METHOD OF TREATING AMYOTROPHIC LATERAL SCLEROSIS WITH PRIDOPIDINE

§102 §103 §112 §DP

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 is a Continuation-in-Part from U.S. application Ser. No. 18/416,210 filed Jan. 18, 2024, which is a Continuation-in-Part from U.S. application Ser. No. 18/172,927 filed Feb. 22, 2023, which is a Continuation-in-Part from U.S. application Ser. No. 17/076,069 filed Oct. 21, 2020, which is a Continuation-in-Part application from U.S. application Ser. No. 16/789,564 filed Feb. 13, 2020, which is a Continuation-in-Part application from International Patent Application No. PCT/US2018/046481 filed Aug. 13, 2018, which claims the benefit of U.S. Provisional Application No. 62/545,315, filed Aug. 14, 2017. Information Disclosure Statement The information disclosure statement (IDS) filed on 18 November 2025 has been acknowledged and considered. Claim Objections Claim 1 is objected to for minor informalities. Claim 1 recites “ALS.” To avoid confusion, acronyms should be defined in the claims, at least in the first instance (e.g., change “ALS” to “amyotrophic lateral sclerosis (ALS).” Appropriate correction is required. Claim Rejections - 35 USC § 112(b) 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. The term “faster” recited in claims 12-13 and 16 is a relative term which renders the claim indefinite. The term “faster” 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. Applicant may overcome the rejection by deleting “faster” or by adding a standard for the term “faster” to the claims from which the claimed disease progression is compared to. Claim Rejections - 35 USC § 102 The following is a quotation of the appropriate paragraphs of 35 U.S.C. § 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claims 1-4, 8, 20-21 and 23 are rejected under 35 U.S.C. 102((a)(1)/(a)(2)) as being anticipated by WO2016138135 (“Squitieri”), evidenced by Toffola et al., Medicina 2025, 61(9), 1685 (“Toffola”). Claims 1-4 and 8 are drawn to “maintaining, improving, or lessening the decline of” specific symptoms associated with ALS. Squitieri teaches a method of treating neurodegenerative disorders such as amyotrophic lateral sclerosis (p. 9, lines 25-26; p. 50, claim 5) by administering a composition comprising pridopidine to a subject (p. 12, lines 17-23; p. 13, line 13-21; p. 20, line 15; claim 11). The term “treatment” is defined by Squitieri such that it encompasses lessening, removing, etc. symptoms of the disorder (p. 12, lines 25-30). Indeed, Squitieri discloses treating motor symptoms. (p. 32, lines 1-7). Thus, Squitieri discloses the active step in the claims of administering pridopidine to an ALS subject. The intended result language recited in the claim preamble is considered a result of the administering step and therefore would be inherent in the administering of the pridopidine to the subject. (MPEP §2111.04 (I)). For example, Toffola, in Table 1, displays the trials that have been conducted to date and the primary endpoints measured in different protocols. Toffola states: “Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting both upper and lower motor neurons (UMNs and LMNs), characterized by the progressive development of muscle weakness and motor dysfunction. In up to 50% of cases, extra-motor manifestations are also observed, including cognitive impairment, executive dysfunction, and language deficits; 10–15% of patients meet the diagnostic criteria for frontotemporal dementia (FTD).” (p. 1). Based on Toffola, the claimed symptoms are present in about half of the patient population for ALS subjects. With respect to claims 20-21, administration of pridopidine in Example 1 was daily (p. 27, line 25) and can also be administered orally (p. 11, line 31). With respect to claim 23, the HCl salt is taught (p. 12, line 20). Accordingly, the teachings of Squitieri anticipate claims 1-4, 8, 20-21 and 23. Claim Rejections - 35 USC § 103 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. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claims 1-5, 7-8, 20-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Squitieri in view of Clinical Trial Nuedexta in Subjects With ALS, Identifier: NCT01806857, March 2013 – February 2017, Accessed 11 June 2026 (“NCT01806857”). Squitieri teaches a method of treating neurodegenerative disorders such as amyotrophic lateral sclerosis (p. 9, lines 25-26; p. 50, claim 5) by administering pridopidine (p. 20, line 15; p. 13, line 13-21; claim 11) or its HCl salt (p. 12, line 20). Administration of pridopidine in Example 1 was daily (p. 27, line 25) and can also be administered orally (p. 11, line 31). The dose of pridopidine can be further optimized to achieve a therapeutic response without undue adverse events and commensurate with a reasonable benefit/risk ratio (p. 12, line 32 - p. 13, line 12). Pridopidine is taught to be a S1R modulator (p. 13, lines 17-19) and would lessen or remove symptoms of the disorder (p. 12, lines 25-30). Dextromethorphan is taught to be an agonist of the S1R receptor (p. 13, line 31; claim 13) and was tested individually in Example 9 (p. 38, lines 19-32). Squitieri does not teach administering sequential therapy of pridopidine and the dextromethorphan/quinidine combination medication or the inclusion criteria of patients that would be eligible to receive pridopidine. NCT01806857 teaches administration of Nudexta to ALS patients to determine whether Nuedexta is effective in the treatment of symptoms (impaired speech, swallowing, and saliva control) associated with ALS (Brief Summary). The Inclusion Criteria identifies patients with bulbar dysfunction manifested by dysarthria and/or dysphagia and slow vital capacity (SVC) ≥ 50%, were eligible to receive Nudexta to treat ALS (Recruitment Information). Some of the outcomes measured include the Bulbar Function Scale (CNS-BFS) total score and the ALSFRS-R total score (Outcome Measures, Primary and Secondary). Nudexta is also known as dextromethorphan hydrobromide and quinidine sulfate (Trial Description, Intervention). Squitieri and NCT01806857 are analogous art to the claimed invention because they are in the same field of administering a therapeutic to a subject possessing ALS. Therefore, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention, to follow the teachings of Squitieri to administer pridopidine, or its HCl salt, orally to a subject having ALS, and further incorporate the teachings of NCT01806857 to administer a dose of pridopidine to patients having impaired speech and swallowing, and a higher SVC. The claimed invention is a combination of prior art elements according to known methods, which to a PHOSITA, would yield predictable results. Furthermore, the teachings of Squitieri and NCT01806857 implicitly establish pridopidine and Nudexta are equivalents since they are both taught to be administered to patients having ALS. Therefore, it would have been prima facie obvious to substitute Nudexta with pridopidine to treat symptoms like impaired speech, swallowing, and saliva control in patients having ALS (MPEP §2144.06(I-II)). Accordingly, claims 1-5, 8, 21, and 23 are prima facie obvious. Regarding claim 7, NCT01806857 teaches the primary outcome measured as a result of Nudexta treatment is the Bulbar Function Scale (CNS-BFS) total score (Outcome Measures, Primary). It would have been prima facie obvious to substitute pridopidine, taught by Squitieri, for Nudexta, taught by NCT01806857, to treat the symptoms associated with ALS and measure the improvement through the CNS-BFS scale (MPEP §2144.06(II)). Regarding claim 17, NCT01806857 teaches the secondary outcome measured as a result of Nudexta treatment is improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) (Outcome Measures, Secondary). It would have been prima facie obvious to substitute pridopidine, taught by Squitieri, for Nudexta, taught by NCT01806857, to treat the symptoms associated with ALS and measure the improvement through the ALSFRS-R (MPEP §2144.06(II)). Claims 6 is rejected under 35 U.S.C. 103 as being unpatentable over Squitieri in view of Clinical Trial Ceftriaxone in Subjects With ALS, Identifier: NCT00349622, July 2006 – April 2014, Accessed 11 June 2026 (“NCT00349622”), evidenced by Rooney J, et al. J Neurol Neurosurg Psychiatry 2016;0:1–5 (“Rooney”). The teachings of Squitieri are discussed above and are incorporated by reference herein. Regarding claim 6, Squitieri does not teach assessing improvement of symptoms after administration of pridopidine by measuring the ALSFRS-R bulbar subdomain (Ql-Q3) score. NCT00349622 teaches assessing the safety and efficacy of ceftriaxone treatment in patients having ALS (Trial Description, Brief Summary). The primary outcome measured as a result of ceftriaxone treatment is change from baseline in ALSFRS-R at One Year [Time Frame: Every 8 weeks for one year]. The ALSFRS-R is a quickly administered (five minute) ordinal rating scale used to determine patients' assessment of their capability and independence in 12 functional activities/questions. The 12 functional activities/questions are rated on a scale of 0 to 4 for a total scoring range of 0-48, with 48 representing optimal function. All 12 activities are relevant in ALS. As evidenced by Rooney, ”… the ALSFRS-R scale captured information corresponding to three latent domains corresponding to bulbar, motor and respiratory functions. The domains were defined as follows: Bulbar score=the sum of ALSFRS-R questions 1–3 (maximum score of 12), motor score= the sum of ALSFRS-R questions 4–9 (maximum score of 24) and finally respiratory score=the sum of ALSFRS-R questions 10–12 (maximum score of 12).” (p. 2, 1st column). Squitieri and NCT00349622 are considered analogous art because they are in the same field of administering therapies to treat patients having ALS. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective filing date of the claimed invention, to combine the teachings of Squitieri and NCT00349622 to arrive at the method instantly claimed. Administering pridopidine, as taught by Squitieri, and assessing the ALFRS-R bulbar subdomain would have yielded reasonably predictable results because NCT00349622 teaches measuring all 12 activities of the ALSFRS-R scale, including the bulbar subdomain, are relevant in ALS (MPEP §2144.06(I)). Claims 9, 15, and 24-28 are rejected under 35 U.S.C. 103 as being unpatentable over Squitieri in view of Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS (MITOTARGET), Identifier: NCT00868166, March 2009 – February 2020, Accessed 11 June 2026 (“NCT00868166”) and Triumeq in Amyotrophic Lateral Sclerosis (LIGHTHOUSE II), Identifier: NCT05193994, December 2021 – July 2025, Accessed 11 June 2026 (“NCT05193994”), evidenced by Miller et al., Neurology 1997; 48(Suppl4):S28432 (“Miller”). The teachings of Squitieri are discussed above and are incorporated by reference herein. Regarding claims 9 and 15, Squitieri does not teach administering pridopidine to patients having a TRICALS Risk Score between >6 and<-2, a disease duration <18 months from symptom onset, and a Slow Vital Capacity (SVC) ≥60% of predicted according to GLI-2012 standards nor does it teach administering pridopidine to patients having early ALS with less than 18 months from symptom onset. NCT00868166 teaches the assessment of the safety and efficacy of TRO19622 330 mg QD as add-on therapy to riluzole 50 mg BID in the treatment of patients suffering from ALS, as compared to placebo, assessed by the 18-month survival rate (Trial Description, Brief Summary). The Inclusion Criteria identifies patients with Onset of ALS Symptoms (weakness) for more than 6 months (inclusive) and less than 36 months (inclusive) and SVC measured three times, one of the measures being ≥ 70% of that predicted (Recruitment Information, Eligibility Criteria). NCT00868166 does not include patients with a TRICALS Risk Score between > 6 and < -2. NCT05193994 teaches administration of Triumeq to assess improvement of survival in Amyotrophic Lateral Sclerosis (ALS) compared with placebo (Trial Description, Brief Summary). The Inclusion Criteria identifies patients with a TRICALS risk profile > -6.0 and < -2.0 (Recruitment Information, Eligibility Criteria). Squitieri, NCT00868166, and NCT05193994 are all considered analogous art because they are in the same field of administering therapies to treat ALS. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective filing date of the claimed invention, to combine the teachings of Squitieri, NCT00868166, and NCT05193994 to arrive at the method instantly claimed. Substituting pridopidine, as taught by Squitieri, for the therapies taught in NCT00868166 and NCT05193994 would have been prima facie obvious to a PHOSITA because the therapies taught are to increase survival in patients having ALS (MPEP §2144.06(II)). Furthermore, a PHOSITA would have yielded reasonably predictable results to include patients having a TRICALS Risk Score between >6 and<-2, a disease duration <18 months from symptom onset, and a Slow Vital Capacity (SVC) ≥60% of that predicted because those are the specific patient populations taught to be treated by administration of an ALS therapy in NCT00868166 and NCT05193994 (MPEP §2144.06(I)). Regarding claims 24-28, NCT00868166 teaches administering TRO19622 as an add-on therapy to riluzole, to patients having ALS. It would have been prima facie obvious to administer in combination pridopidine, as taught by Squitieri, and riluzole, as taught by NCT00868166, to patients having ALS because they are equivalents known for the same purpose (MPEP §2144.06(I)). Furthermore, a PHOSITA would have recognized dosing as a result-effective variable based on the evidence provided by Miller which states: “Treatments might include combinations of drugs from different categories, such as a glutamate antagonist plus a neurotrophic factor, or combinations from the same therapeutic category, such as two neurotrophic factors. Because riluzole is the only drug now approved for the treatment of ALS, combination trials in the near future should include riluzole as the “standard therapy to which other drugs will be added.” (p. S31, Future Directions). Thus, a PHOSITA would have recognized modifications of dosing parameters amounts to routine optimization (MPEP §2144.05(II)). Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Squitieri in view of Radicava® (Edaravone) Findings in Biomarkers From ALS (REFINE-ALS), Identifier: NCT04259255, 4 February 2020 – 3 August 2022, Accessed 11 June 2026 (“NCT04259255”) and Identification of Early Markers for ALS (PremodiALS), Identifier: NCT07213440, January 2025 – October 2025 (“NCT07213440”). The teachings of Squitieri are discussed above and are incorporated by reference herein. Regarding claims 10-11, Squitieri does not assessing improvement of symptoms after administration of pridopidine by measuring Nfl levels or glial fibrillary acidic protein (GFAP). NCT04259255 teaches a prospective, observational, longitudinal, multicenter study designed to identify biomarkers to serve as quantifiable biological non-clinical measures of Edaravone effects in ALS (Oversight, Brief Summary). The primary outcomes measured includes assessing changes in levels of neurofilaments (Nf) (Heavy and Light) as a potential biomarker of oxidative stress, inflammation or neurodegeneration (Outcome Measures, Primary). NCT04259255 does not teach assessing GFAP levels. NCT07213440 teaches a clinical molecular fingerprint of Premotor gene mutation carriers (PGMC) that will provide insight into the molecular pathogenesis of ALS and allow earlier diagnosis (Trial Description, Brief Summary). The primary outcomes measured include GFAP from plasma and CSF in Premotor gene mutation carriers vs. Control group and Early ALS vs. ALS Mimics by single molecule array (SIMOA) technology. Squitieri, NCT04259255 and NCT07213440 are all considered analogous art because they are in the same field of treating ALS and/or assessing relevant biomarkers of ALS. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective filing date of the claimed invention, to combine the teachings of Squitieri, NCT04259255, and NCT07213440 to arrive at the method instantly claimed. Administering pridopidine, as taught by Squitieri, and assessing Nfl levels, as taught by NCT04259255, and GFAP levels, as taught by NCT07213440 would have had yielded reasonably predictable results because those biomarkers are taught to be assessed by NCT04259255 and NCT07213440 in patients having ALS (MPEP §2144.06(I)). Claims 12 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Squitieri in view of A Clinical Trial of Safety and Efficacy of Fasudil in Subjects With Amyotrophic Lateral Sclerosis (ALS), Identifier: NCT01935518, 1 September 2013 – 6 September 2013 Accessed 11 June 2026 (“NCT01935518”). The teachings of Squitieri are discussed above and are incorporated by reference herein. Regarding claims 12 and 16, Squitieri does not teach administering pridopidine to patients having faster disease progression as measured by the ALSFRS-R pre-baseline slope and early ALS with <18 months from symptom onset. NCT01935518 teaches administering fasudil to assess effectiveness and safety in treating patients with ALS (Trial Description, Brief Summary). The Inclusion Criteria identifies patients with decline of ALSFRS-R in the last 3 months before enrollment: 1-8 and Disease duration: 3-36 months (Recruitment Information, Eligibility Criteria). Squitieri and NCT01935518 are considered analogous art because they are in the same field of administering therapies to treat ALS. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective filing date of the claimed invention, to combine the teachings of Squitieri and NCT01935518 to arrive at the method instantly claimed. Substituting pridopidine, as taught by Squitieri, for the therapy taught in NCT01935518 would have been prima facie obvious to a PHOSITA because the therapy taught is administered to increase survival in patients having ALS (MPEP §2144.06(II)). Furthermore, a PHOSITA would have yielded reasonably predictable results to include patients with decline of ALSFRS-R in the last 3 months before enrollment: 1-8 and Disease duration: 3-36 months because those are the specific patient populations taught to be treated by administration of an ALS therapy in NCT01935518 (MPEP §2144.06(I)). Claims 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Squitieri in view of Mach et al., Cor et Vasa (2015) e320-e322 (“Mach”) and Blasco et al., Expert Opinion on Pharmacotherapy, 17:12, 1669-1682. (“Blasco”). The teachings of Squitieri are discussed above and are incorporated by reference herein. Regarding claims 13 and 14, Squitieri does not teach administering pridopidine to patients having faster disease progression as measured by NfL levels, GFAP, YKL-40 or combination thereof, nor does it teach assessing the biomarker cardiac Troponin T (cTnT). Mach teaches, “…a possible connection between chronic elevations in cTnT levels and the evolution of ALS symptoms in a patient without overt clinical evidence of cardiovascular disease, and it raises the need to further investigate this phenomenon in other patients with progressive ALS.” (p. e322, Discussion). Blasco teaches: “Age at onset, site of onset, FVC, change in body mass index, symptom duration, and calculations derived from ALSFRS-R scores (at first examination as well as the ratio between first symptom and first examination/time to diagnosis) are useful clinical markers.” Blasco also states: “The approach has identified elevated levels of neurofilament (NfL), which may, in part, be a result of corticospinal tract degeneration in ALS.” (pp. 1672-1673, 4.3 The Importance of Biomarkers). Squitieri, Mach and Blasco are all considered analogous art because they are in the same field of treating and/or assessing relevant biomarkers of ALS. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective filing date of the claimed invention, to combine the teachings of Squitieri, Mach, and Blasco to arrive at the method instantly claimed. Administering pridopidine, as taught by Squitieri, and assessing cTnT, as taught by Mach, and Nfl, as taught by Blasco would have yielded reasonably predictable results because those biomarkers are taught to be assessed, by Mach and Blasco, in patients having ALS (MPEP §2144.06(I)). Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Squitieri in view of Jenkinson et al., , Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders, 1:1, 33-40 (“Jenkinson”). The teachings of Squitieri are discussed above and are incorporated by reference herein. Regarding claim 18, Squitieri does not assess improvement of symptoms after administration of pridopidine by measuring the ALS Assessment Assessment Questionnaire-40 (ALSAQ-40). Jenkinson teaches that the ALSAQ-40 has high levels of reliability and validity and can be used as an outcome measure in studies evaluating new treatment regimens and therapies in ALS (p. 33, Conclusion). Squitieri and Jenkinson are considered analogous art because they are in the same field of assessing outcome measures of therapies towards ALS. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective filing date of the claimed invention, to combine the teachings of Squitieri and Jenkinson to arrive at the method instantly claimed. Administering pridopidine, as taught by Squitieri, and assessing the ALSAQ-40 questionnaire would have yielded reasonably predictable results because Jenkinson teaches ALSAQ-40 has high levels of reliability and validity and can be used as an outcome measure in studies evaluating new treatment regimens and therapies (MPEP §2144.06(I)). Claims 19 is rejected under 35 U.S.C. 103 as being unpatentable over Squitieri in view of Safety Extension Study of Oral Edaravone Administered in Subjects With Amyotrophic Lateral Sclerosis (ALS), Identifier: NCT04577404, September 2020 – May 2026 (“NCT04577404”). The teachings of Squitieri are discussed above and are incorporated by reference herein. Regarding claim 19, Squitieri does not assess survival through Week 96, with death equivalents defined as tracheostomy or permanent assisted ventilation (>22 hours/day for >7 consecutive days). NCT04577404 teaches a Phase 3, international, multicenter, open-label, long-term extension study. The primary objective of this study is to evaluate the long-term safety and tolerability of oral edaravone in subjects with ALS for up to 96 weeks (Trial Description, Brief Summary). The primary outcomes measured include change from baseline to week 96 and time (days) to death, tracheostomy, or permanent assisted mechanical ventilation (>= 23 hours/day). Squitieri and NCT04577404 are considered analogous art because they are in the same field of assessing outcome measures of therapies towards ALS. Therefore, it would have been prima facie obvious to a PHOSITA, before the effective filing date of the claimed invention, to combine the teachings of Squitieri and NCT04577404 to arrive at the method instantly claimed. Administering pridopidine, as taught by Squitieri, and assessing survival after 96 weeks and death equivalents defined as tracheostomy or permanent assisted ventilation would have yielded reasonably predictable results because NCT04577404 teaches these are outcome measures are relevant to determining the efficacy of an ALS treatment (MPEP §2144.06(I)). Claim 22 is rejected under 35 U.S.C 103 as being obvious over Squitieri in view of US2014037850 (“Bassan”). The teachings Squitieri are discussed above and are incorporated by reference herein. Regarding claim 22, Squitieri does not teach administering 10 mg to 90 mg of pridopidine per day. Bassan teaches a method of treating Huntington’s Disease through oral administration of pridopidine or its HCl salt (¶[0015]). In clinical studies 621 patients received doses of pridopidine ranging from 20-90 mg daily (¶[0083]), but may be given once or twice daily (¶[0084]). Results were taken and showed statistically significant changes from baseline in UHDRS-TMS after 26 weeks of pridopidine administration (¶[0732]). Regarding claim 22, Bassan teaches pridopidine was administered to patients at a dose of 20 to 90 mg daily. This range overlaps with the instantly claimed range and would have been prima facie obvious to a PHOSITA to choose doses within that range with a reasonable expectation of success (MPEP §2144.05(I)). The claimed invention is a combination of prior art elements according to known methods, which to a PHOSITA, would yield predictable results. Double Patenting The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/aply/applying-online/eterminal-disclaimer. Claims 1-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,406,625 (‘625). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-15 of ‘625 anticipate instant claims 1-4 and 20-28. Claims 1-4 of ‘625 recite a method of treating a subject afflicted with sporadic ALS, comprising periodically administering to a subject pridopidine to reduce progression of symptoms like difficulty walking, fasciculations, worsening posture, etc. Instant claims 1-4 are anticipated by claims 1-4 of ‘625 as the scope of the narrower claims in ‘625 are encompassed by the instant claims. The BRI of ALS encompasses any subsets including sporadic ALS and the lessening or improvement of symptoms is inherent with the administration of pridopidine. Claims 5-10 of ‘625 recite administering pridopidine, or its HCl salt, ranging from twice a week to twice daily, including oral administration, where in the dose of pridopidine is 10 mg to 90 mg per day, to a subject that is human which anticipates instant claims 20-23. Claims 11-15 of ‘625 recite administering a second compound with sequential and adjunctive therapy to a subject where either the second compound is administered first, second, or concomitantly with pridopidine which anticipates instant claims 24-28. Claims 1-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/342,730 (‘730) in view of NCT01806857. This is a provisional nonstatutory double patenting rejection. Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims 1-28 encompass claims 1-20 of ‘730. Claims 1-12 of ‘730 recite a method of treating ALS comprising administering pridopidine and a pridopidine analog of Formula 1 and 4. The composition administered is pridopidine and an analog of the same of Formula 1 and/or 4 and their respective pharmaceutically acceptable salts. Also, recited are lessening of symptoms as a result of administration of the composition, recited in claim 5, as well as administration to certain patient populations, recited in claims 6-12. ‘730 does not teach measuring SVC, CNS-BFS, and ALSFRS-R respiratory subdomain. NCT01806857 teaches administration of Nudexta to ALS patients to determine whether Nuedexta is effective in the treatment of symptoms (impaired speech, swallowing, and saliva control) associated with ALS (Brief Summary). The Inclusion Criteria identifies patients with bulbar dysfunction manifested by dysarthria and/or dysphagia and slow vital capacity (SVC) ≥ 50%, were eligible to receive Nudexta to treat ALS (Recruitment Information, Eligibility Criteria). Some of the outcomes measured include the Bulbar Function Scale (CNS-BFS) total score and the ALSFRS-R total score (Outcome Measures, Primary and Secondary). Nudexta is also known as dextromethorphan hydrobromide and quinidine sulfate (Trial Description, Intervention). It would have been prima facie obvious to administer pridopidine, or its HCl salt, orally in view of claims 1-12 of ‘730 and include the patient populations and outcome measures taught by NCT01806857 to arrive at the method instantly claimed. A PHOSITA would have yielded predictable results following the teachings of ‘730, to administer pridopidine to patients having faster disease progression measured through the ALSFRS-R pre-baseline slope, baseline Nfl levels, and early ALS with <18 or <24 months from symptom onset, and modify the teachings to include measurements of CNS-BFS, ALSFRS-R respiratory subdomain, and ≥ 60% SVC, as taught by NCT1806857. The instant claims use the open-ended phrase “comprises” which encompasses the administration of an additional compound such as a pridopidine analog of Formula 1 and 4 as taught in copending claims 1-12 of ‘730. Claim 20 of ‘730 recites administration of a second composition comprising a therapeutically effective amount of a second compound, and the second compound is selected from the same options as those recited in instant claims 24-28. A PHOSITA would have recognized dosing as a result-effective variable based on the claim 20 of ‘730 and therefore modification of dosing parameters amounts to routine optimization (MPEP §2144.05(II)). Claims 13-20 of ‘730 recite a method of treating ALS with a composition comprising pridopidine and/or an analog of the same with Formula 1 and 4, or their respective salts, wherein the composition(s) is administered ranging from twice a week to at least twice daily, including oral administration, wherein the dose of pridopidine is 10 mg to 90 mg per day, to a subject that is human which are recited in instant claims 20-23. Claims 1-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-31 of copending Application No. 18/416,210 (‘210) in view of NCT01806857. This is a provisional nonstatutory double patenting rejection. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 10-31 of ‘210 anticipate instant claims 1-28. Claims 10-14 of ‘210 recite a method of for “maintaining, improving, or lessening the decline of symptoms associated with ALS in a subject in need thereof.” The impaired symptoms include, functionality and bulbar function, like salivation, swallowing, etc.; respiratory function; speech, like reduced speaking rate, articulation rate, etc.; increase of neurofilament light chain (NfL); muscle strength, like stiffness, weakness, etc.; and elevation in anti-inflammatory biomarkers. Claims 15-17 of ‘210 describes the decrease in risk of death upon administration of pridopidine ranging from 20-90% and prolonged survival ranging from 2 to 24 months. Claims 18-21 of ‘210 recite patient populations of ALS namely subjects that have faster disease progression measured by baseline Nfl biomarker levels and the revised ALS Functional Rating Scale (ALSFRS-R), and those subjects with early ALS with less than 18-month prognosis from symptom onset. ‘210 does not teach measuring SVC, CNS-BFS, and ALSFRS-R respiratory subdomain. The teachings of NCT01806857 are discussed above and are incorporated by reference herein. It would have been prima facie obvious to administer pridopidine, or its HCl salt, orally to specific patient populations, including impaired functionality, bulbar function, and speech in view of claims 10-14 of ‘210 and include the patient populations and outcome measures taught by NCT01806857 to arrive at the method instantly claimed. A PHOSITA would have yielded predictable results following the teachings of ‘210, to administer pridopidine to patients having faster disease progression measured through the ALSFRS-R pre-baseline slope, baseline Nfl levels, and early ALS with <18 or <24 months from symptom onset, and modify the teachings to include measurements of CNS-BFS, ALSFRS-R respiratory subdomain, and ≥ 60% SVC, as taught by NCT1806857. Claims 22-31 of ‘210 recite administering pridopidine, or its HCl salt, ranging from twice a week to twice daily, including oral administration, wherein the dose of pridopidine is 10 mg to 90 mg per day, to a subject that is human. Also recited, administration of a second compound with sequential and adjunctive therapy to a subject where either the second compound is administered first, second, or concomitantly with pridopidine. Instant claims 22-28 recite the same limitations as claims 22-31 of ‘210, therefore the scope of the claims in ‘210 are encompassed by the instant claims. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHIL CHANDER AGGARWAL whose telephone number is (571)272-7755. The examiner can normally be reached 7am-5pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623 /CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621