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 .
DETAILED ACTION
Applicant’s amendment of 5 February 2026, in which claims 16, 49, 52, 53 have been amended, and new claim 62 has been added, is acknowledged.
Claims 1, 16, 30, 33, 47-62 are pending in the instant application.
Claims 1, 33, 47, 48 are withdrawn, as being drawn to a non-elected invention.
Claims 16, 30, 49-62 are being examined herein.
Response to arguments of 5 February 2026
In view of Applicant’s amendment of 5 February 2026, the objection to claim 49 is herein withdrawn. Applicant has corrected a typographical error.
In view of Applicant’s amendment of 5 February 2026, the rejection of claims 52, 53 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is withdrawn. A new/modified rejection is made below, based on Applicant’s amendment of 5 February 2026.
On 5 February 2026, Applicant has amended independent claim 16 by adding the recitation “wherein after administration of L-histidine the subject has improved fatigue scores in three fatigue scales relative to a control.”
In view of Applicant’s amendment of 5 February 2026, the rejection of claims 16, 30, 49-53, 56-61 under 35 U.S.C. 102(a)(1) over NCT03266965 (version of 16 August 2019), and the rejection of claims 16, 50, 54, 55 under 35 U.S.C. 103 over NCT03266965, are herein withdrawn. New rejections are made below, based on Applicant’s amendment of 5 February 2026.
Applicant’s arguments (Remarks of 5 February 2026, pages 6-7) are focused on the amendment of 5 February 2026.
Applicant’s amendment of 5 February 2026 necessitated the following new and/or modified rejections.
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 16, 30, 49-62 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.
Independent claim 16, amended on 5 February 2026, recites “wherein after administration of L-histidine the subject has improved fatigue scores in three fatigue scales relative to a control.” It is unclear how the improved scores are to be measured, as the claim fails to establish a standard or threshold level by defining a control. For example, the control can be a healthy control, or patients with other diseases. Alternatively, the control can be a patient with MS with or without fatigue. Alternatively, the control can be the very same subject, before therapeutic intervention, that is before being administered L-histidine. Although claim 16 requires that the fatigue scores are compared to a control, the claim fails to clearly set forth whether this “control” is a standard established from a healthy subject, or from a patient with other diseases, or from an MS patient, with or without fatigue, or from the same subject prior to administering L-histidine. One wishing to practice the instantly claimed invention would thus not recognize the metes and bounds for which Applicant seeks protection.
Appropriate clarification of the claim language is required.
Claims 52, 53 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.
Claim 52 recites that the therapeutically effective amount of carbidopa is unchanged relative to a control and the therapeutically effective amount of L-histidine is increased over a three-week period of time relative to a control. Claim 53 recites that the therapeutically effective amount of L-histidine is increased over a three-week period of time relative to a control.
It is unclear how the increase is to be measured, as the claim fails to establish a standard or threshold level by defining a control. The terms “increased” or “unchanged” require comparison to a predetermined or reference level/ control, yet such reference/control is not defined by the claims. For example, the increase could be relative to another amount of L-histidine administered to the same subject previously, at any time point; there is no requirement that the L-histidine is administered continuously to the subject, or that the same therapeutic amount of L-histidine is administered over time. As such, a dosing schedule in which discontinuation is followed by starting again administration of L-histidine would be encompassed by claim 53, because a restart in administration is an increase in the therapeutic amount of L-histidine administered. Alternatively, the increase could be relative to an amount of L-histidine administered to another subject.
Without defining what a “control” is, claims 52, 53 are indefinite because
the metes and bounds of the present claims cannot be determined and one having ordinary skill in the art would not necessarily be reasonably apprised of the scope of the claims.
Appropriate clarification of the claim language is required.
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 (i.e., changing from AIA to pre-AIA ) 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 30, 49-62 are rejected under 35 U.S.C. 103 as being unpatentable over NCT03266965 (Histaminergic basis of central fatigue in multiple sclerosis- a novel approach, version of 16 August 2019, cited in PTO-892 of 5 November 2025), in view of Kos et al. (BMC Neurology 2006, 6 (27), p. 1-8, cited in PTO-892).
NCT03266965 (version of 16 August 2019) teaches a method of treating patients suffering from multiple sclerosis and severe fatigue (under Eligibility, Inclusion criteria for Patients with Multiple Sclerosis (MS), points 1, 2, 4), which are patients of instant claims 16, 30, comprising administering to the patients (under Arms and Interventions) a dose of dietary supplement L-Histidine 250 mg plus MS drug Carbidopa 50 mg twice a day (BID) oral administration (as lodosyn tablets), for seven days. If there are no safety concerns, the next 5 patients will be recruited (3 MS patients) to test the dose of L-Histidine 500 mg with Carbidopa 50 mg BID, for seven days. If there are no safety concerns then L-histidine 1,000 mg plus Carbidopa 50 mg BID will be tested in the next 5 subjects (3 MS patients) for seven days.
NCT03266965 teaches co-administering L-histidine and carbidopa to the patient, as in instant claim 50, where (Arms and interventions) L-histidine and carbidopa are administered concurrently, as in instant claim 56; and where L-histidine is a dietary supplement, which is consistent with oral administration of L-histidine, as in instant claim 49, and carbodipa is administered as Lodosyn tablets, thus oral administration, as in instant claim 57.
NCT03266965 teaches that carbidopa and L-histidine are taken daily, as in instant claim 51.
NCT03266965 teaches co-administering L-histidine and carbidopa to the patient, using the following dose schedule:
fixed dose of 50 mg lodosyn (Carbidopa) and 250 mg L-histidine twice daily for 7 days; then fixed dose of 50 mg lodosyn (Carbidopa) and 500 mg L-histidine twice daily for 7 days; then fixed dose of 50 mg lodosyn (Carbidopa) and 1,000 mg L-histidine twice daily for 7 days,
which satisfies the limitations of claims 52, 53.
NCT03266965 teaches administering 250 mg L-histidine twice daily (500 mg/day) to patients suffering from fatigue, as in instant claims 58, 59.
NCT03266965 teaches (Secondary Outcome Measures, points 1, 3, 5) evaluating fatigue (point 1, 3) in the patients and evaluating change in the daytime sleepiness (point 5) in the patients before and after administration of L-histidine and carbidopa in the method of treatment.
Specifically, NCT03266965 teaches (Secondary Outcome Measures, points 1, 3, 5) evaluating fatigue (point 1, 3) in the patients using two fatigue scales, namely the Fatigue Severity Scale (FSS) (point 1), and the Modified Fatigue Impact Scale (MFIS) (point 3), which are fatigue scales in instant claim 62.
NCT03266965 teaches (Secondary Outcome Measures, point 1) that each individual completes a screening and baseline visit without any intervention and two weekly visits during intervention with the study medications. The two evaluations off drug will be compared to the two evaluations on drug. A drop of the FSS score by 1 point or more is considered a response. Thus, NCT03266965 defines response to treatment as being an improved score (drop of 1 point or more on the FSS scale) in a fatigue scale achieved after administration of L-histidine and carbidopa to a patient, compared to the score measured in the same patient before treatment begins.
NCT03266965 does not teach measuring fatigue scores using three fatigue scales, as in instant claim 16, including a fatigue scale which is a Visual Analogue Fatigue Scale (VAFS), as in instant claim 62.
NCT03266965 does not teach that the amount of carbidopa administered is 50 mg/day, as in instant claims 54, 55.
Kos et al. (BMC Neurology 2006, 6 (27), p. 1-8, cited in PTO-892) teach (Abstract) evaluating fatigue in patients suffering from multiple sclerosis (MS) using fatigue scales. Three visual analogue scales (VAS) for assessing the impact of fatigue were developed. Sixty two subjects with definite MS and 24 healthy controls completed all VAS scales (range 0–100), the Fatigue Severity Scale (FSS) (range 7–63), the Modified Fatigue Impact Scale (MFIS) (range 0–84) and the Guy's Neurological Disability Scale (GNDS) (range 0–5). All VAS scales were able to discriminate between subjects with MS and controls.
Thus, Kos teaches fatigue scales VAS (or VAFS), FSS and MFIS, which are the fatigue scales in instant claim 62, to evaluate fatigue in patients with multiple sclerosis.
It would have been obvious to use the teachings of NCT03266965 to arrive at the instant invention. The person of ordinary skill in the art would have co-administered L-histidine and carbidopa to a patient suffering from fatigue and multiple sclerosis, in the method of NCT03266965, with the expectation of achieving therapeutic effect.
The person of ordinary skill in the art would have evaluated the efficacy in the method of treatment using three fatigue scales, namely VAFS, FSS and MFIS, measuring fatigue scores before and after treatment, because
NCT03266965 teaches evaluating fatigue in the patients using two fatigue scales, namely the Fatigue Severity Scale (FSS), and the Modified Fatigue Impact Scale (MFIS), and NCT03266965 defines response to treatment as being an improved score (drop of 1 point or more on the FSS scale) in a fatigue scale achieved after administration of L-histidine and carbidopa to a patient compared to the score measured in the same patient before treatment begins, and
Kos teaches fatigue scales VAS (or VAFS), FSS and MFIS, routinely used to evaluate fatigue in patients with multiple sclerosis.
Thus, the person of ordinary skill in the art would have further evaluated the patients treated in the method of NCT03266965 using a third fatigue scale, namely VAFS, with the expectation that treatment with L-histidine and carbidopa results in improved fatigued scores in the fatigue scales used.
Further, the person of ordinary skill in the art would have explored different daily amounts of carbidopa, to be co-administered with L-histidine in the method of treatment, or different frequency of administration of carbidopa (once daily 50 mg), because such an exploration of therapeutic daily dose, or frequency of administration, aimed at optimizing therapeutic effect in a method of treatment, is well within the skill of the artisan.
Regarding claims 60, 61, while NCT03266965 does not explicitly teach “wherein the method increases a level of N- acetylaspartate in the central nervous system of the subject” (claim 60), or “wherein the method increases a level of creatine phosphate in the central nervous system of the subject” (claim 61), the claimed limitations appear to be a result or property of the administration of the effective amount of the L-histidine. As such, the claimed limitations appear to be met by the prior art. Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed method. In the absence of evidence to the contrary, the burden is on the applicant to prove that the function of the product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
As such, claims 16, 30, 49-62 are rejected as prima facie obvious.
Conclusion
Claims 16, 30, 49-62 are rejected.
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.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629