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
Amendments
In the reply filed 05/13/2026, Applicant has amended claims 22 and 28.
Claim Status
Claims 22 and 24-28 are pending and are considered on the merits.
Withdrawn Claim Objections
The prior objection to claim 28 because of abbreviation is withdrawn in light of Applicant’s amendment to the claim.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 22 and 24-28 under 35 U.S.C. 103 as being unpatentable over Lacovich et al., (J. Neurosci., 2017; 37(1): 58-69. Prior art of record) in view of 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 Prior art of record) is withdrawn in light of Applicant’s amendment to claim 22 to remove the limitation of the tau gene encoding isoforms including 2N3R type, which constitutes the ground of the prior rejection.
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 Zempel et al., (J. Biol. Chem. 2017;292(29):12192-12207 and suppl. Fig. S1-S2) in view of Mertens et al., (Am J Pathol. 2013, 182: 1769-1779. Prior art of record).
With respect to claim 22, Zempel teaches the properties and distributions of human and rodent Tau isoforms in primary forebrain rodent neurons (e.g., abstract). Zempel teaches preparation and transfection of all six isoforms of human Tau gene into rat or mouse cortical neurons (e.g., p. 12193, last full para and p. 12204, right col. Also see Fig 1A for diagram of six isoforms, Table 1 for fraction analysis and supplemental Table 1 for distribution analysis on all six isoforms, all including the isoform of 1N4R type). The mouse neurons transfected with 1N4R type isoform are shown in supplemental Figures S1 and S2 (see the last two pages in the file attached). Thus, Zempel teaches a nerve cell comprising an introduced exogenous full-length wild-type tau gene, wherein the introduced exogenous full-length wild-type tau gene is a gene which encodes an isoform of 1N4R type.
However, Zempel is silent on the exogenous full-length wild-type tau gene being expressed under control of 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 exogenous 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 isoform of 1N4R type disclosed by Zempel, by substituting with a drug-inducible promoter (e.g., a Tet-On system) suggested by Mertens with a reasonable expectation of success. Since Zempel aims to study overexpression of Tau isoforms in different developmental stages of neurons (e.g., in early-stage neurons of 8-9 days in vitro (DIV) or more mature well-polarized neurons of 13 DIV, see 12195, left col, para 3), 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 Zempel in order to achieve precise control of the temporal expression of the exogenous Tau isoforms, including 1N4R type, in the nerve cell for the assays.
In regard to the last wherein clause “wherein the nerve cell has aggregates of the exogenous full-length wild-type tau protein, and the nerve cell has fragmentation of βIII tubulin”, Applicant is reminded that MPEP 2145 (II) states that “mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”, and “the fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. In instant case, since the nerve cell comprising introduced exogenous full-length wild-type tau isoform of 1N4R type under control of a drug-inducible promoter as suggested by Zempel in view of Mertens makes obvious the instantly claimed nerve cell, mere recognition of latent properties of the nerve cell, i.e., having aggregates of the exogenous full-length wild-type tau protein and having fragmentation of βIII tubulin, in the prior art does not render nonobvious an otherwise known invention.
Claim 24 is directed to the nerve cell being derived from a human pluripotent stem cell, claim 25 is directed to the human pluripotent stem cell being derived from a healthy subject, and claim 26 is directed to the exogenous tau gene being expressed after differentiation of the human pluripotent stem cell into the nerve cell.
However, although Zempel teaches rat and mouse cortical neurons are isolated from rat and mouse wild-type embryos (i.e., the nerve cell being derived from pluripotent stem cells from a healthy subject), and the neurons are transfected with constructs having the tau gene isoforms (i.e., the exogenous tau gene being expressed after differentiation of the pluripotent stem cell into the nerve cell) (p. 12204, right col, para “Cell culture and transfection”), Zempel is silent on a nerve cell derived from a human pluripotent stem cell from a healthy subject in claims 24-25 or the exogenous tau gene being expressed after differentiation of the human PSC in claim 26.
Mertens teaches a human nerve cell derived from a human pluripotent stem cell (i.e., human neurons differentiated from hESC lines H9.2 and I3 through neuronal differentiation, see p. 1770, left col, para “Neural Stem Cell Culture and Differentiation” and para “Culture and Treatment of Human Neurons”). One of ordinary skill in the art would have immediately appreciated that the H9.2 and I3 hESC lines are both derived from healthy human embryos. Thus, Mertens teaches a human nerve cell being derived from a human pluripotent stem cell in claim 24, wherein the human pluripotent stem cell is a human pluripotent stem cell derived from a healthy subject in claim 25. Mertens teaches after 4 weeks of differentiation, neurons are treated with doxycycline to induce expression of the exogenous tau gene (p. 1771, left col, last para “Measurement of Total Intracellular Tau”), thus teaches the exogenous tau gene is expressed after differentiation of the human pluripotent stem cell into the nerve cell in claim 26.
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 isolated from rat and mouse wild-type embryos for assaying human Tau isoforms as suggested by Zempel, by substituting with a human nerve cell derived from a human pluripotent stem cell from a healthy subject and inducing expression of the exogenous tau gene after differentiation of the human PSC into the nerve cell as suggested by Mertens with a reasonable expectation of success. Since Zempel aims to study properties and distributions of human Tau isoforms that exist in human CNS (e.g., abstract), and since Mertens reduces to practice a human nerve cell derived from a human pluripotent stem cell from a healthy subject and further teaches inducing expression of the exogenous tau gene after differentiation of the human PSC into the nerve cell by the drug-inducible promoter (see above), one of ordinary skill in the art would have had a reason to substitute a human nerve cell of Mertens for the rat or mouse nerve cell of Zempel and to induce expression of the exogenous Tau isoforms after differentiation of the human PSC into the human nerve cell in order to study human Tau isoforms that exist in human CNS in a more relevant human nerve cell system.
With respect to claim 27 directed to aggregation of the exogenous tau occurring due solely to expression of the exogenous tau gene, it is noted that this limitation is directed to the latent properties of the nerve cell, i.e., having aggregates of the exogenous full-length wild-type tau protein, in the prior art of Zempel in view of Mertens, thus, mere recognition of this latent property does not render nonobvious an otherwise known invention. See MPEP 2145 (II). Thus, Zempel 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 multiplicity of infection 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” simply expresses the intended result of the expression of the exogenous tau gene in the nerve cell. 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 “the virus was introduced into the nerve cells at multiplicity of infection 0.1 to 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. Accordingly, claim 28 is examined as the nerve cell having a virus comprising the exogenous tau gene in the genome of the nerve cell.
However, Zempel uses plasmids for introducing the exogenous Tau isoforms (p. 12204, last para), but is silent on using a virus comprising the exogenous tau gene.
Mertens teaches a method of lentiviral transduction of the exogenous Tau gene using lentivirus particles to transduce nerve cells (p. 1770, right col, para “Vector Design and Lentiviral Transduction”). One of ordinary skill in the art would have immediately appreciated that lentivirus-mediated transduction would have resulted in virus integration into the genome of the infected cell. Thus, Mertens teaches the nerve cell, transduced with lentivirus comprising the exogenous tau gene, has a virus in the genome of the nerve cell, thus teaches claim 28.
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 transfected with a plasmid as suggested by Zempel, by substituting with lentivirus comprising the exogenous tau gene as suggested by Mertens with a reasonable expectation of success. Since Mertens’ lentivirus would result in integration into the genome of the infected nerve cell, one of ordinary skill in the art would have had a reason to substitute Mertens’ lentivirus for Zempel’s plasmid in order to obtain genome integration and stable expression of the exogenous tau gene. Furthermore, although Mertens is silent on the multiplicity of infection of the lentivirus, the product of Zempel in view of Mertens, i.e., the nerve cell having the virus comprising the exogenous tau gene in the genome of the nerve cell, is obvious from the product itself in claim 28, thus the claim is unpatentable even though the prior product was made by a different process, i.e., using a possibly different multiplicity of infection.
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 05/13/2026 are acknowledged.
Applicant argues that in claim 22, the isoform is limited to 1N4R type, which is not disclosed or suggested in Lacovich et al. Since the 1N4R type isoform is not disclosed or suggested by the cited references, the claimed invention is not obvious in view of the cited references (Remarks, p. 6, para 1).
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 over Zempel in view of Mertens as discussed above. Specifically, Zempel teaches a nerve cell comprising an exogenous full-length wild-type tau gene which encodes an isoform of 1N4R type.
Applicant further argues that the newly recited limitation “wherein the nerve cell has aggregates of the exogenous full-length wild-type tau protein, and the nerve cell has fragmentation of βIII tubulin" are features of the claimed nerve cell per se and should be considered as features of the claimed nerve cell. These features are not disclosed or suggested by the cited references (Remarks, p. 6, para 2).
Applicant's arguments have been fully considered but they are not persuasive.
As stated supra, these features are directed to the latent properties of the nerve cell in the prior art Zempel in view of Mertens. Thus, mere recognition of these latent properties does not render nonobvious an otherwise known invention, i.e., a nerve cell comprising an introduced exogenous full-length wild-type tau gene which encodes an isoform of 1N4R type and is expressed under control of a drug-inducible promoter, as suggested by Zempel in view of Mertens. See MPEP 2145 (II).
Conclusion
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.
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
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