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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 18, 2025 has been entered.
Election/Restrictions
Applicant's election with traverse of IFNb as the species of pro-inflammatory mediators is maintained.
Priority
The instant application 17/435,784 filed on September 2, 2021 is a 371 of PCT/IB2020/051767 filed on March 2, 2020, which claims priority to, and the benefits of U.S. Provisional Application No.
62/812,987 filed on March 2, 2019, U.S. Provisional Application No. 62/842,296 filed on May 2, 2019, U.S. Provisional Application No. 62/888,894 filed on August 19, 2019, and U.S. Provisional Application No. 62/895,144 filed on September 3, 2019.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/812,987, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. In the present case, the prior-filed application fails to disclose a method of modulating the expression of one or more pro-inflammatory mediator in a subject with a traumatic brain injury; therefore, claims 10-11 are not entitled to the benefit of the prior-filed application and will receive an effective filing date of May 2, 2019, which is the filing date of U.S. Provisional Application No. 62/842,296.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to claims filed on December 18, 2025, wherein claims 1 are amended; claims 2-9, 11, 13-16 and 18 are unchanged; and claims 10, 12, 17 and 19-20 are amended.
Claims 1-20 are pending and under examination in accordance with the elected species.
Information Disclosure Statement
The information disclosure statement filed on 12/18/2025, 3/13/2026, 4/17/2026 and 5/19/2026 fails to comply with the provisions of 37 CFR 1.98(a)(4) because it lacks the appropriate size fee assertion. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
The information disclosure statement filed 12/18/2025 and 3/13/2026, fails to comply with the provisions of 37 CFR 1.97(a) because it lacks the appropriate size fee set forth in 37 CFR 1.17(v). It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
Action Summary
Claims 13-20 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends are withdrawn in light of the claim amendments.
Claims 12 and 19-20 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 are withdrawn in light of the claim amendments.
Claims 1 and 8-9 rejected under 35 U.S.C. 103 as being unpatentable over De Rienzo et al. (US 2019/0046486 A1; cited in the IDS filed on March 31, 2022), in view of Liu et al. (Animal. 2018;12(9):1903-1911) and GPnotebook (“Acetylation of drugs”. Published online on January 1, 2018) are withdrawn in light of the claim amendments.
Claims 1-4 and 8-9 rejected under 35 U.S.C. 103 as being unpatentable over De Rienzo et al. (US 2019/0046486 A1), in view of Liu et al. (Animal. 2018;12(9):1903-1911) and GPnotebook (“Acetylation of drugs”. Published online on January 1, 2018) as applied to claims 1 and 8-9 above, and further in view of De Rienzo et al. (US 2019/0046486 A1) are withdrawn in light of the claim amendments.
Claims 1-9 rejected under 35 U.S.C. 103 as being unpatentable over De Rienzo et al. (US 2019/0046486 A1) in view of Liu et al. (Animal. 2018;12(9):1903-1911) and GPnotebook (“Acetylation of drugs”. Published online on January 1, 2018) as applied to claims 1-4 and 8-9 above, and further in view of De Rienzo et al. (US 2019/0046486 A1) and Rozenbaum et al. (J Steroid Biochem Mol Biol., 2006. Vol. 102(1-5): 256-260) are withdrawn in light of the claim amendments.
Claim 10-11 rejected under 35 U.S.C. 103 as being unpatentable over De Rienzo et al. (US 2019/0046486 A1), in view of Liu et al. (Animal. 2018;12(9):1903-1911) and GPnotebook (“Acetylation of drugs”. Published online on January 1, 2018) are withdrawn in light of the claim amendments.
Claims 10-11 rejected under 35 U.S.C. 103 as being unpatentable over De Rienzo et al. (US 2019/0046486 A1), in view of Liu et al. (Animal. 2018;12(9):1903-1911) and GPnotebook (“Acetylation of drugs”. Published online on January 1, 2018) as applied to claims 10-11 above, and further in view of Karve (eNeuro, 2016. Vol. 3(1): ENEURO.0128-15.2016) are withdrawn in light of the claim amendments.
Claims 1-9 and 12-20 rejected under 35 U.S.C. 103 as being unpatentable over Fabre et al. (US 2009/0318555 A1; cited in the previous Non-Final Office Action mailed on March 11, 2025) in view of Haripriya et al. (Indian J Otolaryngol Head Neck Surg. 2018. Vol. 70(3): 337-341) are maintained, but revisited and modified in light of the claim amendments.
Specification
The disclosure is objected to because of the following informalities:
The use of the terms “Tanganil®” and “TaqMan®”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. While the Examiner has made every attempt to check the specification for trade name or mark compliance, Applicant is required to carefully check the entire specification for any and all issues regarding trade name or mark.
Appropriate correction is required.
Claim Interpretation
The phrase “about… to about …” recites in the claims 2-6 and 13-17 is reasonably construed in light of the specification. According to paragraph [0074] of the specification shown as follows:
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, the term “about” encompass ± 20% of a specified amount; therefore, the phrase “about… to about…” is taken to include the range, where the lower limit is calculated as the specified amount minus 20% of that amount, and the upper limit is calculated as the specified amount plus 20% of that value. For example, if the range is “about 1 g to about 30 g”:
Lower limit:
1
-
0.2
×
1
=
0.8
g
Upper limit:
30
+
0.2
×
30
=
30
+
6
=
36
g
, said range is reasonably interpreted as 0.8 g to 36 g. Applying the same calculation to the range of “about 2 g to about 15 g” gives 1.6 g to 18 g; the range of “about 3 g to about 10 g” gives 2.4 g to 12 g; the range of “about 4 g to about 8 g” gives 3.2 g to 9.6 g; the range of “about 4 g to 5 g” gives 3.2 g to 6 g.
The recitation of “about 5 g” in claims 7 and 18, when construed in light of paragraph [0074] of the specification, is taken to include ± 20% of 5 g, which when calculated by:
Lower limit:
5
-
0.2
×
5
=
5
-
1
=
4
g
Upper limit:
5
+
0.2
×
5
=
5
+
1
=
6
g
, gives a range of 4 g to 6 g.
The claim language of “arresting or ameliorating a traumatic brain injury” in the claims, when given their broadest reasonable interpretation, is taken to include reducing the symptom of traumatic brain injury that makes said condition (TBI) more tolerable.
Claim Objections
Claims 12 is objected to because of the following informalities:
Regarding claim 12, the recitation of “the composition” is not being consistent with the term “pharmaceutical composition” recites prior to said recitation. For the sake of clarity, “the composition” should read ---the pharmaceutical composition--.
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 12 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 12, the recitation of “the composition comprises the therapeutically effective amount of acetyl-L-leucine or a pharmaceutically acceptable salt thereof, as a single active agent” can lead to various interpretations in light of claim 1 it depends upon. For instance, there are at least two possible interpretations: the first scenario is that the claim can be interpreted such that the transitional phrase "consisting essentially of" in claim 1 (which it depends upon) already significantly limits the pharmaceutical composition as a whole by excluding ingredients that would materially affect the basic and novelty characteristic(s) of the invention; and therefore, If the active ingredient materially contributes to the arresting or ameliorating effect is acetyl-L-leucine, then any additional therapeutic active agent(s) is excluded from the pharmaceutical composition as a whole; and another possible scenario is that claim 1 permits inactive ingredients and possibly additional components that do not materially affect the arresting or ameliorating effect; and therefore, the claim permits another active ingredient(s) if that agent does not materially affect the basic and novel characteristic(s) of the invention. The lack of clarity renders the claim indefinite, because one of ordinary skill in the art cannot reasonably determine which interpretation applies.
In order to advance prosecution, the Examiner is examining the claim to the extent that the transitional term “consisting essentially of” is reasonably construed as being equivalent to “comprising”. In other words, the acetyl-L-leucine or a pharmaceutically acceptable salt thereof can be one of many active ingredients in the pharmaceutical composition as long as the other active ingredient(s) do not affect the arresting or ameliorating effect of claim 1, and the modulating effect of claim 10.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 12 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 12, the claim recites “the composition comprises the therapeutically effective amount of acetyl-L-leucine or a pharmaceutically acceptable salt thereof, as a single active agent” fails to further limit the pharmaceutical composition set forth in claim 1, which it depends upon. It is noted that independent claim 1 recites “a pharmaceutical composition consisting essentially of a therapeutically effective amount of acetyl-L-leucine or a pharmaceutically acceptable salt thereof“, such that the transitional term “consisting essentially of” excludes ingredients that would materially affect the basic and novel characteristic(s) of the invention. In other words, If the active ingredient materially contributes to the arresting or ameliorating effect is acetyl-L-leucine, then claim 1 may already effectively exclude additional therapeutic active agents; and in that situation, the transitional term “comprising” recites in claim 12, which can include additional elements that affect the basic and novel characteristic(s), is considered failing to further limit the pharmaceutical composition set forth in claim 1. See MPEP 2111.03 with respect to Transitional Phrases.
In order to advance prosecution, the Examiner is examining the claim to the extent that the transitional term “consisting essentially of” is reasonably construed as being equivalent to “comprising”. In other words, the acetyl-L-leucine or a pharmaceutically acceptable salt thereof can be one of many active ingredients in the pharmaceutical composition as long as the other active ingredient(s) do not affect the arresting or ameliorating effect of claim 1, and the modulating effect of claim 10.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-4, 8-15, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over De Rienzo et al. (US 2019/0046486 A1; cited in the IDS filed on March 31, 2022), in view of Liu et al. (Animal. 2018;12(9):1903-1911; cited in the previous Office Action) and Laksitorini et al. (Ther Deliv, 2014. Vol. 5(10): 1143-63).
De Rienzo et al. teaches a method for treating neuronal injury (e.g., traumatic brain injury (TBI) or stroke), comprising administering to a subject in need thereof an effective amount of a composition, thereby treating the neuronal injury (see e.g., [0032];[0154]). De Rienzo et al. further teaches the composition comprising: a) a branched chain amino acid entity chosen from a leucine amino acid entity, such as L-leucine, N-acetyl-leucine or salts thereof; b) a N-acetylcysteine entity; and c) acetyl-1-carnitine (see e.g., claim 22; [0023]; Table 1). De Rienzo et al. further teaches amino acids referred to therein are L-isomers of amino acids (see e.g., [0050]). De Rienzo et al. further teaches a method of improving a symptom of traumatic brain injury (TBI) comprising administering to a subject in need thereof an effective amount of the composition, wherein the symptom is chosen from, inter alia, dizziness (see e.g., [0030]). De Rienzo et al. further teaches the composition is capable of decreasing pro-inflammatory cytokines (e.g., from the activation of one or both of abnormal microglia or astrocyte), or decreasing inflammation (e.g., inflammation of brain tissue) (see e.g., [0021]). De Rienzo et al. further teaches adults with severe TBI have shown that serum levels of IL-1[Symbol font/0x62], IL-6, CXCL8, IL-10, and tumor necrosis factor (TNF[Symbol font/0x61]) are chronically increased (see e.g., [0225]); and in Example 1, the levels of TNF[Symbol font/0x61] and IL-6 were measured in supernatants of primary microglia cells collected 12 h after LPS stimulation, and these levels in the microglia cells were reduced after treating the mouse with the amino acid combinations (see e.g., Example 1; [0230]-[0234]). De Rienzo et al. further teaches the compositions disclosed therein improve neuronal function by one, two, three, or four of the following: inter alia, decrease mitochondrial dysfunction due to Ca2+ accumulation, or decrease neuroinflammation, e.g., by one, two or three of scavenging free radicals, scavenging ROS, or reducing pro-inflammatory cytokines (see e.g., [0043]). De Rienzo et al. further teaches an exemplary composition including 1.67 g of leucine or the equivalent amount of a leucine amino acid entity shown as follows (see e.g., Table 2; [0091]; Example 3):
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. De Rienzo et al. further teaches the composition includes 1.67 g ± 10% of leucine or the equivalent amount of a leucine amino acid entity (see e.g., [0094]). De Rienzo et al. further teaches N-acetyl-leucine is a derivative of leucine (see e.g., table 1). De Rienzo et al. further teaches the composition is administered one, two, or three times daily (see e.g., [0182]). Please note the term “N-acetyl-L-leucine” and the term “acetyl-L-leucine” are used interchangeably according to paragraph [0021] of the instant specification.
De Rienzo et al. does not expressly teach acetyl-L-leucine for arresting or ameliorating a traumatic brain injury or modulating the expression of one or more pro-inflammatory mediators in a subject with a traumatic brain injury.
Liu et al. teaches mRNA levels of IL-6, IL-10 and TNF-[Symbol font/0x61] were upregulated by the lipopolysaccharide (LPS) treatment by stimulating the secretion of Secretory immunoglobulin A (sIgA) (see e.g., p. 1907, “Leucine treatment on lipopolysaccharide-induced secretory immunoglobulin A and inflammatory responses” section; abstract). Liu et al. further teaches leucine supplementation reverse the effects of LPS on sIgA secretion, gene transcription for IL-6, and the phosphorylation of NF-κB p65 (see e.g., p. 1907, “Leucine treatment on lipopolysaccharide-induced secretory immunoglobulin A and inflammatory responses” section; p. 1907-1908, “Discussion” section). Liu et al. further teaches these results suggested that leucine could alleviate LPS-induced inflammatory responses by down-regulating NF-κB signaling pathway and evoking mTOR/ p70S6K signaling pathway (see e.g., abstract). Liu et al. further teaches the effect of leucine treatment on the messenger RNA level of IgA, IL-6, IL-10 and tumor necrosis factor-α in the presence of LPS shown as follows:
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(see e.g., Figure 4).
Laksitorini et al. teaches prodrugs of small molecules have been designed to increase drug lipophilicity for enhancing drug absorption via partition to cell membranes; and this is done by simple esterification and amidation of the carboxylic acid or acetylation of the amine and alcohol groups (see e.g., p. 6, last paragraph). Laksitorini et al. further teaches one of the major hurdles in developing therapeutic agents is the difficulty in delivering drugs through the intestinal mucosa and blood-brain barriers (BBB) (see e.g., abstract). Laksitorini et al. further teaches one way to improve passive diffusion of drugs via transcellular pathway is by changing the physicochemical properties of the drug to favor membrane partition; and one way to transiently alter the physicochemical properties of a drug is by forming a prodrug using a promoiety that can be removed after crossing the biological barriers (see e.g., p. 6, 2nd paragraph).
Regarding the transitional phrase “consisting essentially of”, according to MPEP 2111.03, “[f]or the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, ‘consisting essentially of’ will be construed as equivalent to ‘comprising.’ See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355”. Applying same logic to instant process claim(s), the transitional phrase “consisting essentially of” is reasonably construed as permitting additional ingredients that do not materially affect the basic and novel characteristic of the claimed pharmaceutical composition.
Furthermore, the presently claimed invention is directed to a method comprising administering a pharmaceutical composition consisting essentially of acetyl-L-leucine, or a pharmaceutically acceptable salt thereof. The transitional phrase “comprising” render the claimed method open-ended and does not exclude additional unrecited method steps. Accordingly, the claimed method reasonably encompass embodiment in which the subject is administered one or more additional pharmaceutical compositions before, during, or after administration of the recited pharmaceutical compositions, provided such additional steps are not expressly excluded by the claim language.
Regarding claims 1 and 8-11, De Rienzo et al. clearly teaches N-acetyl-leucine in the exemplary list of branched chain amino acid entity and leucine amino acid entity that is contemplate for use in the composition for treating traumatic brain injury as the neuronal injury; and teaches that the amino acids referred to therein are L-isomers of amino acids; reading on acetyl-L-leucine instantly claimed. The difference between the method of De Rienzo et al. and the claimed method is that the prior art does not expressly teach the selection of acetyl-L-leucine as the branched chain amino acid entity and leucine amino acid entity in the composition for treating traumatic brain injury as the neuronal injury. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to specifically choose to administer the composition comprising an effective amount of N-acetyl-L-leucine as the branched chain amino acid entity and leucine amino acid entity for treating traumatic brain injury. One would have been motivated to select an acetylated form of leucine, N-acetyl-L-leucine, as the branched chain amino acid and leucine amino acid entity from the list taught by De Rienzo et al., because Liu et al. teaches leucine can alleviate inflammatory response by down-regulating the NF-κB signaling pathway, evoking mTOR/p70S6K signaling pathway, and decreasing the levels of pro-inflammatory cytokines, including TNF[Symbol font/0x61]; and Laksitorini et al. teaches acetylation of the amine forms prodrugs that are more lipophilic, thus, enhancing drug absorption. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the acetylated form of leucine, acetyl-L-leucine, in the list of De Rienzo et al. is a prodrug of leucine that is more lipophilic with better drug absorption, and would have reasonably expected to exhibit same or substantially similar modulating effect against inflammation as leucine; and therefore, by administering a pharmaceutical composition comprising a therapeutically effective amount of acetyl-L-leucine as the branched chain amino acid entity and leucine amino acid entity to the subject would have reasonably expected to treat traumatic brain injury by decreasing pro-inflammatory cytokines including TNF[Symbol font/0x61]; and by treating traumatic brain injury, the traumatic brain injury and a symptom of the traumatic brain injury would necessarily be arrest or ameliorate by targeting the root cause of said symptom; also renders obvious the method of modulating the expression of one or more pro-inflammatory mediators in a subject with a traumatic brain injury as claimed in claims 10-11.
Regarding “wherein the composition comprises the therapeutically effective amount of acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, as a single active agent” in claim 12, the transitional term “comprising” is inclusive or open-ended that does not exclude additional, unrecited elements. See MPEP 2111.03 with respect to transitional phrase. In the present case, Applicant has not identified, and the specification does not clearly define, any basic and novel characteristic that would be materially affected by the presence of additional active ingredients or additional inactive components of a pharmaceutical composition. Therefore, for purpose of examination, the phrase “consisting essentially of” is reasonably construed in accordance to MPEP 2111.03 as permitting components that do not materially affect the basic and novel characteristic of the claimed invention. Under this reasonable interpretation, the pharmaceutical composition disclosed by De Rienzo et al. satisfy the claimed transitional language. Additionally, De Rienzo et al. teaches a pharmaceutical composition comprising N-acetyl-L-leucine together with additional ingredients. Nothing in the instant claims and the instant specification excludes pharmaceutical excipients or components that do not materially affect the basic and novel characteristic of the invention. Therefore, De Rienzo’s disclosed pharmaceutical compositions fall within the reasonable scope of the claimed transitional phrase. Furthermore, De Rienzo’s pharmaceutical composition contains one or more therapeutic amino acid entities selected from the claimed list. When N-acetyl-L-leucine is chosen, said acetyl-L-leucine is an active agent directed to the claimed therapeutic effect, while additional formulation ingredients or excipients do not change the fact acetyl-L-leucine is an active therapeutic agent contains therein.
Lastly, Applicant’s claims do not recite any ingredients that would materially affect the basic and novel characteristic of the pharmaceutical composition, nor do they identify any ingredient that is excluded by virtue of the phrase “consisting essentially of.” Accordingly, the phrase does not patentably distinguish over the pharmaceutical composition disclosed by De Rienzo et al.
Regarding the limitation of “about 1 g to about 30 g of acetyl-L-leucine…is administered to the subject per day” in claims 2 and claim 13, the limitation of “about 2 g to about 15 g of acetyl-L-leucine…per day” in claims 3 and claims 14, and the limitation of “about 3 g to about 10 g of acetyl-L-leucine, or a pharmaceutically acceptable salt thereof …. per day” in claims 4 and claims 15, each of these limitations are drawn to the therapeutically effective amount of acetyl-L-leucine. According to MPEP 2144.05, “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. Applying same logic to instant process claims, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to further modified the method of De Rienzo et al., Liu et al., and Laksitorini et al. set forth above by administering the composition comprising N-acetyl-L-leucine at an daily amount of 10 g. One would have been motivated by the fact that De Rienzo et al. teaches the exemplary composition comprising L-leucine at a daily dosage of 10 g, and further teaches the L-leucine can be substituted with a leucine amino acid in an equivalent amount, such as L-isomers of N-acetyl-leucine. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by administering a pharmaceutical composition comprising acetyl-L-leucine at a daily dosage of 10 g to the subject would have successfully treat the traumatic brain injury, and therefore the traumatic brain injury and a symptom of the traumatic brain injury would necessarily be arrested or ameliorated; readings on claims 19-20.
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.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over De Rienzo et al. (US 2019/0046486 A1), in view of Liu et al. (Animal. 2018;12(9):1903-1911) and Laksitorini et al. (Ther Deliv, 2014. Vol. 5(10): 1143-63) as applied to claims 1-4, 8-15, 19 and 20 above, and further in view of Rozenbaum et al. (J Steroid Biochem Mol Biol., 2006. Vol. 102(1-5): 256-260; cited in the previous Office Action).
The teachings of De Rienzo et al., Liu et al., and Laksitorini et al. are set forth above and applied as before.
De Rienzo et al, Liu et al., and Laksitorini et al. does not teach about 4 g to about 8 g per day as claimed in claims 5 and 16; about 4 g to about 5 g per day as claimed in claims 6 and 17; and about 5 g day as claimed in claims 7 and 18; However, De Rienzo et al. further teaches the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically acceptable excipient(s) and/or carrier(s) utilized, and like factors with the knowledge and expertise of the attending physician (see e.g., [0053]). De Rienzo et al. further teaches in some embodiments, the composition is administered at a dose of 15 g ± 20% to 100 g ± 20% total amino acid entities daily (see e.g., [0189]).
Rozenbaum teaches low-dose therapies theoretically always have had the potential to be safer, give fewer side effects and be useful if therapeutic efficacy can be maintained (see e.g., p. 257, left column, line 3-8).
In the present case, even though De Rienzo et al, Liu et al., and Laksitorini et al. does not expressly teach the daily therapeutically effective amount of acetyl-L-leucine as claimed in claims 5-7 and 16-18, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to optimize the daily dosage of N-acetyl-L-leucine in the method of De Rienzo et al., Liu et al., and Laksitorini et al. set forth above. One of ordinary skill in the art would have been motivated to optimize the daily dosage of 10 mg of acetyl-L-leucine in the composition, because Rozenbaum teaches low-dose therapies are safer and give fewer side effects; and the fact that De Rienzo et al. suggest the composition can be administered at a dose of 15 g ± 20% to 100 g ± 20% total amino acid entities daily. One of ordinary skill in the art would have reasonably determined the ratio of the acetyl-L-leucine to the total amino acid entity using the daily dose amount listed in Table 2 of De Reienzo et al. (34.4 g of total amino acid entity contains 10 g of L-leucine); Then, when replacing L-leucine with a leucine amino acid (N-acetyl-L-leucine) and adjusting the total amino acid entity amount to 15 g ± 20%, one can calculate the amount of N-acetyl-L-leucine by applying the same ratio. For instance, the composition containing 15 g of total amino entities, which when calculated by
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of N-acetyl-L-leucine in 15 g of total amino acid entity
Incorporating - 20%,
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, gives a range of 3.49 g to 5.23 g of N-acetyl-L-leucine per day, and that overlap with the claimed amount. One of ordinary skill in the art would have a reasonable expectation of success to arrive the claimed invention through routine optimization, because one would have reasonably understand that the daily therapeutically effective amount of acetyl-L-leucine is a result-effective variable, and would have reasonably expected that by lowering the daily dose of N-acetyl-L-leucine starting from 10 g/day taught by De Rienzo et al. to a range of 3.49 g/day to 5.23 g/day, it would reasonably treat TBI with the benefits of lower side effects.
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.
Claims 1-4, 8-15, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over De Rienzo et al. (US 2019/0046486 A1), in view of Liu et al. (Animal. 2018;12(9):1903-1911) and Laksitorini et al. (Ther Deliv, 2014. Vol. 5(10): 1143-63) as applied to claims 1-4, 8-15, 19 and 20 above, and further in view of Karve (eNeuro, 2016. Vol. 3(1): ENEURO.0128-15.2016).
The teachings of De Rienzo et al., Liu et al., and Laksitorini et al. are set forth above and applied as before.
To the extent that claim 11 is specifically drawn to the elected IFNb, De Rienzo et al., Liu et al., and Laksitorini et al. does not specifically teach the elected species of one or more pro-inflammatory mediators: IFNb.
Karve et al. teaches injury to the central nervous system leads to up-regulation of type-1 interferons (IFN) gene expression, and it involves in a deleterious role in hematopoietic cells to drive the neuroinflammatory response following traumatic brain injury (TBI) (see e.g., p. 2, right column, line 4-5 and 16-18). Karve et al. further teaches up-regulation of IFN[Symbol font/0x62] was seen 24 h after TBI in wild type compared with mice deficient in the IFNAR1 receptor subunit (IFNAR1-/-), which confirms the release of type 1 IFNS following TBI in mice (see e.g., p. 2, right column, line 10-12; p. 5, left column, line 2-5). Karve et al. further teaches IFN[Symbol font/0x62] mRNA levels were significantly increased in human subjects that had died 6 h after TBI compared with controls (see e.g., p. 11). Please note the IFN[Symbol font/0x62] taught by Karve et al. is a IFNb.
MPEP 2145 II states: "[t]he fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)). Even though De Rienzo et al., Liu et al., and Laksitorini et al. does not expressly teach the elected species of one or more pro-inflammatory mediators (IFNb); However, modulating “the one or more pro-inflammatory mediators are…IFNb” would necessarily present by practicing the method of De Rienzo et al., Liu et al., and Laksitorini et al. set forth above since the pharmaceutical composition comprising the same compound (N-acetyl-L-leucine) is being administered to the same subject with traumatic brain injury. In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances; and therefore, by practicing the method made obvious by the prior art, one will also be modulating “the one or more pro-inflammatory mediators are…IFNb”.
In the alternative, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by administering a pharmaceutical composition comprising an therapeutically effective amount of N-acetyl-L-leucine for treating TBI by modulating IFNb taught by Karve et al. One would have been motivated to do so, because Karve et al. teaches IFN[Symbol font/0x62] levels are up-regulated after TBI, which drives the neuroinflammatory response; and De Rienzo et al. teaches the composition comprising N-acetyl-L-leucine is capable of decreasing neuroinflammation. One would have reasonably expected that by practicing the method of De Rienzo et al., Liu et al., and Laksitorini et al. set forth above for treating TBI, one will also be reducing INF[Symbol font/0x62] by decreasing neuroinflammation in addition to treating TBI.
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.
Response to Arguments
Applicant's arguments filed on December 18, 2025 with respect to (i) the rejection of claims 1 and 8-9 under 35 U.S.C. 103 as being unpatentable over De Rienzo et al. (US 2019/0046486 A1), in view of Liu et al. (Animal. 2018;12(9):1903-1911) and GPnotebook (“Acetylation of drugs”. Published online on January 1, 2018); (ii) the rejection of claims 1-4 and 8-9 under 35 U.S.C. 103 as being unpatentable over De Rienzo et al., in view of Liu et al. and GPnotebook as applied to claims 1 and 8-9 above, and further in view of De Rienzo et al. (US 2019/0046486 A1); (iii) the rejection of claims 1-9 under 35 U.S.C. 103 as being unpatentable over De Rienzo et al., in view of Liu et al., and GPnotebook as applied to claims 1-4 and 8-9 above, and further in view of De Rienzo et al. (US 2019/0046486 A1) and Rozenbaum et al. (J Steroid Biochem Mol Biol., 2006. Vol. 102(1-5): 256-260); (iv) the rejection of claim 10-11 under 35 U.S.C. 103 as being unpatentable over De Rienzo et al., in view of Liu et al. and GPnotebook; and (v) the rejection of claims 10-11 under 35 U.S.C. 103 as being unpatentable over De Rienzo et al., in view of Liu et al., and GPnotebook as applied to claims 10-11 above, and further in view of Karve (eNeuro, 2016. Vol. 3(1): ENEURO.0128-15.2016) have been fully considered.
In the present case, applicant amends independent claims 1 and 10 from the recitation of “comprising administering a therapeutically effective amount of acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject” to the recitation of “comprising administering a pharmaceutical composition consisting essentially of a therapeutically effective amount of acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject”, such that the acetyl-L-leucine or a pharmaceutically acceptable salt thereof is a component or ingredient of a pharmaceutical composition, and the transitional phrase “consisting essentially of” is newly added. Each of these findings demonstrate the amendment changes the scope of the claims. Therefore, the rejection on the record has been withdrawn in light of the claim amendments. Upon further consideration, a new ground(s) of rejection is made (see rejection above).
In Summary, Applicant argues De Rienzo et al. does not teach or suggest a composition “consisting essentially of” acetyl-L-leucine for treating a TBI as recited in amended claim 1, because the composition or “active moiety” taught by De Rienzo et al. means a combination of four or more amino acid entities; thus, one of ordinary skill in the art would have no reason or motivation to select acetyl-L-leucine as the single agent because one would not have expected it would achieve the beneficial effects, e.g., increase in neuroprotection, reduction of neuroinflammation, and increase in motor function and memory. Applicant further argues Liu et al. and Karve et al. both fails to teach acetyl-L-leucine, and argues acetyl-L-leucine is not a metabolite of leucine.
In response, applicant’s arguments are not found persuasive for the reasons set forth below:
Applicant’s arguments with respect to GPnotebook are moot, because the new ground of rejection does not rely on GPnotebook applied in the prior rejection of record.
First, applicant repeatedly recites “acetyl-leucine” throughout the reply (see page 9 of the reply); However, it is respectfully noted that the instant claim(s) are drawn to the administration of “acetyl-L-leucine” rather than acetyl-leucine, such that the claimed invention requires L-isomer of acetyl-leucine. Therefore, applicant’s arguments with respect to “acetyl-leucine” are reasonably construed by the examiner as being drawn to the “acetyl-L-leucine” instantly claimed.
Second, applicant's argument that De Rienzo et al. fails to teach a composition consisting essentially of acetyl-L-leucine for treating a TBI is not found persuasive. According to MPEP 2111.03, III, “[t]he transitional phrase ‘consisting essentially of’ limits the scope of a claim to the specified materials or steps ‘and those that do not materially affect the basic and novel characteristic(s)’ of the claimed invention. In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in original) … For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, ‘consisting essentially of’ will be construed as equivalent to ‘comprising.’ See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355”. Applying the same logic to instant process claims, the mere fact that the composition or active moiety of De Rienzo et al. contains amino acid entities other than L-isomer of N-acetyl-leucine does not mean said composition or active moiety are incapable of arresting or ameliorating traumatic brain injury (TBI) or arresting or ameliorating a symptom of TBI. If applicant contends that additional materials in the prior art are excluded by the recitation of "consisting essentially of", applicant has the burden of showing that the introduction of additional components would materially change the characteristics of the claimed invention. In re De Lajarte, 337 F.2d 870, 143 USPQ 256 (CCPA 1964). See also Ex parte Hoffman, 12 USPQ2d 1061, 1063-64 (Bd. Pat. App. & Inter. 1989). In the absence of evidence showing that the presence of any amino acid entities taught by De Rienzo et al. materially change the arresting or ameliorating effect of claim 1 and modulating effect of claim 10, applicant’s arguments with respect to transitional phrase “consisting essentially of” is not found persuasive. Same reason is applicable to applicant's argument that the references fail to show acetyl-L-leucine is a ”single agent”.
In response to applicant's argument that the references fail to show certain beneficial effects of the invention, it is noted that the beneficial effects upon which applicant relies (i.e., “(e.g., increase in neuroprotection, reduction of neuroinflammation, and increase in motor function and memory)”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). None of the exemplary beneficial effects listed by the applicant are positively recited in the rejected claims, thus, the rejected claim(s) is not limited to the exemplary beneficial effects that applicant relies upon.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is respectfully noted that the rejection of record is form using the combination of references, rather than each individual reference alone. For example, applicant argues Liu et al. and Karve et al. each fail to teach acetyl-L-leucine; However, said acetyl-L-leucine has already been established using De Rienzo et al.; therefore, the arguments with respect to each reference are not found persuasive.
Furthermore, it is true that De Rienzo et al. does not teach N-Acetyl-Leucine is a metabolite of Leucine. It is respectfully noted that the rejection of record is not form on the basis that De Rienzo et al. teaches L isomer of N-Acetyl-Leucine is a metabolite of L-leucine; instead, the rejection of record relies on De Rienzo et al. to teach N-Acetyl-Leucine is a leucine amino acid entity contemplate for use in the composition for treating traumatic brain injury (see e.g., claim 22); and a derivative of leucine (see e.g., Table 1). The rejection of record further relies on Liu et al. and Laksitorini et al., specifically, the rejection of record relies on Liu et al. to teach leucine is known to alleviate inflammatory response by down-regulating the NF-κB signaling pathway, evoking mTOR/p70S6K signaling pathway, and decreasing the levels of pro-inflammatory cytokines, including TNF[Symbol font/0x61]; and Laksitorini et al. to teach acetylation of the amine is known in the art to form prodrugs that are more lipophilic thereby enhancing drug absorption. Therefore, in view of the foregoing, one would have reasonably expected that the acetylated form of leucine, acetyl-L-leucine, in the list of De Rienzo et al. is a prodrug of leucine that is more lipophilic with better drug absorption, and would have reasonably expected to exhibit same or substantially similar modulating effect against inflammation as leucine; and therefore, by administering a pharmaceutical composition comprising an therapeutically effective amount of acetyl-L-leucine as the branched chain amino acid entity and leucine amino acid entity to the subject would have reasonably expected to treat traumatic brain injury by decreasing pro-inflammatory cytokines including TNF[Symbol font/0x61]; and by treating traumatic brain injury, the traumatic brain injury would necessarily be arrest or ameliorate by targeting the root cause of said symptom.
Applicant further argues the claimed invention demonstrate beneficial effects that would not have been expected by one of ordinary skill in the art by directing attention to Fig 28-35, 40, 41, 45, 49-51 and paragraphs [0286], [0288], [0291]-[0293] and [0305] of the specification. In sum, applicant argues acetyl-leucine-treated mice has approximately 4-fold less [Symbol font/0x61]-fodrin fragments and approximately 50% less TUNEL positive cells in the brain; decreased levels of LC3-II and p62/SQSTM1 in the brain; reduce the expression of the pro-inflammatory markers IFN[Symbol font/0x62], Nox2, and Arg-1 by ~8-fold, ~20-fold, and ~1000-fold; and motor function, spatial memory, and non-spatial memory were all increased when compared to vehicle treated mice after TBI.
In response, Applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention. According to MPEP 716.02(d), “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
In the present case, applicant argues unexpected results are demonstrated in Fig 28-35, 40, 41, 45, 49-51 and paragraphs [0286], [0288], [0291]-[0293] and [0305] of the specification. It is respectfully noted that these paragraphs and figures are descriptions of Example 2, except paragraph [0305] and Figure 49-51 are descriptions of Example 8. Each of these figures and paragraphs have been fully considered by the Examiner. It is noted that Example 8 of the specification does not describe the therapeutically effective amount of N-Acetyl-L-Leucine in the pharmaceutical composition, but describes mice subjected to moderate controlled cortical impact TBI or sham surgery were treated with oral N-Acetyl-L-Leucine starting after initial recovery after surgery (via oral gavage, daily for 4 days) and continuing for duration of experiment (in chow, ad lib) (see e.g., [0305]).
According to Example 2 of the specification, about 0.25 ml of the N-Acetyl-L-Leucine solution (10 mg/mL) was orally administered to mice at a 10 mg/kg dose (2.5 mg N-Acetyl-L-Leucine/25 g mouse) after controlled cortical impact induced TBI for 4 days; and then the mice were also fed with N-Acetyl-L-Leucine at 0.5 mg/kg chow powder chow mixed with diet gel for up to 7 days after injury (see e.g., [0282]). TUNEL assay, autophagy flux, inflammatory cytokines and real time PCR were assessed in Example 2, and the corresponding results were disclosed in the Figures noted by Applicant.
In contrast, instant claim 1 broadly recites the administration of a genus pharmaceutical composition consisting essentially of a broad therapeutically effective amount of acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to a subject in need of arresting or ameliorating a traumatic brain injury or a symptom of a traumatic brain injury. Instant claim 10 broadly recites the same active administration step noted above to a subject with a traumatic brain injury for modulating the full scope of expression of one or more pro-inflammatory mediators.
It is noted that Applicant only exemplified unexpected results using a single dosing regimen species, specifically, a pharmaceutical composition species (solution) containing acetyl-L-leucine at a therapeutically effective amount based on the weight of the subject for 4 days (10 mg/mL of N-Acetyl-L-Leucine solution administered at a 10 mg/kg dose), and also another pharmaceutical composition species (powder chow) containing N-Acetyl-L-Leucine at a therapeutically effective amount based on the weight of the subject (0.5 mg/kg) for up to 7 days. In other words, the unexpected results upon which applicant relies is based on oral administration of a pharmaceutical composition containing acetyl-L-leucine at a therapeutically effective amount calculated based on the weight of the subject (0.5 mg/kg or 10 mg/kg), and each weight-based amount depends on the pharmaceutical composition employed for administration (e.g., N-Acetyl-L-Leucine solution uses 10 mg/kg whereas powder chow uses 0.5 mg/kg). Therefore, the disclosure does not provide adequate basis for concluding that similar results would be obtained when administering the pharmaceutical composition through any other routes, nor provides adequate basis for concluding that similar results would be obtained when administering any other pharmaceutical composition(s) containing any therapeutically effective amount of N-Acetyl-L-Leucine, including those with a fixed dosage as broadly encompassed by the instant claims. The unexpected results are exemplified using a single subject species (mice), and that also does not provide adequate basis for concluding that similar results would be obtained in any other subject species that received any other pharmaceutical compositions containing any therapeutically effective amount of N-Acetyl-L-Leucine.
In addition, applicant only exemplified the effect of N-Acetyl-L-Leucine against the levels of NOS2, IL-18, IFNb, IL-1[Symbol font/0x62], TNF[Symbol font/0x61], NOX2, NLRP3, SOCS3, ARG1, IL-4ra and YM1, and that does not provide adequate basis for concluding that similar results would be obtained in any other pro-inflammatory mediators as broadly encompassed by the claims. Moreover, applicant only exemplified the effect of N-Acetyl-L-Leucine on the motor function, spatial memory, and non-spatial memory of the subject, and that does not provide adequate basis for concluding that N-Acetyl-L-Leucine would successfully arresting or ameliorating the full scope of symptom(s) of a traumatic brain injury as broadly encompassed by the claims.
Since the disclosure only exemplifies a limited amount of regimen of acetyl-L-leucine in the pharmaceutical composition noted above, said disclosure is not commensurate in scope to encompass the full scope of administering each and every pharmaceutical composition consisting essentially of any therapeutically effective amount of N-Acetyl-L-Leucine or a pharmaceutically acceptable salt thereof to any subject for arresting or ameliorating the full scope of traumatic brain injury or the full scope of symptom of traumatic brain injury, or modulating the full expression of one or more pro-inflammatory mediators. These findings demonstrate that applicant’s assertion of unexpected results is not commensurate in scope with the claimed invention, thus, the argument is not found persuasive.
Lastly, the unexpected results upon which applicant relies would have been expected by one of ordinary skill in the art. As stated in the rejection of record, De Rienzo et al. teaches the composition comprising a branched chain amino acid entity chosen from a leucine amino acid entity, such as N-acetyl-leucine (see e.g., claim 22; [0023]; Table 1) that are L-isomers (see e.g., [0050]) can administer for treating traumatic brain injury (TBI) as neuronal injury (see e.g., [0032];[0154]); improving a symptom of traumatic brain injury (TBI), including cognitive deficits, dizziness, hearing loss, headache (e.g.,
frequent headache), loss of consciousness, memory loss, confusion, sleep disturbance, nausea, decreased balance, fatigue, drowsiness, blurred vision, ringing in ears, sensitivity to light, sensitivity to sound, decreased ability to concentration, mood swings, or increased anxiety (see e.g., [0030]); decreasing pro-inflammatory cytokines or decreasing inflammation (see e.g., [0021]), including reducing the levels of TNF[Symbol font/0x61] and IL-6 (see e.g., Example 1; [0230]-[0234]); and improving neuronal function by one, two, three, or four of the following: inter alia, decrease mitochondrial dysfunction due to Ca2+ accumulation, or decrease neuroinflammation, e.g., by one, two or three of scavenging free radicals, scavenging ROS, or reducing pro-inflammatory cytokines (see e.g., [0043]). In other words, one would have reasonably expected that the pharmaceutical composition comprising a therapeutically effective amount of N-acetyl-L-leucine would successfully modulating one or more pro-inflammatory mediators, including TNF[Symbol font/0x61] and IL-6; arresting or ameliorating the traumatic brain injury; and improving memory and balance, which are symptoms of traumatic brain injury. If applicant contends the composition of De Rienzo et al. cannot perform any of the modulating effect or arresting or ameliorating effect of the claimed invention, said objective evidence is respectfully requested. Please note that according to MPEP 716.01(c), I, “[o]bjective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984)”; and according to 716.02(e), “[a]n affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979)”.
Therefore, applicant’s arguments are not found persuasive for the reasons set forth herein.
Claims 1-9 and 12-20 are rejected under 35 U.S.C. 103 as being unpatentable over Fabre et al. (US 2009/0318555 A1; cited in the previous Non-Final Office Action mailed on March 11, 2025) in view of Haripriya et al. (Indian J Otolaryngol Head Neck Surg. 2018. Vol. 70(3): 337-341).
Fabre et al. teaches a method of treating vestibular neuritis which comprises administering to a patient in need thereof an effective amount of acetyl-L-leucine and the pharmaceutically acceptable
salts, wherein the acetyl-L-leucine is administered by oral route in a dose between 100
mg and 20 g per day (see e.g., claims 8, 11), advantageously between 100 mg and 4 g per day (see e.g., [0022]). Fabre et al. further teaches the acetyl-L-leucine and pharmaceutically acceptable salts are useful for the treatment of vertigo and other balance disorders (see e.g., [0001], [0016]), and the term “vertigo and other balance disorders” means, in particular, inter alia, benign paroxysmal positional vertigo (BPPV); vestibular neuritis; or recurring vertigo of traumatic or toxic origin (see e.g., [0018]). Fabre et al. further teaches acetyl-leucine in racemate form is currently used successfully in the treatment of acute peripheral vertigo in clinical practice (see e.g., [0011]); However, administration of the acetyl-D-leucine isomer does not provide any improvement compared to a placebo, whereas it appears that restorative activity is only provided by the acetyl-L-leucine isomer (see e.g., [0015]). Fabre et al. further teaches acetyl-L-leucine or the pharmaceutically acceptable salts of same can
be provided in any dosage form suited to, inter alia, oral administration; all such dosage forms are prepared by techniques known by those persons skilled in the art at a suitable dosage in combination with typical pharmaceutically acceptable excipients (see e.g., [0020]).
Fabre et al. does not teach traumatic brain injury.
Haripriya et al. teaches benign paroxysmal positional vertigo (BPPV) is one of the
most common peripheral vestibular disorders (see e.g., p. 337, “introduction” section, 4th paragraph). Haripriya et al. further teaches post traumatic BPPV was found to be 17% of the traumatic brain injury patients (TBI) (see e.g., abstract). Haripriya et al. further teaches BPPV is a disorder characterized by brief attacks of vertigo, with associated nystagmus, precipitated by certain changes in head position with respect to gravity; each episode of vertigo typically lasts for 10–20s; and the vertigo is intense and may occasionally be associated with nausea and/or vomiting (see e.g., p. 33, left column, 1st paragraph). Haripriya et al. further teaches sometimes vertigo may be the single symptom after TBI disturbing social as well as routine activities of the patient resulting in immense loss of man power as well as economic
resources (see e.g., p. 33, left column, 2nd paragraph).
Regarding the transitional phrase “consisting essentially of”, according to MPEP 2111.03, “[f]or the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, ‘consisting essentially of’ will be construed as equivalent to ‘comprising.’ See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355.”. Applying same logic to instant process claims, the transitional phrase “consisting essentially of” followed after the phrase “a pharmaceutical composition” is reasonably construed as “comprising”.
In sum, Fabre et al. clearly teaches the administration of an effective amount of acetyl-L-leucine and the pharmaceutically acceptable salts for treating benign paroxysmal positional vertigo (BPPV) or recurring vertigo of traumatic or toxic origin. The fact that Fabre et al. teaches acetyl-L-leucine or the pharmaceutically acceptable salts can be prepared into dosage forms suitable for oral administration, a person of ordinary skill in the art would have understood the oral dosage form represent a pharmaceutical composition comprising a therapeutically effective amount of acetyl-L-leucine or the pharmaceutically acceptable salts. In the present case, the difference between the method of Fabre et al. and the claimed method is that the prior art does not specifically exemplify the administration of acetyl-L-leucine in a therapeutically effective amount to a patient with benign paroxysmal positional vertigo (BPPV), specifically BPPV origin from the claimed traumatic brain injury. 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 Fabre et al. to selectively choose to treat a patient with benign paroxysmal positional vertigo origin from traumatic brain injury taught by Haripriya et al. as the vertigo and other balance disorders. One would have been motivated to do so, because Fabre et al. clearly teaches acetyl-L-leucine is useful for treating vertigo and other balance disorders, including vestibular neuritis, BPPV, and recurring vertigo of traumatic origin; and Haripriya et al. teaches sometimes vertigo may be the single symptom after TBI, and post traumatic BPPV was found in the TBI patients. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of a therapeutically effective amount of acetyl-L-leucine in an oral dosage form would successfully treat BPPV origin from traumatic brain injury, and therefore by treating BPPV as the symptom of TBI, one would also be ameliorating traumatic brain injury by reducing BPPV.
In addition, in an alternative, 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 Fabre et al. to selectively choose to ameliorate traumatic brain injury associated with benign paroxysmal positional vertigo (BPPV) taught by Haripriya et al. One would have been motivated to do so, because Haripriya et al. teaches traumatic brain injury patients are found to have post traumatic BPPV; and Fabre et al. clearly teaches acetyl-L-leucine is useful for treating BPPV. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of a therapeutically effective amount of acetyl-L-leucine in an oral dosage form would successfully ameliorate a traumatic brain injury associated with benign paroxysmal positional vertigo (BPPV).
Regarding the limitations of “about 1 g to about 30 g of acetyl-L-leucine” in claims 2 and 13, “wherein about 2 g to about 15 g of acetyl-L-leucine” in claims 3 and 14, “about 3 g to about 10 g of acetyl-L-leucine” in claims 4 and 15, “wherein about 4 g to about 8 g of acetyl-L-leucine” in claims 5 and 16, “wherein about 4 g to about 5 g of acetyl-L-leucine” in claims 6 and 17, and “about 5 g of acetyl-L-leucine” in claims 7 and 18, each of these limitations are drawn to the therapeutically effective amount of acetyl-L-leucine. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). 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 Fabre et al. and Haripriya et al. set forth above by incorporating acetyl-L-leucine in a dose between 100 mg and 20 g per day. One would have been motivated to do so, because Fabre et al. teaches when acetyl-L-leucine or the pharmaceutically acceptable salts of same are administered by oral route, the doses may be between 100 mg and 20 g or more per day. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by incorporating the acetyl-L-leucine in an amount of 100 mg-20 g per day would have successfully treat benign paroxysmal positional vertigo origin from traumatic brain injury, and therefore by treating said symptom of the TBI, one would also be ameliorating the TBI.
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.
Response to Arguments
Applicant's arguments filed on December 18, 2025 with respect to the rejection of claims 1-9 and 12-20 under 35 U.S.C. 103 as being unpatentable over Fabre et al. (US 2009/0318555 A1; cited in the previous Non-Final Office Action mailed on March 11, 2025) in view of Haripriya et al. (Indian J Otolaryngol Head Neck Surg. 2018. Vol. 70(3): 337-341) have been fully considered but they are not persuasive.
Applicant amends independent claims 1 and 10 from the recitation of “comprising administering a therapeutically effective amount of acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject” to the recitation of “comprising administering a pharmaceutical composition consisting essentially of a therapeutically effective amount of acetyl-L-leucine, or a pharmaceutically acceptable salt thereof, to the subject”, such that the acetyl-L-leucine or a pharmaceutically acceptable salt thereof is a component or ingredient of a pharmaceutical composition. Each of these findings demonstrate the amendment changes the scope of the claims.
In Summary, Applicant argues that one of skill in the art would not have expected the beneficial effects of acetyl-L-leucine (abbreviated as “NAL” in the reply) with respect to the treatment of a TBI. Applicant further argues the disclosure of Fabre et al. is limited to the effects of acetyl-L-leucine on treating vertigo and is not related to treating a TBI; and Hariprya et al. is silent with respect to acetyl-L-leucine and does not suggest or teaches acetyl-L-leucine for arresting or ameliorating TBI, or arresting or ameliorating symptoms of TBI.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “treatment of a TBI (e.g., increase in neuroprotection, reduction of neuroinflammation, and increase in motor function and memory)” [see page 14-15 of the reply]) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the present case, the instant claim(s) does not recite the term “treat” or “treatment”; and the claim(s) are drawn to “[a] method of arresting or ameliorating a traumatic brain injury in a subject in need thereof, or arresting or ameliorating a symptom of a traumatic brain injury in a subject in need thereof”. None of the exemplary treatment(s) of TBI listed by the applicant are positively recited in the rejected claims, thus, the rejected claim(s) is not limited to the exemplary treatments that applicant relies upon.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is respectfully noted that the rejection on the record is form using the combination of references, rather than each individual reference alone. For example, applicant argues Hariprya et al. fails to teach acetyl-L-leucine; However, said acetyl-L-leucine has already been established using Fabre et al.; therefore, the arguments with respect to each reference are not found persuasive.
In addition, it may well be true Fabre et al. teaches the effects of acetyl-L-leucine on treating vertigo and other balance disorders rather than treating traumatic brain injury; however, as noted above, the rejected claim(s) are not drawn to a treatment of traumatic brain injury, but a method of arresting or ameliorating a traumatic brain injury or a symptom of a traumatic brain injury. It is respectfully noted that the rejection on the record is form on the basis that Fabre et al. teaches the administration of an effective amount of acetyl-L-leucine in, e.g., oral dosage form for treating benign paroxysmal positional vertigo (BPPV) or recurring vertigo of traumatic or toxic origin; and the fact that Haripriya et al. teaches post traumatic BPPV was found in subjects with traumatic brain injury, and said vertigo is a symptom after TBI. In other words, the rejection on the record has established that one would have reasonable expectation of success to treat benign paroxysmal positional vertigo (BPPV) origin from traumatic brain injury by administering a therapeutically effective amount of acetyl-L-leucine in an oral dosage form; and by treating said symptom (benign paroxysmal positional vertigo) of the TBI, one would also be ameliorating the TBI, especially in the absence of evidence to the contrary.
In view of the foregoing, applicant’s argument is not found persuasive for the reasons set forth above. Given that applicant amends the claims, the rejection on the record has been revisited and modified in light of the claim amendments.
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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