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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 26 January 2026 has been entered.
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 26 January 2026.
CLAIMS UNDER EXMAMINATION
Claims 1-2 and 9-18 are pending. Claims 1-2 have been examined on their merits.
PRIORITY
Provisional Application 62798712, filed on 30 January 2019, is acknowledged.
WITHDRAWN REJECTION
The rejection of claim 2 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, has been withdrawn due to claim amendment.
REJECTIONS
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Merbl et al. (previously cited Diagnostic method based on large scale identification of post-translational modification or proteins. US2022/0252612 with benefit of 14/796,408, filed on Jul. 10, 2015, now Pat . No. 11,333,668) in view of Sanchez et al. (previously cited; In vivo strategies for the study of ubiquitination and ubiquitin-related diseases: application to Angelman syndrome. 2016 pages 1-302) and Nash et al. (previously cited; Modified UBE3a Gene For A Gene Therapy Approach For Angelman Syndrome, WO 2016/179584) as evidenced by Huibregste et al. (previously cited; A proteasomal partner goes missing in Angelman syndrome. J.Biol.Chem.(2018)293(47) 18400–18401).
Merbl et al. teach methods which can be used to diagnose neurodegenerative diseases (Abstract; [0052] [0113] [0134). A fluid from a patient is incubated, specific post-translational modification (PTM) reactions are performed and altered PTM of specific proteins are detected ([0006]). The PTM can be ubiquitination ([0024]). After the level of the PTM state for a protein is detected, alteration is identified by comparing to the results obtained using a control sample from another patient ([0131]). The presence or absence of a change is used to diagnose a disease ([0131]). Merbl teaches comparison between samples obtained at different timepoints ([0093]). Merbl discloses a protein of interest can be assayed over time (see Figure 2A; Figure 5A).
Regarding the patient fluid: Merbl identifies CSF as an “extracellular fluid” ([0069]) which can be analyzed to detect functional PTM enzymes ([0091]). Merbl teaches non-cellular bodily fluid (hence, extracellular fluid) contain intracellular content for analysis; such content may be secreted from cells ([0101]). Merbl teaches for ubiquitination reactions requiring E3 enzymes, enzymes are supplied by the patient sample ([0103]).
In Example 3, Merbl analyzes CSF from a patient with a brain tumor (a neurodegenerative disease). Merbl detects the amount/extent of ubiquitination of individual protein substrates resulting from activity in CSF. Proteins with higher signal than control were identified as ubiquitinated. Merbl states these proteins underwent “CSF-mediated ubiquitination” ([0163]).
Merbl teaches a patient can be treated for a disorder ([0093]).
While Merbl uses CSF (an extracellular fluid) for ubiquitination assays using protein substrates and teaches E3 enzymes, Merbl does explicitly teach the E3 enzyme is UBE3a. Merbl does not teach the substrate is S5a. Merbl does not teach of treat Angelman’s disease.
Sanchez teaches UBE3A is an E3 ligase involved in Angelman syndrome (AS) (line 4 of page 143). Loss of enzyme activity is linked to Angelman syndrome (page 50, first paragraph). Sanchez teaches Rpn10 is a direct substrate of Ube3a (last paragraph of page 195). As evidenced by Huibregste, RPN10 is also known as S5a (page 184, right column, second paragraph).
Sanchez measures ubiquitination of Rpn10/S5a in the presence of wild type Ube3a and a ligase-dead mutant, HA-Ube3aLD. Sanchez teaches ubiquitination is significantly increased in the presence of wild type Ube3a as compared to cells expressing the ligase dead mutant (page 196, second paragraph). Therefore Sanchez determines the activity of UBE3A by analyzing S5a ubiquitination.
Nash teaches impaired UBE3A is responsible for Angelman Syndrome (page 2, line 5). Nash discloses a Ube3a protein which is secreted by cells and taken up by neighboring neuronal cells (page 4, last paragraph). This provides a functional protein into the neurons thereby rescuing from disease pathology (page 4, last paragraph).
Nash teaches a UBE3A vector (page 5, line 1). The vector is inserted into an adeno associated virus plasmid (page 7, lines 8-9). The vector is used to treat Angelman syndrome (page 8, lines 15-16). The vector is administered to the brain of a patient suffering from the UBE3A deficiency disease to correct the deficiency (page 8, lines 156-24). The art teaches bilateral injection of a dose of about 5.55 x 1011 genomes/g brain mass to about 2.86 x 1012 genomes/g brain mass (same cited section). The disclosed dose is interpreted to be a therapeutically effective amount.
It would have been obvious combine the teachings of the prior art by using S5a as a substrate in a CSF ubiquitination assay and applying the assay to diagnose Angelman syndrome. Merbl uses protein substrates to assay ubiquitinating enzyme activity in extracellular fluid and teaches using PTM differences for diagnostic purposes.
Sanchez associates loss of UBE3A enzyme activity with Angelman syndrome. One would use Merbl’s assay to analyze S5a ubiquitination in a sample, and compare the results to a control for diagnosis. One would have had a reasonable expectation of success since Merbl demonstrates enzymatic ubiquitination activity present in CSF can ubiquitinate protein substrates.
It would have been obvious to detect extracellular UBE3 activity. Merbl teaches CSF is an extracellular fluid that can be used to detect functional PTM enzymes and supply the enzyme required for substrate ubiquitination. Sanchez teaches the E3 enzyme UBE3a is required for S5a ubiquitination. Therefore measuring S5a ubiquitination in Merbl’s assay would provide a functional readout for detecting UBE3a activity in the extracellular CSF fluid. One would have had a reasonable expectation of success since Nash teaches UBE3A can be secreted and exist extracellularly.
It would have been obvious to administer AAV-UBE3A to treat Angelman syndrome. Nash teaches administering a therapeutically effective amount AAV-UBE3A via bilateral brain injection to treat Angelman syndrome. The skilled artisan would administer the protein taught by Nash to correct the deficiency observed in patients. One would have had a reasonable expectation of success since Nash teaches AAV-UBE3A can successfully treat Angelman syndrome. Therefore claim 1 is rendered obvious.
Nash teaches the majority of cases occur through a de novo deletion of the maternal chromosome which incorporates the UBE3a gene, but can also occur as a result of abnormal methylation of the maternal copy (page 2, lines 20-26). The instant specification identifies deletion/mutation as a typical disruption ([0011]). Methylation is not interpreted to be a gene deletion or mutation. Therefore claim 2 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
EXAMINER’S RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 26 January 2026 are acknowledged.
Argument 1: The arguments state prior to the Applicant, it was not known that UBE3A could be detected in CSF and it was also not known that UBE3A has an extracellular function.
Response: Claim 1 recites “detecting an amount of extracellular UBE3a” by measuring S5a ubiquitination “to determine” extracellular UBE3a activity. The specification does not explicitly define “detecting” or “determining”. UBE3a is not measured. Its presence is determined, indirectly, by substrate ubiquitination.
Merbl teaches CSF is an extracellular fluid that can be used to detect functional PTM enzymes and supply the enzyme required for substrate ubiquitination. Sanchez teaches the E3 enzyme UBE3a is required for S5a ubiquitination. Therefore measuring S5a ubiquitination in Merbl’s assay would provide a functional readout for detecting UBE3a activity in the extracellular CSF fluid.
Argument 2: The Applicant argues Sanchez does not diagnose Angelman’s syndrome. The Applicant argues Merbl does not diagnose or treat Angelman’s syndrome.
Response to Argument 2: Sanchez teaches UBE3A is an E3 enzyme involved in Angelman syndrome. Sanchez teaches an in vitro assay for analyzing ubiquitination using UBE3a and S5a substrate. Merbl teaches ubiquitination of enzyme substrates can be used to diagnose a neurodegenerative disease. Marble teaches CSF is an extracellular fluid which can be analyzed. Merbl teaches for ubiquitination reactions requiring E3 enzymes, enzymes are supplied by the patient sample. Nash is relied upon because it teaches a method of treating Angelman’s syndrome.
Argument 3: The Applicant argues impermissible hindsight reasoning has been used.
Response to Argument 3: Each limitation is taught by the prior art. Merbl compares PTM in a patient and a control to diagnose a neurodegenerative disease. The art teaches an extracellular fluid sample can provide a ubiquitinating enzyme. The art teaches a ubiquitin substrate can be analyzed. Sanchez teaches UBE3A is a ubiquitinating enzyme involved in Angelman’s syndrome. The art analyzes ubiquitination of its substrate. Nash teaches a method of treating Angelman’s syndrome. The rejection relies on the teachings of the prior art. The arguments are not persuasive.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 270-8439.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NATALIE M MOSS/ Examiner, Art Unit 1653
Prosecution Insights