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 .
Election/Restrictions
Applicant’s response to the restriction/ election requirement from 7/16/2025 is acknowledged. Applicant has elected without traverse the invention of Group I (claims 26-29, 32-44 and 47-50).
Applicant was further required to elect a single species of acute or chronic traumatic brain injury (TBI). A single species would have been, for instance, concussion, post-concussion syndrome (PCS), chronic traumatic encephalopathy (CTE), per Applicant’s claims 27-29. Applicant did not respond in accordance, but noted that it has elected chronic TBI, which more or less restates the genus of the claim. Either way, in lieu of sending a miscellaneous communication, and in the interest of compact prosecution, the Examiner hereby withdraws the election of species requirement.
The restriction/ election requirement is hereby MADE FINAL. Claims 26-29, 32-44 and 47-50 are pending, and have been examined herewith across their breadth.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 37-39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 37-39 recite the following (with particular attention drawn to the “such as” limitations):
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A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, the claims recites the respective broad recitations “wherein the vitamin A comprises a preformed vitamin A", “wherein the vitamin A comprises a provitamin A”, “wherein the vitamin A comprises a bioactive form of vitamin A”, and the claim also recites, respectively, “such as a retinyl ester or retionol”, “such as a carotenoid”, “such as retinal or retinoic acid”, which are the narrower statement of the range/limitations. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 26-29, 32, 33, 36, 37, 38, 43, 44 and 47-50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by 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).
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.
Claims 26, 32, 33, 36, 37, 39, 40-42, 47 and 48 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2007/104030 A1 to Hellerstein et al. (‘Hellerstein”, of record).
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).
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]). 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.
Claims 26-29, 32-35 and 48 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by 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.
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.
Other relevant art
The Examiner also notes 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).
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.
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, 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