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 .
Status of Claims
Claims 1-11 are pending and are under examination.
Priority
The instant application 18/794,153 filed on August 5, 2024 claims priority to, and the benefits of U.S. Provisional Application No. 63/532,457 filed on August 14, 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 5, 2024 is in compliance with the provisions of 37 CFR 1.97 unless otherwise noted. Accordingly, the information disclosure statement is being considered by the examiner.
WO2013191724 A1 (cited under “Foreign Patent Documents”, no. 2 in IDS filed on September 5, 2024) does not have a legible copy in the application file. Thus, while the reference has been cited in the IDS filed on September 5, 2024, the document has not been considered by the Examiner.
Arun et al., Haidar, Jardim et al., Singleton et al. and Long et al. (cited under “Foreign Patent Documents”, no. 1 to 5 in IDS filed on September 5, 2024) do not have a legible copy in the application file. Thus, while the reference have been cited in the IDS filed on September 5, 2024, the documents have not been considered by the Examiner.
Claim Interpretation
The claimed term “patient”, when given its broadest reasonable interpretation, is taken to include rat.
Claim Objections
Claims 6-7 and 11 are objected to because of the following informalities:
Regarding claims 6, 7, and 11, the term “comprises” recites therein is not being consistent throughout the claims, and should read –comprising—for the sake of consistency.
Appropriate correction is required.
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.
Claim 9 is 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.
Regarding claim 9, the term “and/or” used in the phrase of “the patient has acute, sub-acute, and/or chronic post-traumatic brain injury”, which recites a list of more than two items, is ambiguous, because it is not clear if applicant is intending to refer to all items together (i.e., the patient has acute, sub-acute and chronic post-traumatic brain injury together), any single item (e.g., the patient has acute post-traumatic brain injury), a specific combination of the items (e.g., (i) the patient has acute post-traumatic brain injury; or (ii) the patient has sub-acute and chronic post-traumatic brain injury), or any combination of the items (e.g., the patient has acute and sub-acute chronic post-traumatic brain injury). The lack of clarity renders the claim indefinite, because one of ordinary skill in the art cannot reasonably determine which interpretation applies.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Institute of Medicine (US) Committee on Nutrition, Trauma, and the Brain et al. (National Academies Press (US), 2011; referred to herein as “IOM et al.”), Lunsmann et al. (US 2011/0009496 A1), and Biasutto et al. (Ann. N.Y. Acad. Sci., 2017. Vol. 1403, no. 1: 27-37).
IOM et al. teaches there have been no human trials or observational studies conducted to study resveratrol’s potential to impart resilience against traumatic brain injury (TBI); However, animal studies have been conducted to evaluate the effectiveness of resveratrol in providing resilience or treating TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy) in the acute phases (see e.g., p. 218, line 15-18; p. 219-220, Table 14-2). IOM et al. further teaches a trial with a TBI rat model, a controlled cortical impact model, conducted by Singleton and colleagues (2010) demonstrated the benefits of resveratrol; in this case, resveratrol was given intraperitoneally at 10 or 100 mg/kg three times after injury (i.e., 5 minutes, 1 day, and 2 days after injury), in which the 100 mg/kg dose showed significantly better improvement in cognitive test results and motor skills (see e.g., p. 222, 1st paragraph; Table 14-2). IOM et al. further teaches the positive findings from studies using animal models of ischemia and TBI likewise support the notion that resveratrol may also be beneficial for resilience or treatment of TBI in humans (see e.g., p. 222, “Conclusions and recommendations”, 3rd paragraph). IOM et al. further teaches an expanding body of preclinical evidence suggests resveratrol may be beneficial in treating a variety of human diseases; for this reason, resveratrol is being sold as a dietary supplement, despite the absence of definitive information about resveratrol’s effects in humans, and while research into the potential health benefits of resveratrol is continuing (see e.g., p. 218, “Use and Safety”, 1st paragraph). IOM et al. further teaches CDC defines traumatic brain injury (TBI) as being caused by a bump, blow, or jolt to the head or a penetrating head injury that disrupts the normal function of the brain; and a penetrating brain injury is the result of an object, such as a bullet, shrapnel, or debris, piercing to the skill (see e.g., p. 16, “traumatic brain injury”). IOM et al. further teaches brain injuries, such as TBI, have implicated oxidative stress as a key pathological factor in secondary injury progression; and mitochondria, are susceptible to reactive oxygen species (ROS), which generate localized oxidative stress (see e.g., p. 61, “reduction of oxidative stress and inflammation and repair of cellular damage”). IOM et al. further teaches resveratrol has shown to exert anti-inflammatory and antioxidative stress effect in normal human when measured by blood biomarker; and its suppressive effect on ROS generation and a range of inflammatory mediators suggest that resveratrol may induce its effects through increased expression of anti-inflammatory cytokines and a reduction in proinflammatory molecules, all potentially beneficial implication for TBI (see e.g., p. 63, line 32-38). IOM et al. further teaches metabolic characteristics of TBI include cerebral acidosis, hypoxia, decreased adenosine triphosphate production, and resultant mitochondrial malfunction followed by apoptotic cell death; and the series of events that triggers the malfunctioning of mitochondria severely disrupts the energetics of the cell, thus, restoration of mitochondrial function or providing sources of energy other than glucose is a key objective after a TBI event (see e.g., p. 60, “Restoration of Cellular Energetics” section, 1st paragraph). IOM et al. further teaches the acetate precursor glyceryl triacetate, a food additive and dietary supplement, has also been found to effectively supply acetyl coA as an alternative energy source in an animal model of TBI, which can contribute to more immediate energy production for mitochondria than glucose (see e.g., p. 61, line 13-16).
IOM et al. fails to teach resveratrol triacetate.
Lunsmann et al. teaches the liquid formulations of the invention (e.g., solutions, emulsions) include at least 11 % by weight of resveratrol or a salt or ester thereof (see e.g., [0042]). Lunsmann et al. further teaches the formulations of the invention can be used to treat patients suffering from traumatic or mechanical injury to the central nervous system, spinal cord or peripheral nervous system; and a subject suffering from mitochondrial disorder arising from, but not limited to, post-traumatic head injury and cerebral edema (see e.g., [0095]; [0235]). Lunsmann et al. further teaches the pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients; for example, compositions may be formulated for administration by, inter alia, injection (e.g., IM), inhalation or insufflation (either through the mouth or the nose), or oral (see e.g., [0276]). Lunsmann et al. further teaches the invention provides dietary compositions comprising formulations of the invention (see e.g., [0268]). Lunsmann et al. further teaches the formulation can also be administered to a subject suffering from an acute disease (see e.g., [0079]). Lunsmann et al. teaches methods for treating a subject suffering from mitochondrial disorder arising from, but not limited to, post-traumatic head injury (see e.g., [0235]).
Biasutto et al. teaches the development of prodrugs designed to temporarily protect resveratrol during absorption and first passage through the liver and able to release the active natural compound at the desired site of action (see e.g., p. 28, left column, “Strategies to improve bioefficacy of resveratrol”, 2nd paragraph). Biasutto et al. further teaches many approved prodrugs are carboxyesters, and carboxyester prodrugs of resveratrol were also synthesized by attaching promoieties, including acyl groups, shown below:
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(see e.g., p. 29, left column, “Carboxyesters”, 1st paragraph; Table 1). Biasutto et al. further teaches the triacetate (RTA) were rapidly hydrolyzed in blood and during transport experiments with explanted rat intestine; when the total amount of species permeating a section of explanted rat intestine was examined, no significant differences were observed using these prodrugs or resveratrol itself (see e.g., p. 29, right column, line 3-10). Please note resveratrol triacetate taught by Biasutto et al. is an esterified resveratrol. Biasutto et al. further teaches other have reported that administration of RTA to rats resulted in a higher plasma area under the curve than resveratrol (see e.g., p. 29, right column, line 16-19).
In Summary, IOM et al. teaches 100 mg/kg of resveratrol i.p. administered at 5 minutes, 1 day, and 2 days after injury successfully treat traumatic brain injury (TBI) in TBI rat model. The difference between the method of IOM et al. and the claimed method is that the prior art administer resveratrol rather than the claimed esterified resveratrol. Please note the administration of 100 mg/kg of resveratrol at 5 minutes is the amount of resveratrol administered in a day. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of IOM et al. by substituting the resveratrol with an resveratrol triacetate as the ester of resveratrol in the composition to arrive at the claimed invention. One would have been motivated to do so, because Lunsmann et al. teaches the resveratrol or ester thereof is contemplated for use in the liquid formulation for treating patients suffering from traumatic injury to the central nervous system, and Biasutto et al. teaches resveratrol triacetate is a carboxyester prodrug of resveratrol designed to temporarily protect resveratrol during absorption, and is reported to have higher plasma area under the curve than resveratrol. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that resveratrol triacetate, an esterified derivative and prodrug of resveratrol, can successfully release parent compound resveratrol; and therefore, by substituting resveratrol with resveratrol triacetate in the method of IOM et al., one would successfully treat traumatic brain injury. The fact that the prior art discloses resveratrol is administered at an effective amount of 100 mg/kg at 5 minutes after traumatic brain injury, a person of ordinary skill in the art would have been motivate to incorporate the same effective amount and time of administration for the resveratrol triacetate with a reasonable expectation of success, and that renders obvious the limitations set forth in claims 2 and 5.
Regarding “wherein said administering is by an oral supplement” in claim 3, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to administer the resveratrol triacetate in the method set forth above by an oral dietary composition, because IOM et al. teaches resveratrol is being sold as a dietary supplement, and Lunsmann et al. teaches the formulation comprising an ester of resveratrol may be formulated for oral administration and provided as dietary compositions. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the resveratrol triacetate, which is an ester of resveratrol, can successfully formulated into a dietary supplement suitable for oral administration; and that renders obvious the structural limitation of “oral supplement” instantly claimed.
Regarding “wherein said administering is by … intramuscular injection” in claim 4, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to administer the resveratrol triacetate in the method set forth above by intramuscular injection, because Lunsmann et al. teaches the formulation comprising an ester of resveratrol may be formulated for administration such as intramuscular injection. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the resveratrol triacetate, which is an ester of resveratrol, can successfully formulated into a dietary composition suitable for oral administration.
Regarding “further comprising administering to the patient an effective amount of at least one of acetyl-L-carnitine…” in claim 8, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method of IOM et al., Lunsmann et al. and Biasutto et al. set forth above by further administering the glyceryl triacetate of IOM et al. to the rat having TBI, because IOM et al. teaches glyceryl triacetate can effectively supply acetyl coA as an alternative energy source in an animal model of TBI, and contributes to more immediate energy production for mitochondria to help restore its function. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by further administering an effective amount of glyceryl triacetate to the patient having TBI can help restore mitochondrial function by providing alternative energy sources.
Regarding “the patient has acute…post-traumatic brain injury” in claim 9, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to administer the resveratrol triacetate in the method set forth above to treat the patient having acute post-traumatic brain injury, because IOM et al. clearly teaches resveratrol is effective for treating TBI or related diseases or conditions in the acute phases, and Lunsmann et al. teaches the formulation comprising resveratrol or ester thereof can be administered to a subject suffering from an acute disease, and mitochondrial disorder arising from post-traumatic head injury. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the resveratrol triacetate, which is an ester of resveratrol, can exerted the same or substantially similar effect as resveratrol for treating post-traumatic head injury in the acute phases.
Regarding “wherein said administering preserves or increases mitochondrial antioxidant levels in the patient” in claim 10, the claimed limitation is drawn to the result or outcome of the method steps positively recited. By practicing the method renders obvious by IOM et al., Lunsmann et al. and Biasutto et al. (see rejection above), the outcome of “preserves or increases mitochondrial antioxidant levels in the patient” will necessarily be present since the same compound (100 mg/kg of resveratrol triacetate) is being administered to the same patient (rat having traumatic brain injury). In the alternative, the claimed limitation is obvious by practicing the method of IOM et al., Lunsmann et al. and Biasutto et al. set forth above, because IOM et al. teaches resveratrol has antioxidative stress effect by suppressing reactive oxygen species generation, which mitochondria are susceptible to after brain injuries, such as TBI. One would have reasonably expected that the administration of resveratrol triacetate, which is an ester and a prodrug of resveratrol, can exerted the same or substantially similar antioxidative stress effect to the mitochondrial as resveratrol for treating traumatic brain injury.
Regarding “wherein said traumatic brain injury comprises a penetrating brain injury” in claim 11, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to administer the resveratrol triacetate in the method set forth above to treat traumatic brain injury comprises a penetrating brain injury, because IOM et al. teaches the definition of traumatic brain injury includes penetrating brain injury. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the resveratrol triacetate, which is an ester of resveratrol, can exerted the same or substantially similar effect as resveratrol for treating TBI that includes penetrating brain injury.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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