DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01 December 2025 has been entered.
3. Applicant's arguments and amendments to the claims presented in the reply of 01 December 2025 have been fully considered but do not place the application in condition for allowance. All rejections and objections not reiterated herein are hereby withdrawn. In particular, the previous rejection of the claims under 35 U.S.C. 112(a), written description, has been obviated by the amendment to the claims.
The Declaration under 37 CFR 1.132 filed 01 December 2025 is insufficient to overcome the rejection of the claims under 35 U.S.C. 112(a), written description and enablement as set forth in the last Office action for the reasons discussed in detail below.
Claim Status
4. Claims 1, 3, 4, 8, 9, 11, 12, 15, 16, 21 and 22 read on the elected invention and have been examined herein.
Claim Objections
5. Claims 1, 3, 4, 8, 9, and 11 are objected to because of the following informalities:
Claims 1, 3, 4, 8, 9, and 11 recite “administering intracranially to the human patient an NSun2 gene when the hippocampal or cerebrospinal fluid sample from the human patient with an increase” whereas the claims should recite “administering intracranially to the human patient an NSun2 gene when the hippocampal or cerebrospinal fluid sample from the human patient has an increase”. Appropriate correction is required.
New Claim Rejections - 35 USC § 101
6. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 12, 15, 16, 21 and 22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between the level of the 5’-tRFs and Alzheimer’s disease. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
As stated in MPEP 2106.04(a)(2) III “the "mental processes" abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observations, evaluations, judgments, and opinions.”
The claims require performing a step of "comparing" the level of 5’-tRFs in the sample the human patient to a comparator sample. Neither the specification nor the claims set forth a limiting definition for "comparing" and the claims do not set forth how comparing is accomplished. The broadest reasonable interpretation of the “comparing” step is that this step may be accomplished by critical thinking processes. Such “comparing” thereby encompasses only an abstract idea / process.
The claims also recite “determining" that the sample has an increase in one or more the 5’-tRFs. Neither the specification nor the claims set forth a limiting definition for “determining” and the claims do not set forth how “determining” is accomplished. As broadly recited, “determining” may be accomplished mentally when comparing the level of the 5’-tRFs in the sample with that in the comparable sample. Thus, the determining step is also an abstract idea / process.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited steps of obtaining the samples from a human patient and determining the level of one or more 5’-tRFs are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
Note that in the reply of 01 December 2025, Applicant amended the claims so that the administering step is no longer specifically performed after an increase in one or more of the 5’-tRFs is detected. That is, the claims no longer require that the administering step is performed “when the human patient has an increase in the one or more 5-tRFs.” In view of the open claim language of comprising, the administering step may be performed prior to steps of obtaining the sample from the human patient and determining the level of the 5’-tRFs in the sample. In such instances, the administering step is extra-solution activity that is performed as part of the data gathering step. The administering step does not integrate the recited judicial exception into a practical application. Applicant’s attention is directed to M.P.E.P. § 2106.04(d)(2)(c), which states:
“The treatment or prophylaxis limitation must impose meaningful limits on the judicial exception, and cannot be extra-solution activity or a field-of-use. For example, consider a claim that recites (a) administering rabies and feline leukemia vaccines to a first group of domestic cats in accordance with different vaccination schedules, and (b) analyzing information about the vaccination schedules and whether the cats later developed chronic immune-mediated disorders to determine a lowest-risk vaccination schedule. Step (b) falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). While step (a) administers vaccines to the cats, this administration is performed in order to gather data for the mental analysis step, and is a necessary precursor for all uses of the recited exception. It is thus extra-solution activity, and does not integrate the judicial exception into a practical application.”
Herein, the administering step is performed only to gather information as to the effect of the treatment on the 5’-tRF levels and thereby is extra-solution activity and does not integrate the recited judicial exceptions into a practical application
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited steps of obtaining a biological sample from a subject and determining the level of one or more RNA fragments (tRFs) are recited at a high degree of generality and were well-known, routine and conventional in the prior art. Additionally, regarding claim 21, methods of qRT-PCR without a probe and melting curve qRT-PCR analysis were well-known in the prior art, as evidenced by the teachings of Pryor et al (Real-Time Polymerase Chain Reaction and Melting Curve Analysis. 2006. Methods in Molecular Biology. Vol. 336. Clinical Applications of PCR, 2nd Edition, Y.M. Dennis Lo, Rossa W.K. Chiu and K.C. Allen Chan, Eds. Humana Press, Inc., Totowa, NJ). See also Olvedy et al (Oncotarget. March 2016. 7(17): 24766; cited in the IDS), Shao et al (Chem Biol Drug Des. 2017. 90: 730-738; cited in the IDS) Torrent et al (Signal Sept 2018. 11: eaat6409; cited in the IDS), and Wang et al (Molecular Medicine Reports. 2019. 19:3564-3574) which evidence the fact that qRT-PCR methods without the use of a probe to detect tRNAs were well-known, routine and conventional in the prior art (see, e.g., p. 10, col. 2 of Olvedy; p. 731, col. 2 of Shao; p. 7, col. 1 of Torrent; and p. 3565, col. 2 of Wang).
See also MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims recite detecting the expression of particular RNAs i.e.,5’- tRFs, the identity of the RNAs is part of the judicial exception and not something in addition to the recited judicial exceptions. The claims do not require using a particular non-conventional reagent, such as a particular, non-conventional probe or primer consisting of or comprising a specific nucleotide sequence so as to add something ‘significantly more’ to the recited judicial exceptions.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
New Claim Rejections - 35 USC § 112(a) – New Matter
7. 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, 4, 8. 9, and 11 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a New Matter Rejection.
The disclosure as originally filed does not provide basis for the amendment to claims 1, 3, 4, 8, 9 and 11 to recite administering “intracranially” to the human patient an NSun2 gene. The originally filed disclosure teaches the general concept of administering an NSun2 agonist or activator to a human patient when it is determined that the recited tRFs are increased in hippocampal or cerebrospinal fluid samples from the human patient, as compared to healthy control patients, wherein the NSun2 agonist or activator increases the expression or activity of NSun2, and includes a genetically modified NSun2 or naturally occurring nucleic acid (e.g., para [0037] and [0045]; and originally filed claims 1 and 8). However, the originally filed disclosure does not provide any information regarding the route of administration of a NSun2 gene to a human patient and particularly does not disclose administering an NSun2 gene intracranially to a human patient to treat Alzheimer’s disease.
If Applicant maintains that the originally filed disclosure provides basis for the amended claims, Applicant should point to specific teachings (e.g., by paragraph number) in the present application to establish basis for each of the recitations set forth in the claims.
See MPEP 2163 II at “(b) New Claims, Amended Claims, or Claims Asserting Entitlement to the Benefit of an Earlier Priority Date or Filing Date under 35 U.S.C. 119, 120, 365, or 386” which states:
“To comply with the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, or to be entitled to an earlier priority date or filing date under 35 U.S.C. 119, 120, 365, or 386, each claim limitation must be expressly, implicitly, or inherently supported in the originally filed disclosure.”
Maintained / Modified Claim Rejections - 35 USC § 112 - Enablement
8. Claims 1, 3, 4, 8, 9, 11, 12, 15, 16, 21 and 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for treating Alzheimer’s disease in a human patient suspected of having Alzheimer’s disease, the method comprising the steps of: a) providing a hippocampal sample or a cerebrospinal fluid sample from the human patient; b) measuring the level of 5’-tRNA derived RNA fragments (tRF5s) in the hippocampal sample or cerebrospinal fluid sample, wherein the tRF5s are tRF5-ProAGG, tRF5-CysGCA, tRF5-GlyGCC, tRF5-GlyCCC-2, and tRF5-GluCTC; c) determining that the hippocampal sample from the human patient has an increase in the level of tRF5-ProAGG, tRF5-CysGCA, tRF5-GlyGCC, tRF5-GlyCCC-2, or tRF5-GluCTC, as compared to that in a normal control sample, or that the cerebrospinal fluid sample from the human patient has an increase in the level of tRF5-ProAGG or tRF5-GlyCCC-2, as compared to a normal control sample; and d) administering a NSun2 gene to the human patient with the increased level of tRF5-ProAGG, tRF5-CysGCA, tRF5-GlyGCC, tRF5-GlyCCC-2, or tRF5-GluCTC in the hippocampal sample or the increased level of tRF5-ProAGG or tRF5-GlyCCC-2 in the cerebrospinal sample,
does not reasonably provide enablement for methods wherein the sample is a serum or blood sample; methods in which the control is any positive control, a negative control, wild-type control, historical control, or historical norm or methods wherein an increase in tRF5-CysGCA, tRF5-GlyGCC, or tRF5-GluCTC is detected in the cerebrospinal fluid sample as indicative of the need to treat the human patient by administering the NSun2 gene. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
Claims 1, 3, 4, 8, 9 and 11 are drawn to methods for treating Alzheimer’s disease in a human patient and comprise (in part) detecting an increase in each of tRF5-GlyGCC, tRF5-GluCTC, tRF5-GlyCCC-2, tRF5-ProAGG, and tRF5-CysGCA in a hippocampal or cerebrospinal fluid sample of a human patient and then administering a NSun2 gene to the human patient determined to have the increased levels of each of the 5’-tRFs.. Claims 12, 15, 16 and 21-22 are drawn to methods for treating Alzheimer’s disease comprising (in parr) detecting in an increase in any one of tRF5-GlyGCC, tRF5-GluCTC, tRF5-GlyCCC-2, tRF5-ProAGG, or tRF5-CysGCA in a hippocampal, cerebrospinal fluid, blood or plasma sample of a human patient
However, the specification identifies a limited number of tRNA fragments whose level is increased in hippocampus tissue or cerebrospinal fluid of human subjects, as compared to that of normal control human subjects (see, e.g., Figures 2 and 3 and para [0093]). In particular, the specification teaches that tRF5-ProAGG, tRF5-CysGCA, tRF5-GlyGCC, tRF5-GlyGCC-2, and tRF5-GluCTC are present at increased levels in hippocampal samples from human patients having AD as compared to normal, control samples (Figures 2 and 3). It is disclosed that tRF5-GlyCCC is present at higher levels in EOAD versus young control, normal samples and in LOAD as compared to “old” control samples. tRF5-LeuCAG did not show a difference in its level in hippocampus tissue samples obtained from patients with AD as compared to control subjects (Figure 3C).
Regarding cerebrospinal fluid samples, the disclosure teaches that tRF5-ProAGG and tRF5-GlyCCC-2 are present at increased levels in cerebrospinal fluid samples from AD patients as compared to normal, control cerebrospinal fluid samples (Figures 9A and 9B and p. 32 of the specification). The specification does not provide any information regarding the level of tRF5-CysGCA, tRF5-GlyGCC, and tRF5-GluCTC in cerebrospinal fluid samples from patients with AD and healthy control subjects.
There is a high level of unpredictability in the art in determining which of the multitude of possible tRF5s will have an increased level in a sample as compared to a comparator sample as diagnostic of AD. This finding is supported by the teachings in the specification which establish that different results are obtained with different tRF5s such that the findings obtained with one tRF5 cannot be extrapolated predictably to other tRF5s.
Regarding the type of biological sample, as set forth above, results are provided for cerebrospinal fluid samples only for tRF5-ProAGG and tRF5-GlyCCC-2. The specification has not established that a representative number of distinct tRF5s have an increased or decreased level in cerebrospinal fluid samples of AD patients, as compared to a control subjects.
With respect to serum samples (as encompassed by claims 12, 15, 16, and 21-22), Figure 10B shows that there was no difference in the level of tRF5-ProAGG in serum samples from early onset AD (EOAD) patients as compared to young, normal controls, whereas tRF5-ProAGG levels were lower in serum samples from AD patients as compared to normal control serum samples (Figure 10A) and in late onset AD (LOAD) serum samples as compared to “old” control, normal samples (Figure 10C). The results in Figures 10A and 10C are opposite of the results obtained in hippocampus tissue samples and in opposition to the results required for the claims.
The specification does not provide any results obtained with blood samples and particularly does not teach that there is an increase in the levels of tRF5-ProAGG, tRF5-CysGCA, tRF5-GlyGCC, tRF5-GlyGCC-2, and tRF5-GluCTC in blood samples obtained from AD patients as compared to any control sample.
Further note that the claims encompass methods wherein the comparator sample is any sample, including positive control, a negative control, a normal control, a wild-type control, a historical control, and a historical norm. However, the results provided in the specification are with respect to a normal control sample. There is no showing that each of tRF5-ProAGG, tRF5-CysGCA, tRF5-GlyGCC, tRF5-GlyGCC-2, and tRF5-GluCTC are increased in hippocampal, CSF, blood and/or serum samples of AD patients as compared to a positive control sample, or an undefined historical control or historical norm, including historical controls and norms that are from subjects having AD or other neurological diseases.
It is unpredictable as to what other types of body fluids and tissues may be monitored for the level of tRF5s in order to diagnose Alzheimer’s disease. Modification of the level of a biomarker, such as a tRF5, may occur only in a subset of cells that are directly involved in a disease or phenotype. The levels of particular RNAs are well known to vary significantly between different cell, tissue and fluid types. This high level of unpredictability in extrapolating the results obtained with one type of sample to other types of samples is supported by the above noted teachings in the specification regarding serum samples.
Accordingly, while methods for detecting RNA levels are known in the prior art, such methods provide only the general guidelines that allow researchers to search for tRF5s whose level is increased in different samples from different subjects having the AD phenotype. The results of performing such methodology are highly unpredictable.
The unpredictability in the art is further supported by Applicant’s post-filing date reference of Wu et al (J Alzheimers Dis. 2023. 96(3): 1285-1304). Wu teaches that there is variation in the identity of tRF5s that are present at increased levels in AD patients as dependent on the source of the sample – i.e., hippocampus, cerebrospinal fluid or serum. As with the present specification, Wu teaches that in CSF samples, the levels of “tRF5-GluCTC, tRF5-GlyGCC, and tRF5-CysGCA were comparable in AD and CN groups” (p. 7). Thus, the teachings of Wu indicate that an increase level of tRF5-GluCTC, tRF5-GlyGCC, and tRF5-CysGCA is not detectable in CSF samples from AD patients as compared to normal, control samples.
Regarding serum samples, Wu (p. 8) states:
“Our results suggested that serum tRF5-ProAGG was less in the AD group than in the CN group, while tRF5-GlyCCC2 was comparable between AD and CN (Figs. 4A and 4B). We are currently collecting more samples to investigate the impact of gender and other AD risk factors on serum tRF expression by subgroup analyses.” Emphasis added.
Thus, the teachings of Wu further establish the unpredictability in the art of extrapolating the results obtained with one tRF5 to other tRF5s and with extrapolating the results obtained with one sample type to other sample types.
Ss set forth in Rasmusson v. SmithKline Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention.
Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Response to Remarks:
It is first noted that those aspects of the prior rejection as they applied to any NSun2 agonist have been obviated by the amendment to the claims to recite administering an NSun2 gene.
Regarding the remaining aspects of the rejection, Applicant’s arguments and the Declaration of Dr. Xiayong Bao filed on 01 December 2025 have been fully considered but do not obviate the rejection.
The response states “as averred by Dr. Bao in paragraphs 11-15 of Dr. Bao's Declaration, using ordinary skill and following the teachings of the specification, it was possible to detect the presence of the 5-tRFs in a blood/serum sample. As such, the claims as amended are enabled in the specification.”
However, the rejection is not on the basis that it would require undue experimentation to detect the 5’-tRFs in a hippocampal, cerebrospinal fluid (CSF), blood or serum sample, but rather on the basis that it is unpredictable as to whether there is an increase in the level of each of tRF5-GlyGCC, tRF5-GluCTC, tRF5-GlyCCC-2, tRF5-ProAGG, and tRF5-CysGCA in hippocampal, CSF, blood and serum samples of patients with AD as compared to any comparator sample and that undue experimentation would be required to practice the claimed method of treating a human patient for AD by administering a NSun2 gene when it is determined that there is an increase in the level of each of tRF5-GlyGCC, tRF5-GluCTC, tRF5-GlyCCC-2, tRF5-ProAGG, and tRF5-CysGCA in hippocampal, CSF, blood and serum samples of patients with AD as compared to any comparator sample.
Secondly, the data provided in the declaration is unclear and does not appear to establish that the level of each of tRF5-GlyGCC, tRF5-GluCTC, tRF5-GlyCCC-2, tRF5-ProAGG, and tRF5-CysGCA are increased in blood and serum samples of AD patients, as compared to any comparator sample or that the level of tRF5-GlyGCC, tRF5-GluCTC, and tRF5-CysGCA are increased in CSF samples of AD patients as compared to any comparator sample.
The declaration states “We also analyzed blood cells from patients with Alzheimer’s Disease for comparison and found the disease-specific tRF signatures (Table 1 below).” Yet, para 13 of the declaration refers to “AD serum samples” and Table 1 recites “Healthy donors vs AD patient serum.” The declaration also refers to “blood/serum samples.” However, (whole) blood samples are distinct from serum samples in that serum lacks the clotting factors and the cells (red blood cells, white blood cells and platelets) present in blood. Para 12 of the declaration states that “buffy coat samples (white blood cells and platelets)” were harvested from healthy donors and AD patients. It appears that the data provided in the declaration may have been obtained with the buffy coat fraction of blood. However, the present specification does not provide support for methods in which this particular fraction of blood is analyzed to detect an increase in the level of the tRFs as indicative of a human patient who should be treated with the NSun2 gene.
Additionally, the data in Table 1 appears to show that there is a decrease (i.e., negative log2FoldChange) in the levels of tRF5-GlyGCC, tRF5-GluCTC, tRF5-GlyCCC-2, tRF5-ProAGG. No information appears to have been provided for tRF5-CysGCA. It is acknowledged that the table recites “Healthy donors vs AD patient serum,” however again it is not clear that log2FoldChange values are for the healthy donors or that the samples are serum samples. Also, if the results are intended to show an increase in the level of the tRF5s, particularly in serum samples, of AD patients, the results would be inconsistent with the teachings in the specification (Figures 10A and 10C). For instance, see Figure 10A of the specification below wherein the level of tRF5-ProAGG in serum of AD patients is less than or the same as (but not on average more than) that of normal, control (CN) subjects:
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Also, the stated findings in the declaration are not consistent with the post-filing date teachings of Wu et al (co-authored by the present inventors) in which it is disclosed (at p. 8) that in serum samples, the level of “tRF5-ProAGG was less in the AD group than in the CN group, while tRF5-GlyCCC2 was comparable between AD and CN (Figs. 4A and 4B).
The declaration also does not provide any additional information regarding the level of tRF5-GluCTC, tRF5-GlyGCC, and tRF5-CysGCA in cerebrospinal fluid samples of human patients with AD, as compared to normal, control CSF samples.
Para 17 of the declaration states:
“Thus, following the teachings in the specification, we were able to detect an increase in the levels of 5'-tRNA from hippocampal, cerebrospinal, blood, or serum samples, and using known NSun2 nucleic acids and constructs, it is possible to administer an NSun2 gene that increases the expression of NSun2 in the affected cells.”
However, for the reasons set forth above, the information provided in the declaration, as well as the teachings in the specification do not in fact establish that there is an increase in the level of tRF5-GlyGCC, tRF5-GluCTC, tRF5-GlyCCC-2, tRF5-ProAGG, and tRF5-CysGCA in hippocampal, CSF, blood and serum samples of AD patients, as compared to any comparator sample. Rather, it has only been established that there is an increase in the level of tRF5-GlyGCC, tRF5-GluCTC, tRF5-GlyCCC-2, tRF5-ProAGG, and tRF5-CysGCA in hippocampal samples of human AD patients as compared to normal, control hippocampal samples and an increase in the level of tRF5-GlyCCC-2 and tRF5-ProAGG in CSF samples of human AD patients as compared to normal, control AD samples.
For these reasons, the rejection is maintained.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682