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
This office action is a response to applicant’s communication submitted August 22, 2025, wherein new claims 43-45 are introduced. This application is a continuation of US application 16/604055, now abandoned, filed October 9, 2019, which is a national stage application of PCT/EP2018/058710, filed April 5, 2018, which claims benefit of provisional applications 62/580574, filed November 2, 2017, 62/484156, filed April 11, 2017, and 62/484119, filed April 11, 2017, as well as foreign applications EP17193916.8, filed September 29, 2017, PCTEP2017074731, filed September 29, 2017, and PCTEP2017082148, filed December 11, 2017.
Claims 1-4, 6, 7, 15-18, 23-26, and 43-45 are pending in this application.
Claims 1-4, 6, 7, 15-18, 23-26, and 43-45 as amended are examined on the merits herein.
The following rejections of record in the previous action are maintained:
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.
Claims 1-4, 6, 7, 23-26, and 45 are rejected under 35 U.S.C. 103 as being obvious over Pan. (PCT international publication WO2016/207794, reference of record in previous action) in view of Kumanagi et al. (US pre-grant publication 2015/0306125, reference of record in previous action) in view of Asensi-Fabado et al. (Reference of record in previous action) in view of Birch et al. (Reference included with PTO-892) in view of Gliszczyńska-Świgło et al. (Reference of record in previous action)
The claimed invention is directed to a method of treating a non-demented individual (claims 1 and 22) or achieving various benefits in a subject, (claim 24) comprising administering to the subject a combination of four elements, namely an omega-3 fatty acid, a nitric oxide releasing compound, vitamin B12, and citicoline. Various dependent claims define the amounts of vitamin B12 and citicoline administered, the specific identity of the fatty acid and nitric oxide releasing compound, and additional compounds which can be administered.
Pan discloses methods for enhancing neurogenesis in an animal, comprising administering to the animal a composition comprising an unsaturated fatty acid, a nitric oxide releasing compound, a B vitamin, and an antioxidant, in an amount effective for enhancing neurogenesis. (p. 2 paragraphs 7-8) In a particular embodiment the animal is suffering from cognitive decline or at risk of becoming cognitively impaired. (p. 7 paragraph 31) Animals “at risk of” cognitive decline are by definition not suffering from dementia as they would already be experiencing cognitive decline if they were demented. In one embodiment the unsaturated fatty acid includes an omega-3 fatty acid, for example docosahexaenoic or eicosapentaenoic acid. (pp. 7-8 paragraph 32, p. 3 paragraph 13) B vitamins include vitamin B12, as well as B1, B2, B3, B5, B6, B7, B8, and B9. (p. 8 paragraph 34) Antioxidants include any antioxidant suitable for administration to an animal. (pp. 8-9 paragraph 35) Nitric oxide releasing compounds include arginine. (p. 8 paragraph 33) Citrulline can also be substituted for arginine. (p. 19 paragraph 66) B-vitamins (e.g. B12) are included at about 1.2-40 times the recommended daily allowance. (p. 9 paragraph 36) Further ingredients such as choline can be added to the composition. (p. 10 paragraph 37) In one embodiment the subject is an aging animal. (p. 20 paragraph 70) In another embodiment the composition is intended for either humans or companion animals. (p. 11 paragraph 44) With respect to instant claim 24, enhancing neurogenesis would reasonably be considered to additionally be a method of decreasing brain atrophy. Administration of the composition can be for example daily. (pp. 19-20 paragraph 68) The claimed invention differs from the disclosure of Pan et al. in that it includes citicoline rather than other forms of choline.
Kumanagi et al. discloses a composition for preventing or improving decline in brain function. (p. 1 paragraph 19) Specifically the composition comprises citrulline and citicoline. (p. 1 paragraph 20) Citicoline is specifically described as a source of choline, which is one of the ingredients described by Pan. (p. 1 paragraph 7) The daily amount of citicoline to be administered is preferably 200mg-3g. (p. 3 paragraph 46) Since, as described in p. 3 paragraph 11 of the specification as originally filed, the recommended daily allowance (RDA) of choline is defined by Applicant as 550 mg/day, Kumanagi’s dosage of citicoline is about 0.36-5.45 times the RDA, falling within the range recited in present claims 23 and 25.
It would have been obvious to one of ordinary skill in the art at the time of the invention to use citicoline either as the source of choline in the method described by Pan, or in place of choline in said method. One of ordinary skill in the art would have found either of these modifications to be obvious based on the fact that the compositions described by Kumanagi are disclosed as having the same utility as the compositions described by Pan, and would therefore be obvious to administer to the same subject population, and furthermore that citicoline would be reasonably expected to perform the same function as other forms of choline as it is described to be a dietary source of choline.
Pan et al. further differs from the present claims in that it describes including “an antioxidant” which is not one of the ingredients specifically recited in the present claims. Kumanagi et al. also does not specifically list which B-vitamins are to be included.
Asensi et al. discloses that vitamin B6 acts as an antioxidant in vivo. (p. 586 left column) Birch et al. discloses a study of the effects of cobalamins (Vitamin B12 as an antioxidant to protect cells against oxidative stress. (p. 184 right column last paragraph – p. 185 left column first paragraph) Cobalamins were found to be protective against HCY-induced oxidative cell death. (p. 185 right column second paragraph) Gliszczyńska-Świgło et al. discloses a study of the antioxidant capacity of folates. (Vitamin B9) (p. 1480 right column second paragraph – p. 1481 left column first paragraph) Various folates were found to be antioxidants. (p. 1482 left column last paragraph – right column first paragraph) Folates haec antioxidant activity comparable to other dietary antioxidants, and good bioavailability. (p. 1483 left column first paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to include vitamins B6, B9, and B12 as the antioxidants in the compositions described by Pan et al. One of ordinary skill in the art would have considered using these compounds because the reference generally discloses using known vitamins as antioxidants and these specific B-vitamins are described as such elsewhere in the art.
Furthermore with respect to the specific dosages of vitamin B12 recited in instant claims 2, 3, 25, and 26, and the specific doses recited in new claim 45 it would have been obvious to one of ordinary skill in the art at the time of the invention to determine the optimal amount of each of these active agents within the broad range disclosed by the reference. In particular, paragraph 36 on pp. 9-10 of Pan, as well as paragraphs 59-60 on pp. 16-17 discuss the optimal dosages of the recited components. Tables 1 and 2 on p. 18 disclose preferred amounts for other components including pyridoxine, (vitamin B6) folic acid, (vitamin B9) and cyanocobalamin. (Vitamin B12) Paragraph 46 on p. 3 of Kumanagi et al. describes specific dosages of citrulline and citicoline. Therefore the dosages of all of these compounds would be regarded by one of ordinary skill in the art as result-effective variables, and furthermore there is no evidence of record demonstrating that the specific range claimed by Applicant is critical.
Therefore the invention taken as a whole is prima facie obvious.
Claims 15 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Pan in view of Kumanagi in view of Asensi et al. in view of Birch et al. in view of Gliszczyńska-Świgło et al. as applied to claims 1-4, 6, 7, and 23-26 above, and further in view of Baierle et al. (Reference of record in previous action)
The disclosure of Pan is discussed above. Pan in view of Asensi et al. in view of Birch et al. in view of Gliszczyńska-Świgło et al. does not specifically disclose that the subject being treated is a subject having low DHA or plasma homocysteine above 12 µmol/L.
Baierle et al. discloses a study of the relation between fatty acid status, homocysteine, and cognitive function in elderly subjects. (p. 3626 second paragraph) Cognitive impairment was found to be associated with low DHA levels. (p. 3628 last paragraph, p. 3629 first paragraph) Homocysteine was also related to decreased cognitive performance. (p. 3633 table 5) HCY levels in the cognitive impairment group were on average 19.92 µmol/L.
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer the therapeutic method described by Pan in view of Kumanagi to a subject having low DHA or elevated Hcy. One of ordinary skill in the art would have been motivated to do so and would have reasonably expected success because Baierle et al. discloses that these subjects are at greater risk of cognitive impairment.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Pan in view of Kumanagi in view of Asensi et al. in view of Birch et al. in view of Gliszczyńska-Świgło et al. as applied to claims 1-4, 6, 7, and 23-26 above, and further in view of Morris et al. (Reference of record in previous action)
The disclosures of Pan and Kumanagi are discussed above. Pan in view of Kumanagi in view of Asensi et al. in view of Birch et al. in view of Gliszczyńska-Świgło et al. does not specifically disclose that the subject has a clinical dementia rating of 0.5.
Morris et al. discloses that mild cognitive impairment is staged as a CDR rating of 0.5. (p. 397 right column) A population of patients were evaluated for CDR. (p. 298 “Clinical Data”) Patients having CRD=0.5 were seen to have higher rates of progression to dementia, such as Alzheimer’s disease, than those having a CDR of zero. (p. 402 figure 2, left column under the heading “Neuropathology”)
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer the therapeutic method described by Pan and Kumanagi to subjects having a CDR of 0.5. One of ordinary skill in the art would have been motivated to treat these patients and would reasonably have expected success in doing so because Morris et al. discloses that they are at increased risk for further cognitive decline.
Therefore the invention taken as a whole is prima facie obvious.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Pan in view of Kumanagi in view of Asensi et al. in view of Birch et al. in view of Gliszczyńska-Świgło et al. as applied to claims 1, 2, 4, 6, 24, and 25 above, and further in view of Kivipelto et al. (Reference of record in previous action)
The disclosures of Pan and Kumanagi are discussed above. Pan in view of Kumanagi in view of Asensi et al. in view of Birch et al. in view of Gliszczyńska-Świgło et al. does not specifically disclose that the subject has a CAIDE score of 10-15.
Kivipelto et al. discloses a method for predicting risk of later in life dementia based on data from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study. (p. 735 left column last paragraph) Higher CIADE scores. (e.g. 12-15) were associated with greater risk of progression to dementia. (p. 737 table 3, p. 738 left column last paragraph – right column first paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer the therapeutic method described by Pan and Kumanagi to subjects having a high CAIDE risk score as described by Kivipelto et al. One of ordinary skill in the art would have been motivated to treat these patients and would reasonably have expected success in doing so because Kivipelto et al. discloses that they are at increased risk for further cognitive decline.
Therefore the invention taken as a whole is prima facie obvious.
Claims 1-4, 7, 15, 17, 23-26, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Smith et al. (Reference of record in previous action) in view of Oulhaj et al. (Reference of record in previous action) in view of Kumanagi et al. (US pre-grant publication 2015/0306125, reference of record in previous action)
The claimed invention is directed to a method of treating a non-demented individual (claims 1 and 22) or achieving various benefits in a subject, (claim 24) comprising administering to the subject a combination of four elements, namely an omega-3 fatty acid, a nitric oxide releasing compound, vitamin B12, and citicoline. Various dependent claims define the amounts of vitamin B12 and citicoline administered, the specific identity of the fatty acid and nitric oxide releasing compound, and additional compounds which can be administered.
Smith et al. discloses a study of the effects of B-vitamin supplementation on patients at risk for brain atrophy and cognitive decline. (p. 2 left column first and second paragraphs) Subjects suffered from mild cognitive impairment but subjects suffering from dementia were excluded. (p. 2 left column fourth paragraph – right column third paragraph) Subjects were administered a composition containing folic acid, (vitamin B9) cyanocobalamin, (Vitamin B12) and pyridoxine HCl, (vitamin B6) for a period of two years. (p. 2 right column third paragraph) Treatment with B vitamins reduced the rate of brain atrophy. (p. 3 right column last paragraph – p. 5 left column first paragraph) Furthermore the treatment effect was greater in patients having higher total homocysteine at baseline. (p. 5 left column last paragraph – right column last paragraph, p. 6 figure 2) The rate of brain atrophy was strongly correlated with cognitive decline, indicating that the risk of dementia would be reduced in these subjects. (p. 7 right column last paragraph – p. 8 left column first paragraph)
While Smith et al. does not disclose additionally administering eicosapentaenoic acid (EPA) and docosahexaenoic acid, (EPA) Oulhaj et al. discloses a further analysis of the data from the same study described by Smith et al., particularly focusing on the impact of omega-3 fatty acid status. (p. 548 left column second paragraph, right column third paragraph) Patients were administered cognitive tests and assays of plasma EPA and DHA. (p. 549 left column first and second paragraphs) Omega-3 fatty acid levels were found to be correlated with increased effect of B-vitamin treatment on memory, cognition, and clinical dementia rating. (pp. 550-553) Subjects having low plasma fatty acids did not benefit from treatment. (p. 553 right column last paragraph) Oulhaj et al. further suggests testing the administration of B-vitamins and omega-3 fatty acids together. (p. 555 right column second paragraph)
It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to administer the B-vitamin supplement used by Smith et al. in combination with EPA and DHA. One of ordinary skill in the art would have found this to be obvious because Oulhaj et al. specifically suggests that improving omega-3 fatty acid levels in a subject would increase the benefit of B-vitamin supplementation. In particular, regarding the patient populations described in claims 15 and 17, the disclosures of Smith and Oulhaj identify patients with elevated homocysteine as especially likely to benefit from B-vitamin supplementation, and subjects with low DHA as being less able to benefit without also increasing their omega-3 fatty acid levels by administering said fatty acids.
Smith et al. furthermore does not disclose administering citrulline and citicoline to a subject. However, Kumanagi et al. discloses a composition for preventing or improving decline in brain function. (p. 1 paragraph 19) Specifically the composition comprises citrulline and citicoline. (p. 1 paragraph 20) Citicoline is specifically described as a source of choline, which is one of the ingredients described by Pan. (p. 1 paragraph 7) The daily amount of citicoline to be administered is preferably 200mg-3g. (p. 3 paragraph 46) Since, as described in p. 3 paragraph 11 of the specification as originally filed, the recommended daily allowance (RDA) of choline is defined by Applicant as 550 mg/day, Kumanagi’s dosage of citicoline is about 0.36-5.45 times the RDA, falling within the range recited in present claims 23 and 25.
It would have been obvious to one of ordinary skill in the art at the time of the invention to further add citrulline and citicoline to the B-vitamin supplement described by Smith. One of ordinary skill in the art would have found this to be obvious based on the fact that the compositions described by Kumanagi are disclosed as having the same utility as the compositions described by Smith, and would therefore be obvious to administer to the same subject population.
Furthermore with respect to the specific dosages of vitamin B12 recited in instant claims 2, 3, 25, and 26, and the amounts of each agent recited in claim 45, it would have been obvious to one of ordinary skill in the art at the time of the invention to determine the optimal amount of each of these active agents within the broad range disclosed by the reference. The third paragraph on p. 2 0f Smith describes specific dosages for all three B-vitamins. Paragraph 46 on p. 3 of Kumanagi et al. describes specific dosages of citrulline and citicoline. Therefore the dosages of all of these compounds would be regarded by one of ordinary skill in the art as result-effective variables, and furthermore there is no evidence of record demonstrating that the specific range claimed by Applicant is critical.
Therefore the invention taken as a whole is prima facie obvious.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Smith in view of Oulhaj in view of Kumanagi as applied to claims 1-4, 7, 15, 17, and 23-26 above, and further in view of Morris et al. (Reference of record in previous action)
The disclosures of Smith, Oulhaj, and Kumanagi are discussed above. Smith in view of Oulhaj in view of Kumanagi does not specifically disclose that the subject has a clinical dementia rating of 0.5.
Morris et al. discloses that mild cognitive impairment is staged as a CDR rating of 0.5. (p. 397 right column) A population of patients were evaluated for CDR. (p. 298 “Clinical Data”) Patients having CRD=0.5 were seen to have higher rates of progression to dementia, such as Alzheimer’s disease, than those having a CDR of zero. (p. 402 figure 2, left column under the heading “Neuropathology”)
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer the therapeutic method described by Smith in view of Oulhaj in view of Kumanagi to subjects having a CDR of 0.5. One of ordinary skill in the art would have been motivated to treat these patients and would reasonably have expected success in doing so because Morris et al. discloses that they are at increased risk for further cognitive decline.
Therefore the invention taken as a whole is prima facie obvious.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Smith in view of Oulhaj in view of Kumanagi as applied to claims 1-4, 7, 14, 17, and 23-26 above, and further in view of Kivipelto et al. (Reference of record in previous action)
The disclosures of Smith, Oulhaj, and Kumanagi are discussed above. Smith in view of Oulhaj in view of Kumanagi does not specifically disclose that the subject has a CAIDE score of 10-15.
Kivipelto et al. discloses a method for predicting risk of later in life dementia based on data from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study. (p. 735 left column last paragraph) Higher CIADE scores. (e.g. 12-15) were associated with greater risk of progression to dementia. (p. 737 table 3, p. 738 left column last paragraph – right column first paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer the therapeutic method described by Smith in view of Oulhaj in view of Kumanagi to subjects having a high CAIDE risk score as described by Kivipelto et al. One of ordinary skill in the art would have been motivated to treat these patients and would reasonably have expected success in doing so because Kivipelto et al. discloses that they are at increased risk for further cognitive decline.
Therefore the invention taken as a whole is prima facie obvious.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Smith in view of Oulhaj in view of Kumanagi as applied to claims 1-4, 7, 14, 17, and 23-26 above, and further in view of Cory. (Reference of record in previous action)
The disclosures of Smith, Oulhaj, and Kumanagi are discussed above. Smith in view of Oulhaj in view of Kumanagi does not specifically disclose treating a companion animal. However, Cory discloses that companion animals suffer from cognitive decline that shares features with Alzheimer’s disease in humans. (p. 291 left column first paragraph – p. 292 left column first paragraph) A wide variety of nutraceutical products have been used for nutritional management of companion animals suffering from cognitive decline, including folate, pyridoxine, and omega-3 fatty acids. (p. 298 right column second paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer the therapy described by Smith in view of Oulhaj in view of Kumanagi to a companion animal such as a dog or cat that is at risk of cognitive decline. One of ordinary skill in the art would have been motivated to treat this subject population in view of the disclosure by Cory that these patients suffer from cognitive decline as well and are known to be treatable by the same interventions including nutritional supplementation.
Therefore the invention taken as a whole is prima facie obvious.
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/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 6, 7, 23-26, and 45 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9, 11, 24, 26, and 28 of U.S. application No. 16/603688 (US pre-grant publication 2021/0263048, of record in previous action, herein referred to as ‘688) in view of Pan. (PCT international publication WO2016/207794, reference of record in previous action) in view of Kumanagi et al. (US pre-grant publication 2015/0306125, of record in previous action) in view of Asensi-Fabado et al. (Reference included with PTO-892) in view of Birch et al. (Reference included with PTO-892) in view of Gliszczyńska-Świgło et al. (Reference included with PTO-892)
Claims 9 and 11 of ‘688 claim methods of reducing or preventing cognitive decline in a subject comprising administering to the subject an omega-3 fatty acid and possibly vitamin D. Claims 24 and 28 further define the subject as a human or companion animal and claim 26 defines the fatty acid as EPA or DHA. While the method claimed by ‘688 does not comprise administering all of the components recited in the present claims, as described previously Pan et al. in view of Kumanagi et al. in view of Asensi-Fabado et al. in view of Birch et al. in view of Gliszczyńska-Świgło et al. renders such a method obvious. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to administer the therapeutic method disclosed by the aforementioned references to a subject identified as at risk by the method claimed by ‘688. One of ordinary skill in the art would have reasonably believed that such a subject would benefit from the therapeutic method disclosed by the claims of ‘688.
Claims 1-4, 6, 7, 10, 14, 23-26, and 45 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-28 of U.S. application No. 18/378404 (US pre-grant publication 2024/0041915, of record in previous action, herein referred to as ‘404) in view of Pan. (PCT international publication WO2016/207794, reference of record in previous action) in view of Kumanagi et al. (US pre-grant publication 2015/0306125, of record in previous action) in view of Asensi-Fabado et al. (Reference included with PTO-892) in view of Birch et al. (Reference included with PTO-892) in view of Gliszczyńska-Świgło et al. (Reference included with PTO-892)
Claim 19 of ‘404 claim methods of reducing or preventing cognitive decline in an elderly subject comprising administering to the subject a composition comprising vitamin B6. Claims 22 and 23 further specifies administering citrulline. While the method claimed by ‘404 does not comprise administering all of the components recited in the present claims, as described previously Pan et al. in view of Kumanagi et al. in view of Asensi-Fabado et al. in view of Birch et al. in view of Gliszczyńska-Świgło et al. renders such a method obvious. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to administer the therapeutic method disclosed by the aforementioned references to a subject identified as at risk by the method claimed by ‘404. One of ordinary skill in the art would have reasonably believed that such a subject would benefit from the therapeutic method disclosed by Pan.
Claims 1, 4, 7, 16-18, and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-10, 13, 14, and 18 of U.S. Patent No. 10821130 (of record in previous action, herein referred to as ‘130) in view of Kumanagi et al. (US pre-grant publication 2015/0306125, of record in previous action)
Independent claim 1 of ‘130 claims a method of attenuating, treating, or reducing the risk and/or severity of cognitive aging in a non-demented subject comprising administering to the subject a combination of an omeda-3 fatty acid, citrulline, vitamin B12, and one or more additional B vitamins which can include B6 and B9. Independent claims 13 and 14 further describe providing additional benefits by the same method. These methods differ from the methods of present claims 1, 22, and 24 in that they do not specifically describe a method further comprising administering citicoline to the subject.
Kumanagi et al. discloses a composition for preventing or improving decline in brain function. (p. 1 paragraph 19) Specifically the composition comprises citrulline and citicoline. (p. 1 paragraph 20) Citicoline is specifically described as a source of choline, which is one of the ingredients described by Pan. (p. 1 paragraph 7) The daily amount of citicoline to be administered is preferably 200mg-3g. (p. 3 paragraph 46) Since, as described in p. 3 paragraph 11 of the specification as originally filed, the recommended daily allowance (RDA) of choline is defined by Applicant as 550 mg/day, Kumanagi’s dosage of citicoline is about 0.36-5.45 times the RDA, falling within the range recited in present claims 23 and 25.
It would have been obvious to one of ordinary skill in the art at the time of the invention to additionally administer citicoline in the method described in the claims of ‘130. One of ordinary skill in the art would have found either of these modifications to be obvious based on the fact that the compositions described by Kumanagi are disclosed as having the same utility as the methods claimed by ‘130 and would therefore be obvious to administer to the same subject population.
Additionally, dependent claims 3-10 and 18 of ‘130 recite the same additional limitations as present claims 4, 7, and 16-18. Therefore these claims are additionally obvious over the claims of ‘130 in view of Kumanagi et al.
Claims 1-4, 6, 7, 23-26, and 45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, and 6-11 of U.S. Patent No. 11813233 (of record in previous action, herein referred to as ‘323) in view of Pan. (PCT international publication WO2016/207794, reference of record in previous action)
Claim 1 of ‘323 recited a method comprising achieving one of the benefits described in present claim 24, comprising administering to a subject who is an older adult a combination of choline, docosahexaenoic acid, and vitamin B12. Claims 2, 3, and 6-10 further provide the same limitations recited in present claims 4, 9, 10, 14, and 16-18. Claim 11 of ‘323 further describes the source of choline as selected from a list including citicoline. Furthermore administering the compositions described by claim 1 of ‘323 to an older adult would accomplish the benefits recited in present claims 1 and 22. The claims of ‘323 differ from the present claims in that they do not further describe administering citrulline. However, as discussed previously, Pan et al. describes administering a composition comprising the ingredients described by ‘323 and further comprising citrulline in order to achieve the same benefits described by the claims of ‘323. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to further include administering citrulline in the method claimed by ‘323, since the disclosure of Pan would have provided a reasonable expectation that citrulline would produce an additional benefit in this method.
Applicant’s amendment necessitates the following new grounds of 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.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Pan in view of Kumanagi in view of Asensi et al. in view of Birch et al. in view of Gliszczyńska-Świgło et al. as applied to claims 1-4, 6, 7, 23-26, and 45 above, and further in view of Chételat et al. (Reference included with PTO-892)
The disclosures of Pan, Kumanagi et al., Asensi et al., Birch et al., and Gliszczyńska-Świgło et al. are discussed above. Pan in view of Kumanagi et al. in view of Gliszczyńska-Świgło et al. does not specifically disclose a method wherein the patient is amyloid positive.
Chételat et al. discloses a study of the contributions of factors including beta-amyloid deposition to episodic memory deficits in non-demented individuals. PET scans were acquired for the subjects. (p. 800 left column third and fourth paragraphs) Correlations were found between beta-amyloid deposition and memory deficits. (p. 801 right column first paragraph, p. 805 left column third paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer a therapy for enhancing neurogenesis and reversing decline in brain function as described in the cited prior art to a subject who is amyloid positive on PET scans as discussed in claim 43. One of ordinary skill in the art would have been motivated to administer this therapy to this patient because this diagnostic indicator is known to be associated with cognitive decline and memory deficits.
Therefore the invention taken as a whole is prima facie obvious.
Claims 43 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Pan in view of Kumanagi in view of Asensi et al. in view of Birch et al. in view of Gliszczyńska-Świgło et al. as applied to claims 1-4, 6, 7, 23-26, and 45 above, and further in view of Susanto et al. (Reference included with PTO-892)
The disclosures of Pan, Kumanagi et al., Asensi et al., Birch et al., and Gliszczyńska-Świgło et al. are discussed above. Pan in view of Kumanagi et al. in view of Gliszczyńska-Świgło et al. does not specifically disclose a method wherein the patient has a high-risk ApoE genotype.
Susanto et al. discloses that Apolipoprotien E (ApoE) influences the risk of sporadic Alzheimer’s disease, and the ε4 allele is correlated with greater MTL atrophy and memory decline. (p. 254 left column last paragraph, right column first paragraph) Subjects were genotyped according to ApoE status (p. 255 right column second paragraph) and subjected to neuropsychological testing (p. 255 right column last paragraph) and brain imaging. (p. 257 left column first – third paragraphs) Brain atrophy was observed in Aβ+ subjects, (p. 259 left column – p. 260 left column first paragraph) This effect was furthermore modulated by the presence of the ApoE ε4 carrier genotype. (p. 262 left column third paragraph – right column second paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer a therapy for enhancing neurogenesis and reversing decline in brain function as described in the cited prior art to a subject who is amyloid positive on PET scans as discussed in claim 43, or carrying the ApoE ε4 genotype as recited in claim 44. One of ordinary skill in the art would have been motivated to administer this therapy to this patient because both of these diagnostic indicators are known to be associated with cognitive decline and memory deficits.
Therefore the invention taken as a whole is prima facie obvious.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over of Oulhaj in view of Kumanagi as applied to claims 1-4, 7, 14, 17, and 23-26 above and further in view of Chételat et al. (Reference included with PTO-892)
The disclosures of Oulhaj et al. and Kumanagi et al. are discussed above. Oulhaj et al. in view of Kumanagi et al. does not specifically disclose a method wherein the patient is amyloid positive.
Chételat et al. discloses a study of the contributions of factors including beta-amyloid deposition to episodic memory deficits in non-demented individuals. PET scans were acquired for the subjects. (p. 800 left column third and fourth paragraphs) Correlations were found between beta-amyloid deposition and memory deficits. (p. 801 right column first paragraph, p. 805 left column third paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer a therapy for enhancing neurogenesis and reversing decline in brain function as described in the cited prior art to a subject who is amyloid positive on PET scans as discussed in claim 43. One of ordinary skill in the art would have been motivated to administer this therapy to this patient because this diagnostic indicator is known to be associated with cognitive decline and memory deficits.
Therefore the invention taken as a whole is prima facie obvious.
Claims 43 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Oulhaj in view of Kumanagi as applied to claims 1-4, 7, 14, 17, and 23-26 above and further in view of Susanto et al. (Reference included with PTO-892)
The disclosures of Oulhaj et al. and Kumanagi et al. are discussed above. Oulhaj et al. in view of Kumanagi et al. does not specifically disclose a method wherein the patient has a high-risk ApoE genotype.
Susanto et al. discloses that Apolipoprotien E (ApoE) influences the risk of sporadic Alzheimer’s disease, and the ε4 allele is correlated with greater MTL atrophy and memory decline. (p. 254 left column last paragraph, right column first paragraph) Subjects were genotyped according to ApoE status (p. 255 right column second paragraph) and subjected to neuropsychological testing (p. 255 right column last paragraph) and brain imaging. (p. 257 left column first – third paragraphs) Brain atrophy was observed in Aβ+ subjects, (p. 259 left column – p. 260 left column first paragraph) This effect was furthermore modulated by the presence of the ApoE ε4 carrier genotype. (p. 262 left column third paragraph – right column second paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to administer a therapy for enhancing neurogenesis and reversing decline in brain function as described in the cited prior art to a subject who is amyloid positive on PET scans as discussed in claim 43, or carrying the ApoE ε4 genotype as recited in claim 44. One of ordinary skill in the art would have been motivated to administer this therapy to this patient because both of these diagnostic indicators are known to be associated with cognitive decline and memory deficits.
Therefore the invention taken as a whole is prima facie obvious.
Response to Arguments
Applicant’s arguments, submitted August 22, 2025, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejections. With respect to the rejections over Pan in view of Kumanagi et al. in view of Asensi-Fabado in view of Birchg in view of Gliszczyńska-Świgło et al., Applicant argues that one of ordinary skill in the art would not have modified the invention of Pan to include only the claimed ingredients and exclude any additional ingredients. Applicant alleges that the reasoning provided in the previous office action amounts to a piecemeal analysis of the reference in view of the specification. However, this argument discounts the actual reasoning provided in the office action. Contrary to Applicant’s assertion, the finding of obviousness does not pick and choose only some parts of Pan’s disclosure. As stated in the rejection, Pan discloses a combination of an unsaturated fatty acid, a nitric oxide releasing compound, a B vitamin, and an antioxidant. Only the antioxidant is at issue, as all of the other elements are clearly recited in the present claims. In the present case, the reasoning for obviousness is based not on arbitrarily leaving out the antioxidant, but rather the fact that as discussed, the disclosure Pan is extremely broad as to what antioxidant can be used in this composition, allowing for essentially any antioxidant known in the art to be used in this role. Seen in this light, the fact that, as disclosed by Asensi-Fabado et al., Birch et al., and Gliszczyńska-Świgło et al., B vitamins can act as antioxidants, would thereby suggest that B vitamins, including B6, B9, and B12, can all be included in the list of antioxidants usable in the compositions described by Pan. Such a rationale is a proper use of knowledge already available in the art and not piecemeal use of Applicant’s disclosure to interpret the art.
Furthermore Applicant argues that the data presented in example 3 in paragraphs 87-93 of the specification and figure 2 in the drawings show evidence of unexpected results. In traversing the decision of the previous office action, Applicant argues, “However, the reliance of the obviousness rejection upon a combination of references does not somehow obligate Applicant to compare the claimed invention to that combination. To the contrary, requiring Applicant to demonstrate a property not possessed by the combination proposed by the Patent Office is improper. Such an obligation “would be requiring comparison of the results of the invention with the results of the invention.”” To support this assertion, Applicant cites MPEP 716.02(E)(III). However, looking to the actual text of MPEP 716.02(e)(III), this section states that the claimed invention may be compared with the closest subject matter that exists in the art, but need not be compared with a closer hypothetical invention that does not exist in the art. In the present case, the closest subject matter that exists in the art is, as described by Pan (e.g. paragraph 8 of Pan) a composition comprising an unsaturated fatty acid, a nitric oxide releasing compound, a B vitamin, and a generic antioxidant. The mere concept of combining multiple nutritional ingredients to provide benefits to brain function is not new, and is in fact routinely practiced in the art as evidenced by Pan. Thus it is proper to require comparison not to various single ingredients or dual combinations of UFAs or B vitamins as is shown in example 3, but rather to a combination of several types of ingredients such as that described by Pan.
Regarding the rejection over Smith in view of Oulhaj in view of Kumanagi, Applicant repeats the assertion that the rejection is based on piecemeal analysis and does not provide motivation to somehow only include the claimed ingredients. No further explanation is given, and Applicant is reminded that combining prior art elements according to known methods to yield predictable results is a recognized rationale for obviousness and not piecemeal analysis. Furthermore because the disclosure of Oulhaj specifically cites Smith and presents its results as an extension to or improvement on Smith’s results, as evidenced that Smith is citation number 10 referenced by the disclosure of Oulhaj, and is cited in the background section of Oulhaj as part of the rationale for the study. Furthermore Oulhaj analyzes data from the same study (VITACOG) described by Smith. All of these facts together lead to a strong suggestion to modify Smith in view of Oulhaj, beyond the already adequate case for their combination based merely on their describing similar patient populations.
Applicant additionally references the alleged finding of unexpected results with respect to this combination of references. Similarly to the rejection over Pan in view of Kumanagi et al. in view of Asensi-Fabado in view of Birch in view of Gliszczyńska-Świgło et al., the proper comparison is to the closest prior art rather than to arbitrarily separated individual ingredients. In this case the closest prior art could be, for example, a combination of multiple B-vitamins with DHA and EPA, as suggested by Oulhaj, or a combination of citrulline and citicoline, as suggested by Kumanagi. Therefore the alleged evidence of unexpected results is also not sufficient to overcome the finding of prima facie obviousness.
For these reasons the above grounds of rejection are deemed proper and maintained.
Conclusion
No claims are allowed in this action. 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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/ERIC OLSON/ Primary Examiner, Art Unit 1693 10/8/2025