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 .
Priority
This application, filed on 01/06/2021, claims priority from U.S. Provisional Applications No. 62/698,558 filed on 07/16/2018 and PCT/MY2019/000025 filed on 07/16/2019.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/07/2026 has been entered.
DETAILED ACTION
The Applicant’s Amendment and Arguments submitted on 01/07/2026 have been received and have been carefully considered.
Claims 16 and 30 were amended, and claims 1-15, 17-18, and 21, were previously cancelled. Claims 16, 19-20 and 22-30 are pending.
Rejection Maintained/Slightly Modified in view of the Amendment
Claim Rejections - 35 USC § 103
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 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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 16, 19-20, and 22-30 remain rejected under 35 U.S.C. 103 as being unpatentable over U. Heresco-Levy (WO 2014/191992A1, 12/04/2014, “Heresco-Levy” cited on the previous PTO-892 dated 08/23/2023) in view of H. Lane et al. (JAMA Psychiatry. 2013; 70(12):1267-1275, “Lane” cited in the previous PTO-892 dated 08/23/2023), Y. Wang et al. (J. Neuroimmunol. 2017 Nov 15; 312:59-65, “Wang” cited in the PTO-892 dated 08/01/2024), and H. Guan et al. (Neuroimmunology and Neuroinflammation, 2016 3. 189, “Guan” cited in the previous PYO-892 dated 08/23/2023).
Applicants’ claimed invention is directed to a method for treating anti-N-methyl-D-aspartate receptor (anti- NMDAR) encephalitis in a subject in need thereof, comprising administering to the subject an effective amount of a benzoic acid salt in combination with an immune therapy with intravenous immunoglobulin, wherein the subject is refractory to immune therapy, plasmapheresis, and/or pulse therapy with a steroid, and wherein the benzoic acid salt is sodium benzoate.
With respect to claim 16, Heresco-Levy teaches a method of mitigating the severity of lowering the incidence of NMDAR antibody production and treating a disease associated with NMDAR antibody production, comprising administering a NMDAR agonist, D-amino acid oxidase inhibitor, wherein the disease associated with NMDAR antibody is anti-NMDAR encephalitis, [Pg. 7, [0026-0027], claim 5], wherein the D-amino acid oxidase inhibitor is benzoic acid, [Claim 14], and wherein the method further comprises combination with immunotherapy [Pg. 10, [0039]]. Heresco-Levy teaches that the D-amino acid oxidase inhibitor, benzoic acid is administered at a dosage of 500-2000 mg/day, [Claim 14]. Heresco-Levy teaches that the patients selected for the studies have treatment-resistance to pharmacotherapy with presently available antipsychotic drugs. [Pg. 13, [0060]]. Heresco-Levy also teaches an example wherein a patient is refractory to treatment with various classes of antipsychotic drugs. [Pg. 14, [0064]].
Heresco-Levy teaches that immunotherapy is the most important component in the treatment of anti-NMDAR encephalitis, wherein 5 -days course of concurrent IVIG (intravenous immunoglobulin) and methyl prednisolone should be given, and if clear improvement is seen within 10 days, supportive care should be continued. [Pg. 4, [0014]].
While Heresco-Levy teaches the use of benzoic acid in an amount of 200-2000 mg/day for treating anti-NMDAR encephalitis and that Heresco-Levy’s IVIG refers to intravenous immunoglobulin as evidenced by Wang, Heresco-Levy does not specifically teach benzoic acid salt, sodium benzoate in combination of immunoglobulin immunotherapy. Also, while Heresco-Levy teaches that the patients are refractory to available therapy, Heresco-Levy does not specifically teach refractory to the therapy recited in amended claim 1.
However, this deficiency is cured by Lane, Wang and Guan.
In the same field of endeavor, Lane teaches a method of using D-amino acid oxidase inhibitor, sodium benzoate for enhancing NMDAR-mediated neurotransmission and treating disorder mediated by hypofunction of the N-methyl-D-aspartate receptor, wherein patients with schizophrenia treated with antipsychotic medications were treated with 1000 mg/day of sodium benzoate for six weeks. Lane teaches that sodium benzoate enhances NMDAR function, produced significant improvement of symptoms and neurocognition in patients and its well tolerated without significant adverse effects. [Lane, Abstract].
In the same field of endeavor, Wang teaches treatment for anti-NMDAR encephalitis in children, who are patients, wherein the patients received first-line immunotherapy and a second-line immunotherapy and more than 86% of the patients achieved good outcomes, wherein the first-line immunotherapy is intravenous methylprednisolone or intravenous immunoglobulin (IVIG, 0.4 g/kg per day for 5 days). [Wang, Abstract, pg. 61, col. 2, 2nd para., and Table 3].
In the same field of endeavor, Guan teaches administration of N-methyl-D-aspartate (NMDA)-agonist, to a patient with anti-NMDAR encephalitis refractory to immunotherapy, wherein administration of NMDA-agonist improved patient’s symptoms gradually and significantly. [Abstract]. Guan teachings and case report proved that NMDA-agonists can be great option for anti-NMDAR encephalitis refractory to immunotherapy. [Guan entire document].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to combine the teachings of the cited references and substitute Heresco-Levy’s D-amino acid oxidase inhibitor, benzoic acid, with other D-amino acid oxidase inhibitors, such as 1000 mg/day sodium benzoate, taught by Lane in treating anti-NMDAR encephalitis in a subject refractory to immune therapy as taught by Guan. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because Heresco-Levy teaches D-amino acid oxidase inhibitor, benzoic acid for treating anti-NMDAR encephalitis and Lane teaches a method of using D-amino acid oxidase inhibitor, sodium benzoate for treating disorder mediated by hypofunction of the N-methyl-D-aspartate receptor and teaches that sodium benzoate enhances NMDAR function and NMDAR-mediated neurotransmission, produced significant improvement in patients, and its well tolerated without significant adverse effects.
One of ordinary skill in the art would have been motivated with reasonable expectation of success to combine sodium benzoate with immunoglobulin in treating anti-NMDAR encephalitis because Heresco-Levy teaches that intravenous immunoglobulin immunotherapy is the most important components in the treatment of anti-NMDAR encephalitis, and Wang teaches treating patients with anti-NMDAR encephalitis with immunoglobulin immunotherapy as a first-line therapy achieved good outcomes. Moreover, immunoglobulin as taught by Heresco-Levy and Wang is the first-line therapy for anti-NMDAR encephalitis, and benzoate is taught by Heresco-Levy and Lane for treating the very same condition, anti-NMDAR encephalitis, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
One of ordinary skill in the art would have been motivated to treat anti-NMDAR encephalitis in a subject refractory to immune therapy because Heresco-Levy teaches that the NMDAR agonist treat subject refractory to pharmacotherapy with presently available antipsychotic drugs and various classes of antipsychotic drugs, and Guan teaches that administration of NMDA-agonist, to a patient with anti-NMDAR encephalitis refractory to immunotherapy improved patient’s symptoms gradually and significantly.
Therefore, one of ordinary skill in the art would have been motivated to substitute Heresco-Levy’s D-amino acid oxidase inhibitor with Lane’s D-amino acid oxidase inhibitor, sodium benzoate, and combine sodium benzoate with immunoglobulin immunotherapy for treatment of anti-NMDAR encephalitis refractory to immune therapy, to arrive at each and every structural/method limitation of claim 16. Claim 16 new recitation of:
“… wherein a psychotic symptom is reduced, wherein the psychotic symptom comprises dissociation, agitation or a combination thereof …”,
are inherently met by the administration of 1000 mg/day sodium benzoate to subjects because they necessarily flow from the administration. MPEP § 2112. Furthermore, claim scope is not limited by claim language that does not limit a claim to a particular structure. MPEP § 2111.04 (citing In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005) (whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited). The above claim 16 limitations do not limit the method steps in any fashion, but merely reflect the intended result of the claimed administration.
Moreover, the combination of Heresco-Levy, Lane, Wang, and Guan teach a method for treating anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis in a subject in need thereof by administering sodium benzoate. the combination of Heresco-Levy, Lane, Wang, and Guan are silent on the positive effects of sodium benzoate administration of reducing dissociation and agitation but otherwise teaches a substantially identical method as claimed. As such, it is reasonable to presume that the resulting psychotic symptom is inherently reduced. The burden is on Applicant(s) to show that this property is different from those taught by the prior art and to establish patentable differences. See MPEP 2112.
With regard to claim 19, Heresco-Levy teaches that the antibodies of patients with anti-NMDAR encephalitis decrease the surface density and synaptic localization of NMDAR clusters via antibody mediated capping and internalization, [Pg. 3, [0011]].
With regard to claim 20, Heresco-Levy teaches that the method enhances NMDAR-mediated neurotransmission for encephalitis associated with antibodies against NMDAR, [Pg. 5, [0019]].
With regard to claims 22-24, Heresco-Levy teaches that the D-amino acid oxidase inhibitor, benzoic acid is administered at a dosage of 500-2000 mg/day, [Claim 14].
With regard to claims 25-26, and 28, Heresco-Levy teaches an example wherein a patient refractory to treatment with various classes of antipsychotic drugs is treated with the different doses of NMDAR agonist while the ongoing antipsychotic medication remained fixed throughout the study of 6 weeks. [Pg. 14-15, [0064-0066]].
With regard to claim 27, Heresco-Levy teaches a method of treating anti-NMDAR encephalitis comprising administering an agent, which is an NMDAR agonist, an alanine-serine-cysteine transporter inhibitor, a D-amino acid oxidase inhibitor, a glycine transport inhibitor, D-cycloserine or a combination thereof, [Pg. 7, [0026]]. Heresco-Levy also teaches that the method includes other active agents, [Pg. 12, [0050]]. Administering a combination of NMDAR agonist reads on claim 27 “in combination with an additional active ingredient”.
With regard to claims 29 and 30, Heresco-Levy teaches that the method further comprises combination with immunotherapy, [Pg. 9, [0039]]. The immunotherapy is interpreted as one of the additional therapies taught by the specification. Furthermore, Heresco-Levy teaches that the above patient underwent treatment with antipsychotic drugs and electroconvulsive therapy and no changes in theses medication were performed when the patient treated with different doses of the NMDAR agonist, [Pg. 14, [0064] and Pg. 15, [0066]].
Response to Arguments
Applicant argues:
"contrary to the Examiner's assertion, Lane does not disclose sodium benzoate as an NMDAR agonist. Rather, Lane teaches that sodium benzoate functions by inhibiting the metabolism of D-amino acids, thereby increasing endogenous D-amino acid levels, which in turn indirectly enhances NMDA receptor function and further enhances NMDAR-mediated neurotransmission. In particular, the abstract of Lane explicitly states that "[a]nother method to enhance NMDA function is to raise the levels of d-amino acids by blocking their metabolism. Sodium benzoate is a d-amino acid oxidase inhibitor." Accordingly, Lane attributes the observed effects to a metabolic inhibition mechanism upstream of the NMDA receptor, rather than to any direct agonistic or co- agonistic activity at the NMDAR itself, as alleged by the Examiner.
In contrast to this, Guan reports clinical results demonstrating that D-cycloserine, used as a partial NMDA receptor agonist, improved outcomes in anti-NMDAR encephalitis patients who are refractory to first-line and second-line immunotherapies. Moreover, page 190 of Guan explicitly explains that the cellular mechanism of anti- NMDAR encephalitis involves autoantibody-mediated cross-linking and internalization of NMDARs, resulting in a reduced density of receptors on the neuronal surface and, consequently, insufficient NMDAR-mediated neurotransmission. Based on this shared pathological basis and therapeutic rationale, Guan proposes the use of NMDA receptor agonists capable of enhancing NMDAR activity to compensate for signaling deficits resulting from receptor loss. [Remarks, pg. 1-2].
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive. Heresco-Levy teaches a method of treating anti-NMDAR encephalitis by administering a NMDAR agonist, D-amino acid oxidase inhibitor, [Pg. 7, [0026-0027], claim 5], wherein the D-amino acid oxidase inhibitor is benzoic acid, [Claim 14]. Lane teaches a method of using D-amino acid oxidase inhibitor, sodium benzoate for treating disorder mediated by hypofunction of the N-methyl-D-aspartate receptor by administering 1000 mg/day of sodium benzoate. Lane teaches that sodium benzoate enhances NMDAR function. [Lane, Abstract]. Thus, Lane explicitly teaches that sodium benzoate is D-amino acid oxidase inhibitor, and Heresco-Levy teaches that anti-NMDAR encephalitis treated by administering D-amino acid oxidase inhibitor, and specifically teaches benzoic acid as D-amino acid oxidase inhibitor. Therefore, Skilled artisan would have been motivated to use a D-amino acid oxidase inhibitor such as sodium benzoate for treating anti-NMDAR encephalitis. Moreover, Lane teaches explicitly teaches that sodium benzoate enhances NMDAR function, which indicates that sodium benzoate act as a NMDAR agonist. Regardless of how sodium benzoate enhances the function of NMDAR and what its mechanism, sodium benzoate is D-amino acid oxidase inhibitor that function as a NMDAR agonist. Note that obviousness does not require absolute predictability, but a reasonable expectation of success. See MPEP 2143.02. Heresco-Levy and Lane provide skilled artisan with the requisite reasonable predictability to utilize Lane’s D-amino acid oxidase inhibitor, sodium benzoate in place of D-amino acid oxidase inhibitor, benzoic acid to predict success in treating anti-NMDAR encephalitis.
In response to applicant's argument that “Guan teaches direct promotion of receptor activation through mechanisms that are fundamentally distinct and not interchangeable”, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Guan would motivate skilled artisan to treat anti-NMDAR encephalitis in a subject refractory to immune therapy utilizing Heresco-Levy and Lane method because Guan teaches that administration of NMDA-agonist, to a patient with anti-NMDAR encephalitis refractory to immunotherapy improved patient’s symptoms gradually and significantly. See MPEP 2143.02.
Applicant argues:
Although Heresco-Levy discusses agents involved in the modulation of NMDAR activity, which include NMDA receptor agonists, ASC-1 transporter inhibitors, DAAO inhibitors, glycine transport inhibitors, and sodium benzoate, Heresco-Levy fails to teach or suggest that sodium benzoate is an NMDA receptor agonist. To the contrary, as expressly stated in paragraph [0042] of Heresco- Levy, D-serine used in the experimentation of Heresco-Levy is an NMDA receptor agonist. Moreover, based on the clinical results disclosed in paragraphs [0064]-[0074] of Heresco-Levy, a person of ordinary skill in the art could only learn that D-serine exhibits therapeutic efficacy in treating schizophrenia refractory to antipsychotic drugs. Heresco-Levy provides no teaching, suggestion, or reasonable inference regarding the therapeutic effects of DAAO inhibitors, nor does Heresco-Levy permit extrapolation of the results obtain with an NMDA receptor agonist to a DAAO inhibitor.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091,231 USPQ 375 (Fed. Cir. 1986). Lane teaches a method of using D-amino acid oxidase inhibitor, sodium benzoate for treating disorder mediated by hypofunction of the N-methyl-D-aspartate receptor, and Heresco-Levy teaches that anti-NMDAR encephalitis treated by administering D-amino acid oxidase inhibitor. Therefore, Skilled artisan would have been motivated to use a D-amino acid oxidase inhibitor such as sodium benzoate for treating anti-NMDAR encephalitis.
Heresco-Levy expressly teaches that NMDAR agonist is D-serine, glycine or the D-amino acid oxidase inhibitor benzoic acid [see Heresco-Levy claim 14]. Heresco-Levy provides examples for treating anti-NMDAR Encephalitis using D-serine or glycine, but teaches that “it will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof.” [see Heresco-Levy, pg. 21, 0077]. patents are relevant as prior art for all they contain and “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994),” see MPEP 2123.
Applicant argues:
Additionally, Wang is limited to immunotherapeutic therapies for the treatment of anti-NMDAR encephalitis and does not mention NMDA receptor agonists or DAAO inhibitors for such treatment. Accordingly, Wang is silent on the modulation of NMDAR
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive when Wang is combined with the cited references. One of ordinary skill in the art would have been motivated with reasonable expectation of success to combine sodium benzoate with immunoglobulin in treating anti-NMDAR encephalitis because Wang teaches treating patients with anti-NMDAR encephalitis with immunoglobulin immunotherapy as a first-line therapy achieved good outcomes. Moreover, immunoglobulin as taught by Heresco-Levy and Wang is the first-line therapy for anti-NMDAR encephalitis, and benzoate is taught by Heresco-Levy and Lane for treating the very same condition, anti-NMDAR encephalitis, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Applicant argues:
The Examples presented in the specification of the present application demonstrate that the treatment with a combination of sodium benzoate and IVIg is effective in treating anti-NMDAR encephalitis in subjects' refractory to immune therapy, plasmapheresis and/or steroid pulse therapy. The disclosed combination therapy further ameliorates the psychotic symptoms, including dissociation and agitation, and accordingly improves patients' cognitive function. Importantly, the unexpected clinical benefits demonstrated in the Examples, namely, efficacy in patients unresponsive to multiple immune-based therapies and the marked improvement of psychotic symptoms and cognitive function, could not have been predicted from the cited art.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive. It appears that Applicant is attempting to show unexpected results. As provided in MPEP 716 (b), the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). "[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). However, in the instant case, the applicant’s aforementioned results appear to be statistically insignificant in view of the teachings of Heresco-Levy and Lane, because Heresco-Levy teaches clinical trial results to anti-NMDAR encephalitis patient who are refractory to other therapy, [Pg. 14, [0064]], wherein the patient administered NMDAR agonist, D-serine, and the patient underwent multiple assessments including neurocognitive examinations, motor and psychiatric symptoms as well as side-effects, cognitive performance, accuracy and speed of performance in major cognition domains, including attention/vigilance, planning, short-term and working memory, decision making, abstraction and mental flexibility, wherein the quality of life of the patient improved considerably during treatment with NMDAR agonist, and all the symptoms improved during the treatment with NMDAR agonist including favorable effect upon cognitive performance, improvements in the domains of working memory, abstraction and mental flexibility. [pg. 15-17, [0065]-0072]]. As such, ameliorates the psychotic symptoms, including dissociation and agitation, and accordingly improves patients' cognitive function appears to be a property of the NMDAR agonist e.g., benzoic acid and sodium benzoate, and it is expected that sodium benzoate administration would also show improvement in these symptoms.
Conclusion
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/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622