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 .
Election/Restrictions
Applicant’s election of Group I and SEQ ID NO: 60 in the reply filed on 7/13/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Accordingly, claims 60-63 are withdrawn from consideration for being directed to non-elected subject matter. Claims 44-59 are currently under examination.
Specification
The disclosure is objected to because of the following informalities: On page 63, 1st paragraph, the specification states “However, we do not observe obvious alleviation of PD symptoms in the control monkey injected with AAV-GFAP-Cherry + AAV-GFAP-CasRx that does encode gRNA targeting Ptbp1.” It appears that the control should not have gRNA, thus should be “does not encode gRNA” would make more sense.
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 44-59 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.
Regarding claims 44-47, 51-53, 56, 57 and 59, the word “preferably” “more preferably” and “most preferred” renders the claim indefinite because it is unclear whether the limitation following the word is part of the claim limitation.
Dependent claims 48-50, 54, 55 and 58 are rejected for same reason because they depend on above claims and do not remedy the indefiniteness.
Regarding claim 51, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 59 recites the limitation "the cell programming agent" in line 3. There is insufficient antecedent basis for this limitation in the claim.
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 44-59 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
The nature of the invention
The claimed invention of claim 44 is drawn to a method of treating a neurological condition associated with degeneration of functional neurons in a region in the nervous system of a non-human primate or a human, comprising administering to a non-neuronal cell in the region in the nervous system of a subject in need, an effective amount of a composition comprising a nucleic acid molecule that targets a target sequence or its complement in a primate PTB gene, transcript or mRNA, to suppress the expression or activity of PTB, allowing the non-neural cell to reprogram into a functional neuron. Dependent claims 45-52 further limits the method to use Cas effector combined with gRNA.
The breadth of the claim
The scope of the claim is rather broad. The broadest claim (44) encompasses a method of treating a wide variety of neurological condition with degeneration of functional neuron in different regions of nervous system of a primate or human body, using different types of inhibitory nucleic acid targeting a primate PTB gene in the region 951-1487 of SEQ ID NO: 87.
The teaching from the specification and the presence of working examples
The specification teaches two working examples relevant to the claimed method. Example 1 teaches a CasRx+gRNA system that targets Ptbp1 expression in mice, Macaca Fascicularis and human cells, which directly convert astrocyte into dopamine neurons in the striatum of Macaca Fascicularis. Example 1 determines the non-neuronal to dopamine neuron conversion by measuring neuronal marker and fluorescent reporter gene expression. Example 1 also demonstrate combining the down regulation of PTB1 with expression of dopamine neuron conversion related transcription factors such as FoxA, Lmx1a or Nurr1 increased the efficiency of dopamine neuron conversion in mouse striatum. Example 2 describes a monkey PD model in which downregulating PTB1 converts astrocyte to dopamine neuron in putamen, wherein said cells express dopamine neuron markers. Example 2 further demonstrates that enhancement of presynaptic dopaminergic function and transporter signal in putamen area. However, the specification does not teach whether treating human or primate with other types of nucleic acid targeting the same region would achieve same result. The specification fails to teach animal models other than PD that show improved symptoms for other types of neurological condition as broadly claimed. As such, whether the experimental data from the examples may be extended to predicting therapeutic effect to other disorder, and/or using other types of nucleic acid targeting sequence that differ significantly in mechanism of downregulating PTB1 gene is unpredictable.
The state of prior art and level of predictability in the art
The research in treatment of neurological condition is robust at the time of filing. With the advancement in CRISPR-Cas genome editing technology, it is becoming a powerful tool for precise DNA and RNA modulation, offering promising therapeutic strategies for neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease…etc. However, substantial challenges still remains. Yashooa et al., published in 2026 discussed in detail about the current understanding of mechanistic insights, therapeutic potential and translational challenges in this field (Frontiers in Neurobiology, 2026, pages 1-36). Yashooa et al. teach the challenges and strategies for applying CRISPR-Cas in treating neurological disorders include delivery mechanism, off target effects, immune response, and ethical issues (Figure 4 and legend on page 21). Yashooa states “the utilization of CRISPR-Cas in neurodegenerative diseases presents numerous significant hurdles, each necessitating inventive solutions.” (page 26, 1st col., 2nd paragraph, line 3-5). Based on such teaching, even 6 years after the filing of the instant application, the state of art regarding using CRISPR Cas platform to treat neurological disorder is still considered unpredictable. A skilled artisan would have to rely solely on the teaching from the specification to implement the method as claimed.
The amount of experimentation required to practice the claimed invention
The teaching from the specification is rather limited to one example of monkey PD model, wherein inhibiting PTB1 gene expression in putamen region with AAV encoding CasRx and gRNA demonstrated dopaminergic neuron function and improved symptom. However, the specification does not provide teaching with regard to using other types of inhibitory nucleic acid, and/or in other disease model in primates or humans that may be treated with the claimed method. In view of substantial hurdles for translating the animal model treatment to human trial, and substantial hurdles for treating a wide variety of neurological disorder caused by different mechanism, a skilled artisan would have to engage in undue experimentation to practice the method as claimed. Therefore, the claimed invention is not enabled by the instant specification.
The following obviousness rejection is based on the claim interpretation of the method step, wherein the 112 1st paragraph rejection is based on the method of treatment as stated in preamble. Therefore, they do not contradict each other.
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.
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.
Claim(s) 44, 53, 55, 56, 58 and 59 is/are rejected under 35 U.S.C. 103 as being unpatentable over McCown (US 2019/0224256), in view of the sequence having accession number BBA32269 (disclosed in US 20130315885).
The claimed method of claim 44 is drawn to a method that comprises a single step: administering to a non-neuronal cell in the region in the nervous system of a non-human primate or a human subject an effective amount of a composition comprising a nucleic acid molecule that target a sequence or its complement in a primate PTB gene, transcripts or mRNA to suppress the expression or activity of PTB in the non-neuronal cell, wherein the target sequence is comprises in a sequence that has 95% and above homology with 951-1487 of SEQ ID NO: 87.
McCown teaches an expression cassette comprising a polynucleotide encoding an antisense RNA or an interfering RNA targeted to a polynucleotide encoding a mammalian polypyrimidine tract binding protein 1 (PTBP1) and method of treating and a method of treating a central nervous system disorder responsive to increase in the number of neurons in a mammalian subject (human or laboratory animal) by delivering the polynucleotide to the brain (paragraph [0008], paragraph [0145]). McCown teaches the expression cassette is delivered to oligodendrocyte (paragraph [0147]).
McCown does not teach which region of PTBP1 the siRNAs are targeting.
The nucleic acid sequence having accession number BBA32269 has 100% homology with SEQ ID NO: 87 nucleotide 951-1487 claimed in claim 44. The ‘885 application teaches it is a human PTBP1 isoform B gene (see attached alignment).
It would have been obvious to an ordinary skilled in the art that the method taught by McCown may include using antisense and/or siRNA that targets isoforms of PTBP1 such as the one disclosed by ‘885 application that has 100% sequence homology with SEQ ID NO: 87 (951-1487). Since the sequence of this isoform is known in prior art, it would have been routine experimentation to design and make antisense RNA and/or siRNA targeting said sequence. Therefore, the claimed invention of claim 44 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claim 53, oligodendrocytes are known to present in striatum, substantia nigra, spinal cord, prefrontal cortex, motor cortex and ventral tegmental area.
Regarding claim 55, McCown teaches the disorder to be treated includes Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, stroke and spinal cord injury (paragraph [0146]).
Regarding claim 56, McCown teaches the method further comprise delivering to the oligodendrocyte or the brain a factor that promote neuron growth, such as neurotrophic factor, brain derived neurotrophic factor (BDNF) (paragraph 0149]), which is known for support dopamine neuron survival and plasticity.
Regarding claim 58, McCown teaches the method further includes administration of SOX2 (paragraph [0147]).
Regarding claim 59, McCown teaches the method further includes administration additional therapeutic agent including methylprednisolone (paragraph [0150], line 16), which is a corticosteroid.
Claim(s) 44-47, 50-55 and 57 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (WO020205664), in view of the sequence having accession number BBA32269 (disclosed in US 20130315885).
Zhang teaches a pharmaceutical composition for treating an ophthalmic condition in a mammal comprising a Cas nuclease or polynucleotide encoding the Cas nuclease; at least one guide RNA that is complementary to a portion of an PTB gene, and the pharmaceutical composition is formulated for administration to the eye (paragraph [0013], and page 83, embodiment 12-14). Zhang teaches the result of example 9 demonstrate the efficacy of transdifferentiating strategy that includes switching Muller glia to a retinal neuronal cell fate by depleting a general neuronal induction gatekeeper PTB and then subsequently channeling these cells to photoreceptor (page 81, paragraph [00315]).
Zhang does not teach which region of PTBP1 the gRNAs are targeting.
The nucleic acid sequence having accession number BBA32269 has 100% homology with SEQ ID NO: 87 nucleotide 951-1487 claimed in claim 44. The ‘885 application teaches it is a human PTBP1 isoform B gene (see attached alignment).
It would have been obvious to an ordinary skilled in the art that the method taught by Zhang may include using Cas effector proteins and gRNA that targets isoforms of PTBP1 such as the one disclosed by ‘885 application that has 100% sequence homology with SEQ ID NO: 87 (951-1487). Since the sequence of this isoform is known in prior art, it would have been routine experimentation to design and make antisense RNA and/or siRNA targeting said sequence. Therefore, the claimed invention of claim 44 and 45 would have been prima facie obvious to an ordinary skilled in the art at the time the application was filed.
Regarding claims 46 and 47, Zhang teaches the spacer may be at least 10, at least 15, 18 or 19 nucleotides (paragraph [00152]). Zhang teaches the spacer of the gRNA may be 20-60 nucleotides (paragraph [00152]). Zhang teaches the Cas effector is an RNA targeting Cas effector protein, C2c2 (paragraph [00116]).
Regarding claim 50, Zhang teaches that Cas9 may be used to target different sections of the same target using multiple different gRNA paragraph [00227]).
Regarding claim 51, Zhang teaches that the nucleic acid encoding Cas effector is linked to a promoter that is glial specific such as GFAP promoter (paragraph [00307]), and gRNA linked to promoter suitable for eukaryotic cells (paragraph [00241]).
Regarding claim 52, Zhang teaches the expression vector may be an AAV vector (paragraph [0264]).
Regarding claim 53, Zhang teaches the vector is administered to retinal cell (paragraph [0093]).
Regarding claim 54, Zhang teaches the glial cell is Muller glia cell (paragraph [0032]).
Regarding claim 55, Zhang teaches a method of treating retinitis pigmentosa (RP), which meets the limitation of a dysfunction (paragraph [0081]).
Regarding claim 57, Zhang teaches administering the composition to a Muller glia cell in retina to generating a functional retinal photoreceptor (paragraph [0307]).
Claim(s) 48 and 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang and sequence having accession number BBA32269, as applied to claims 44-47, 50-55 and 57 above, and further in view of the sequence having accession number BIA602208 (disclosed in CN111394458).
The teaching from Zhang has been discussed above.
However, Zhang does not teach a gRNA comprises SEQ ID NO: 60, or gRNA having at least 10 nucleotides overlap with SEQ ID NO: 60.
The sequence having accession number BIA602208 has 100% sequence homology with SEQ ID NO: 60 and is a portion of PTBP1 (see attached alignment).
It would have been obvious to an ordinary skilled in the art to design gRNA for targeting PTBP1 because the sequence encoding PTBP1 is known in the art as taught by Zhang and the isoform B taught in ‘885 application. As shown by the sequence having accession number BIA602208, which is a portion of PTBP1, identify gRNA sequence comprising SEQ ID NO: 60 (30 bp) or 10 bp segment thereof that serve as spacer to PTBP1 would have been within the capability of an ordinary skilled in the art at the time the application was filed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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/CELINE X QIAN/Primary Examiner, Art Unit 1637
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