DETAILED ACTION
Claims 1-9, 11-15, and 34-39 are pending. Of these, claims 3 and 13 are withdrawn as directed to a nonelected species or invention. Therefore, claims 1-2, 4-12, 14-15, and 34-39 are under consideration on the merits.
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 .
Status of the Rejections
The claim objection is withdrawn in view of the amendment.
The 112(b) rejection is withdrawn in view of the amendment, but a new rejection was necessitated by the amendment.
The 103 rejection is withdrawn in view of the amendment and replaced with new rejections incorporating the teachings of a new secondary reference, Geracitano et al.
The 112(a) rejection is withdrawn in view of the amendment.
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 1-2, 4-12, 14-15, and 34-38 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as 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.
Claim 1 has been amended to recite that the hydrogen peroxide has a concentration of between about 100 and 200 micromolar, but it is unclear what this range is in reference to, e.g., is it the concentration of the hydrogen peroxide in the overall composition which is a liquid, or is it rather the concentration of hydrogen peroxide in a solution that is added to the composition? Clarification is required. Since the dependent claims do not clarify the point of confusion, they are also rejected.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-2, 4-12, 14-15, and 35-39 are rejected under 35 U.S.C. 103 as unpatentable over McCleary (US Pat. Pub. 2002/0182196) in view of Pickering et al. (US Pat. Pub. 2009/0035275; of record in IDS), Yan (Redox Biology 2 (2014) 165-169; of record in IDS), and Geracitano et al. (J Physiol 568.1 (2005) pp 97-110).
As to claims 1-2, 4-12, 4-12, and 35-39, McCleary discloses a composition for normalizing impaired or deteriorating neurological function such as ischemic situations, the composition comprising NADH as an antioxidant and as a promoter of ATP production in neurons (a “repair system activator”(paragraphs 3, 113, and 127), and one or more methyl donors such as betaine, choline, and zinc (and wherein zinc is also an “antioxidant defense activator” recited by claim 1)(paragraphs 156, 158, 163, 165-166)(claims 1 and 4). McCleary teaches that the neurodegenerative changes are associated with aging of brain cells (paragraph 57).
Regarding claim 11, the composition may comprise water as a carrier (paragraph 175).
Regarding claims 14-15, and 37, the composition may be administered orally as a tablet or parenterally (i.e., intravenously as an “injectable formulation” as recited by the claims)(paragraphs 182-183).
As to claims 36-38, these claims recite steps regarding a timing of administration of the composition (claim 36), the location of administration (claim 37), and a step of administering a compound in a pulsed burst (claim 38). Base claim 1, however, is a composition claim and not a method claim. Therefore, the recitations of claims 36-38 are treated as intended uses of the composition of claim 1, and as such are not granted any additional patentable weight.
As to claims 1-2, 4-12, 14-15, and 35-39, McCleary does not further expressly disclose that the composition comprises the elected species of repair system activator (NAD+) as opposed to NADH as taught by McCleary, or that the composition comprises the elected species of antioxidant defense activator (i.e., hydrogen peroxide of claims 1 and 6) and in an amount within the range of claim 1. Additionally, while McCleary discloses ranges for the amounts of the active ingredients including the repair system activators, antioxidant defense activators, and methyl donors (see, e.g., the ranges given for vitamin A, vitamin E, zinc, NADH, and betaine at paragraph 177) and further teaches that the inactive ingredients can be present in any conventional amount used in oral or parenterally administered compositions (paragraph 180), McCleary does not specify that the total amounts of these ingredients are within the ranges recited by claims 2 and 12, and which will result in the functional changes recited by claims 6-10. Nor does McCleary teaches a repair system activator, methyl donor, and antioxidant defense activator in separate dosage forms configured for sequential administration as recited by claim 35 as a three compound sequence as recited by claim 39.
Pickering discloses a method for treating aging by administering a formulation that optimizes the intracellular concentration of NAD+, and states that doing so facilitates a balance among the numerous interactions of NAD+, leading to an increase in the health, longevity, and healing of cells and increase their resistance to stress and trauma (Abstract and paragraphs 1, 8, 53, 134). Pickering teaches that the formulation may comprise NAD+ itself, or alternatively other forms of nicotinamide such as NADH, which Pickering discloses is merely the reduced form of NAD+ (paragraph 52, 56-57).
Yan discloses inducing positive oxidative stress such as ischemic tolerance may be a valuable prophylactic or therapeutic approach targeting aging and aging associated diseases, and teaches that hydrogen peroxide is an example of a compound that can induce positive oxidative stress, and which has been found to have beneficial effects in inducing ischemic tolerance (Abstract, Introduction on pages 165-166, Table 1 on page 166, and last paragraph on page 167).
Geracitano discloses that hydrogen peroxide is one of the reactive oxygen species generated during metabolic stress, but that while it is potentially a toxic compound responsible for free radical dependent neuronal damage, in conditions of reduced oxygen supply as may occur during stroke, it may exert a protective role via its metabolic degradation in molecular oxygen (see abstract; the first five paragraphs of the body of the paper on pages 97-98; discussion section and conclusion section on pages 106-108). Specifically, Geracitano found that administration of hydrogen peroxide to dopamine neurons during hypoxic conditions resulted in a dose dependent reversal of membrane depolarization associated with oxygen deprivation at a concentration range of between 0.1 and 3 mM (i.e., 100 to 3000 micromolar, which encompasses the range recited by claim 1)(Abstract).
As to claims 1-2, 4-12, 14-15, and 35-39, it would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the composition of McCleary by incorporating NAD+, instead of, or in addition to, NADH, because McCleary expressly teaches that the composition may comprise NADH as an antioxidant and as a promoter of ATP production in neurons, and Pickering discloses that NADH is merely the reduced form of NAD+, and that both of these compounds are forms of nicotinamide that can be used interchangeably in compositions for the treatment of aging, such that the skilled artisan reasonably would have expected that NAD+ could be used as the form of nicotinamide in the McCleary composition. Such a modification is merely the substitution of one known element for another according to known methods to yield predictable results, which is prima facie obvious. MPEP 2143.
It further would have been prima facie obvious to incorporate hydrogen peroxide in order to further enhance the efficacy of the composition in treating aging such as neurodegenerative aging, since Pickering teaches that administering a form of nicotinamide such as NAD+ to a subject in a pharmaceutical composition can treat aging, and Yan expressly teaches that hydrogen peroxide can induce positive oxidative stress which is believed to be useful in treating aging or aging associated diseases. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). MPEP 2144.06 I.
It further would have been prima facie obvious to use an amount of the hydrogen peroxide that is within the range of claim 1, because Geracitano discloses that hydrogen peroxide in concentrations within the recited range can protect neurons in conditions of reduced oxygen supply as may occur during stroke, such that the skilled artisan would have been motivated to also use such amounts in the McCleary composition which is intended to treat deteriorating neurological functions such as that caused by ischemic conditions.
As to claims 2 and 12, it further would have been prima facie obvious to optimize the amounts of the repair system activator, methyl donor, and antioxidant defense activator to arrive at the amounts recited by these claims, since said amounts are result effective variables that the skilled artisan would have expected to influence the ability of these active ingredients to exhibit the functional activity taught by the cited references. Discovering optimum or working ranges involves only routine skill in the art in cases where the general conditions of a claim are disclosed in the prior art. In re Aller, 105 USPQ233.
Regarding claims 35 and 39, "it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Here, modifying the composition of the prior art as combined above to arrive at claim 35 requires merely separating out components of the McCleary composition so that they may be administered separately instead of together. Just as it is obvious for the skilled artisan to combine the recited ingredients which are taught by the prior art as useful for the same purpose of treating neurodegenerative conditions, it also would have been just as obvious to go in the reverse direction by separating them out into separate dosage forms, because if the prior art teaches that each of the active ingredients in the composition are useful for treating a neurodegenerative condition in combination when part of the same composition, the skilled artisan reasonably would have expected that they also would be useful for treating the neurodegenerative condition in combination when administered separately and sequentially.
The resulting composition will have the functional properties recited by claims 6-9 because it comprises the same ingredients in the same amounts recited by the claims, and a product cannot be separated from its properties. The U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the countless ways that an Applicant may present previously unmeasured characteristics. When the prior art appears to contain the same ingredients that are disclosed by Applicants' own specification as suitable for use in the invention, a prima facie case of obviousness has been established, and the burden is properly shifted to Applicants to demonstrate otherwise. See MPEP 2112.01.
Claim 34 is rejected under 35 U.S.C. 103 as unpatentable over McCleary (US Pat. Pub. 2002/0182196) in view of Pickering et al. (US Pat. Pub. 2009/0035275; of record in IDS) and Yan (Redox Biology 2 (2014) 165-169; of record in IDS) as applied to claims 1-2, 4-12, 14-15, and 35-39 above, and further in view of Fahmy et al. (US Pat. Pub. 2015/0118318).
The teachings of McCleary, Pickering, and Yan are relied upon as discussed above, but they do not further expressly disclose that the composition is in microparticles or liposomes for sustained release.
Fahmy discloses compositions comprising an active for sustained release, and teaches that liposomes, polymeric microparticles, or nanolipogels (“microparticles”) all can be used to incorporate an active and provide the sustained release (Abstract and paragraphs 6, 15, 47, 72-73).
It would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of the present invention to modify the composition of McCleary, Pickering, and Yan as combined supra by incorporating the composition into liposomes or microparticles when extended release of the actives over time is desired, because Fahmy teaches that doing so will impart sustained release delivery of the actives.
Response to Applicant’s Arguments
Applicant argues that Yan does not disclose or suggest adding hydrogen peroxide to any nutritional or pharmaceutical composition, nor provide any quantitative concentration range for this ingredient.
In response, the new grounds of rejection rely upon Geracitano to provide a motivation to use hydrogen peroxide in amounts within the claimed concentration range, and the cited references must be considered not individually but rather for what they suggest as a whole. The primary reference McCleary itself discloses a composition comprising ingredients that are selected for their usefulness in normalizing deteriorating neurological function such as is observed in ischemic disorders, and the skilled artisan therefore would have had a motivation to add hydrogen peroxide to the composition since Yan teaches that is can be useful in targeting aging associating diseases such as by inducing ischemic tolerance which can protect against ischemic disorders.
Conclusion
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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/GAREN GOTFREDSON/Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600