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 . 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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11 May, 2026 has been entered.
Election/Restrictions
Applicants elected treating Alzheimer’s patients with a nucleic acid encoding a TERT sequence without traverse in the reply filed on 23 Sept, 2024.
Claims Status
Claims 1, 6, 8-12, 15-17, 19-21, 23-27, and 32 are pending.
Claim 1 has been amended.
Claims 6, 8-11, 15-17, 19-21, 23-27, and 32 have been withdrawn due to an election/restriction requirement.
Maintained Objections
The objection to the drawings due to the use of color is hereby withdrawn due to the granting of a petition to allow color drawings.
Withdrawn Rejections
The rejection of claim 33 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph due to the addition of new matter is hereby withdrawn due to amendment.
The rejection of claim 33 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is hereby withdrawn due to amendment.
Maintained/Modified Rejections
Claim Rejections - 35 USC § 112(a)
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 and 12 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 MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is if a person of skill in the art would know what TERT polypeptides encoded by the nucleic acid of claim 1 are beneficial in treating Alzheimer’s disease.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants state that TERT with a D712A mutation is catalytically inactive, and reduce expression levels of App and ApoE, and upregulate HSP70 (paragraph 152). There is no discussion of what the resulting polypeptide is interacting with.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Applicants are claiming a method of treating Alzheimer’s disease, comprising administering a nucleic acid encoding a catalytically inactive TERT polypeptide with a specific mutation. This is a functional limitation that the nucleic acid (and presumably the polypeptide it encodes) must provide a benefit to an Alzheimer’s patient. However, applicants have provided no description of what structural features are required to meet this functional requirement. A person of skill in the art would not know what sequence/hydrophobicity/charge parameters are required to meet this requirement. In essence, applicants are defining critical parts of their invention by function. That is not sufficient to meet the written description requirement.
There is no suggestion in the disclosure or the prior art of what the modified sequence binds to that provides the required benefit. Even if the binding partner by which the polypeptide exerts its effects is known, it is not clear how that would help figure out which mutants were active and inactive. As of applicant’s priority date, it was not possible to predict if a given molecule bound to a receptor. Lowe (blog “In the pipeline” entry of 7 Sept, 2022, previously cited) describes an experiment where that was attempted. 39K compounds, including known antibiotics, were screened against E. coli for growth inhibition, finding 218 active compounds (1st page, 3d paragraph). These were computer docked to a set of 296 essential bacterial proteins by multiple docking procedures (1st page, 3d paragraph), along with 100 random inactive compounds (2nd page, 1st paragraph). The number of strong binders predicted were essentially the same between the active compounds and the controls, and out of 142 compound/target interactions previously known, the methodology found only 3 (2nd page, 2nd paragraph). While a given docking program may accurately predict if compound A binds to protein B, it is impossible to a priori know if the prediction is accurate. In other words, several years after applicant’s priority date, it was not possible to predict if a given compound and target bound to each other.
Nor is it possible to modify known sequences to reliably find new compounds. Guo et al (PNAS (2004) 101(25) p9205-9210) looked at the effect of random mutations (title). In a DNA repair enzyme, about one mutation in three killed the activity of the protein, consistent with studies with other proteins (abstract). Yampolsky et al (Genetics (2006) 170 p1459-1472), using a different methodology, found that even conservative substitutions were prone to problems (table 3, p1465, top of page). In other words, unless there is some information known about the binding, mutating the sequence is likely to be detrimental, making it a poor way to generate new compounds.
Nor is it clear that applicants have demonstrated a real effect. Applicants use RNA expression to look at gene upregulation, yet RNA expression levels have low correlation with protein expression (Gry et al, BMC Genomics (2009) 10:365, previously cited, abstract). Furthermore, the CNS is a very difficult field to work in. CNS drugs have higher clinical failure rates than non-CNS drugs, and for major neurodegenerative disorders (such as those claimed by applicants), the failure rate for disease modifying treatments has been 100% (Gribkoff et al, Neuropharmacology (2017) 120 p11-19, previously cited, abstract).
(d) representative number of samples: Applicants have demonstrated in vitro that differentiated human neurons transfected with a nucleotide encoding a catalytically inactive TERT sequence from Weinrich et al in vitro lead to upregulation of some genes, which applicants believe will be beneficial. Ignoring how well an in vitro test can predict in vivo work in Alzheimer’s disease, and that gene expression correlates poorly to protein expression, applicants have only 1 example. And, given that no one knows how the polynucleotide is causing the effect, and that random mutation tends to be detrimental, it would be difficult for a person of skill in the art to extrapolate to all sequences that are useful in this invention. Thus, the claims lack written description.
response to applicant’s arguments
Applicants state that they have demonstrated that a TERT activating polynucleotide that encodes an inactive sequence with a D712A mutation provides a benefit to patients.
Applicant's arguments filed 11 May, 2026 have been fully considered but they are not persuasive.
Applicants have, at best, demonstrated one sequence will have the required activity. However, while applicants have not defined “TERT polypeptide,” it clearly allows for homologs (paragraph 58) and variants that have been mutated to the point where any percent identity is a coincidence, such as 1000 mutations or at least 3 non-variant amino acids (paragraph 59). Applicants simply cannot extrapolate from their single experiment to every sequence that can be considered a TERT polypeptide under the claims.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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