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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 24, 2025 has been entered.
Status of Claims/Rejections
Claims 1, 3, 12-14, and 18-22 are currently pending and under examination on the merits in the instant application.
Any rejections not repeated in this Office action are withdrawn, and the following rejections are the only rejections applied in this application.
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.
Claim 1 is 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 1 recites “a second polynucleotide” in line 4. The claim, however, does not recite “a first polynucleotide” preceding the aforementioned limitation in line 4. Hence, it is unclear whether a “first polynucleotide” is missing in the claim or whether the “second polynucleotide” in line 4 should not be a “second” polynucleotide.
Claim Rejections - 35 USC § 112
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, 3, 12-14, and 18-22 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims recite that a viral particle comprising a polynucleotide comprising a nucleotide sequence that is at least 80% identical to SEQ ID NO:7 encode an interfering RNA that should bind to human PTBP1 and inhibit human PTBP1 expression in oligodendrocytes or precursor cells thereof, thereby increasing the number of neurons in the brain of a human subject.
It is noted that SEQ ID NO:7 is disclosed in paragraph 0175 of the specification as the “siRNA 4” “Top” strand “primer” sequence and is annealed with the “Bottom” strand “primer” sequence of SEQ ID NO:8 followed by being packaged into the rAAV2 virus, which was transduced or transfected into HEK293 cells, which had been transfected with “100 ng of rat ptbp1 expression plasmid” (emphasis added). See also paragraphs 0176-0177. See also the sequence listing information as reproduced below:
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Now, it is noted that SEQ ID NO:7 is 64 nucleotides in length and there is no disclosure of nucleotide sequence variants of at least 80% identical to SEQ ID NO:7 having the function of binding to and inhibiting human PTBP1. The specification is completely silent as to which bases within the 64-mer sequence should be changed in order to satisfy the claimed structural limitation (“at least 80% identical to SEQ ID NO:7”) as well as the claimed functional limitation (“inhibits PTBP1 expression” in the human brain or in a human subject). In other words, since the specification contains no disclosure of nucleotide sequence variant species of SEQ ID NO:7 having at least 80% sequence identity with the required function recited in the instant claims, the specification fails to provide the requisite structure-function correlation for the nucleotide sequence variants as encompassed by the claims.
Most importantly, there is no adequate written description support, either implicit or explicit, that describes that SEQ ID NO:7 was intended and contemplated to be used for reducing human PTBP1 and for administering to the brain of a human subject, nor is there a disclosure for making a nucleotide sequence that is 80% identical to SEQ ID NO:7 to inhibit human PTBP1. The specification as filed at best reasonably conveys that SEQ ID NO:7 was designed and used exclusively for inhibiting “rat ptbp1” and testing it in “male Sprague-Dawley rats”. See paragraphs 0177-0178. That is, if SEQ ID NO:7, which is based on SEQ ID NO:4 that was commercially purchased as a rat Ptbp1-specific siRNA sequence, was indeed contemplated and/or was reduced to practice by the instant co-inventors for inhibiting human PTBP1 as now claimed, it is unclear why the human cell line HEK293 was not transfected with a human PTBP1-encoding construct and why the cell line was exclusively transfected with a rat Ptbp1-encoding construct. There does not appear to be any disclosure in the specification that teaches using SEQ ID NO:7 as the nucleotide sequence for practicing the claimed method specific for a human, and there does not appear to be a disclosure in the specification for teaching making and using a nucleotide sequence variant of SEQ ID NO:7 for inhibiting human PTBP1. As such, there is no implicit or explicit disclosure throughout the entire specification that SEQ ID NO:7 or a nucleotide sequence that is at least 80% identical to the 64-mer sequence of SEQ ID NO:7 is for inhibiting human PTBP1 expression and for being used in the brain of a human subject as now claimed. Hence, the instant specification as filed fails to adequately describe the claimed composition as well as the claimed method of using the composition comprising the 64-mer sequence of SEQ ID NO:7 or a sequence that is at least 80% identical to SEQ ID NO:7 for inhibiting human PTBP1 and providing effects in the brain of a human subject in vivo.
In view of the foregoing, it is concluded that the instant specification fails to reasonably convey that the instant co-inventors had contemplated and had possession of the claimed subject matter as of the filing date sought in the instant case.
Claims 20-22 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.
The instant claims are directed to an in vivo method that requires an increased number of neurons in the brain of a human subject as a result of administering a viral particle comprising SEQ ID NO:7, which is expressly admitted on the record in the instant specification as being designed based on the rat ptbp1-specific siRNA sequence comprising SEQ ID NO:4. See paragraphs 0174-0175.
The instant specification at best enables an in vivo method of providing an increased number of striatal neurons in the brain of a rat subject as a result of directly administering an “Oligo001 AAV vector” comprising SEQ ID NO:7 into the rat striatum.
As of the filing date sought in the instant case, which is September 6, 2016, use of a rat-specific siRNA sequence for inhibiting a human-specific target sequence in vivo in a human subject was not deemed routine or predictable, nor was such in vivo method practiced in the relevant art as evidenced by the complete lack of relevant prior art references pertaining to the administration of a rat-specific RNAi molecule into a human subject with a resultant effect of inhibiting the expression and function of the human target sequence in the human subject. In fact, regarding the claimed target, the §1.132 declarations filed on November 7, 2024 and July 24, 2025 at best show that the rat-specific siRNA sequence is capable of inhibiting human PTBP1 expression levels in non-oligodendrocyte and non-neuronal cells, HEK293 cells (human embryonic kidney cells), which are engineered to overexpress exogenous human PTBP1 by transfecting the human embryonic kidney cells with a PTBP1-encoding construct. As such, the use of a rat-specific PTBP1 RNAi molecule was at best reasonably enabled to reduce human PTBP1 expression only in human embryonic kidney cells overexpressing the human PTBP1 plasmid, wherein the HEK293 cell example showing reduced human PTBP1 expression does not reflect the inhibition of the function of endogenous human PTBP1 in human oligodendrocytes and neurons for the required effect of oligodendrocyte transdifferentiation and increased number of neurons.
In view of the complete lack of relevant prior art references pertaining to the claimed human-specific in vivo method comprising using a rat-specific RNAi molecule, and further in light of the complete lack of working examples commensurate in scope with the claimed method in the instant specification, it is concluded that an undue amount of experimentation would be necessary for one of ordinary skill in the art to successfully practice the method of claims 20-22 that is performed in a human subject who is administered with a construct comprising a rat-specific RNAi sequence. Accordingly, claims 20-22 fail to comply with the enablement requirement under §112(a).
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.
Claims 1, 3, 12-14, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Fu et al. (US 2015/0299698 A1, of record) in view of McCown et al. (US 2015/0238550 A1, of record), Carroll et al. (US 2017/0183662 A1, of record), Thermo Scientific Dharmacon ON-TARGETplus siRNA, The Standard for siRNA Specificity (2009, Thermo Fisher Scientific Inc.), NCBI GenBank Accession number NM_022516.1 (Rattus norvegicus polypyrimidine tract binding protein (Ptb), mRNA, July 14, 2002), NCBI GenBank Accession number NM_002819.2 (Homo sapiens polypyrimidine tract binding protein 1(PTBP1), transcript variant 1, mRNA, January 27, 2002), Liu et al. (PLoS ONE, 2012, 7:e38659), and Invitrogen User Manual (Block-iTTM Pol II miR RNAi Expression Vector Kits, Catolog nos. K4935-00, K4936-00, K4937-00, K4938-00, Version F, December 29, 2010, applicant’s citation).
It is noted that PTBP1 is also known as PTB.
Fu teaches making a composition that reduces the expression/activity of a polypyrimidine tract binding protein (PTB) mRNA/protein for “trans-differentiating, re-differentiating, or re-programming a mammalian cell to a neuronal cell,” wherein the mammalian cell is “a human cell” or “a rat cell” and the “inactivation of a single RNA polypyrimidine tract binding protein (PTB) is sufficient to induce the expression of a specific set of transcription factors, which act together to trigger trans-differentiation of diverse cell types into functional neurons.” See paragraphs 0006-0008, 0020, and 0133.
Fu exemplifies “shPTB-induced neurons”, wherein shPTB reprogrammed “non-neuronal cells” to “neurons” such that “PTB knockdown converted highly transformed HeLa cells to neuronal-like cells” and similarly “human embryonic carcinoma stem cells (NT2), mouse neural progenitor cells (N2A), human retinal epithelial cells (ARPE19), and primary mouse embryo fibroblasts (MEFs)” all “exhibited a neuronal-like morphology” upon PTB knockdown thus the PTB inhibitory “shPTB” is useful for treating “a neurodegenerative disease”. See paragraphs 0051, 0071, and 0138-0139.
Fu discloses that “PTB down-regulation potently induced these cells to differentiate (in the case of N2A cells) or trans-differentiate (in the case of MEFs) into neurons” and that “shPTB had trans-differentiated MEFs into functional neurons.” See paragraphs 0141 and 0144.
Fu reports “action potentials in response to step current injections on shPTB-induced neurons after co-culturing with rat glial cells” that are “prepared from GFP-transgenic rat brain that ubiquitously expresses GFP from a chicken b-actin promoter”. See paragraphs 0051, 0185, 0253-0255, and 0340.
Fu teaches one can commercially purchase and use “shRNAs against human PTBP1”. See paragraph 0335.
Fu discloses that the nucleotide sequence of PTB is known and published in the art “thus, one of skill in the art can design and construct antisense, miRNA, siRNA molecules and the like to modulate, e.g., to decrease or inhibit, the expression of PTB” so as “to practice the methods of this invention.” See paragraph 0090.
Fu does not teach that the shRNA against human PTBP1 comprises a nucleotide sequence comprising SEQ ID NO:7 claimed in the instant case. Fu also does not teach expressing the human PTBP1-targeting shRNA using an AAV with a tropism for oligodendrocytes, wherein the AAV comprises a promoter that is active in oligodendrocytes and neurons.
McCown teaches making an AAV particle/vector comprising a heterologous nucleic acid encoding “RNAi such as siRNA or shRNA”, wherein the AAV particle/vector “exhibits a tropism for oligodendrocytes” having “efficient transduction of oligodendrocytes with only low transduction in neurons” and is “useful to express a polypeptide or nucleic acid that provides a beneficial effect to cells near the oligodendrocytes (e.g., neurons)”, wherein the particle/vector is delivered to the CNS of a mammalian subject including a human subject. See paragraphs 0005, 0009-0011, 0022, 0039, 0054, 0069, 0074-0075, 0106, 0153-0156, 0191, and 0195.
McCown teaches using “a rat model of Parkinson’s disease” for delivering the AAV serotypes with “a constitutive promoter” (“CBh”) to “oligodendrocytes in rat caudate” (95%) and some, “minimal neuronal transduction”. See paragraphs 0229-0233.
McCown teaches that the oligodendrocyte-specific AAV particle/vector is useful for treating “a disorder that is not directly associated with oligodendrocyte dysfunction but would benefit by expression of a heterologous polypeptide or nucleic acid in oligodendrocytes in addition to or instead of expression in neurons, astrocytes, or other CNS cell types. Examples include, without limitation, neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease”. See paragraph 0156.
Caroll teaches using rats as “an experimental model of neuropathic pain” for intrathecal injection of a rat-specific Fxyd2 siRNA for studying neuropathic pain or hyperalgesia, wherein Fxyd2 is expressed “in somatosensory neurons” and the target sequence-specific siRNA is commercially purchased from Thermo Scientific by disclosing an ““ON-TARGET plus” siRNA directed against the rat Fxyd2 mRNA (ref. TMOSLR-005187) was purchased from Thermo Scientific.” (emphasis added). See paragraphs 0009, 0071-0074, and 0077-0078.
The ON-TARGETplus siRNA brochure of 2009 as provided by Thermo Scientific discloses that a consumer can purchase “Set of 4 siRNAs” of target-specific ON-TARGETplus siRNA product with “Guaranteed 75% target silencing by 3 of 4 siRNAs” with “Sequence information provided.” See page 7 disclosing the following:
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As disclosed by Fu (see paragraph 0090), the nucleotide sequences of PTB including the rat Ptb and human PTBP1 were publicly available with the GenBank Accession Nos. NM_022516.1 and NM_002819.2, respectively, wherein the 19-mer sense strand sequence corresponding to SEQ ID NO:4 of the instant application identified as a commercially purchased product “Thermo Scientific ON-TARGETplus Rat ptbp1 gene” (see paragraph 0174) is underlined below.
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The 19-mer human sequence homologous to the above underlined rat sequence is underlined in NM_002819.2 as shown below.
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Liu teaches that it was already suggested in the relevant art that “optimized shRNA constructs based on miRNAs may provide more efficient and safer therapeutic RNAi expression” and “miR155-based artificial miRNAs” using “the Block-iTTM-Pol II miR RNAi Expression Vector Kit” provides efficient in vitro and in vivo target downregulation. See pages 1-2.
Liu discloses the “Top strand oligo” design using “the Block-iTTM-Pol II miR RNAi Expression Vector Kit”, wherein the first 5-mer is 5’-TGCTG, followed by a 21-mer antisense strand sequence, a miR-155 loop sequence, and a 19-mer sense strand with a 2-nt deletion at positions 9-10 as illustrated in Figure 1B as shown below:
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Indeed, the instruction manual included in the commercial product, “Block-iTTM-Pol II miR RNAi Expression Vector Kit”, discloses the following instruction for generating the “top oligo sequence” at page 16.
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It would have been obvious to one of ordinary skill in the art before the effective filing date to use the commercially available “Set of 4 siRNAs” targeting the art-recognized rat Ptb sequence (NM_022516.1) purchased from Thermo Scientific and to make a construct for each of the “4 siRNAs” by utilizing the commercially available Invitrogen’s “Block-iTTM-Pol II miR RNAi Expression Vector Kit”. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to experimentally investigate the neuronal-transdifferentiation/differentiation capabilities of an efficient, “optimized” inhibitor of PTB expression and function in oligodendrocytes and the surrounding neurons in the brain of a rat in vivo so as to determine whether PTB (PTBP1) inhibition via the art-recognized, commercially available, “optimized” shRNA construct comprising miR-155-derived sequences has a potential therapeutic application translatable in a human, because use of rats was an art-recognized, routinely-practiced methodology in the relevant art for investigating neuron-related conditions as evidenced by McCown and Caroll, wherein successful use of a commercially available rat-specific siRNA product “ON-TARGETplus siRNA” purchased from Thermo Scientific in the nociceptive, “somatosensory neurons” of a rat in vivo was demonstrated by Caroll, wherein investigation of shRNA targeting PTB in a rat cell for neuronal-transdifferentiation and neuronal-differentiation/redifferentiation was expressly suggested by Fu, and because expression of an siRNA via the “Block-iTTM-Pol II miR RNAi Expression Vector Kit” was suggested as an “optimized” way to “provide more efficient and safer therapeutic RNAi expression” as taught by Liu. Since it was known in the art that Thermo Scientific sold “Set of 4 siRNAs” of target-specific ON-TARGETplus siRNA product with “Guaranteed 75% target silencing by 3 of 4 siRNAs” with “Sequence information provided” as evidenced by the product brochure, and since the detailed instructions for generating the “top oligo sequence” using the Invitrogen kit were expressly provided and available to the extent that a relevant artisan such as Liu successfully made “miR155-based artificial miRNAs” using “the Block-iTTM-Pol II miR RNAi Expression Vector Kit” with a resultant effect of efficient in vitro and in vivo target downregulation, one of ordinary skill in the art would have had a reasonable expectation of success in obtaining SEQ ID NO:7 using one of the commercially available “4 siRNAs” with the provided sequence information including the 19-mer sense strand sequence of 5’-CCAACACTATGGTTAACTA, which is admitted on the record in the instant specification (see paragraph 0174) as being purchased from Thermo Scientific. Now, it is noted that the Invitrogen’s product manual expressly instructed to “combine” five elements “from 5’ end to 3’ end” for generating the top oligo sequence such that the 5’ end comprises 5’-TGCTG; the reverse complement of the 21-nt sense target sequence; 5’-GTTTTGGCCACTGACTGAC; nucleotides 1-8 of the sense target sequence; and nucleotides 11-21 of the sense target sequence. As shown above, the nucleotide sequence information pertaining to NM_022516.1 reveals that the sequence information provided by the Thermo Scientific’s one of “Set of 4 siRNAs” targeting NM_022516.1 has the target sequence of 5’-CCAACACTATGGTTAACTA at nucleotide positions 344-362, which is a 19-mer. Since a 21-mer antisense strand that is reverse complement of the 21-mer sense target sequence is required per the instruction of Invitrogen’s “Block-iTTM-Pol II miR RNAi Expression Vector Kit”, a person of ordinary skill in the relevant art would have had reasonably identified a 21-mer target sequence by extending the aforementioned 19-mer target sequence by two nucleotides upstream (positions 342-343) or downstream (positions 363-364) of NM_022516.1. See the following showing the 19-mer target sequence (see underlined) of a rat Ptb-targeting siRNA sold by Thermo Scientific.
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When making a 21-mer that is reverse complementary to nucleotide positions 342-364 of NM_022516.1, one of ordinary skill in the art would have obtained a 21-mer sequence of 5’-TAGTTAACCATAGTGTTGGCA. Further, one of ordinary skill in the art would have known that the “Nucleotides 1-8 (5’-3’) of sense target sequence” that is complementary to the last 8 nucleotides of the above 21-mer sequence is 5’-TGCCAACA and the “Nucleotides 11-21 (5’-3’) of sense target sequence” is 5’-ATGGTTAACTA. Again, see the following instruction comprising five elements for generating the top oligo sequence for utilizing Invitrogen’s “Block-iTTM-Pol II miR RNAi Expression Vector Kit”.
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When all five elements are combined as instructed above, a person of ordinary skill in the art would have obtained, without fail, the following 64-mer sequence:
5’-TGCTG-TAGTTAACCATAGTGTTGGCA-GTTTTGGCCACTGACTGAC- TGCCAACA-ATGGTTAACTA, wherein each element is separated by a hyphen. It is noted that this 64-mer comprising five elements is 100% identical to SEQ ID NO:7 claimed in the instant case.
Now, one of ordinary skill in the art whose primary goal involves saving money and resources would have been motivated to test the rat Ptb-specific 64-mer sequence that was intended to be tested in the rat brain for reducing human PTBP1 in vitro in view of the fact that the target sequence has a high level of sequence homology (two mismatches; see the underlined 19-mers of NM_022516.1 and NM_002819.2 above) thus would have been motivated to try the 64-mer rendered obvious above in reducing human PTBP1 expression for a purely preliminary in vitro experimental purpose without investing additional money and resources for making (or purchasing) human-specific PTBP1 RNAi molecules, wherein one of ordinary skill in the art would have had reasonably predicted in obtaining some reduction in human PTBP1 expression in cells in vitro by the RNAi sequence whose target has two mismatches with the rat counterpart sequence.
Note that “an implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the "improvement" is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient.” (emphasis added). See MPEP §2144.
It would have been obvious to one of ordinary skill in the art to utilize McCown’s RNAi molecule-encoding AAV particle/vector having oligodendrocyte tropism with a constitutive promoter, wherein the AAV particle/vector was shown to be transduced in oligodendrocytes with 95% tropism for oligodendrocytes with some, minimal transduction in surrounding, nearby neurons. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to investigate the potential of the construct comprising the “optimized” 64-mer sequence rendered obvious above in inducing trans-differentiation of human oligodendrocytes in vitro and/or differentiation/redifferentiation of surrounding human neurons in vitro for potential application in treating a neurodegenerative disorder such as Parkinson’s disease, which is “not directly associated with oligodendrocyte dysfunction but would benefit by expression of a heterologous polypeptide or nucleic acid in oligodendrocytes in addition to or instead of expression in neurons, astrocytes, or other CNS cell types” as taught by McCown (see paragraph 0156), who also taught that it is “useful” to express a nucleic acid (e.g., RNAi) “that provides a beneficial effect to cells near the oligodendrocytes (e.g., neurons)”.
In view of the foregoing, claims 1, 3, 12-14, and 18-19 taken as a whole would have been prima facie obvious before the effective filing date.
Response to Arguments/Declaration
Applicant's arguments filed on July 24, 2025 have been fully considered but they are not persuasive and moot because they do not pertain to the new ground of rejection set forth above.
However, the examiner will address applicant’s arguments that are deemed relevant to the instant rejection. Applicant argues that Fu does not teach/show transdifferentiation of oligodendrocytes into neurons, whereas paragraphs 0184-0186 of the specification demonstrate the instantly claimed transdifferentiation in vitro and in vivo. In response, applicant’s attention is directed to the fact that there is no legal requirement that a cited prior art reference must disclose a working example of the claimed subject matter in order to render the claimed subject matter obvious under §103. If a cited prior art discloses such working example of applicant’s claimed subject matter, such prior art reference would qualify as a §102 reference anticipating the claimed subject matter. Hence, the mere fact that Fu did not exemplify “functional” “shPTB-induced neurons” by oligodendrocyte transdifferentiation is not sufficient to render the rejected claims nonobvious as knockdown of PTB in non-neuronal cells would have been reasonably, if not absolutely, predicted to be transdifferentiated into neurons, wherein oligodendrocytes that are adjacently present with neurons in the brain of a mammalian subject were art-recognized non-neuronal cells CNS cell types as evidenced by McCown. Hence, what is disclosed in paragraphs 0184-0186 and Figure 4B would have been obvious in view of the knowledge disclosed in the cited art.
Applicant argues that Carroll’s commercial product is SEQ ID NO:4 thus is irrelevant to the rejected claims. In response, applicant’s attention is directed to the fact that the Carroll reference was cited to provide evidence that one skilled in the relevant art would have been capable of purchasing a rat-specific siRNA sequences from the same commercial source from which the instant co-inventors purchased SEQ ID NO:4 before the effective filing date. That is, Carroll was not whatsoever cited to allegedly teach SEQ ID NO:4 thus, applicant’s argument is irrelevant and unpersuasive to support that one of ordinary skill in the art would not have been able to simply order a commercial product that was clearly available from the same commercial vendor from which the instant co-inventors purchased SEQ ID NO:4 before the effective filing date.
Applicant even goes further to allege that not all commercially purchased siRNAs are effective in HeLa cells by pointing out paragraphs 0174 and 0183 of the specification and that siRNAs have “variability in knockdown efficacy”. In response, it is noted that applicant’s arguments do not objectively rebut the objective fact/admission of record that SEQ ID NO:4, which was purportedly used for making SEQ ID NO:7 that is now claimed, was not of the inventive work of the instant co-inventors themselves but is a mere product that was purchased from a commercial vendor. That is, the mere fact that there were less effective siRNA sequences targeting rat ptbp1 is not sufficient to negate the objective fact that the rat ptbp1-reducing nucleotide sequence included in SEQ ID NO:7 was not originated/invented by the instant co-inventors of this application but rather was a work of others, Thermo Scientific, which was publicly available to any person to access and purchase the exactly same rat ptbp1 siRNA sequence comprising SEQ ID NO:4 as the sense strand sequence.
Applicant argues that because commercially purchased siRNA sequences showed “variability”, the commercial availability “does not provide a reasonable expectation that said siRNA suitable for the purposes required by the claims of the present invention.” In response, it appears that applicant has misapplied the meaning of a “reasonable” expectation of success, which simply means a reasonable “likelihood of success” in obtaining the claimed subject matter thus does not require an “absolute” degree of expectation. That is, in order for applicant to state on the record “no” reasonable expectation of success for a person of ordinary skill in the art to simply purchase and use SEQ ID NO:4 from Thermo Scientific, applicant must provide objective evidence that was a high level of expected failure for the person to purchase and use SEQ ID NO:4 before the effective filing date. Applicant’s attention is directed to the fact that use of an shRNA targeting PTBP1 for the purpose of transdifferentiating non-neuronal cells to functional neurons was already known and practiced by relevant artisans before the instant application was filed as evidenced by Fu. That is, the skills pertaining to selecting and using a suitable RNAi molecule targeting PTBP1 for inducing neuron cell fate/differentiation were within the technical grasp of one of ordinary skill in the relevant art before the effective filing date. Hence, applicant’s argument pertaining to the lack of a reasonable expectation of success, especially when the instantly claimed sequence of SEQ ID NO:7 is a mere adaptation of a commercially purchased product is not found persuasive.
Applicant argues that McCown’s AAV is targeting oligodendrocytes only, not both oligodendrocytes and neurons as claimed. In response, it is noted that McCown’s AAV comprising a constitutive promoter was reported to mainly transduce oligodendrocytes (95%) in rat brain with some, minimal neuronal transduction as explained in the rejection above. Applicant’s attention is further directed to the fact that it was already known and practiced in the relevant prior art that reduction of PTBP1 in neurons “potently induced” neuronal cells (N2A) to differentiate as expressly demonstrated by Fu, and furthermore, delivery of a therapeutic agent to oligodendrocytes “in addition to” neurons was deemed useful as expressly disclosed and contemplated by McCown. As such, use of a promoter that would drive and express PTBP1 in both oligodendrocytes (for neuronal transdifferentiation) and neurons (for promoting/inducing neuronal differentiation) would have been a prima facie obvious choice as explained in the rejection above. Note that the claims do not require any specific percentages for the activity of the promoter in oligodendrocyte (e.g., 50%) and in neurons (e.g., 50%). As such, McCown’s AAV with a constitutive promoter providing a 95% level of transduction in oligodendrocytes with some neuronal transduction fully satisfies the structural and functional limitations of viral particle with a promoter as set forth in the claims.
Applicant argues that the claims are not obvious in view of the §1.132 declaration. The declaration under 37 CFR 1.132 filed on July 24, 2025 is insufficient to overcome the instant obviousness rejection for the following reasons:
As an initial matter, applicant’ attention is directed to the fact that the “siRNA4” miR-155 backbone construct used in the declaration does not appear to be disclosed in the instant specification, nor is a legible copy of the post-filing reference (Weinberg, 2017), from which the “siRNA” miR-155 backbone construct was made, is submitted for examiner’s consideration. As such, it is unclear to the examiner as to why the H1 promoter-containing vector using the post-filing reference that was never submitted for examiner’s consideration is used in order to support the claimed subject matter. In addition, the H1 promoter-containing vector is not whatsoever commensurate in scope with the rejected claims, which require “a promoter active in both oligodendrocytes and neurons”. Hence, it is unclear how the specific vector disclosed in the declaration, which does not satisfy the claimed structural elements, can possibly support the alleged nonobviousness of the instantly rejected claims.
The declarant states that the claims as amended are not obvious because incorporating an RNA sequence into a miRNA backbone for RNAi applications “is not a simple procedure,” and “does not necessarily produce an effective RNAi molecule.” In response, it is noted that whether or not a procedure for making/obtaining the claimed viral particle is “simple” or complex cannot support the asserted nonobviousness of the claims because there is no factual, objective evidence supporting that there was no reasonable expectation of success in making/obtaining the claimed viral particle. In addition, the mere conjecture/ possibility that the “not a simple procedure” comprising incorporating an RNA sequence into a miRNA backbone “does not necessarily produce an effective RNAi molecule” is far from supporting no motivation or no reasonable expectation of success in making and using the claimed viral particle.
The examiner expressly notes on the record that SEQ ID NO:7 now recited in the amended claims appears to have been designed and incorporated into a vector using the commercial product of the “BLOCK-iTTM Pol II miR RNAi expression vector kit” and by following the instructions included therein. See paragraph 0175 of the specification. Indeed, the examiner was fully able to obtain the 64-mer sequence of SEQ ID NO:7 claimed in the instant case by merely following the instructions provided by Invitrogen’s manual as illustrated in the rejection above. As such, the examiner is bewildered by the declarant’s exaggerated, factually incorrect statement that making a construct using a miRNA backbone “is not a simple procedure” as if the instant co-inventors invented such “not a simple procedure” when in fact the construct disclosed in paragraph 0175 was made by merely using the commercially available product, thereby involving no inventive effort by the instant co-inventors.
The declarant provides Figure 1 illustrating three constructs, two of which are designed to include the structure in Figure 2, and states that “the miRNA sequence chosen to incorporate the siRNA can significantly reduce the efficacy” of the siRNA by pointing out Figure 3 showing “an average of 1.13-fold downregulation using the miR-E backbone” compared to “an average 1.55-fold downregulation” using the miR-155 backbone thus “it is not straightforward nor obvious to create expression cassettes comprising interfering RNA that are effective to inhibit gene expression of a target gene.” As an initial matter, it is unclear whether the 1.55-fold vs. 1.13-fold are different with a statistical difference. Further, it is highly questionable as to validity of the alleged “not a simple process” for “incorporating an RNA sequence into a miRNA backbone”, because the instant specification expressly discloses that the instant co-inventors merely utilized the commercially available synthesis kit, namely the “BLOCK-iTTM PolII miR RNAi expression vector kit (Invitrogen, La Jolla, CA)”. See paragraph 0175. As such, even a laboratory technician without an advanced academic degree would have been able to merely follow the instructions included in the kit and would have reasonably succeeded in incorporating the rat-specific ptbp1 top and bottom sequences (SEQ ID NOs:7-8) into Invitrogen’s “RNAi expression vector kit”. Again, note that the examiner was fully able to obtain the 64-mer sequence of SEQ ID NO:7 claimed in the instant case by merely following the instructions provided by Invitrogen’s manual as illustrated in the rejection above. Even more interestingly, relevant artisans actively and successfully used the same “BLOCK-iTTM PolII miR RNAi expression vector kit (Invitrogen, La Jolla, CA)” used by the instant co-inventors in order to make and use an RNAi molecule targeting a user’s desired target. See for instance the following:
Liu et al. (PLoS ONE, 2012, 7:e38659) disclosing use of “the Block-iTTM-Pol II miR RNAi Expression Vector Kit.” See page 2. Now, see Figure 1B showing the following:
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Feng et al. (FEBS Letters, 2011, 585:2488-2492) disclosing use of “Block-iT PolII miR RNAi expression vector kit (Invitrogen, Carlsbad, CA)” for “specifically targeting rat iNOS gene”, wherein the RNAi molecule comprises 5’-TGCTG as the first 5-mer and the miR-155 loop sequence of 5’-GTTTGGCCACTGACTG. See pages 2488-2489 and Table 1.
Zhang et al. (Tumor Biology, 2014, 35:5401-5407) disclosing a successful use of the “BLOCK-iTTM Pol II miR RNAi Expression Vector Kit (Invitrogen)” for producing an RNAi molecule targeting STAT3 and BIRC3, wherein the RNAi molecule’s top strand comprises 5’-TGCTG as the first 5-mer and the miR-155 loop sequence of 5’-GTTTGGCCACTGACTG. See page 5402 and Table 1.
Gao et al. (World Journal of Gastroenterology, 2008, 14:4684-4689) disclosing use of “miR plasmid” with “polymerase II” that provides “engineered pre-miRNA sequence structure” that is based on “miR-155”, which is purchased from “Invitrogen” (see page 4685; Table 1), wherein the plasmid’s top oligo strand comprises 5’-TGCTG first 5-mer and the miR-155 loop sequence of 5’-GTTTGGCCACTGACTG.
Note that all of the above-cited prior references merely followed the instruction manual provided by the commercial vendor, Invitrogen, to make and use the various target-specific RNAi molecules, wherein the Invitrogen’s user manual (Version F, December 29, 2010) specifically discloses the following at page 16:
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As shown above, there is ample evidence demonstrating that merely using the commercially available product and instructions contained therein was far from being “difficult” as alleged by the declarant in view of the objective fact that many relevant artisans were able to simply use the commercial product and the instructions contained therein in order to make the user-desired, functional RNAi product. As such, declarant’s statement that it was “difficult” to make and use SEQ ID NO:7 amounts to a mere assertion without any objective, factual evidence thus is not found persuasive, nor is it found credible in view of the above-provided ample evidence, which shows that it is indeed “a simple procedure”, contrary to the declarant’s alleged “not a simple procedure.” Again, the declarant stated as if the construct comprising SEQ ID NO:7 was an inventive effort that was originally developed by the instant co-inventors, wherein the objective evidence provided by the examiner herein clearly counters declarant’s statement.
As such, declarant’s statement that there would have been no reasonable expectation of success in obtaining and using SEQ ID NO:7 is not found persuasive because the same “miR-155 backbone”, not “using different miRNA backbones”, was amply used successfully by relevant artisans by merely following the user manual provided in the Invitrogen’s “Block-iTTM Pol II miR RNAi Expression Vector Kits, Catolog nos. K4935-00, K4936-00, K4937-00, K4938-00”.
The examiner would like to explicitly note on the record that the declarant’s statement that “Significant experimentation went into selecting a combination of miR backbone and siRNA modification” is not factually supported, unless there is objective, factual evidence that SEQ ID NO:7 claimed in the instant case was not designed by merely following the Invitrogen’s user manual contrary to the instant specification’s express acknowledgment that “The Block-iTTM Pol II miR RNAi expression vector kit (Invitrogen, La Jolla, CA) was used to prepare pol II-based miRNA from the successful siRNA constructs.” See paragraph 0175. See also paragraph 0183 expressly admitting on the record that the construct disclosed in the §1.132 declaration is made merely using SEQ ID NO:4 (the commercial product) and converting SEQ ID NO:4 in accordance with the Invitrogen’s instructions as evidenced by the following: “Based upon these two findings, 2 siRNAs were identified that significantly inhibited PTBP1 expression in HeLA cells (Fig. 1A) and then these siRNA sequences were converted into miRNAs using the Block-iTTM Pol II miR RNAi expression vector kit.” (emphasis added). That is, the declarant appears to have expressly contradicted the disclosure of the instant specification that expressly admitted on the record that SEQ ID NO:7 or the vector disclosed in the declaration is not the invention of the instant co-inventors, despite the statement made “under Section 1001 of Title 18 of the United States Code” in paragraph 9 of the §1.132 declaration.
For the reasons detailed above, the examiner finds the credibility of the §1.132 declaration is highly questionable. Further, what was disclosed in the declaration would have been prima facie obvious as explained in the rejection above, and as further evidenced by the widely art-recognized utility of the Invitrogen’s miR-155-backbone-containing “Block-iTTM Pol II miR RNAi Expression Vector Kits, Catolog nos. K4935-00, K4936-00, K4937-00, K4938-00”.
In view of the foregoing, applicant’s arguments and the declaration are not found persuasive to show that the claimed subject matter taken as a whole would not have been prima facie obvious in view of the knowledge/skills known and utilized by relevant artisans before the effective filing date.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, and 12-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending Application No. 18/740,874.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed vector are anticipated by and/or encompassed by the ‘874 claims drawn to a vector comprising a “miRNA” comprising a nucleotide sequence that is at least 85% complementary to SEQ ID NO:4 (5’-CCAACACTATGGTTAACTA). It is noted that SEQ ID NO:7 claimed in the instant case comprises a nucleotide sequence that is complementary to SEQ ID NO:4. In addition, it is noted that the “miRNA” comprising SEQ ID NO:4 as claimed in the ‘874 claims appears to be described as comprising SEQ ID NO:7. See paragraph 0174 of the ‘874 specification. Hence, the vector of the ‘874 claims anticipates and encompasses the claimed vector, absent objective evidence to the contrary.
Claims 1, 3, 12-14, and 18-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-21 of copending Application No. 18/740,877.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed vector and the method are anticipated by and/or encompassed by the ‘877 claims drawn to a method that requires a vector encoding SEQ ID NO:7, which