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
The instant application was received 20 December 2021; it is a national stage application of PCT/EP2020/066994, filed 18 June 2020, and claims foreign priority to EP19181008.4, filed 18 June 2019. Acknowledgment is made of Applicant’s claim for foreign priority and certified copies of the priority documents have been received.
Status of the Claims
The listing of claims filed 11 September 2026 has been examined.
Claims 14, 17-26, 29, and 31-37 are pending.
Claims 14, 17, and 20-21 are amended.
Claims 34-37 are newly added.
Claims 1-13, 15-16, 27-28, 30 are cancelled.
Claims 22-26 and 33 remain withdrawn pursuant to 37 CFR § 1.142(b), as being drawn to a nonelected invention.
Claims 14, 17-21, 29, 31-32, and 34-37 read on an elected invention and species and are being examined on the merits as such.
Information Disclosure Statement
The Information Disclosure Statement (IDS) filed on 11 September 2026 is acknowledged and has been considered.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11 September 2026 has been entered.
Response to Arguments
Applicant arguments, filed 11 September 2026, with respect to the rejections under 35 USC § 103 have been fully considered.
With respect to the rejection of claims 14, 17-21, 29, and 31-32 under 35 U.S.C. 103 as being unpatentable over Hermann (CH 710 163 A2; IDS dated 08 November 2022, Cite No. 3) in view of Shapiro (US 8,178,516 B2) and further in view of Laursen (Laursen et al., “Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab”, Multiple Sclerosis and Related Disorders 10 (2016) p. 169-173) and Halder (Halder et al., (2019) Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease International Journal of Molecular Sciences, 20(4), 896.), as evidenced by Stahl et al. (Stahl et al., A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor. Prim Care Companion J Clin Psychiatry. 2004;6(4):159-166.) and as evidenced by Mount Sinai (Multiple Sclerosis, Mount Sinai, 2024), Applicant’s arguments have been fully considered and are not persuasive.
Applicant argues none of the cited references teach or suggest administering the specific combination of a bupropion compound, vitamin D3, and either vitamin K1 or K2 for treating multiple sclerosis at the instantly recited daily doses (Remarks, p. 8).
Hermann discloses administering 0.5-1,200 mg/day bupropion for treating multiple sclerosis (p. 4, ¶ [0029]).
Shapiro discloses administering 400-40,000 units vitamin D3 daily (p. 11, Col. 19, Lines 14-15).
Shapiro discloses administering 100 µg-100 mg vitamin K2 daily (p. 11, Col. 19, Lines 26-27).
Shapiro suggests administering compounds such as vitamin D3 and/or vitamin K2 is useful for treating multiple sclerosis (p. 24, Col. 46, Example 18).
Thus, while neither Hermann nor Shapiro discloses a single, exemplary composition comprising all three of bupropion, vitamin D3, and vitamin K2, Hermann discloses bupropion amounts which overlap the instantly recited ranges and Shapiro discloses vitamin D3 and K2 amounts which overlap the instantly recited ranges. MPEP 2144.05(I) states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” Furthermore, Hermann indicates bupropion is useful in treating multiple sclerosis and Shapiro indicates vitamin D3 and/or K2 is/are useful in treating multiple sclerosis, so the instantly claimed composition is using bupropion, vitamin D3, and vitamin K2 each according to an art-recognized purpose. MPEP 2144.06 states, “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, in order to form a third composition to be used for the very same purpose… [T]he idea of combining them flows logically from their having been individually taught in the art.”
Applicant argues that a skilled artisan would have had no motivation to combine Hermann, which discloses bupropion, and Shapiro, which does not disclose bupropion, noting that although Shapiro discloses a relatively long list of potential MS active agents, bupropion is not mentioned (Remarks, p. 9, ¶ 3).
As mentioned above, each compound (i.e., bupropion, vitamin D3, and vitamin K2) had been individually known as being useful for treating MS. Accordingly, a skilled artisan, seeking to develop a composition for treating MS, would have been motivated to prepare a composition comprising multiple compounds which had been known to improve MS pathophysiology.
Applicant argues a skilled artisan, following the teachings of Hermann and Shapiro, would arrive at a composition containing bupropion, vitamin D3, and vitamin K2 as well as an additional active agent selected from the list disclosed by Shapiro in Cols. 46-47 (Remarks, p. 9, ¶ 4).
Examiner notes instant claim 14 recites, “A method for the treatment of multiple sclerosis comprising…” [Emphasis added.] In accordance with the transitional term “comprising”, the recited composition is open-ended and does not exclude additional, unrecited elements or method steps. Thus, even if a skilled artisan included an additional component besides bupropion, vitamin D3, and vitamin K2 in the composition, said composition would still render instant claim 14 obvious.
Additionally, because each instantly recited component had been individually recognized for its ability to improve MS symptoms, a skilled artisan still would have predicted a composition comprising bupropion, vitamin D3, and vitamin K2, minus a theoretical fourth component, would improve MS symptoms.
Applicant notes none of the cited references disclose bupropion with both a vitamin D compound and a vitamin K compound, stating this combination is a distinguishing feature over the prior art. Applicant argues vitamins D3 and K2 are not “result-effective variables” because (a) the prior art fails to recognize the variables as achieving a recognized result and (b) there would have been no reasonable expectation of success in optimizing the vitamins D3 and K2 amounts to within the claimed range (Remarks, p. 9, ¶ 6 – p. 10).
Additionally, Applicant notes Laursen actually recommends 2000, 3000, and/or 4000 IU/day vitamin D3 and states, “The lower limits of claim 14 (350 IU and claim 20 (500 IU) are therefore not disclosed by Laursen.” (Remarks, p. 10, ¶ 10). Applicant indicates a prior art reference mentioned in the instant Specification (i.e., Steinwart et al., “High-Dose Vitamin D3 Intake Is Associated with Decreased Symptoms of Multiple Sclerosis” Am. J. Immunol., Vol. 14(1), p. 7-14; IDS dated 08 November 2022, Cite No. 39) cites a study wherein an about 2,800 IU vitamin D3 dose was found to be ineffective in maintaining bone health (Steinwart, p. 10, Col. 2). Thus, Applicant asserts the prior art taught low-dose vitamin D3 is ineffective for MS.
Furthermore, Applicant indicates, according to Steinwart, 10,000 IU/day-equivalent dosing of vitamin D3 was believed to be needed to observe clinical benefit in MS and, consequently, a skilled artisan would not has regarded 350-3000 IU/day vitamin D3 as a result-effective variable.
As mentioned above, the combination of Hermann and Shapiro suggests bupropion, vitamin D3, and/or vitamin K2 are each individually beneficial for treating MS (i.e., achieving a recognized result).
As noted by Applicant, Laursen does suggest 2000 and 3000 IU/day vitamin D3. Claims 14 and 20 recite 350-3000 IU/day and 500-2000 IU/day vitamin D3, respectively. Thus, regardless of whether or not the lower limits of claims 14 and 20 are disclosed by Laursen, the instantly recited ranges are overlapped by Laursen and, accordingly, rendered obvious. See MPEP 2144.05(I).
Citing another study, Steinwart writes, “The authors concluded that supplementation of Vitamin D3 up to 10,000 IU daily was safe and tolerable in both healthy and CIS [MS patients with Clinically Isolated Syndrome] patients… They further concluded that the possible role of D3 as in immunomodulator would require additional investigation in larger randomized controlled clinical trials over a longer period of time.” (Steinwart, p. 11, Col. 2, Bottom Paragraph). Thus, a skilled artisan would have known a vitamin D3 dose up to 10,000 is generally safe and also would have been motivated to use lower doses, such as 2000 or 3000 IU/day, as suggested by Laursen. Laursen’s study is also mentioned by Steinwart (Steinwart, p. 9, Table 1), with Steinwart stating Laursen’s results showed, “D3 supplementation significantly associated with decreased relapse rate.”
Applicant argues the Vitamin K2 dose suggested by Halder (i.e., 5-600 µg/day) is only a North American dietary-intake estimate, not a therapeutic MS dose, and the closest prior art which explicitly links vitamin K2 and MS (JP 2006-290772) only discloses an effective dose of 10-200 mg/day and, consequently, a PHOSITA would not have recognized microgram-level vitamin K2 amounts as being a result-effective variable.
MPEP 2144.05(C) states, “…if the prior art does recognize that the variable affects the relevant property or result, then the variable is result-effective. Id. (‘A recognition in the prior art that a property is affected by the variable is sufficient to find the variable result-effective.’)”. In light of Sakoda (JP 2006-290772; IDS dated 08 November 2022, Cite No. 4), which states, “The present invention confirms the effectiveness of vitamin K2, preferably menatetrenone, as a therapeutic and prophylactic agent for autoimmune diseases, preferably multiple sclerosis…” (¶ [0010]), as well as Shapiro, a skilled artisan would have recognized as vitamin K2 as improving MS and been motivated to optimize the vitamin K2 amount in a composition to achieve the desired improvement in MS symptoms. Furthermore, because Halder recommends 5-600 µg/day vitamin K2 as a daily dietary-intake, a skilled artisan would have been motivated to optimize the vitamin K2 amount based on this range.
Applicant argues that because the prior art taught that the instantly claimed low-dose amounts of vitamins D3 and K2 were individually subtherapeutic for MS, a PHOSITA would not have had a reasonable expectation of success in combining vitamins D3 and K2 in low doses to treat MS and, accordingly, the routine optimization rationale in the previous Office Action does not apply.
Vitamins D3 and K2 had each, individually, been identified as being useful for MS. Additionally, dose ranges overlapping the instantly recited dose ranges had been disclosed in the prior art. While the relatively low vitamin K2 dose disclosed by Halder is a recommended dietary-intake amount, not specifically a therapeutically effective dose for MS, a skilled artisan would have had a reasonable expectation of success in using the dietary-intake amount because one would expect said amount would be unlikely to cause adverse reactions.
In the claims filed 11 September 2026, new claims 34-37 are presented. Applicant argues newly added claims 34 and 37 require the bupropion-group compound, vitamin D3, and either vitamin K1 or K2 be the only pharmaceutically active agents administered to the patient, with this three-agent therapy being free of the prior art.
In light of the prior art (i.e., Herman, Shapiro, Laursen, and Sakoda) disclosing bupropion, vitamin D3, and vitamin K2 are each useful for improving MS symptoms, it would have been obvious to try combining these three compounds. Additional details related to newly added claims 34-37 are provided below in the modified 103 rejection.
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 14, 17-21, 29, 31-32, and 34-37 are rejected under 35 U.S.C. 103 as being unpatentable over Hermann (CH 710,163 A2; IDS dated 08 November 2022, Cite No. 3) in view of Sakoda (JP 2006-290772 A; IDS dated 08 November 2022, Cite No. 4) in view of Shapiro (US 8,178,516 B2; Previously Cited in the Office Action dated 20 March 2025) and further in view of Laursen (Laursen et al., “Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab”, Multiple Sclerosis and Related Disorders 10 (2016) p. 169-173; Previously Cited in the Office Action dated 20 March 2025).
Regarding 14, 17-21, 29, 31-32, and 35-36, Hermann teaches multiple sclerosis (MS) symptoms can be improved by administering bupropion (p. 4, ¶ [0025]), specifically 0.5-1,200 mg/day bupropion (p. 4, ¶ [0029]). Hermann states, “Daily administration of 300 mg of restricted bupropion hydrochloride results in a significant improvement in the condition.” (p. 4, ¶ [0032]). Additionally, Hermann states, “There are various forms of MS. This invention explicitly includes all currently described forms and all other forms of MS with typical symptoms. Currently described symptom groups of MS are relapsing, remitting, and primary or secondary progressive.” (p. 3, ¶ [0014]).
Hermann does not explicitly teach vitamin D3, vitamin K1, or vitamin K2.
Sakoda teaches vitamin K2 as a therapeutic agent for multiple sclerosis, stating, “The present invention has confirmed the effectiveness of vitamin K2, preferably menatetrenone, as a therapeutic and prophylactic agent for autoimmune diseases, preferably multiple sclerosis, and more preferably as a therapeutic agent and prophylactic agent for relapses of multiple sclerosis.” (English Translation, p. 3, ¶ [0010]). Sakoda describes the vitamin K2 effective dose as being 10-200 mg/day and notes the time period over which vitamin K2 is administered may be 1-1,000 days (English Translation, p. 9, ¶ [0032]).
Sakoda does not explicitly teach a vitamin K2 daily dose which overlaps the instantly recited range, nor does Sakoda explicitly teach bupropion or vitamin D3.
Shapiro teaches discloses various compositions which can be used for the treatment of various chronic inflammatory diseases, including MS (p. 2, Col. 2, Line 13). Shapiro suggests said compositions can contain 400-40,000 units/day vitamin D3 (p. 11, Col. 19, Lines 14-15) and/or 100 µg-100 mg vitamin K2 (p. 11, Col. 19, Lines 26-27).
Shapiro does not explicitly teach bupropion.
Laursen teaches supplementing a therapeutic used for treating multiple sclerosis (i.e., natalizumab) with vitamin D3 reduces the annualized relapse-rate for MS patients (p. 169, Abstract). Laursen states, “Low serum levels of 25-hydroxyvitamin D (25(OH)D), low intake of dietary vitamin D and lack of sun exposure have been suggested as environmental risk factors for multiple sclerosis (MS), indicating a potential role of vitamin D in the pathogenesis of MS.” (p. 169, Introduction, Col. 1). Additionally, the MS patients included in Laursen’s clinical substudy had a mean MS duration of about 11.6 years (p. 170, Table 2). Laursen recommends various vitamin D3 supplement amounts including 2000, 3000, and 4000 IU/day vitamin D3 based on the individual patient’s serum 25(OH)D level (p. 170, Table 1). Laursen concludes the, “…simple recommendation of vitamin D supplements (50-100 µg/day) to RRMS [Relapsing-Remitting MS] patients… was associated with a significant increase in mean 25(OH)D, and that this increase was inversely associated with ΔARR.” (p. 172, Col. 1, ¶ 3). Note 50-100 µg/day is equivalent to 2000-4000 IU/day (i.e., 1 µg = 40 IU).
Laursen does not explicitly teach bupropion, vitamin K2, or vitamin K1.
Prior to the filing of the instant application, a person having ordinary skill in the art (PHOSITA) following the teachings of Hermann would have found it prima facie obvious to prepare a composition comprising bupropion, vitamin D3, and vitamin K2 and use said composition for the treatment of MS based on the teachings of Sakoda, Shapiro, and Laursen because Hermann, Sakoda, and Laursen disclose bupropion, vitamin K2, and vitamin D3, respectively, can be used for the treatment of MS. Furthermore Hermann discloses bupropion daily doses which overlap the recited ranges and Shapiro, which also provides compositions for the treatment of MS, discloses vitamin K2 and vitamin D3 daily doses which overlap the instantly recited ranges. Accordingly, a PHOSITA, guided by the teachings of Hermann, Sakoda, and Laursen and according to the dosage amount suggestions provided by Hermann and Shapiro, would have predicted success in preparing a composition containing bupropion, vitamin D3, and vitamin K2. Furthermore, a skilled artisan would understand MS is a chronic condition and, because Sakoda indicates vitamin K2 may be administered for up to 1,000 days (i.e., >24 months), the artisan would have been motivated to administer said composition over a relatively long time period.
Additionally, claim 35 recites, “The method according to claim 14, wherein during the treatment no new brain lesions are detected by magnetic resonance imaging (MRI) and no new MS attacks occur, and the physical performance and the cognitive performance of the patient improve,” which are interpreted as intended results. Since a PHOSITA would have found it prima facie obvious to prepare a composition according to Hermann’s, Sakoda’s, Shapiro’s, and Laursen’s disclosures, said composition, meeting all the structural limitations required by claim 14 upon which claim 35 depends, would be expected to exhibit the same intended results as recited in claim 35.
Note Hermann disclosing the use of bupropion for treating MS is sufficient to render the treatment of a specific type of MS (i.e., relapsing-remitting) obvious as a skilled artisan would recognize MS as a chronic condition requiring long-term treatment.
Conclusion
Claims 14, 17-21, 29, 31-32, and 34-37 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANNA L BAUER whose telephone number is (571)272-5752. The examiner can normally be reached 8am-5pm.
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/B.L.B./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
