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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/14/2025 has been entered.
Applicant' s amendment and response filed on 07/15/2025 has been received and entered into the case.
Amendments
In the reply filed 07/15/2025, Applicant has amended claim 22, has newly canceled claims 1-8, 12-21 and 23, and has added new claims 24-28.
Claim Status
Claims 22 and 24-28 are pending and are considered on the merits.
Withdrawn Claim Objections
The prior objection to claim 22 is withdrawn in light of Applicant’s amendment.
New Claim Objections
Claim 28 is objected to because of the following informalities:
Claim 28 recites the abbreviation “MOI” in the last line. An abbreviation should be preceded in its first occurrence by the specific identity of the entity which said abbreviation is intended to represent. Thereafter, the use of the abbreviation in the claims will be understood.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claim 22 under 35 U.S.C. 102 (a)(1) as being anticipated by Mertens et al., (Am J Pathol. 2013, 182: 1769-1779. Prior art of record) is withdrawn in light of Applicant’s amendment to claim 22 to remove the limitation of the tau gene encoding isoform 2N4R type, which is the only isoform disclosed in Mertens.
New Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 22 and 24-28 are rejected under 35 U.S.C. 103 as being unpatentable over Lacovich et al., (J. Neurosci., 2017; 37(1): 58-69) in view of Mertens et al., (Am J Pathol. 2013, 182: 1769-1779. Prior art of record).
With respect to claim 22, the last wherein clause recites “wherein the exogenous full-length wild-type tau aggregates through the expression of the exogenous wild type tau gene controlled by the drug-inducible promoter, so that fragmentation of βIII tubulin, and death of the nerve cell occurs” (underline added). It is noted that this wherein clause is directed to a contingent limitation, i.e., based on the condition of expression of the tau gene driven by the drug-inducible promoter (e.g., through the addition of the drug), and does not limit the structure of the claimed nerve cell. Furthermore, it is noted that this wherein clause simply expresses the intended results of the expression of the exogenous tau gene in the nerve cell (i.e., the exogenous tau aggregates, and fragmentation of βIII tubulin and death of the nerve cell occurs), but does not limit the structure of the claimed nerve cell. Thus, the wherein clause does not provide any patentable weight in determining the patentability of the claimed product. See MPEP 2111.04 I and II. Accordingly, claim 22 is reasonably interpreted as a nerve cell comprising an introduced exogenous full-length wild-type tau gene encoding one or more isoforms selected from a group of 5 isoforms in which the expression of the exogenous tau gene is controlled by a drug-inducible promoter.
Lacovich teaches an assay of tau isoforms 3R:4R imbalance on axonal transport of the amyloid precursor protein (see e.g., abstract). Lacovich teaches generation of neurons derived from hESCs (p. 59, right col, para “Cell culture and neuronal differentiation”) and transduction of the neurons with lentivirus comprising PTM-4R or PTM-3R (p. 59, right col, para “Neuron plating, transduction, and transfection”). Lacovich teaches the PTM-3R comprises a pre-trans-splicing molecule (PTM) of exons 11-13 that results in a trans-spliced mRNA comprising exons 1-9 and 11-13 of the tau gene (see Fig 1E and legend. It is noted that this isoform is equivalent to the claimed 2N3R type). Thus, Lacovich teaches a nerve cell comprising an introduced exogenous full-length wild-type tau gene encoding one isoform of 2N3R type.
However, Lacovich teaches the tau gene is expressed under the neural specific synapsin promoter (p. 59, right col, para “Neuron plating, transduction”), but is silent on a drug-inducible promoter.
Mertens teaches a lentiviral Tet-On system used in introducing into a neuron an exogenous full-length wild-type tau gene to achieve inducible overexpression of the tau gene (e.g., abstract, p. 1770, right col, para 2, see Fig 2), thus teaches a drug-inducible promoter controlling expression of the tau gene. Mertens teaches the Tet-On system results in only marginal leak expression with induction efficiencies ranging >90% after doxycycline treatment (see p. 1773, and Figure 2E).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the nerve cell comprising an exogenous tau gene controlled by a synapsin promoter disclosed by Lacovich, by substituting with a drug-inducible promoter (e.g., a Tet-On system) suggested by Mertens with a reasonable expectation of success. Since Lacovich aims to conditionally express the exogenous tau gene (using a neural specific synapsin promoter, see p. 59, right col, para “Neuron plating”), and since Mertens reduces to practice a drug-inducible promoter (Tet-On system based on doxycycline treatment) that achieves inducible overexpression of the exogenous tau gene with high induction efficiencies and very low leakage (see p. 1773, and Figure 2E), one of ordinary skill in the art would have had a reason to substitute with a drug-inducible promoter as suggested by Mertens in the nerve cell of Lacovich in order to achieve precise control of the temporal expression of the exogenous tau gene in the nerve cell for the assay.
With respect to claim 24 directed to the nerve cell being derived from a human pluripotent stem cell, and claim 25 directed to the human pluripotent stem cell being derived from a healthy subject, Lacovich teaches the neurons are obtained by differentiation of hESCs (Hues9) (p. 60, last para). One of ordinary skill in the art would immediately appreciate that the Hues9 hESC line is derived from a healthy human embryo. Thus, Lacovich teaches the nerve cell is derived from a human pluripotent stem cell (i.e., hESCs), which is derived from a healthy subject.
With respect to claim 26 directed to the exogenous tau gene being expressed after differentiation of the pluripotent stem cell into the nerve cell, Lacovich teaches hESCs are differentiated into neurons (p. 59, right col, para “Cell culture and neuronal differentiation”) and the neurons are transduced with lentivirus comprising the exogenous tau gene that is expressed under the human synapsin promoter (p. 59, right col, para “Neuron plating, transduction, and transfection”). Mertens teaches neuroepithelial stem cells (previously generated from hESC lines) undergo neuronal differentiation (p. 1770, left col, para “Neural Stem Cell Culture and Differentiation”) and after 4 weeks of differentiation, neurons are treated with doxycycline to initiate expression of the exogenous tau gene (p. 1771, left col, last para). Thus, both Lacovich and Mertens teach the exogenous tau gene is expressed after differentiation of the pluripotent stem cell into the nerve cell.
With respect to claim 27 directed to aggregation of the exogenous tau occurring due solely to expression of the exogenous tau gene, this limitation is directed to the contingent limitation (the last wherein clause) in claim 22. Furthermore, it is noted that this wherein clause in claim 27 simply expresses the intended result of the expression of the exogenous tau gene (i.e., the exogenous tau aggregates without any other seed added). Thus, this limitation does not limit the structure of the claimed nerve cell and does not provide any patentable weight in determining the patentability of the claimed product. Lacovich, in view of Mertens make obvious claim 27 for the same reason set forth above for claim 22.
With respect to claim 28 directed to the nerve cell having a virus comprising the tau gene in the genome of the nerve cell wherein the virus was introduced into the nerve cell at MOI 0.1-10 and 20% to 90% of nerve cell death occurs, as a first matter, it is noted that the limitation “20% to 90% of nerve cell death occurs” is directed to the contingent limitation (the last wherein clause) in claim 22. Additionally, it is noted that this limitation simply expresses the intended result of the expression of the exogenous tau gene in the nerve cell (i.e., 20% to 90% of nerve cell death occurs). Thus, this limitation does not limit the structure of the claimed nerve cell and does not provide any patentable weight in determining the patentability of the claimed product. Secondly, it is noted that the limitation that “the virus was introduced into the nerve cells at MOI 0.1-10” is directed to a product-by-process claim. The applicant is reminded that “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” See MPEP § 2113. In summary, claim 28 is reasonably interpreted as the nerve cell having a virus comprising the exogenous tau gene in the genome of the nerve cell.
As stated supra, Lacovich teaches the neurons are transduced with lentivirus comprising the exogenous tau gene (p. 59, right col, para “Neuron plating, transduction, and transfection”) and teaches “after integration into the neuron genome, the PTM cassette is transcribed into an RNA molecule” (p. 61, left col, last sentence). Thus, Lacovich teaches the nerve cell has a virus (i.e., a lentivirus) comprising the exogenous tau gene in the genome of the nerve cell. Regarding the MOI of the virus used, Lacovich teaches the concentrated lentivirus is added to neurons to achieve a multiplicity of infection between 5 and 10 (p. 59, right col, para “Neuron plating, transduction, and transfection”), within the claimed range of MOI 0.1 to 10.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 07/15/2025 are acknowledged.
Applicant argues that Mertens in the prior rejection only discloses an isoform of 2N4R tau gene, thus fails to disclose the element in amended claim 22 in which the isoform of 2N4R type is removed (Remarks, p. 5-6).
Applicant's arguments have been fully considered and they are persuasive. Therefore, the prior rejection has been withdrawn. However, as necessitated by amendments, new grounds of rejection have been made by Lacovich in view of Mertens as discussed above. Specifically, Lacovich teaches a nerve cell transduced with an exogenous full-length wild type tau gene having a 2N3R isoform type.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631