You 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/27/2026 has been entered.
Claims 18 and 22-36 are currently pending and under consideration.
Information Disclosure Statement
The information disclosure statement filed on 9/11/2026 is acknowledged and has been considered except where lined through. It is noted that the two reference provided in the IDS were previous cited by the Examiner in the 5/15/2025 Non-Final office action.
Rejections Withdrawn:
The rejection of Claim(s) 18, 22-24, 27-33 under 35 U.S.C. 103 as being unpatentable over Masters (US20070037848A1) in view of Rumia et al. (Epilepsy Research, 2013, Vol. 107, Issues 1-2, pp75-81) is withdrawn in view of Applicants amendments to include the limitation functional Phgdh since it appears to be recognized, as evidenced by the specification, that drug resistant epilepsy has malfunctioning or deficient Phgdh activity.
The rejection of Claim(s) 18 and 22-33 under 35 U.S.C. 103 as being unpatentable over Masters (US20070037848A1) in view of Pearson-Smith and Patel (Int. J. Mol. Sci. 2017, 18, 2365, pp1-13) as evidenced by Brigo et al (Expert Opinion on Emerging Drugs 2008, Vol. 23, No. 4, 261-269) is withdrawn in view of Applicants amendments.
The rejection of Claim(s) 34 under 35 U.S.C. 103 as being unpatentable over Masters (US20070037848A1) in view of Pearson-Smith and Patel (Int. J. Mol. Sci. 2017, 18, 2365, pp1-13) as evidenced by Brigo et al (Expert Opinion on Emerging Drugs 2008, Vol. 23, No. 4, 261-269), as applied above to claims 18, 22-33, in further view of Ceulemans et al. (Epilepsia 2012,53(7),1131-1139) is withdrawn in view of Applicants arguments.
New Rejections:
Claim Objections
Claims 1 and 35-36 are objected to because of the following informalities: The claims recite “Phdgh”. In view of the specification, this acronym should be “Phgdh”. All reference to this acronym within this office action will be consistent with the specification. Appropriate correction is required.
Claim Interpretation
Claim 18 has been amended to recite “A method of treating epilepsy in a human individual having functional Phgdh activity….”. Accordingly, the human needs to be suffering from epilepsy, as well as, has functional Phgdh activity. A review of the specification and claims do not appear to define what is encompassed by “functional”. Cambridge Dictionary (dictionary.cambridge.org/dictionary/english/functional ) defines functional as: working in the usual way. As such, the examiner will be interpreting the phrase functional as being synonymous as operating in a normal fashion or way.
Claim Rejections - 35 USC § 112
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 18 and 22-36 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. THIS IS A NEW MATTER REJECTION.
Claim 18 has been amended to include the limitation “having functional Phgdh activity” attempting to further define the human individual suffering from epilepsy. Applicants have asserted that support for this amendment is found throughout the Specification and claims as originally filed. A careful review of the specification and claims, as originally filed, does not appear to lend support for a human individual suffering from epilepsy and also having functional Phgdh activity. In contrast, the specification appears to discuss the malfunctioning and/or deficiency of Phgdh . For example, the specification teaches that drug resistant epilepsy might be associated with Phgdh malfunctioning/deficiency (see page 1, lines 21-22). The specification further cites two articles which disclose that mice with reduced Phgdh expression, induced by a diet resulting in development of fatty liver disease, have a severe predisposition for development of seizures (increase seizure episodes, decreased seizure thresholds) (page 1, lines 29-32). Moreover, the specification teaches that the present invention allows to identify a cohort of patients with an epilepsy resulting from a Phgdh deficiency. Such cohort can be identified via a DL-serine assay kit (Abcam) to identify an abnormal L vs D serine content and/or Phgdh activity measurement kit to identify individuals with impaired Phgdh activity and/or Phgdh expression levels (page 2, lines 11-15). Thus, the specification only appears to contemplate a human individual suffering from epilepsy and malfunctional and/or deficient Phgdh activity. A review of the prior art around the time of filing (google scholar search KW Phgdh and epilepsy) appears to support the notion that deficiencies or mutations in Phgdh are associated with epilepsy. For example, Furukawa et al. (Epilepsy Research, 2020; 168: 106502) looked at the proteomic profile differentiating between mesial temporal lobe epilepsy with and without hippocampal sclerosis (Title). Furukawa et al. teach that Hippocampal sclerosis (HS) is the most common neuropathological condition in adults with drug-resistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy (MTLE) syndrome, wherein the authors found that decreased expression of PHGDH and increased expression of neuronal stathmin 1 can be involved in the continuation of seizure disorders in MTLE-HS (Abstract and Conclusions). More recently, Thevissen et al. (Epilepsia 2025; 66: 3769-3784) suggests that mounting evidence indicates a link between seizures and dysfunction of PHGDH , either due to genetic mutations in the PHGDH gene or through inhibition of PHGDH (page 3771, 1st column, 1st full paragraph). Thus, the amendment to Claim 18 to include the limitation “having functional Phgdh activity” attempting to further define the human individual suffering from epilepsy appears to be new matter.
New Claim 35 recites the limitation “…, wherein the human individual is determined to have functional Phgdh activity prior to administering the therapeutically effective amount of clioquinol….”. Applicants contend support can be found throughout the Specification (e.g., page 2, lines 11-15) and the claims as originally filed. The examiner has carefully reviewed the specification and claims, as originally filed, specifically page 2, lines 11-15. As noted above, page 2, lines 11-15 of the specification teach the present invention allows to identify a cohort of patients with an epilepsy resulting from a Phgdh deficiency. Such cohort can be identified via a DL-serine assay kit (Abcam) to identify an abnormal L vs D serine content and/or Phgdh activity measurement kit to identify individuals with impaired Phgdh activity and/or Phgdh expression levels. Thus, this portion of the specification appears to identify a patient population with has a deficiency in Phgdh and not Phgdh functioning normally. Moreover, a review of the two examples provided in the specification do not appear to teach or suggest determining Phgdh activity prior to administration of the compounds nor teach or suggest functional Phgdh activity as a prerequisite for administration of the compounds. In particular, both of these examples appear to model drug resistant epilepsy which in view of the specification, above, appear to be associated with Phgdh malfunctioning/deficiency As such, the new claim appears to be new matter.
It should be noted that the Examiner recognizes that the claimed compounds appear to increase Phgdh activity. However, it appears that the specification and claims, as originally filed, are directed to increasing Phgdh in epileptic patients whom have Phgdh malfunctioning or are deficient in Phgdh . NOTE: In applicants response, Applicants makes a distinction that a human having functional Phgdh activity excludes patients with dysfunctional Phgdh or Phgdh deficiency.
Claims 18 and 22-36 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.
Note: The following rejection is necessitated by Applicants arguments that a human having functional Phgdh activity excludes patients with dysfunctional Phgdh or Phgdh deficiency.
The claims recite a method of treating epilepsy in a human individual having functional Phgdh, the method comprising administering to the human individual a therapeutically effective amount of clioquinol or 8-hydroxyqinoline. Accordingly, the human individual needs to be suffering from epilepsy, as well as, has functional Phgdh activity.
The specification teaches that L-serine biosynthetic enzyme 3-phosphoglycerate dehydrogenase (Phgdh) is one of the enzymes implicated in de novo serine synthesis, wherein Phgdh deficiencies have been reported in humans with hallmarks of Phgdh deficiency being microcephaly of prenatal onset, severe psychomotor disability, early intractable seizures (of various type), and progressive spasticity (page 1, lines 9-14). The specification further teaches that Phgdh malfunctioning/deficiency/reduced expression may be associated with epilepsy or seizures. For example, the specification teaches that drug resistant epilepsy may be associated with Phgdh malfunctioning/deficiency (page 1, lines 21-22). Moreover, the specification teaches that the present invention allows to identify a cohort of patients with an epilepsy resulting from a Phgdh deficiency. Such cohort can be identified via a DL-serine assay kit (Abcam) to identify an abnormal L vs D serine content and/or Phgdh activity measurement kit to identify individuals with impaired Phgdh activity and/or Phgdh expression levels (page 2, lines 11-15). Thus, the specification when referring to Phgdh and epilepsy, appears to contemplate a cohort of patients with an epilepsy resulting from a Phgdh deficiency.
Regarding epilepsy, the specification defines epilepsy as a condition of the brain marked by a susceptibility to recurrent seizures and provides a list of different subtypes of epilepsy (page 6-page 7, starting at line 25). Moreover, the specification provides two examples of haloquinolines ability to block seizures in zebrafish models for drug-resistant epilepsy (including a genetic model of Dravet) (See Example 2). The specification appears to be silent of whether the subtypes of epilepsy listed or whether the zebrafish models had functional Phgdh. In view of the specification, it can be assumed that the models contained deficient or malfunction Phgdh activity since the models mirrored drug resistant epilepsy.
As noted above in the New Matter rejection and incorporated herein, the state of the art around the time of filing (google scholar search KW Phgdh and epilepsy) appears to support the notion that deficiencies or mutations in Phgdh are associated with epilepsy.
Thus, while the specification appears to provide a nexus between human individuals having epilepsy and deficiencies or mutations in Phgdh, the specification is silent on any human individual having epilepsy and functional Phgdh activity. In other words, it is unclear which of the subtypes of epilepsy identified on page 7-8 of the specification are also associated with functional Phgdh activity. As such, Applicants are not in possession of a human individual having epilepsy and functional Phgdh activity.
Expedite Prosecution:
While the examiner has withdrawn the previous rejections based on Applicants amendments to include the limitation functional Phgdh since it appears to be recognized, as evidenced by the specification, that drug resistant epilepsy has malfunctioning or deficient Phgdh activity, the Examiner would like to respond to or highlight some of the remarks made by Applicants. First, Applicants make the argument that a human individual having functional Phdgh activity excludes patients with dysfunctional Phgdh or Phgdh deficiency (page 6 of 9, (1)). This argument I find interesting since it is unclear based on the specification and state of the art, as noted above, what type of epilepsy this is. In other words, the specification and art appears suggest a nexus between epilepsy and dysfunctional Phgdh or Phgdh deficiency. Assuming, arguendo, that Applicants believe the zebrafish models in Example 2 shows functional Phgdh activity, the Examiner would caution this line of thinking in view of the experimental for the following reason:
There is no measurement of Phgdh activity prior to administration of the compounds. In addition to the measurement, there is no measurement compared to a control, e.g., did not receive ethyl ketopentonoate. The reason this is important is because while there may have been Phgdh activity prior to administration of the compounds, the question is whether this was normal, e.g. functional. The models used are drug resistant models and based on the specification, drug resistant models may be associated with malfunctioning/deficient Phgdh. As such, there may have been some activity, e.g., malfunctioning or a deficiency, but it is not considered to be normal compared to the control.
Another interesting argument by Applicants is that the claimed invention, however, is based (at least in part) of the understanding that Phgdh activity levels are documented to differ among epilepsy patients (page 6 of 7, 1st paragraph). It is interesting to the examiner because no documents have been submitted to show this differing among epilepsy. Specifically, Applicants have not provided evidence that Phgdh is functioning normally in epileptic patients. In addition, Applicants make the argument that the claimed invention is directed to treating a subpopulation that will experience an even greater and unexpected benefit from certain 8-hydroxyquinolines, such as clioquinol via Phgdh activation; namely those with functional Phgdh activity. In response to this argument, it appears that Applicants may be referring to the zebrafish models in Example 2 which the Examiner has expressed their concerns pertaining to interpretation of these results. Moreover, Applicants makes the assertion that the claimed invention as excludes a subpopulation that will not benefit from Phgdh activation by Clioquinol, i.e., those with Phgdh dysfunction/deficiency. In response to this argument, it is unclear how Applicants are coming to this conclusion. Secondly, the examiner is honestly confused and this seems to be in contrast to the totality of the teachings of the specification. For example, the specification teaches that the present invention allows to identify a cohort of patients with an epilepsy resulting from a Phgdh deficiency (page 2, lines 11-12). Lastly, regarding Applicants arguments pertaining to oxidative stress and the Phgdh pathways being different. The examiner does not dispute that these pathways are different. However, the question is whether or not these two pathways can exist at the same time in epileptic patients. In this regard, Applicants appears to have shown an additional unappreciated pathway Clioquinol functions in epilepsy treatment. Applicants are reminded that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). See MPEP 2112.
Conclusion
Therefore, No claim is allowed.
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 BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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/BRANDON J FETTEROLF/ Primary Examiner, Art Unit 1626