DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's 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 June 10, 2025, wherein claims 1, 5 and 8-9 are amended; claims 2-4, 6-7 and 10-11 are unchanged; and claims 12-20 are newly added.
Claims 1-20 are pending and under examination in accordance to the elected species.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 10, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Please note that the foreign references and non-patent literatures without an English translation but have an English translation of the abstract will only have the abstract considered by the Examiner.
Action Summary
Claim 5 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 amendment.
Claim 1 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fabre et al. (US 2009/0318555 A1) are withdrawn in light of the claim amendment.
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 maintained, but revisit and modified in light of the claim amendment.
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 maintained, but revisit and modified in light of the claim amendment.
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 maintained, but revisit and modified in light of the claim amendment.
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 maintained.
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 maintained.
Claims 1-7 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14, 19, and 22 of copending Application No. 17/623,313 (reference application; referred to herein as ‘313 application) are withdrawn in light of the claim amendment.
Claims 1-7 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14, and 22 of copending Application No. 17/999,598 (reference application; referred to herein as ‘598 application) are withdrawn in light of the claim amendment.
Claims 1-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 25, and 28 of copending Application No. 17/758,759 (reference application; referred to herein as ‘759 application) are withdrawn in light of the claim amendment.
Claim Interpretation
The phrase “about… to about …” recites in claims 2-6 is reasonably construed in light of the specification. According to paragraph [0074] of the specification shown as follows:
PNG
media_image1.png
112
732
media_image1.png
Greyscale
, 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
, the 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 claim 7, 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 Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12 and 19-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention (newly applied as necessitated by amendment).
With regard to claim 12, the recitation of “comprising administering a therapeutically effective amount of acetyl-L-leucine as the single active agent” renders the claim indefinite, because it is not clear if applicant is intending to claim a method that further comprising another step of administering a therapeutically effective amount of acetyl-L-leucine as the single active agent, or applicant is intending to limit the step of administering a therapeutically effective amount of acetyl-L-leucine set forth in claim 1 to be a single active agent. In addition, the article “a” recites in the phrase of “a therapeutically effective amount” is often used to refer to a subject matter that has not been mentioned before; therefore, it is not clear if applicant is referring to the same therapeutically effective amount set forth in claim 1 or a therapeutically effective amount that is different than the therapeutically effective amount set forth in claim 1. In order to advance prosecution, the claim is being examined by the examiner to the extent that the “administering a therapeutically effective amount of acetyl-L-leucine as the single active agent” is referring to the same administration step set forth in claim 1 (“the method comprising administering a therapeutically effective amount of acetyl-L-leucine…to the subject”).
With regard to claims 19-20, the recitation of “a therapeutically effective amount” renders the claim indefinite, because it is not clear what “therapeutically effective amount” is being referred to by the applicant. The article “a” is often used to refer to a subject matter that has not been mentioned before; therefore, it is not clear if applicant is intending to refer to the “therapeutically effective amount” set forth in claim 1, or the “therapeutically effective amount” set forth in claim 12, or “a therapeutically effective amount” that is different than the one in claims 1 and 12. In order to advance prosecution, the claim is being examined by the examiner to the extent that the “therapeutically effective amount” is referring to the therapeutically effective amount set forth in claim 12 (“the method comprising administering a therapeutically effective amount of acetyl-L-leucine…to the subject”).
With further regard to claim 20, “a traumatic brain injury” recites in the phrase of “the symptom of a traumatic brain injury” renders the claim indefinite, because it is not clear what “traumatic brain injury” is being referred to by the applicant. The article “a” is often used to refer to a subject matter that has not been mentioned before; therefore, it is not clear if applicant is intending to refer to the same traumatic brain injury set forth in claim 1, or another traumatic brain injury that is different than the one previously mentioned. In order to advance prosecution, the claim is being examined by the examiner to the extent that the “traumatic brain injury” is referring to the same traumatic brain injury set forth in claim 1.
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.
Claims 13-20 are 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 (newly applied as necessitated by amendment).
With regard to claims 13-20, to the extent that the “acetyl-L-leucine, or a pharmaceutically acceptable salt thereof” is intending to refer to the “acetyl-L-leucine” in the administration step set forth in claim 12 and said step is not the same as the one set forth in claim 1, then “a pharmaceutically acceptable salt thereof” recites in claims 13-20 fail to further limit the acetyl-L-leucine set forth in claim 12, because the administration step recite in claim 12 (“comprising administering a therapeutically effective amount of acetyl-L-leucine as the single active agent”) does not include “a pharmaceutically acceptable salt thereof”.
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 and 8-9 remain 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).
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 herein 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 levels of TNF[Symbol font/0x61] an 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]).
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 specifically teach the administration of a therapeutically effective amount of acetyl-L-leucine to a subject for arresting or ameliorating a traumatic brain injury or arresting or ameliorating a symptom of 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:
PNG
media_image2.png
312
383
media_image2.png
Greyscale
(see e.g., Figure 4).
GPnotebook teaches many drugs require acetylation for their metabolism (see e.g., line 1).
Even though De Rienzo et al. does not specifically teach administering a therapeutically effective amount of acetyl-L-leucine to a subject for treating a traumatic brain injury or treating a symptom of a 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 specifically choose to administer the composition comprising N-acetyl-L-leucine in an effective amount to the subject 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 from the list taught by De Rienzo et al., because Liu et al. teaches leucine is known to decrease the levels of pro-inflammatory cytokine IL-6, and GPnotebook teaches many drugs require acetylation for their metabolism. One would have reasonably expected that administering an effective amount of acetyl-L-leucine, which is an acetylated form of leucine, to the subject would have successfully arrested or ameliorating traumatic brain injury by decreasing pro-inflammatory cytokines IL-6, and therefore the symptom of traumatic brain injury would necessarily be arrest or ameliorate by treating the root cause of the said symptom.
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 and 8-9 remain 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).
The teachings of De Rienzo et al., Liu et al., and GPnotebook are set forth above and applied as before.
De Rienzo et al, Liu et al., and GPnotebook does not specifically teach administering acetyl-L-leucine in the therapeutically effective amount of about 1 g to about 30 g per day as claimed in claim 2. De Rienzo et al, Liu et al., and GPnotebook also does not specifically teach administering acetyl-L-leucine in the therapeutically effective amount of about 2 g to about 15 g per day as claimed in claim 3. De Rienzo et al, Liu et al., and GPnotebook also does not specifically teach administering acetyl-L-leucine in the therapeutically effective amount of about 3 g to about 10 g per day as claimed in claim 4.
In addition to the teachings set forth above, 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):
PNG
media_image3.png
279
512
media_image3.png
Greyscale
. 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]).
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). In the present case, even though De Rienzo et al, Liu et al., and GPnotebook does not specifically teach administering acetyl-L-leucine in the therapeutically effective amount as claimed, 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 GPnotebook by administering the composition comprising N-acetyl-L-leucine in an daily amount of 10 g. One would have been motivated by the fact that De Rienzo et al. teaches a composition comprising L-leucine in 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 reasonably expected that administering acetyl-L-leucine in a daily dosage of 10 g to the subject would have successfully arrest or ameliorate traumatic brain injury, and therefore the symptom of traumatic brain injury would necessarily be arrest or ameliorate by treating the root cause of the said symptom.
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 1-9 remain 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).
The teachings of De Rienzo et al., Liu et al., and GPnotebook are set forth above and applied as before.
De Rienzo et al, Liu et al., and GPnotebook does not specifically teach administering acetyl-L-leucine in the therapeutically effective amount of about 4 g to about 8 g per day as claimed in claim 5. De Rienzo et al, Liu et al., and GPnotebook also does not specifically teach administering acetyl-L-leucine in the therapeutically effective amount of about 4 g to about 5 g per day as claimed in claim 6. De Rienzo et al, Liu et al., and GPnotebook also does not specifically teach administering acetyl-L-leucine in the therapeutically effective amount of about 5 g day as claimed in claim 7.
In addition to the teachings set forth above, 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 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). In the present case, even though De Rienzo et al, Liu et al., and GPnotebook does not specifically teach the daily effective amount of acetyl-L-leucine as claimed in claims 5-7, 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 GPnotebook 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
N
-
a
c
e
t
y
l
-
L
-
l
e
u
c
i
n
e
t
o
t
a
l
a
m
i
n
o
a
c
i
d
e
n
t
i
t
i
e
s
=
10
g
34.4
g
=
x
g
15
g
x
=
4.36
g
of N-acetyl-L-leucine in 15 g of total amino acid entity
Incorporating - 20%,
N
-
a
c
e
t
y
l
-
L
-
l
e
u
c
i
n
e
t
o
t
a
l
a
m
i
n
o
a
c
i
d
e
n
t
i
t
i
e
s
=
10
g
34.4
g
=
x
g
15
g
-
15
×
0.2
x
=
3.49
g
Incorporating + 20%,
N
-
a
c
e
t
y
l
-
L
-
l
e
u
c
i
n
e
t
o
t
a
l
a
m
i
n
o
a
c
i
d
e
n
t
i
t
i
e
s
=
10
g
34.4
g
=
x
g
15
g
+
15
×
0.2
x
=
5.23
g
, 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 expected that 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 would successfully arrest or ameliorate TBI and incorporates the benefits of lower side effects.
Claim 10-11 remain 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).
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 herein are L-isomers of amino acids (see e.g., [0050]). Please note L-isomers of N-acetyl-leucine taught by De Rienzo et al. is an acetyl-L-leucine. De Rienzo et al. further teaches the subject has TBI (see e.g., [0214]). 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) and/or decreasing inflammation (e.g., inflammation of brain tissue) (see e.g., [0021]). De Rienzo et al. further teaches the composition improves neuronal function by decreasing neuroinflammation (see e.g., [0043]). De Rienzo et al. further teaches TBI can cause persistent neuroinflammation and microglial activation that can lead to chronic neurodegeneration, dementia and encephalopathy (see e.g., [0225]). De Rienzo et al. further teaches the prospective studies of TBI biomarkers in 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]). De Rienzo et al. further teaches levels of TNF[Symbol font/0x61] an 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. does not specifically teach administering a therapeutically effective amount of acetyl-L-leucine to a subject with a traumatic brain injury for modulating the expression of one or more pro-inflammatory mediators instantly claimed.
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:
PNG
media_image2.png
312
383
media_image2.png
Greyscale
(see e.g., Figure 4).
GPnotebook teaches many drugs require acetylation for their metabolism (see e.g., line 1).
Even though De Rienzo et al. does not specifically teach administering a therapeutically effective amount of acetyl-L-leucine to a subject with a traumatic brain injury for modulating the expression of one or more pro-inflammatory mediators, 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 composition comprising L-isomers of N-acetyl-leucine in an effective amount to a subject with traumatic brain injury for decreasing pro-inflammatory cytokines, such as TNF[Symbol font/0x61]. One would have been motivated to select an acetylated form of leucine, N-acetyl-L-leucine, from the list of leucine amino acid entity taught by De Rienzo et al. for decreasing pro-inflammatory cytokines in a subject with TBI, because Liu et al. teaches leucine treatment decreases TNF[Symbol font/0x61], and GPnotebook teaches many drugs require acetylation for their metabolism. One would have reasonably expected that administering acetyl-L-leucine, which is an acetylated form of leucine, in a therapeutically effective amount would successfully modulate the expression of pro-inflammatory mediators such as TNF[Symbol font/0x61].
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 10-11 remain 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).
The teachings of De Rienzo et al., Liu et al., and GPnotebook 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 GPnotebook do not specifically teach administering a therapeutically effective amount of acetyl-L-leucine to a subject with a traumatic brain injury for modulating the elected 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: "The 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 GPnotebook does not specifically teach the elected IFNb, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to administer an effective amount of N-acetyl-L-leucine to the subject with TBI for modulating IFNb. One would have been motivated by the fact that 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 taught by De Rienzo et al., Liu et al., and GPnotebook, one will also be reducing INF[Symbol font/0x62] by treating 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.
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) (newly applied as necessitated by amendment).
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. 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).
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 an 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 a therapeutically effective amount of acetyl-L-leucine 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 a therapeutically effective amount of acetyl-L-leucine 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 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 June 10, 2025 have been fully considered but they are not persuasive.
Applicant amends claim 1 from the recitation of “a method of treating 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” to the recitation of “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”. It is noted that the claimed term “treating”, when construed in light of paragraph [0103] of the specification, it taken to include prevention; therefore, the claim amendment changes the scope of the claims. In addition, the term “treat” recites in claims 8-9 is also being replaced by the phrase of “arrest or ameliorate”. Furthermore, applicant newly added claims 12-20 and that necessitated a new search and the new ground rejection set forth herein.
In Summary, applicant argues the rejection on the record relies on impermissible hindsight reasoning, because one of ordinary skill in the art would have had no reason to select leucine, let alone the acetylated form of leucine, to arrest or ameliorate TBI at the time the application was filed based on the teachings of De Rienzo et al., Liu et al. and GPnotebook. Applicant further argues all 5 exemplary amino acids, including leucine, isoleucine, valine, N-acetylcysteine ("NAC"), and acetyl-L-carnitine ("ALCAR") listed in Table 1 of De Rienzo et al. are known in the art to decrease the levels of IL-6; therefore, one would have been equally motivated choose to administer a composition comprising these exemplary amino acid or any of the other amino acid entities listed in the Table 1 in an effective amount to the subject for treating TBI. Applicant further argues the method of De Rienzo et al. teaches compositions comprising at least three components that includes a branched chain amino acid chosen from a leucine amino acid entity for treating TBI, and that does not suggest using any single component of this composition for treating TBI. Applicant further argues Liu et al. and GPnotebook does not cure the deficiencies of De Rienzo et al., because Liu et al. teaches leucine for decreasing the pro-inflammatory cytokine IL-6 and the teachings of GPnotebook is not specifically direct to acetyl-L-leucine. Applicant further argues Rozenbaum is an non-analogues art, because the teachings of said reference is exclusively with hormone replacement therapy. Applicant further argues Karve et al. fails to teach the use of acetyl-L-leucine for modulating the expression of one or more pro-inflammatory mediators in a subject with TBI.
In response, applicant argument is not found persuasive for the reasons set forth herein.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the present case, De Rienzo et al. clearly teaches N-Acetyl-Leucine is a derivative of leucine in Table 1 shown below:
PNG
media_image4.png
202
490
media_image4.png
Greyscale
(see e.g., Table 1); and further teaches that amino acids referred therein are L-isomers of amino acids unless otherwise indicated (see e.g., [0050]). In other words, the amino acid entities taught by De Rienzo et al. in Table 1 clearly includes L-isomer of N-Acetyl-Leucine.
In response to applicant's argument that De Rienzo et al. teaches compositions rather than any single component of this composition for treating TBI, it is noted that the claims of instant application recites the transitional term "comprising" that does not exclude any additional, unrecited ingredients. Please note according to MPEP 2111.03, “[t]he transitional term ‘comprising’, which is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). In other words, the fact that De Rienzo et al. teaches other ingredients in the compositions, in this case, a NAC entity and a ALCAR entity for treating TBI, these ingredients does not render the rejection non-obvious, because the claimed invention does not exclude these entities from the method of treating TBI; therefore, the fact that De Rienzo et al. teaches a composition comprising an effective amount of L-isomer of N-Acetyl-Leucine as the amino acid entities is useful for treating TBI by decreasing pro-inflammatory cytokines; the fact that Liu et al. teaches leucine is known to decrease the levels of pro-inflammatory cytokine IL-6; and the fact that GPnotebook teaches many drugs require acetylation for their metabolism. One would have reasonably expected that administering an effective amount of acetyl-L-leucine, which is an acetylated form of leucine, to the subject with TBI would have successfully arrested or ameliorating traumatic brain injury by decreasing pro-inflammatory cytokines IL-6, and therefore the symptom of traumatic brain injury would necessarily be arrest or ameliorate by treating the root cause of the said symptom.
In response to applicant's argument that Rozenbaum is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Rozenbaum clearly provides a general teachings that low-dose therapies theoretically 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 3-5). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). In other words, it may well be true that Rozenbaum specifically exemplified dose optimization using the hormone replacement therapy; however, regardless of the drug being selected as the therapies in the preferred embodiments, one of ordinary skill in the art of pharmacology would have reasonably recognized that by lowering the dose of any therapies in the filed of pharmacology through routine experimentation would successfully improve safety by reducing side effects while maintaining therapeutic effect, absent factual evidence to the contrary.
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). In the present case, applicant argues Karve et al. fails to teach the use of acetyl-L-leucine; However, the rejection on the record is form on the basis that De Rienzo et al. teaches compositions comprising a leucine amino acid entity, including L-isomer of N-Acetyl-Leucine, for treating TBI in a subject in need thereof in view of other prior arts (see rejection above). Karve et al. is applied based on the fact that it teaches injury to the central nervous system leads to up-regulation of IFN gene expression, including IFN[Symbol font/0x62], that plays 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). In other words, one would have reasonably expected that by practicing the method of treating TBI set forth in the rejection above, one would necessarily be modulating the expression of IFN[Symbol font/0x62] as the pro-inflammatory mediators by treating the root cause.
Therefore, the rejection is maintained, but revisited and modified in light of the amendment for the reasons on the record and for the reasons set forth herein.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L. Clark can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
Prosecution Insights