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 .
Application Status
The amendment filed on 9/4/2026 in response to the Non-Final rejection of 3/24/2026 is acknowledged and has been entered. Claims 18, 22, 24-34 and 36 are currently pending and under consideration.
Rejections Withdrawn:
The rejection of Claims 18 and 22-36 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. (New Matter rejection) is withdrawn in view of Applicants amendments.
The rejection of Claims 18 and 22-36 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of Applicants amendments. Written Description rejection
New Rejections Necessitated by Amendment:
Claim Interpretation
Claim 18 has been amended to recite “A method of treating drug-resistant epilepsy in a human individual having some residual Phgdh activity, the method comprising:
Detecting a residual level of Phgdh activity in the human individual….”. The specification teaches one location which discusses residual activity when discussing classical Phgdh deficiency which appears to be characterized by 12-25% residual Phgdh activity. A review of the specification and claims do not appear to define what is encompassed by “residual”. Cambridge Dictionary (dictionary.cambridge.org/dictionary/english/residual) defines residual as: remaining after most of something is taken away. Thus, in the context of the invention, the examiner is interpreting residual to encompass that the subject having drug resistant epilepsy is characterized as having Phgdh activity which is lower, but still detectable than that of a normal subject not suffering from drug resistant epilepsy.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 18, 22, 24-34 and 36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “residual” in claim 1 and 36 is a relative term which renders the claim indefinite. The term “residual” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As noted in the claim interpretation above, residual is defined as remaining after most of something is taken away. As such, it is unclear if at least 50% activity remains, 40% and so on falls within the scope of the invention.
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, 22, 24-34 and 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 and 36 have been amended to recite “A method of treating drug-resistant epilepsy in a human individual having some residual Phgdh activity, the method comprising:
Detecting a residual level of Phgdh activity in the human individual….”. Thus, the claims are drawn to drug-resistant epilepsy characterized as having some residual Phgdh activity.
It is noted that the specification teaches residual Phgdh activity but associates this with one of the two severe recessive phenotypes of PhgdH deficiencies referred to as Classical Phgdh deficiency and cites Tabatabaie et al. (2011) J. Inherit Metab Dis. 34, 181-184 (see Specification, page 1, lines 14-16). When discussing drug resistant epilepsy, the specification teaches that drug resistant epilepsy might be associated with Phgdh malfunctioning/deficiency, but this appears to be a conclusion based on the second severe recessive phenotype of PhgdH deficiencies referred to as Neu-Laxova syndrome (NLS) type 1 which is characterized by severe, early onset, drug resistant epilepsy, wherein no Phgdh enzymatic activity has been reported so far (Specification, page 1, lines 18-22). Thus, the specification and claims, as originally filed, does not appear to correlate drug-resistant epilepsy having some residual Phgdh activity.
In arguments filed with the amendment, Applicants assert that support for the amendments is found throughout the present Specification and claims as originally filed, e.g. on page 1, lines 11-16 and Example 2. Applicants further provide evidence (see Appendix A) showing that the drug-resistant zebrafish model used in the Examples of the present Application exhibits some residual Phgdh activity. For example, Applicants contend that as shown in Fig. 1 of Appendix A:
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, Phgdh expression was significantly increased in HOM larvae compared with both WT and HET larvae, whereas no significant difference was observed between HET and WT larvae. Notably, Applicants contend that both WT and HET larvae exhibited some residual Phgdh expression.
In response, the Examiner has reviewed the portions of the specification cited, including Example 2 and Appendix A and provides the following comments:
Regarding the specification and specific teaching that Classical Phgdh deficiency is characterized by residual Phgdh activity and citation of Tabatabaie et al. (2011) J. Inherit Metab Dis. 34, 181-184, the Examiner recognizes that Tabatabaie et al.. reports on a mild form of 3-PGDH deficiency which displayed biochemical abnormalities indistinguishable from those with the severe phenotype, wherein the 3-PGDH enzyme activity in cultured skin fibroblasts showed residual activity compared to patients with the infantile phenotype (page 183, 2nd column, fist full paragraph). Of note, Tabatabaie et al. is silent on whether the seizures were drug resistant. Regarding Example 2 of the specification, the Examiner recognizes that while Example 2 provides two drug resistant epilepsy models in zebrafish (one model inducing epilepsy with EKP and one using a Scn1Lab mutant larvae which mimics Dravet syndrome), none of the models measure Phgdh activity.
Regarding Appendix A which corresponds to the Dravet syndrome of the specification (2nd experiment of Example 2), it is first noted that Figure 1 measures RNA expression level which is different than the actual enzymatic activity. In particular, there does not seem to be a 1 to 1 correlation between RNA expression and enzymatic activity. In other words, just because RNA expression may be higher, this does not necessarily correlate with an increased expression of enzymatic activity. Assuming, arguendo, that there is a reasonable correlation between RNA expression and enzymatic activity, the Examiner is confused on Applicants conclusion that both WT and HET larvae exhibited some residual Phgdh expression. For example, it would appear that WT or HET larvae would be the control, e.g. non-epileptic, and the HOM would be the seizure model. This appears to be consistent with Thevissen et al. (Epilepsia 2025; 66: 3769-3784, cited in previous office action) whom performed the same experiment on page 3778, 1st column, 1st full paragraph, Note: CQ is clioquinol:
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Thus, one would expect that the HOM would be lower (e.g. residual expression) vs. the control non-epileptic zebrafish larvae, WT and Het (see claim interpretation above). However, this is not the case and it appears that Phgdh is actually overexpressed compared to the control. Thus, if there is a direct correlation between RNA expression and enzymatic activity, the results actually show that there is increase in enzymatic activity in Dravet syndrome and NOT residual activity. Accordingly, the specification and claims as originally filed do not appear to provide explicit or implicit support for drug resistant epilepsy having some residual Phgdh activity.
Claims 18, 22, 24-34 and 36are 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 WRITTEN DESCRIPTION REJECTION.
The claims recite a method of treating drug-resistant epilepsy in a human individual having some residual Phgdh activity, the method comprising detecting a residual level of Phgdh activity in the human individual; and administering to the human individual a therapeutically effective amount of clioquinol or 8-hydroxyqinoline. Accordingly, the drug-resistant epilepsy is characterized as having some residual 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 residual Phgdh activity. 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.
Applicants response to the Non-Final rejection of 3/24/2026 includes Appendix A which attempts to show that the zebrafish model for Dravey syndrome implicitly shows residual Phgdh enzymatic activity. However, as set forth above in the New Matter rejection, it is first noted that Figure 1 measures RNA expression level which is different than the actual enzymatic activity. In particular, there does not seem to be a 1 to 1 correlation between RNA expression and enzymatic activity. In other words, just because RNA expression may be higher, this does not necessarily correlate with an increased expression of enzymatic activity. Assuming, arguendo, that there is a reasonable correlation between RNA expression and enzymatic activity, the Applicants conclusion that both WT and HET larvae exhibited some residual Phgdh expression is confusing. For example, it would appear that WT or HET larvae would be the control, e.g. non-epileptic, and the HOM would be the seizure model. This appears to be consistent with Thevissen et al. (Epilepsia 2025; 66: 3769-3784) whom performed the same experiment on page 3778, 1st column, 1st full paragraph, Note: CQ is clioquinol:
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Thus, one would expect that the HOM would be lower (e.g. residual expression) vs. the control non-epileptic zebrafish larvae, WT and Het (see claim interpretation above). However, this is not the case and it appears that Phgdh is actually overexpressed compared to the control. Thus, if there is a direct correlation between RNA expression and enzymatic activity, the results actually show that there is increase in enzymatic activity in Dravet syndrome and NOT residual 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, cited in prior office action) 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). Regarding residual Phdgh enzymatic activity and epilepsy, Tabatabaie et al. ((2011) J. Inherit Metab Dis. 34, 181-184) reports on a mild form of 3-PGDH deficiency which displayed biochemical abnormalities indistinguishable from those with the severe phenotype, wherein the 3-PGDH enzyme activity in cultured skin fibroblasts showed residual activity compared to patients with the infantile phenotype (page 183, 2nd column, fist full paragraph). Of note, Tabatabaie et al. is silent on whether the seizures were drug resistant.
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 drug-resistant epilepsy characterized by some residual Phgdh enzymatic activity. As such, Applicants are not in possession of a drug-resistant epilepsy characterized by some residual epileptic activity.
Conclusion
Therefore, No claim is allowed.
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.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRANDON J FETTEROLF/ Primary Examiner, Art Unit 1626
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