequence or a variant containing an amino acid sequence with 100% homology to SEQ ID NO: 1) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, the claims under 35 U.S.C. § 102 have been withdrawn due to amendment.
Applicant argues that neither Arancio nor Passini teach administering a AAV2 vector expressing UCHL1 by injection into the motor cortex as recited in amended claim 8 (Remarks pg. 11 para. 5). The Applicant’s amendments limiting claim 8 to include injection into the motor cortex necessitated a new rejection. Applicant’s arguments are drawn to Arancio and Passini failing to teach this new limitation. However, this new limitation is addressed in the new rejection.
Applicant argues that neither Arancio nor Esteves disclose a UCHL1 sequence or a variant containing an amino acid sequence with 100% homology to SEQ ID NO: 1 (Remarks pg. 12 para. 2). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a UCHL1 sequence or a variant containing an amino acid sequence with 100% homology to SEQ ID NO: 1) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, the claims under 35 U.S.C. § 102 have been withdrawn due to amendment.
Applicant argues that neither Arancio nor Esteves teach administering a AAV2 vector expressing UCHL1 by injection into the motor cortex as recited in amended claim 8 (Remarks pg. 12 para. 2). The Applicant’s amendments limiting claim 8 to include injection into the motor cortex necessitated a new rejection. Applicant’s arguments are drawn to Arancio and Esteves failing to teach this new limitation. However, this new limitation is addressed in the new rejection.
Conclusion
No claims are allowed.
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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/EMILY A CORDAS/Primary Examiner, Art Unit 1632