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 .
Response to Arguments
Applicant’s response from 7/23/2026 is acknowledged.
Claim Rejections - 35 USC § 112
In view of Applicant’s claim amendments, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 102
In view of Applicant’s claim amendments, this rejection is hereby withdrawn.
Applicant has amended the claims and made arguments to the claims as amended. In view of Applicant’s claim amendments a modified rejection has been made under 35 USC 103, which now renders Applicant’s arguments moot.
The Examiner would further like to clarify the following issue for the record concerning Hellerstein, over which a modified rejection has been made below. Applicant has argued vis-à-vis Hellerstein as follows:
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In response, Applicant’s quote from Hellerstein, para [0042] is taken out of context, both with respect to the dose, as well as with respect to the full spectrum of compounds to which Hellerstein applies.
With respect to the dose, the full paragraph [0042] discloses that it is possible to optimize the dose using a variety of parameters, to include guidance from animal models. More than that, it very explicitly discloses doses exactly per Applicant’s claims as amended.
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With respect to the compounds, Applicant has again misrepresented Hellerstein, as it does not apply solely to 13-cis-retinoic acid, but to retinoic acid, to include retinoic acid is selected from the group consisting of multiple compounds beyond 13-cis-retinoic acid, e.g. retinol, etc. (See, e.g. claim 5).
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Applicant’s specification gives the following guidance on conversion.
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So, if one is to take, for instance, a dose of Hellerstein of 1 mg/kg/day (where Hellerstein discloses a range of 0.01 mg/kg/day to about 200 mg/kg/day), as applied to retinol, and converts it to IU for retinol, one gets that this equals 333.3 IU RAE. For a 70 kg man, this translates to about 23,333 IU RAE. A dose of 2 mg/kg/day, then discloses 46,666, and falls straight with Applicant’s claimed range of 25,000 to 75,000 IU vitamin A per day.
Thus, there is no doubt that Applicant has claimed a range within a range of Hellerstein.
Further, Applicant is incorrect that conversion cannot be done for other retinoic acid compounds, e.g. 13-cis-retinoic acid (isotretinoin/ Accutane). See, e.g., Emma, How Much Vitamin A Is in Accutane? | Essential Facts Revealed, available at https://snuggymom.com/how-much-vitamin-a-is-in-accutane/, Copyright © 2026 Snuggy Mom (“Emma”)
Emma discloses that “1 mg of isotretinoin roughly equals about 3,333 International Units (IU) of vitamin A activity. Therefore, a standard daily dose of 20 mg isotretinoin corresponds to approximately 66,660 IU of vitamin A activity—far exceeding the recommended daily allowance (RDA) for vitamin A.” Therefore, if one is to take a dose of 0.2 mg/kg/day of isotretinoin, this translates for a 70 kg man to 46,666 IU RAE, and again falls within Applicant’s claimed dose range.
For the foregoing reasons, in view of Applicant’s claim amendments, a modified rejection has been made below. Claims 26-29, 32, 34-40, 42-44 and 47-54 are pending, and have been examined herewith.
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.
Claims 26-29, 32, 34-40, 42-44 and 47-54 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al., B-carotene provides neuroprotection after experimental traumatic brain injury via the Nrf2-ARE pathway, Journal of Integrative Neuroscience, vol. 18, no. 2, pages 153-161, published online, June 30, 2019 (“Chen”, of record), and further in view of WO 2007/104030 A1 to Hellerstein et al. (‘Hellerstein”, of record).
Chen discloses that β-carotene improves cognitive performance and neural functions in a model of traumatic brain injury. In addition, β-carotene reduced brain edema and reactive oxygen species levels after traumatic brain injury. TBI was induced by a blunt force weight injury. Mice received beta-carotene orally 30 minutes after TBI and then once daily for a week; the dose of 30 mg/kg provided the best response (abstract; page 154, column 1, paragraph 3 - column 2, paragraph 1; figure 1; page 159, column 1, paragraph 4). This disclosure is consistent with where the TBI is concussion or post-concussion syndrome (PCS). The dose of β-carotene administered to mice was 10 mg/kg, 20 mg/kg, 30 mg/kg, and 50 mg/kg orally. (page 156, column 2). β-carotene was administered to mice by gavage and then once daily for one week. (page 154, column 1). This is indicative of systemic administration, per Applicant’s claim 47.
Chen discloses that β-carotene had beneficial effects on a number of other parameters: cognitive performance and neural functions were improved with β carotene administration, and β-carotene reduced brain edema and reactive oxygen species levels after traumatic brain injury (abstract). Reduction of brain edema is consistent with reduction in chronic traumatic encephalopathy (CTE). In this regard, Chen explicitly outlines the mechanism of secondary TBI in the entire Introduction section, to include the different mechanisms that contribute to secondary injury, such as oxidative stress, hypoxia and edema, the involvement of oxidative stress and apoptosis, and how reducing oxidative stress has been hypothesized to be beneficial for TBI patients. It further goes on to explicitly disclose that several studies have indicated that β-carotene, an antioxidant, has a protective effect on numerous diseases, such as cardiovascular disease, cancer and age-related degenerative disorders, that it functions as a free radical scavenger with chainbreaking antioxidant properties, and that previous studies have demonstrated that β-carotene is converted into retinol in the body, and its antioxidant activity plays an important role in preventing neurodegenerative disorders, including Alzheimer's disease. (pages 153-154). Chen further discloses that numerous studies have demonstrated that the pleiotropic transcription factor Nrf2 is important for regulating antioxidant enzymes, as demonstrated in several CNS diseases (i.e., Parkinson’s disease, Alzheimer’s disease (AD), depression, and memory loss), and that as demonstrated by us and previous studies, the activation of the Nrf2-ARE pathway provides protection against brain injury. Per Chen, they demonstrated that β-carotene alleviates brain injury after TBI by modulating the Nrf2/Keap1-mediated antioxidant pathway. (page 159).
Per Chen, lesion volume was not significantly reduced (abstract)- in line with knowledge that the brain is more sensitive to oxidative stress compared to other tissues (page 159, column 2), but reduced nonetheless. In that regard Chen reports that β-carotene had a neuroprotective effect in lesioned cortex. (page 159, column 1). Further, TUNEL-positive cells were reduced in TBI mice administered 30 mg/kg β carotene compared to mice in the TBI group. (page 159, column 2).
Applicant’s specification does not define “subject” per se, in view of which the broadest reasonable interpretation applies to include both humans and animals. This is further consistent with Applicant’s specification, i.e. paragraph [0098], which discloses that “[t]he term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects”, and with Example 5, which shows testing in horses. It is further noted that Chen has, to include in disclosure cited above, multiple references linking the studies to human patients, or directly referring to studies in human patients.
Since the same compound is administered to a subject with the same condition in therapeutically effective amounts it will have the same effect of inhibiting formation of glial scar tissue.
The β-carotene fits Applicant’s claim 36 term “isolated”- i.e. it is pure. As noted above, Chen discloses administration of retinol from β-carotene. Per Applicant’s specification at [0035], β-carotene is a provitamin A carotenoid.
Chen does not specifically disclose all forms of vitamin A, per Applicant’s new claims 51 and 53. Chen provides rationale to optimize Applicant’s claimed dose of amended claim 26, but does not explicitly disclose it. This is cured by the disclosure of Hellerstein.
Hellerstein discloses retinoic acids or derivatives such as retinol or retinal, for use in treating neuroinflammatory conditions, such as stroke, Parkinson's disease or traumatic brain injury (TBI) (page 1, paragraph [0002]; page 4, paragraph [0012]; pages 7-8, paragraph [0025]; page 17, paragraph [0058]; page 16, paragraph [0056]; claims 1, 2, 5, 8-12). Administration is systematic, and can include intravenous. (paragraphs [0041] and [0052]). The findings extend to both animals and patients. (Table, page 20, claim 1).
Hellerstein defines “retinoic acid” to comprise multiple forms of vitamin A.
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Since the same compound is administered to a subject with the same condition in therapeutically effective amounts it will have the same effect of inhibiting formation of glial scar tissue.
Hellerstein discloses that initial dosage for each component in the pharmaceutical composition may be in the range of about 0.01 mg/kg/day to about 200 mg/kg/day. (paragraph [0042]).
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200 mg of retinol is equivalent to approximately 666,667 IU (International Units). This calculation is based on the standard conversion factor for retinol, where 1 IU equals 0.3 micrograms (mcg) of retinol. Per Applicant’s Table 2, paragraph [0044], this is a dose in excess of a Tolerable Upper Limit Intake Level (UL) for the subject.
Applicant’s specification gives the following guidance on conversion.
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So, if one is to take, for instance, a dose of Hellerstein of 1 mg/kg/day (where Hellerstein discloses a range of 0.01 mg/kg/day to about 200 mg/kg/day), as applied to retinol, and converts it to IU for retinol, one gets that this equals 333.3 IU RAE. For a 70 kg man, this translates to about 23,333 IU RAE. A dose of 2 mg/kg/day, then discloses 46,666, and falls straight with Applicant’s claimed range of 25,000 to 75,000 IU vitamin A per day.
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of Chen and Hellerstein in order to practice Applicant’s claimed invention with a reasonable chance of success. The skilled artisan would have been motivated to do so since both references disclose treating chronic TBI with various forms of vitamin A in humans, provide motivation to optimize the dose, as well as explicitly disclose a dose overlapping Applicant’s claimed dose.
Other relevant art
The Examiner also restates for the record the following prior art of record over which no rejections were made solely in view of its cumulative nature.
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(d) Document D3 describes vitamin A (i), preferably in combination with (ii) vitamin D, and/or (iii) an omega- 3 PUFA (p. 9, I. 10 - p. 10, I. 11) for use in treating, reducing and/ or preventing neuroinflammation, associated with i.a. depression, Parkinson's disease or traumatic brain injury (TBI). Each of the individual nutrients (i), (ii) and (iii), act on convergent pathways involved in neuroinflammation, and the combination yields a synergistic effect. Vitamin A includes retinol, retinal, retinoic acid, beta-carotene, provitamin A or retinyl esters. Vitamin A is advantageously administered in a daily dose of 0.05 - 3 mg/day (= 10,000 IU). Administration preferably starts at the first day after the neuroinflammation and preferably is continued for at least 4 weeks (p. 19, I. 29 - p. 20, I. 12). As shown in figure 1, vitamin A alone also has an effect on neuroinflammation (page 3, lines 2-5; page 19, line 29 - page 20, line 12; page 20, lines 15-20; claims 1, 2; figure 1).
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Document D4 discloses a 9-cis-carotenoid for use in treating CNS related diseases, including depression, Parkinson's disease or neurodegenerative related dementias due to changes in the brain caused by trauma. The compounds can be administered orally in dosages from 1 -100 mg, daily or one to 6 times per week (page 28, line 35 - page 29, line 3; page 31, lines 4-10; claims 13, 21).
-WO 2015073055 A1 to Haase et al. (“Haase”, of record).
Haase discloses a micronutrient formulation for treatment of prevention of TBI such as concussion comprising, inter alia, vitamin A, natural mixed carotenoids, vitamin C, vitamin D, coenzyme Q10, alpha lipoic acid, which is to be taken by humans twice a day. (Abstract, page 1). Haase discloses that sports-related concussive injuries are included. (page 4). The formulation is consumed twice per day to be taken year round by young athletes. (page 11). The method relates to acute of chronic concussion or PCS, and also includes resistance to a variety of disorders such as Parkinson’s disease, and to repeated concussions, which may increase the risk of chronic traumatic encephalopathy (CTE) and Parkinson’s disease. The formulation is to be consumed orally.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SVETLANA M IVANOVA whose telephone number is (571)270-3277. The examiner can normally be reached 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L. Klinkel can be reached at (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SVETLANA M IVANOVA/ Primary Examiner, Art Unit 1627
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