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.
Amendments & Claim Status
The amendment to the claims filed on 20 June 2025 is acknowledged and entered.
Claims 14-33 are pending.
Claims 14 and 20 are amended.
Claims 22-26 and 33 remain withdrawn pursuant to 37 CFR § 1.142(b), as being drawn to a nonelected invention.
Claims 14-21 and 27-32 read on an elected invention and species and are being examined on the merits as such.
Claims 1-13 are canceled.
Response to Arguments
Applicant’s arguments, filed 20 June 2025, with respect to the rejections under 35 USC § 112(a), 112(d), and 103 have been fully considered.
Applicant’s arguments, filed 20 June 2025, with respect to the rejection of claims 14-18, 20-21, and 27-32 under 35 USC § 112(a) and rejection of claim 20 under 35 USC 112(d) have been fully considered and are persuasive. Amendments moot the rejections. The rejections in the Office Action of 20 March 2025 have been withdrawn.
Applicant’s arguments, filed 20 June 2025, with respect to the rejection of claims 14-21 and 27-32 under 35 USC § 103 have been fully considered but are not persuasive.
Regarding the argument that Hermann teaches away from the instantly claimed element that the first compound be administered at 10 mg to less than 300 mg/day (p. 9), Hermann’s disclosure does not constitute teaching away from the instantly claimed method as Hermann does not expressly discourage or criticize administering bupropion in amounts as low as 10 mg/day. Phrased differently, just because Hermann specifically teaches 300 mg/day bupropion in one example (p. 3, ¶ [0021]) does not constitute teaching away from administering 10 mg to less than 300 mg/day. See MPEP 2143.01(I). Furthermore, Hermann states, “The dosage ranges from 0.5 mg per day to 1200 mg per day in exceptional cases.” (p. 4, ¶ [0029]), which indicates dosages of 10 mg to less than 300 mg would be acceptable.
Regarding the arguments that Hermann does not teach or suggest a treatment of relapsing-remitting type MS or indicate the long-term efficacy of the treatment, teaching the use of bupropion for treating MS is sufficient to render treatment of a specific type of MS using bupropion or using bupropion in long-term treatment of MS obvious as a skilled artisan would recognize MS as a chronic condition requiring long-term treatment.
On p. 9 and 11 of the arguments, Applicant argues that the Examiner has not established the obviousness of claims 14-21 and 27-32, purporting the Examiner has used impermissible hindsight in making the instant rejection of claim 14 under 35 USC § 103, by listing deficiencies in each cited reference which would render the combination of cited references insufficient to have given a person having ordinary skill in the art (PHOSITA) a reasonable expectation of success at arriving at the claimed invention. Arguing against references individually is discussed in MPEP § 2145(IV). Applicant’s reply fails to address the combined teachings of the cited references and instead only argues that each reference individually does not teach all of the claim limitations. One cannot show nonobviousness by attacking the cited references individually where the rejections are based on a combination of references. All of the limitations of the instant claims are disclosed in either Hermann, Shapiro, Laursen, and/or Halder, and the combination of the references renders the claimed invention obvious. Arguing impermissible rationales for combining references, specifically impermissible hindsight, is discussed in MPEP § 2145(X)(A), which cites In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971), stating, “[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in that art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” As disclosed by Hermann (p. 4, ¶ [0032]) and Shapiro (p. 11, Col. 19), respectively, bupropion administration can reduce MS symptoms and compositions used in treating inflammatory diseases such as MS may include vitamin co-agents like vitamin D3 and vitamin K2. Thus, while Shapiro is drawn to a different combination, which lacks an NDRI (Remarks, p. 10), Shapiro’s teachings (i.e., vitamins are useful components in compositions for treating inflammatory diseases) can still be applied. Furthermore, because each instantly claimed element is being used for an art-recognized purpose, there would have been a reasonable expectation of success. Thus, although Shapiro lacks data demonstrating the efficacy of the treatment, a PHOSITA still would have had a reasonable expectation of success in using vitamin D3 and/or vitamin K2 in treating inflammatory diseases because Shapiro indicates vitamins D3 and K2 are useful for this purpose.
Regarding the argument that Halder does not suggest MS could be treated by administering vitamin K2 or suggest a suitable dosage for treating MS (Remarks, p. 10), this is factually correct, although Halder does indicate vitamin K2 has been shown to have a role in regulating inflammatory diseases (Abstract) and states the recommended daily vitamin K2 intake in North America is 5-600 µg (p. 3, Last Sentence). However, while Halder does not explicitly correlate the 5-600 µg/day vitamin K2 dosage to MS, Shapiro does suggest the co-administration of vitamin K2 in treating chronic inflammatory diseases, like MS (p. 11, Col. 19, Lines 26-27; p. 2, Col. 2, Line 13). Thus, based on the teachings of Halder and Shapiro as a whole, a skilled artisan would have had a reasonable expectation of success in utilizing 5-600 µg/day vitamin K2 in the treatment of MS.
Regarding the arguments that Laursen teaches natalizumab, which is unrelated to an NDRI compound, and fails to demonstrate vitamin has a significant effect in MS patients, although Laursen is drawn to a different combination, Laursen’s teachings (i.e., vitamin D3 may be beneficial for patients with MS) can still be applied. While Laursen does not demonstrate a significant effect when vitamin D3 is administered to MS patients, a PHOSITA still would have had a reasonable expectation of success in using vitamin D3 for treating MS because Laursen suggests it confers some therapeutic benefit (Laursen, p. 169, Abstract) and because Shapiro indicates vitamin D3 may be co-administered alongside other medicaments for the treatment of inflammatory diseases like MS.
Applicant is reminded that the standard used for deciding obviousness is the preponderance of evidence, and the evidence of record in totality – while some arguments may be considered convincing in isolation – supports a conclusion of prima facie obviousness for the reasons outlined above. Hermann teaches a composition for treating MS which includes bupropion and Shapiro teaches the co-administration of vitamin D3 and vitamin K2 for treating chronic inflammatory conditions, like MS, so it would have been prima facie obvious to combine the teachings of Shapiro and Hermann guided by the vitamin D3 and vitamin K2 dosage ranges taught by Laursen and Halder to treat inflammatory diseases using the instantly claimed method. Arguments presented in opposition to this, such as teachings which are alleged to teach away and identifying the elements each prior art reference lacks individually, are insufficient to support a conclusion of nonobviousness given the evidence supporting obviousness. Accordingly, Applicant’s arguments are not persuasive and the rejection of claims 14-21 and 27-32 as obvious over Hermann in view of Shapiro and further in view of Laursen and Halder is maintained.
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 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.
Claim(s) 14-21 and 27-32 are rejected under 35 U.S.C. 103 as being unpatentable over Hermann (CH 710 163 A2 – provided as reference 3 on IDS dated 11/08/2022) in view of Shapiro (US 8,178,516 B2) and further in view of Laursen et al. (Laursen et al., Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab, Multiple Sclerosis and Related Disorders, Volume 10, 2016) and Halder et al. (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).
Regarding instant claims 14 and 16, Hermann teaches an invention that treats multiple sclerosis by administering a pharmaceutical composition that includes bupropion (page 4, claim 2), a known norepinephrine-dopamine reuptake inhibitor (NDRI) as evidenced by Stahl et al. (page 159, lines 1-5 of Conclusions). Regarding instant claims 27-29, Hermann teaches daily administration of the norephrine-dopamine reuptake inhibitor (bupropion) in a dosage amount that is between 0.5 mg/day – 1200 mg/day where this dosage amount of bupropion is orally administered and can be included in an unretarded mixed composition (page 4, [0029]). Hermann also teaches a pharmaceutical composition where the physiologically acceptable salt is bupropion hydrochloride (page 4, claim 2). Regarding instant claims 15 and 17, Hermann teaches that multiple sclerosis is a chronic inflammatory disease of the human nervous system (page 3, lines 1-2 of [0012]) and teaches symptom groups of multiple sclerosis that are relapsing and remitting in nature (page 3, lines 2-3 of [0014]). As evidenced by Mount Sinai, multiple sclerosis (MS) is an autoimmune disease that impacts the brain and spinal cord (central nervous system) (page 1, lines 1-2), therefore meeting the limitations of instant claim 15.
Hermann does not teach a compound or dosage amount selected from the group consisting of vitamin D3, calcifediol, calcitriol, vitamin D2, ercalcidiol, ercalcitriol, nor does it teach a dosage amount or a compound selected from the group consisting of vitamin K1, vitamin K2 and vitamin K3 to be administered with a norepinephrine-dopamine reuptake inhibitor for the treatment of MS.
This limitation is remedied by Shapiro, which teaches the co-administration of vitamin D3 with a dosage amount ranging from 400-40,000 units daily (IU) (page 11, col., 19, lines 14-15), and also teaches the co-administration of vitamin K2 with a dosage amount ranging from 100 micrograms daily to 100 mg daily (page 11, col., 19, lines 26-27). This meets the limitations of instant claims 30-31. Shapiro teaches oral administration of a composition for the treatment of chronic inflammatory diseases, such as multiple sclerosis, where vitamin D3 and vitamin K2 can be co-administered with a primary therapeutic to human patients with MS (page 1, Abstract, lines 1-11 of Abstract, and page 2, col., 2, line 13 and page 1, Abstract, lines 18-30). Shapiro also teaches this treatment as being administered over 12 months, which meets the limitation of instant claim 19 (page 14, col., 25, lines 46-47).
Shapiro does not teach the reason for selecting an optimized dosage amount described within instant claims 14, 20, or 21 of vitamin D3 or vitamin K2 for patients suffering from an inflammatory disease such as multiple sclerosis.
This limitation can be remedied by Laursen et al. and Halder et al. which teach reasons as to why these respected dosage ranges of vitamin D3 and vitamin K2 are optimized in instant claims 14, 20 and 21 for patients suffering from an inflammatory disease, such as multiple sclerosis. Laursen et al. teach how vitamin D3 supplements impact 25-hydroxyvitamin D (25(OH)D) levels in patients with relapsing-remitting MS (RRMS), and how hypovitaminosis D is associated with multiple sclerosis (MS) risk and increased disease activity (page 169, lines 1-5 of Abstract). Laursen et al. teach how recommending vitamin D3 supplements for patients with vitamin D insufficiency was associated with a significant increase in serum 25(OH)D concentrations, which was significantly related with decreases in annualized relapse-rate (ARR) (page 169, lines 11-14 of Abstract), further demonstrating how a correction of hypovitaminosis D in clinical practice by recommending oral D3 supplements resulted in increases in 25(OH)D levels in serum, which were associated with decreases in ARR in RRMS. Laursen et al. also teach how these patients who suffered from RRMS had a mean disease duration of 11 years, meeting the claim limitations of instant claim 18. Laursen et al. also teach the National recommendations of vitamin D3 supplements for daily administration based off of patients’ 25(OH) D serum levels being below 50 nmol/l (page 170, lines 10-12 of 2. Participants and methods) and the associated recommended supplement dosage forms of oral vitamin D3, ranging from 200 IU daily – 4,000 IU daily (50 µg – 100 µg daily) (page 170, Table 1). Halder et al. teach how vitamin K2 has been shown to be a bioactive compound in regulating osteoporosis, atherosclerosis, cancer and inflammatory diseases without risk of negative side effects (page 1, lines 7-9 of Abstract). Halder et al. also teach how vitamin K2 is synthesized by bacteria and is primarily found in food where bacteria are part of the production process (page 2, lines 2-3 of 2. Dietary Vitamin K) and how the recommended daily dosage amount of vitamin K2 is 5 - 600 µg/day in North America (page 3, line 7 of 3. Adequate Intake is an Estimate and page 4 line 1). Furthermore, Halder et al. teach how vitamin K2 levels were greatly reduced in patients with MS and also demonstrated a correlation between vitamin K2 levels and neurological spasms and lesions of optic nerves, suggesting an important role of vitamin K2 in neurological development and diseases (page 8, lines 7-12 of 8.8. Vitamin K2: Neurological Disease).
It would have been prima facie obvious to one of skill in the art before the effective filing date of the instant invention to modify the teachings of Hermann to include the optimized dosage amounts of vitamin D3 and vitamin K2 for the treatment of multiple sclerosis, as taught by Shapiro, and further in view of Laursen et al. and Halder et al. One would have been motivated to include the optimized dosage ranges of vitamin D3 and vitamin K2 in order to treat patients suffering from inflammatory diseases (such as MS and RRMS) because Hermann teaches a lack of sufficient pharmacological treatment trials needed to improve MS and mitigate deterioration (lines 1-4 of [0002]), and the teachings of Laursen et al. and Halder et al. demonstrate the importance of needed concentrations of vitamin K2 (Halder et al., page 8, lines 7-12 of section 8.8) and vitamin D3 (Laursen et al., lines 1-14 of Abstract) to improve treatment outcomes for MS patients. One would have been motivated to include the optimized dosage amounts of vitamin D3 and vitamin K2 taught by Shapiro due to the fact that Laursen et al. and Halder et al. already provide nationally-accepted and recommended dosage amounts of these vitamins for the treatment of inflammatory neurological diseases, such as multiple sclerosis (page 170, Table 1 of Laursen et al. and page 3, line 7 of 3. Adequate Intake is an Estimate and page 4 line 1 of Halder et al.). Shapiro teaches ranges that overlap with the dosage amounts taught in Laursen et al. and Halder et al. (page 11, col., 19, lines 14-15 and page 11, col., 19, lines 26-27 of Shapiro). One skilled in the art would optimize the dosage amounts based on National recommended amounts as taught in Laursen et al. and Halder et al. and arrive at the ideal amounts recited within the instant claims 14, 20, and 21. Thus, the amounts of D3 and K2 are recognized as result effective variables where increasing the amount of D3 and K2 administered results in a decrease in overall ARR and neurological flareups in MS patients.
In the case where the claimed dosage ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In reWertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In reWoodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of “about 1-5%” while the claim was limited to “more than 5%.” The court held that “about 1-5%” allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of “50 to 100 Angstroms” considered prima facie obvious in view of prior art reference teaching that “for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms].” The court stated that “by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.”). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range). See MPEP 2144.05.
One would have had a reasonable expectation of success because the above references discuss producing pharmaceutical compositions administered orally to humans for the treatment of inflammatory diseases including multiple sclerosis.
Conclusion
Claims 14-21 and 27-32 are rejected.
Claims 22-26 and 33 remain withdrawn.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANNA L BAUER whose telephone number is (571)272-5752. The examiner can normally be reached 8am-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.
/B.L.B./Examiner, Art Unit 1623
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
Prosecution Insights