DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-18 are pending and examined on the merits.
Drawings
The drawings are objected to because the single view is numbered as “FIGURE 1.” As set forth in 37 C.F.R. 1.84(u)(1), where only a single view is used in an application to illustrate the claimed invention, it must not be numbered.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Note: In filing a corrected drawing sheet in which the single view is not numbered, then page 3, paragraph [0009] and page 34, paragraph [0124] in the specification reciting “Fig. 1” should be amended accordingly.
Claim Objections
Claims 13 and 16 are objected to because of the following informalities:
Claim 13 is objected to because the recitation “consisting of vitamin” is grammatically incorrect. The article “a” should be inserted before the recitation “vitamin.” Since claim 13 is objected to, then its dependent claim, claim 16, is objected to.
Appropriate correction is required.
Claim Interpretation
Claim 17 is being interpreted as requiring that both the content of the (C) in the tablet is less than 10 mass% (as in parent claim 1) and is 3 mass% or more.
Notice Re: Prior Art Available Under Both Pre-AIA and AIA
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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 7, 14, 17, and 18 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Yonejima (WO 2014/119605. Machine Translation cited below), as evidenced by Klein (International Journal of Food Microbiology. 1998. 41: 103-125).
Yonejima discloses Comparative Example 3 which is directed to the claimed invention. In particular, Yonejima discloses producing 260 mg tablets by mixing 15 g of bifidobacteria powder with 25 g hydroxypropylcellulose, 10 g crystalline cellulose, and 6 g “stearic acid magnesium,” amongst other materials, and compressing the mixture with a rotary tableting machine (page 10, second paragraph with header “Comparative Example 3”). The material recited as “stearic acid magnesium” is magnesium stearate based on page 7, sixth full paragraph and the other examples (e.g. page 10, first paragraph). As evidenced by Klein, the Bifidobacterium genus is amongst the most important genera of lactic acid bacteria (LAB) (page 104, left column, second paragraph of Klein). Additionally, hydroxypropylcellulose, i.e. hydroxypropyl cellulose, and crystalline cellulose meet the excipient limitations of instant claims 1-3 and 18. Further still, magnesium stearate is a lubricant (page 7, sixth full paragraph). Also, the mass per tablet of 260 mg falls within the claimed range of ‘200 mg or more.’ Therefore, the tablet of Yonejima is directed to a lactic acid bacterium-containing tablet comprising: (A) a lactic acid bacterium (Bifidobacterium); (B) an excipient (contains hydroxypropyl cellulose and crystalline cellulose); and (C) a lubricant (magnesium stearate), wherein a mass per tablet is 260 mg (falling in claimed range of ‘200 mg or more’), meeting limitations of the claimed invention.
The total mass of the mixture is 1,170 g, so the content of (C) (the lubricant which is magnesium stearate) is about 0.513 mass%, which falls in the claimed range of ‘less than 10 mass%.’ See the calculations below:
T
o
t
a
l
m
i
x
t
u
r
e
m
a
s
s
=
15
g
b
i
f
i
d
o
b
a
c
.
p
o
w
d
e
r
+
250
g
e
r
y
t
h
r
i
t
o
l
+
819
g
l
a
c
t
o
s
e
+
25
g
H
P
C
+
10
g
c
r
y
s
t
a
l
l
i
n
e
c
e
l
l
u
l
o
s
e
+
30
g
l
i
g
h
t
a
n
h
.
s
i
l
i
c
i
c
a
c
i
d
+
15
g
c
a
r
m
e
l
l
o
s
e
s
o
d
i
u
m
+
6
g
m
a
g
n
e
s
i
u
m
s
t
e
a
r
a
t
e
=
1170
g
C
o
n
t
e
n
t
o
f
m
a
g
n
e
s
i
u
m
s
t
e
a
r
a
t
e
=
6
g
m
a
g
n
e
s
i
u
m
s
t
e
a
r
a
t
e
1170
g
t
o
t
a
l
m
i
x
t
u
r
e
×
100
=
0.513
%
Therefore, Yonejima anticipates instant claims 1, 2, 3 (crystalline cellulose), and 18 (crystalline cellulose).
Regarding instant claim 4, according to the calculation below, the content of the (B1) (hydroxypropyl cellulose) in the tablet is about 2.14 mass%, which falls in the claimed range of ‘1 to 20 mass%.’ Therefore, instant claim 4 is anticipated
C
o
n
t
e
n
t
o
f
H
P
C
=
25
g
H
P
C
1170
g
t
o
t
a
l
m
i
x
t
u
r
e
×
100
=
2.14
%
Regarding instant claim 5, according to the calculation below, a ratio of the content (mass%) of the (B1) (hydroxypropyl cellulose) to the content (mass%) of the (C) (magnesium stearate), expressed as (B1)/(C), is about 4.17 which falls in the claimed range of ‘0.5 to 6.’ Therefore, instant claim 5 is anticipated.
R
a
t
i
o
=
2.14
%
H
P
C
0.513
%
m
a
g
n
e
s
i
u
m
s
t
e
a
r
a
t
e
=
4.17
Regarding instant claim 7, according to the calculation below, a ratio of a content (mass%) of the (A) (lactic acid bacterium, the bifidobacteria powder) to the content (mass%) of the (C) (magnesium stearate), expressed as (A)/(C), is 2.5 which falls in the claimed range of 0.5 to 7.5. Therefore, instant claim 7 is anticipated.
R
a
t
i
o
=
15
g
b
i
f
i
d
o
b
a
c
.
p
o
w
d
e
r
1170
g
t
o
t
a
l
m
i
x
t
u
r
e
×
100
6
g
m
a
g
n
e
s
i
u
m
s
t
e
a
r
a
t
e
1170
g
t
o
t
a
l
m
i
x
t
u
r
e
×
100
=
15
g
b
i
f
i
d
o
b
a
c
.
p
o
w
d
e
r
6
g
m
a
g
n
e
s
i
u
m
s
t
e
a
r
a
t
e
=
2.5
Regarding instant claim 14, the term “food product” is defined in the instant specification as meaning to include supplements (page 15, paragraph [0047]). Yonejima discloses their invention in the context of delivering bifidobacteria to the intestine of a subject (page 9, third paragraph), and in the field of the use of probiotics in the food or pharmaceutical field (page 2, second paragraph with header “TECHNICAL FIELD”). Therefore, the tablet of Yonejima is directed to a supplement (meeting the definition of “food product”) and is in a form suitable for the claimed intended use as a “food product.” As such, instant claim 14 is anticipated.
Regarding instant claim 17, the mixture used to prepare the tablets of Comparative Example 3 comprises 30 g light anhydrous silicic acid (page 10, second paragraph with header “Comparative Example 3”). Yonejima recognizes light anhydrous silicic acid as a lubricant (page 7, sixth full paragraph). The combination of light anhydrous silicic acid and magnesium stearate is directed to a ‘lubricant.’ Therefore, the content of the (C) (a lubricant, which is the combination of light anhydrous silicic acid and magnesium stearate) in the tablet is about 3.03 mass%, which falls in the claimed range of ‘3 mass% or more,’ as well as falling in the range of parent instant claim 1 of ‘less than 10 mass%.’ See the calculation below. As such, instant claim 17 is anticipated.
C
o
n
t
e
n
t
o
f
l
u
b
r
i
c
a
n
t
=
30
g
l
i
g
h
t
a
n
h
y
d
.
s
i
l
i
c
i
c
a
c
i
d
+
6
g
m
a
g
n
e
s
i
u
m
s
t
e
a
r
a
t
e
1170
g
t
o
t
a
l
m
i
x
t
u
r
e
×
100
=
3.08
%
Claims 1, 3, 8, 14, and 17 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Borek (US 2005/0152966).
Borek discloses a controlled release solid dosage form for biological components (paragraph [0002]). The biological component (BC) includes agents such as microbes, including a beneficial microorganism such as probiotic bacteria (paragraphs [0048] and [0050]). Furthermore, the solid dosage form may take the form of a tablet (paragraph [0048]). Examples of Borek anticipate the claimed invention.
In particular, Example 7 discloses a tablet of approximately 443 mg containing 150 g lactic acid bacteria pre-blend as the biological component (BC), 50 mg hydroxypropyl methylcellulose (HPMC), 200 mg microcrystalline cellulose (MCC), and 16 mg stearic acid (paragraph [0096]; Table 6 on page 9; paragraph [0049] for full names of abbreviations). HPMC is directed to an excipient; this is recognized in the instant specification in paragraph [0026] on page 8. MCC is a crystalline cellulose. Crystalline cellulose is directed to an excipient; this is recognized in the instant specification in paragraph [0026] on page 8, and instant claim 3 recites it. Also, Borek teaches that stearic acid is a lubricant (paragraph [0068]). The mass per tablet of approximately 443 mg falls within the claimed range of ‘200 mg or more.’ Therefore, the tablet of Borek is directed to a lactic acid bacterium-containing tablet comprising: (A) a lactic acid bacterium; (B) an excipient (each of HPMC and MCC; also, the combination of HPMC and MCC is directed to an excipient comprising HPMC and MCC directed to a crystalline cellulose); and (C) a lubricant (stearic acid), wherein a mass per tablet is approximately 443 mg (falling in the claimed range of ‘200 mg or more’), meeting limitations of the claimed invention.
The content of (C) (the lubricant which is stearic acid) is about 3.61 mass% in Example 7, which falls in the ranges of ‘less than 10 mass%’ of instant claim 1 and ‘3 mass% or more’ of instant claim 17. See the calculation below:
C
o
n
t
e
n
t
o
f
s
t
e
a
r
i
c
a
c
i
d
=
16
m
g
s
t
e
a
r
i
c
a
c
i
d
443
m
g
t
a
b
l
e
t
×
100
=
3.61
%
A similar tablet is disclosed in Example 10 of approximately 684 mg comprising 150 g lactic acid bacteria pre-blend as the biological component (BC), 100 mg hydroxypropyl methylcellulose (HPMC), 200 mg microcrystalline cellulose (MCC), and 16 mg stearic acid (paragraph [0102] and Table 10 on pages 9 and 10). The mass per tablet of approximately 684 mg falls within the claimed range of ‘200 mg or more,’ and the tablet of Example 10 comprises the same components of Example 7 discussed above which meet limitations of the claimed invention. The content of (C) (the lubricant which is stearic acid) is about 2.34 mass% in Example 10, which falls in the range of ‘less than 10 mass%” of instant claim 1. The calculation is according to that for Example 7, with the denominator being substituted with 684 mg. Furthermore, the content of (A) (the lactic acid bacteria) in the tablet of this example is about 21.9 mass%, which falls in the range of ‘5 to 30 mass%’ of instant claim 8. See the calculation below:
C
o
n
t
e
n
t
o
f
l
a
c
t
i
c
a
c
i
d
b
a
c
t
e
r
i
u
m
=
150
m
g
l
a
c
t
i
c
a
c
i
d
b
a
c
t
e
r
i
a
684
m
g
t
a
b
l
e
t
×
100
=
21.9
%
Therefore, Borek anticipates claims 1, 3 (crystalline cellulose), 8 (at least Example 10), and 17 (at least Example 7).
Regarding instant claim 14, the term “food product” is defined in the instant specification as meaning to include supplements (page 15, paragraph [0047]). Borek discloses the tablet of their invention as an orally administered dosage form (paragraph [0048]), and Borek teaches the use of the beneficial microorganisms for a therapeutic goal (paragraph [0029]). Therefore, the tablet of Borek is directed to a supplement (meeting the definition of “food product”) and is in a form suitable for the claimed intended use as a “food product.” As such, instant claim 14 is anticipated.
Claims 1, 7, 8, and 13-15 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Hodal (US 2009/0117056), as evidenced by Amin (US 2008/0107729) and Fu (US 2006/0134195).
Hodal discloses probiotic compositions that have enhanced stability under various storage conditions (abstract). Hodal teaches examples of tablets which anticipate the claimed invention. In particular, at least Examples 1 and 8 anticipate the claimed invention.
Regarding Example 1 of Hodal, it is discloses a 500 mg tablet comprising 10.0% w/w Lactobacillus acidophilus, PHARMABURST ® C1, and 2.0% w/w magnesium stearate as the lubricant (paragraph [0073] including Table 1). Lactobacillus acidophilus is directed to a lactic acid bacterium; see paragraphs [0010] and [0017] of the instant specification. As evidenced by Amin, PHARMABURST ® C1 is an excipient (paragraph [0063]). The mass per tablet of Example 1 of 500 mg falls within the claimed range of ‘200 mg or more.’ The content of the lubricant (magnesium stearate) of 2.0 mass% falls in the claimed range of ‘less than 10 mass%.’ Therefore, Hodal anticipates claim 1.
Example 8 of Hodal likewise anticipates instant claim 1 since it discloses a 670 mg tablet (falling in the claimed range of ‘200 mg or more’) comprising 7.46% w/w Lactobacillus acidophilus (the claimed ‘lactic acid bacterium’), PHARMABURST ® C1 (an excipient, as evidenced by Amin), and 1.49% w/w magnesium stearate as the lubricant (falling in the claimed range of ‘less than 10 mass%’). See paragraph [0096] including Table 19.
Regarding instant claim 7, the ratio of the content (mass%) of the (A) (lactic acid bacterium which is Lactobacillus acidophilus) to the content (mass%) of the (C) (the lubricant which is magnesium stearate) in the tablet of Example 1 is 5.00 which falls in the clamed range of 0.5 to 7.5 [Calculation: 10.0 mass% L. acidophilus/2.00 mass% magnesium stearate = 5.00]. Therefore, instant claim 7 is anticipated.
Regarding instant claim 8, the content of the (A) (lactic acid bacterium which is Lactobacillus acidophilus) in the tablet of Example 1 is 10.0 mass% which falls in the claimed range of ‘5 to 30 mass%.’ Therefore, instant claim 8 is anticipated.
Regarding instant claim 13, the tablet of Example 8 of Hodal comprises vitamin A palmitate (paragraph [0096] including Table 19). Therefore, instant claim 13 (vitamin) is anticipated.
Regarding instant claim 14, the term “food product” is defined in the instant specification as meaning to include supplements (page 15, paragraph [0047]). Hodal discloses tablets as oral dosage forms of their invention (paragraph [0029]). Hodal also discloses that the probiotic of their invention has a beneficial effect in animal organs (paragraph [0037]). Therefore, the tablet of Borek is directed to a supplement (meeting the definition of “food product”) and is in a form suitable for the claimed intended use as a “food product.” As such, instant claim 14 is anticipated.
Regarding instant claim 15, the hardness of the tablets of Example 1 was 8-10 kp (kilopond) (paragraph [0074]). As evidenced by Fu, 1 kilopond is equivalent to 9.807 N (paragraph [0024]). Therefore, the hardness of the tablets of Example 1 converts to about 78 N to about 98 N. This tablet hardness range fully falls within the claimed range of ’50 N to 200 N.’ Thus, instant claim 15 is anticipated.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 6, 8, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Yonejima, as evidenced by Klein.
As discussed above, Yonejima (as evidenced by Klein) anticipates claims 1-5, 7, 14, 17, and 18. Yonejima differs from the invention of claim 6 in that Yonejima does not disclose that the excipient of the tablet of Comparative Example 3 further contains maltose. Yonejima differs from claim 8 in that Yonejima does not expressly disclose that the content of the (A) (the lactic acid bacterium which is bifidobacterium) in the tablet of Comparative Example 3 is 5 to 30 mass%. Instead, the content is about 1.28 mass% [Calculation: 15 g bifidobacteria powder/1170 g total mixture x 100 = 1.28%]. Yonejima differs from claim 13 in that Yonejima does not expressly disclose that the tablet of Comparative Example 3 further comprises one or more selected from the group consisting of vitamin, 3-hydroxyisovaleric acid, 3-hydroxyisovaleric acid calcium, ornithine, and ornithine hydrochloride.
Regarding instant claim 6, Yonejima discloses that their composition comprising bifidobacteria (abstract; page 3, second paragraph) may contain other components, including additives (page 5, seventh paragraph). Examples of additives include flavoring agents (page 6, last paragraph). Further still, examples of the flavoring agent include reduced maltose water candy (page 7, fifth full paragraph). Before the effective filing date of the claimed invention, it would have been prima facie obvious to further include maltose in the tablet of Comparative Example 3 of Yonejima because Yonejima teaches inclusion of additives including a flavoring agent comprising maltose in their bifidobacterium-containing composition. Therefore, instant claim 6 is rendered obvious.
Regarding instant claim 8, Yonejima discloses that the content of the dry weight of bifidobacteria in the composition of their invention, in terms of mass, is preferably 0.1 to 70% by mass, and particularly preferably 0.3 to 30% by mass with respect to the total amount of the composition (page 3, fifth paragraph). Before the effective filing date of the claimed invention, it would have been prima facie obvious to include the bifidobacterium powder at 0.3 to 30% by mass in the tablet of Comparative Example 3 of Yonejima because Yonejima teaches this bifidobacterium content as particularly preferred in their bifidobacterium-containing composition. Since that content range overlaps the claimed range, then instant claim 8 is rendered obvious.
Regarding instant claim 13, Yonejima discloses that their composition comprising bifidobacteria (abstract; page 3, second paragraph) may contain other components, including drugs (page 5, seventh paragraph). Examples of drugs include vitamins (page 5, second-to-last paragraph). Before the effective filing date of the claimed invention, it would have been prima facie obvious to further include a vitamin in the tablet of Comparative Example 3 of Yonejima because Yonejima teaches inclusion of drugs including vitamins in their bifidobacterium-containing composition. Therefore, instant claim 13 is rendered obvious.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Yonejima, as evidenced by Klein, as applied to claim 13 above, and further in view of Shibuya (US 2013/0172542).
As discussed above, Yonejima (as evidenced by Klein) anticipates claims 1-5, 7, 14, 17, and 18. Furthermore, Yonejima (as evidenced by Klein) renders obvious claim 13 (vitamin embodiment). However, Yonejima differs from claim 16 in that Yonejima does not expressly disclose that the vitamin is L-ascorbic acid-2-glucoside.
However, Yonejima discloses that examples of vitamins for inclusion in their invention include vitamin C and derivatives and salts thereof (page 6, second-to-last paragraph).
Shibuya discloses ascorbic acid 2-glucoside, abbreviated as “AA-2G,” as a compound that is composed of one molecule of D-glucose bound to the hydroxyl group at the C-2 position of L-ascorbic acid, i.e. vitamin C (paragraph [0002]). Because of L-ascorbic acid in the compound, then AA-2G is directed to L-ascorbic acid 2-glucoside. Shibuya points out that unlike L-ascorbic acid, AA-2G is non-reducible and superior in stability and therefore it is also called “stable vitamin C” (paragraph [0002]). Furthermore, AA-2G is readily hydrolyzed by an in vivo enzyme into L-ascorbic acid and D-glucose in living bodies and exerts the physiological activities inherent to L-ascorbic acid (paragraph [0002]). Shibuya discloses a novel crystalline AA-2G (paragraph [0005]). Since their hydrous crystalline AA-2G and particulate composition containing the same have a satisfactory formativeness, they can be advantageously used in producing shaped products such as tablets (paragraph [0008]). Unlike a conventional particulate composition containing anhydrous crystalline AA-2G, a tablet with a relatively high hardness can be prepared without inducing any cracking and chipping with the hydrous crystalline AA-2G powder of Shibuya when used as a filler/diluent/excipient/vehicle/adjuvant (paragraphs [0040] and [0098]). Furthermore, Shibuya discloses that their particulate composition containing hydrous crystalline AA-2G is superior in free-flowing ability (paragraph [0098]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to substitute the vitamin of the tablet rendered obvious by Yonejima with the hydrous crystalline L-ascorbic acid 2-glucoside (AA-2G) of Shibuya. One of ordinary skill in the art would have been motivated to do this in order to provide vitamin C (i.e. L-ascorbic acid) or derivative thereof in the tablet which is recognized in Yonejima for inclusion in their invention. Moreover, one of ordinary skill in the art would have been motivated to specifically select the hydrous crystalline AA-2G of Shibuya for providing the vitamin C (or derivative thereof) in the tablet rendered obvious by Yonejima because AA-2G is non-reducible and superior in stability than vitamin C, being called “stable vitamin C;” AA-2G is readily hydrolyzed by an in vivo enzyme into L-ascorbic acid and D-glucose in living bodies and exerts the physiological activities inherent to L-ascorbic acid; Shibuya’s hydrous crystalline AA-2G has a satisfactory formativeness and can be advantageously used in producing shaped products such as tablets; and Shibuya’s hydrous crystalline AA-2G use as an adjuvant in a tablet advantageously results in a tablet with a relatively high hardness without inducing any cracking and chipping which is superior as compared to conventional anhydrous crystalline AA-2G. Therefore, instant claim 16 is rendered obvious.
Claims 12 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Yonejima, as evidenced by Klein, in view of Nakamura (Chem. Pharm. Bull. 2017. 65: 432-441).
As discussed above, Yonejima (as evidenced by Klein) anticipates claims 1-5, 7, 14, 17, and 18. Yonejima differs from the invention of claim 12 in that Yonejima does not expressly disclose that the (C) (lubricant) is a fatty acid ester; instead, the lubricant comprised in the tablet of Comparative Example 3 is magnesium stearate. Yonejima differs from the invention of claim 15 in that Yonejima does not expressly disclose that the hardness of the tablet of Comparative Example 3 is 50 N to 200 N.
Nakamura discusses lubricants in tablets, pointing out that magnesium stearate (Mg-St) is a frequently used lubricant (page 432, left column, first paragraph). However, magnesium stearate forms a continuous hydrophobic thin layer on other powder particles which decreases tablet hardness, increases disintegration time, and affects the pharmacokinetics of the compounded active pharmaceutical ingredient (API) (page 432, left column, first paragraph). Therefore, Nakamura investigated the usefulness of sucrose fatty acid esters (SEs) as a lubricant in the manufacturing of tablets (page 432, right column, first full paragraph). Tablet hardness was determined for various amounts of magnesium stearate and sucrose fatty acid esters of different hydrophile-lipophile balance (HLB) values (page 439, right column, second paragraph). Nakamura observed that tablet hardness decreases with increasing magnesium stearate or sucrose fatty acid ester content, and that tablets containing sucrose fatty acid ester were harder than those containing magnesium stearate (page 439, right column, second paragraph). See Figure 8 on page 438.
It is noted that the tablet of Yonejima comprises about 0.513% magnesium stearate (see rejection of instant claim 1 above). Figure 8 of Nakamura indicates that at 0.5% magnesium stearate, the tablet hardness is about 80 N. Additionally, Figure 8 of Nakamura shows that at 0.5% for the various sucrose fatty acid esters tested, the tablet hardness was about 100N to about 110 N.
Nakamura concluded that it is possible to use sucrose fatty acid ester as a lubricant in the direct powder compression process (page 440, right column, second paragraph). Also, it was further concluded that sucrose fatty acid esters having low HLB values are extremely useful lubricants to replace magnesium stearate because of their ability to achieve high tablet hardness and short disintegration time (page 440, right column second paragraph).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to expect that the tablet of Comparative Example 3 of Yonejima has a hardness of about 80 N because it comprises about 0.513% magnesium stearate. The skilled artisan would have expected this hardness based on Nakamura which shows that a tablet comprising 0.5% magnesium stearate has a hardness of about 80 N (see discussion above regarding Figure 8 of Nakamura). A tablet hardness of about 80 N falls in the tablet hardness range of 50 N to 200 N of instant claim 15. Therefore, Yonejima in view of Nakamura renders obvious instant claim 15.
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to substitute the magnesium stearate of the tablet of Comparative Example 3 of Yonejima with a sucrose fatty acid ester, such as a sucrose fatty acid ester having a low HLB value. It would have been an obvious matter of simple substitution of one lubricant for another lubricant recognized for inclusion in a tablet. Moreover, one of ordinary skill in the art would have been motivated to make this substitution because it would have increased the hardness of the tablet, and because magnesium stearate is disadvantageous since it forms a continuous hydrophobic thin layer on other powder particles, with sucrose fatty acid ester disclosed as an alternative to magnesium stearate, as pointed out in Nakamura. There would have been a reasonable expectation of success since sucrose fatty acid ester has been recognized as a lubricant in tablets. Since sucrose fatty acid ester is directed to a fatty acid ester, then instant claim 12 is rendered obvious.
Moreover, in making the substitution, then the tablet rendered obvious by Yonejima in view of Nakamura comprises about 0.513% sucrose fatty acid ester. Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to expect that the tablet of Comparative Example 3 of Yonejima in view of Nakamura comprising about 0.513% sucrose fatty acid ester has a hardness of about 100 N to about 110 N. The skilled artisan would have expected this hardness based on Nakamura which shows that a tablet comprising 0.5% sucrose fatty acid ester has a hardness of about 100 N to about 110 N (see discussion above regarding Figure 8 of Nakamura). A tablet hardness of about 100 N to about 110 N falls in the tablet hardness range of 50 N to 200 N of instant claim 15. Therefore, Yonejima in view of Nakamura also renders obvious instant claim 15 for a tablet comprising about 0.513% sucrose fatty acid ester.
Claims 2, 4, 5, 10, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Borek.
As discussed above, Borek anticipates claims 1, 3, 8, 14, and 17. Borek differs from claims 2 and 18 in that Borek does not expressly disclose that any tablet of their examples (which anticipate the claimed invention) contains an excipient containing at least (B1) hydroxypropyl cellulose. Borek further differs from claim 4 in that Borek does not expressly disclose a content of the (B1) (hydroxypropyl cellulose) in the tablet is 1 to 20 mass%. Borek further differs from claim 5 in that Borek does not expressly disclose that a ratio of the content (mass%) of the (B1) (hydroxypropyl cellulose) to the content (mass%) of the (C) (lubricant which is stearic acid in Borek), expressed as (B1)/(C), is 0.5 to 6. Also, Borek differs from the invention of claim 10 in that Borek does not expressly disclose that the lactic acid bacterium of any tablet of their examples (which anticipate the claimed invention) is a bacterium of the genus Lactococcus.
Regarding instant claims 2 and 18, Borek discloses in their Examples 7 and 10 that hydroxypropyl methylcellulose (HPMC) is a hydrophilic agent employed in the tablet (paragraph [0102]; paragraph [0094] also referring to Table 6 of Example 7). However, in discussing the invention, Borek discloses that the hydrophilic polymers are selected from a group of cellulose derivatives that include both HPMC and hydroxypropyl cellulose (HPC) (paragraph [0049]). Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to substitute HPMC in the examples of Borek with hydroxypropyl cellulose for the predictable result of providing a hydrophilic polymer in the tablets. It would have been an obvious matter of simple substitution of the hydrophilic polymer with another recognized for practice in Borek itself. In doing so, Borek renders obvious the tablets of Examples 7 and 10 comprising an excipient containing at least hydroxypropyl cellulose. Thus, instant claims 2 and 18 (crystalline cellulose) are rendered obvious.
Further regarding instant claim 4, in making the substitution of HPMC with HPC in Examples 7 and 10 of Borek, then the content of the (B1) (HPC) in the tablet of Example 7 is about 11.3 mass% and in the tablet of Example 10 is about 14.6 mass%, which each fall in the claimed range of ‘1 to 20 mass%.’ See the calculations below. Therefore, instant claim 4 is rendered obvious.
C
o
n
t
e
n
t
o
f
H
P
C
=
50
m
g
H
P
C
443
m
g
t
a
b
l
e
t
×
100
=
11.3
%
C
o
n
t
e
n
t
o
f
H
P
C
=
1
0
0
m
g
H
P
C
684
m
g
t
a
b
l
e
t
×
100
=
1
4
.
6
%
Further regarding instant claim 5, in making the substitution of HPMC with HPC in Example 7 of Borek, then a ratio of the content (mass%) of the (B1) (HPC) to the content (mass%) of the (C) (stearic acid), expressed as (B1)/(C), is 3.13 which falls in the claimed range of ‘0.5 to 6.’ See the calculation below. Therefore, instant claim 5 is rendered obvious
R
a
t
i
o
=
11.3
%
H
P
C
3.61
%
s
t
e
a
r
i
c
a
c
i
d
=
3.13
Regarding instant claim 10, Borek discloses that biological components for oral administration include probiotics which include Lactococcus lactis subsp. lactis (paragraph [0004]). Before the effective filing date of the claimed invention, it would have been obvious to include Lactococcus lactis subsp. lactis as the lactic acid bacteria of the lactic acid bacteria pre-blend of the tablets of the examples of Borek. One of ordinary skill in the art would have been motivated to do this because Borek recognizes it as a biological component for oral administration that is a probiotic, thus being desirable for inclusion in their invention as a beneficial microorganism. Therefore, instant claim 10 is rendered obvious.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Borek in view of Murakami (US 2003/0138485).
As discussed above, Borek anticipates claims 1, 3, 8, 14, and 17. Borek differs from claim 6 in that Borek does not expressly disclose that any tablet of their examples (e.g., Examples 7 and 10 which anticipate claim 1) comprises an excipient which further contains maltose.
However, Borek discloses including a disintegration agent in their system (paragraph [0054]).
Murakami discloses a disintegrant which is incorporated into solid compositions used in the field of drug products, health food products, etc. (paragraph [0001]). The disintegrant is effectively incorporated into tablets (paragraphs [0019]-[0020]). Examples of the disintegrant include maltose (paragraph [0014]). Also, Murakami points out that maltose can be employed as an excipient (paragraph [0017]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to include maltose as a disintegration agent included in the tablets of the examples of Borek (including Examples 7 and 10 which anticipate claim 1). It would have been prima facie obvious to further include a disintegration agent in the tablets of the examples of Borek because Borek teaches inclusion of a disintegration agent in their invention. Moreover, one of ordinary skill in the art would have been motivated to include maltose as the disintegration agent in the tablets of the examples of Borek because maltose is known as a disintegrant for incorporation into tablets in the field of drug products and health food products. Therefore, instant claim 6 is rendered obvious.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Borek in view of Ohishi (US 2006/0068047).
As discussed above, Borek anticipates claims 1, 3, 8, 14, and 17. Borek differs from claim 9 in that Borek does not expressly disclose that the lactic acid bacteria pre-blend in any tablet of their examples (e.g., Examples 7 and 10 which anticipate at least claim 1) is a lactic acid bacterium-sterilized dry powder.
However, Borek discloses that lactic acid bacteria pre-blend of their examples is a lyophilized powder and starch (paragraphs [0094] and [0102]). When discussing the pre-blend for their invention, Borek teaches that the dosage form may be formed from a pre-blend in which a lyophilized biological component (e.g., a lyophilized beneficial microorganism) is mixed with a pre-blend of one or more controlling excipients, fillers, desiccants, and flow agents that has been mechanically, chemically, or otherwise dried to reduce the available water present for the purpose of preventing undesirable interactions of the beneficial organisms and hydrophilic agents with any available water within the dosage form (paragraph [0067]). Therefore, the lyophilized powder of lactic acid bacteria in the tablets of the examples in Borek is directed to a dry powder of the lactic acid bacteria. Additionally, when speaking of the biological component (BC) included in their invention, Borek discloses that the biological component may be non-viable (paragraph [0051]).
Ohishi discloses using enterobacteria as the adsorbent for endocrine-disrupting chemicals, wherein the enterobacteria are microorganisms known as bacterial strains used for the production of food (lactic acid bacteria beverage, yogurt, etc.) and are extremely safe for humans (paragraph [0033]). Examples of enterobacteria include microorganisms belonging to the genera Lactobacillus, Bifidobacterium, Lactococcus, etc. (paragraph [0034]). See also claim 10 of Ohishi disclosing a method for reducing the absorption of at least one endocrine-disrupting chemical comprising administering to a subject in need thereof an amount of enterobacteria or an enterobacteria fraction effective to reduce the absorption of said endocrine-disrupting chemical. Additionally, Ohishi discloses that heat treated bacteria (dead bacteria) of the enterobacteria can be used in combination with known pharmaceutically acceptable carriers as the adsorbent for endocrine-disrupting chemicals of their invention (paragraph [0057]). In one example, the heat treated bacteria (a strain of Lactobacillus casei) were confirmed to adsorb a larger amount of bisphenol A (an endocrine-disrupting chemical, see the abstract and paragraphs [0015] and [0060]) than live bacteria (paragraph [0157]).
Additionally, in Example 10, Ohishi teaches tablets as a health supplement comprising dried enterobacterial cells (paragraphs [0186]-[0196]). The dried enterobacterial cells were prepared by freeze-drying the live bacteria or heat treated bacteria of a strain of Lactobacillus casei (paragraph [0196]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to substitute the lactic acid bacteria pre-blend of the tablets of the examples of Borek, in particular the tablets of Examples 7 and 10, with a lyophilized dry powder of heat treated (dead) lactic acid bacteria. One of ordinary skill in the art would have been motivated to do this because Borek discloses that their biological component may be non-viable, Borek discloses the powder form of the lyophilized lactic acid bacteria in their examples, Borek discloses that the lyophilized biological component (e.g., a lyophilized beneficial microorganism) should be dried in their invention, and because Ohishi teaches that lactic acid bacteria, which are directed to enterobacteria, in the form of heat treated (dead) bacteria are suitable for the beneficial effect of reducing the absorption of endocrine-disrupting chemicals when administered to a subject. Moreover, one of ordinary skill in the art would have been motivated to include the heat treated (dead) lactic acid bacteria because heat treated bacteria of a lactic acid bacteria (a strain of Lactobacillus casei) was found to adsorb a larger amount of an endocrine-disrupting chemical than live bacteria, according to Ohishi. There would have been a reasonable expectation of providing a lyophilized dry powder of heat treated (dead) lactic acid bacteria in the tablets of the examples of Borek for the advantageous use of reducing the absorption of endocrine-disrupting chemicals because Ohishi discloses the successful inclusion of freeze-dried heat treated bacteria (the lactic acid bacteria Lactobacillus casei) in tablets as a health supplement. A lyophilized dried powder of heat treated (dead) lactic acid bacteria is directed to lactic acid bacterium-sterilized dry powder. Therefore, Borek in view of Ohishi renders obvious instant claim 9.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Borek as applied to claim 10 above, and further in view of Fujiwara (US 2014/0234379).
As discussed above, Borek renders obvious claim 10 by rendering obvious the inclusion of Lactococcus lactis subsp. lactis as the lactic acid bacteria in the tablets of their examples. However, Borek differs from claim 11 in that Borek does not expressly disclose that the Lactococcus lactis subsp. lactis is Lactococcus lactis subsp. lactis JCM5805.
Fujiwara discloses an agent for inducing IFN production in vivo comprising, as an active ingredient, lactic acid bacteria (paragraph [0085]). The preferred lactic acid bacteria is Lactococcus lactis subsp. lactis JCM5805 (paragraph [0088]). The lactic acid bacteria preferably exert activity of IFN induction in an organism when such bacteria are ingested orally (paragraph [0089]). Also, the agent can be used in the form of a pharmaceutical product that induces IFN production and enhances immune activity of an organism (paragraph [0099]). Such pharmaceutical products can be used for preventive or therapeutic agents for diseases which are already known to be associated with a type 1 IFN, such as cancer (paragraph [0099]). Furthermore, dosage forms of the agent for inducing IFN production include tablets (paragraph [0101]).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to substitute the Lactococcus lactis subsp. lactis of the tablets rendered obvious by Borek with Lactococcus lactis subsp. lactis JCM5805. It would have been an obvious matter of simple substitution of known Lactococcus lactis subsp. lactis for another for the predictable result of including a beneficial microorganism in the tablets rendered obvious by Borek. Moreover, one of ordinary skill in the art would have been motivated to include the JCM5805 strain as the L. lactis subsp. lactis strain of the tablets rendered obvious by Borek because the JCM5805 strain has the beneficial effect of inducing IFN in an organism that ingests the tablets, thereby preventing or treating diseases known to be associated with a type 1 IFN, such as cancer. There would have been a reasonable expectation of success in providing the JCM5805 strain as the biological component in the tablets rendered obvious by Borek for their therapeutic effect because Fujiwara indicates that their agent for inducing IFN production, which is preferably the JCM5805 strain, can be in the form a tablets, and Borek teaches inclusion of beneficial microorganisms in general as the biological component of their invention. As such, Borek in view of Fujiwara renders obvious instant claim 11.
Claims 12 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Borek in view of Nakamura (Chem. Pharm. Bull. 2017. 65: 432-441).
As discussed above, Borek anticipates claims 1, 3, 8, 14, and 17. Borek differs from the invention of claim 12 in that Borek does not expressly disclose that the (C) (lubricant) is a fatty acid ester; instead, the lubricant comprised in the tablets of the examples of Borek (in particular, Examples 7 and 10 anticipating at least claim 1) is stearic acid. Borek differs from the invention of claim 15 in that Borek does not expressly disclose that the hardness of the tablets of their examples (in particular, Examples 7 and 10 anticipating at least claim 1) is 50 N to 200 N.
It is noted that Borek teaches that the flow agents included in their invention include, but are not limited to, magnesium stearate and stearic acid (paragraph [0055]). Borek also teaches formulations through standard dry blend and direct compression with an appropriate lubricant such as magnesium stearate and stearic acid (paragraph [0068]).
Nakamura discusses lubricants in tablets, pointing out that magnesium stearate (Mg-St) is a frequently used lubricant (page 432, left column, first paragraph). However, magnesium stearate forms a continuous hydrophobic thin layer on other powder particles which decreases tablet hardness, increases disintegration time, and affects the pharmacokinetics of the compounded active pharmaceutical ingredient (API) (page 432, left column, first paragraph). Therefore, Nakamura investigated the usefulness of sucrose fatty acid esters (SEs) as a lubricant in the manufacturing of tablets (page 432, right column, first full paragraph). Tablet hardness was determined for various amounts of magnesium stearate and sucrose fatty acid esters of different hydrophile-lipophile balance (HLB) values (page 439, right column, second paragraph). Nakamura observed that tablet hardness decreases with increasing magnesium stearate or sucrose fatty acid ester content, and that tablets containing sucrose fatty acid ester were harder than those containing magnesium stearate (page 439, right column, second paragraph). See Figure 8 on page 438.
It is noted that the tablet of Example 10 of Borek comprises about 2.34% stearic acid (see rejection of instant claim 1 above). Figure 8 of Nakamura shows that at 2% for the various sucrose fatty acid esters tested, the tablet hardness was about 75 N to about 100 N.
Nakamura concluded that it is possible to use sucrose fatty acid ester as a lubricant in the direct powder compression process (page 440, right column, second paragraph). Also, it was further concluded that sucrose fatty acid esters having low HLB values are extremely useful lubricants to replace magnesium stearate because of their ability to achieve high tablet hardness and short disintegration time (page 440, right column second paragraph).
Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to substitute the stearic acid of the tablets of the examples of Borek, including Examples 7 and 10, with a sucrose fatty acid ester, such as a sucrose fatty acid ester having a low HLB value. It would have been an obvious matter of simple substitution of one lubricant for another lubricant recognized for inclusion in a tablet. Moreover, one of ordinary skill in the art would have been motivated to make this substitution because it would have provided a desirable high hardness of the tablet, as pointed out in Nakamura. There would have been a reasonable expectation of success since sucrose fatty acid ester has been recognized as a lubricant in tablets. Since sucrose fatty acid ester is directed to a fatty acid ester, then instant claim 12 is rendered obvious.
Moreover, in making the substitution, then the tablet of Example 10 rendered obvious by Borek in view of Nakamura comprises about 2.34% sucrose fatty acid ester. Before the effective filing date of the claimed invention, it would have been obvious to the person of ordinary skill in the art to expect that the tablet of Example 10 of Borek in view of Nakamura comprising about 2.34% sucrose fatty acid ester has a hardness less than the hardness of about 75 N to about 100 N as found in Nakamura for tablets comprising 2% sucrose fatty acid ester (Figure 8). In view of the rate of the decrease in tablet hardness with increasing percentage of sucrose fatty acid ester as shown in Figure 8 of Nakamura, it would have been obvious to the skilled artisan to extrapolate that the hardness decreases to about 60 N to about 85 N at about 2.34% sucrose fatty acid ester. A tablet hardness of about 60 N to about 85 N falls in the tablet hardness range of 50 N to 200 N of instant claim 15. Therefore, Borek in view of Nakamura also renders obvious instant claim 15 for a tablet comprising about 2.34% sucrose fatty acid ester (the tablet of Example 10 of Borek modified in view of Nakamura).
Claims 13 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Borek in view of Shibuya (US 2013/0172542).
As discussed above, Borek anticipates claims 1, 3, 8, 14, and 17. Borek differs from the invention of claim 13 in that Borek does not expressly disclose that the tablets of their examples (in particular, Examples 7 and 10 anticipating at least claim 1) further comprise one or more selected from the group consisting of vitamin, 3-hydroxyisovaleric acid, 3-hydroxyisovaleric acid calcium, ornithine, and ornithine hydrochloride. Further still, Borek differs from claim 16 in that Borek does not expressly disclose that the vitamin is L-ascorbic acid-2-glucoside.
Shibuya discloses ascorbic acid 2-glucoside, abbreviated as “AA-2G,” as a compound that is composed of one molecule of D-glucose bound to the hydroxyl group at the C-2 position of L-ascorbic acid, i.e. vitamin C (paragraph [0002]). Because of L-ascorbic acid in the compound, then AA-2G is directed to L-ascorbic acid 2-glucoside. Shibuya points out that unlike L-ascorbic acid, AA-2G is non-reducible and superior in stability and therefore it is also called “stable vitamin C” (paragraph [0002]). Furthermore, AA-2G is readily hydrolyzed by an in vivo enzyme into L-ascorbic acid and D-glucose in living bodies and exerts the physiological activities inherent to L-ascorbic acid (paragraph [0002]). Shibuya discloses a novel crystalline AA-2G (paragraph [0005]). Since their hydrous crystalline AA-2G and particulate composition containing the same have a satisfactory formativeness, they can be advantageously used in producing shaped products such as tablets (paragraph [0008]). Unlike a conventional particulate composition containing anhydrous crystalline AA-2G, a tablet with a relatively high hardness can be prepared without inducing any cracking and chipping with the hydrous crystalline AA-2G powder of Shibuya when used as a filler/diluent/excipient/vehicle/adjuvant (paragraphs [0040] and [0098]). Furthermore, Shibuya discloses that their particulate composition containing hydrous crystalline AA-2G is superior in free-flowing ability (paragraph [0098]).
Additionally, Shibuya discloses in Example 4 a tablet comprising their hydrous crystalline AA-2G. See paragraph [0095]. Similarly as commercialized vitamin C tablets, the product can be advantageously used as a vitamin-C-supplementing tablet for use in physical exhaustion and declined physical strength (paragraph [0095]).
Before the effective filing date of the claimed invention, it would have been obvious to include the hydrous crystalline L-ascorbic acid 2-glucoside (AA-2G) of Shibuya in the tablets of the examples of Borek, including Borek’s Examples 7 and 10. One of ordinary skill in the art would have been motivated to do this order to provide the additional benefits of vitamin C-supplementing tablets recognized for use in physical exhaustion and declined physical strength. There would have been a reasonable expectation of obtaining tablets suitable for use by this modification because Shibuya’s hydrous crystalline AA-2G has a satisfactory formativeness and can be advantageously used in producing shaped products such as tablets; and Shibuya’s hydrous crystalline AA-2G use as an adjuvant in a tablet advantageously results in a tablet with a relatively high hardness without inducing any cracking and chipping which is superior as compared to conventional anhydrous crystalline AA-2G that serves as a stable vitamin C. Therefore, instant claims 13 (vitamin) and 16 are rendered obvious.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSAN EMILY FERNANDEZ whose telephone number is (571)272-3444. The examiner can normally be reached 10:30am - 7pm.
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, Melenie Gordon can be reached at 571-272-8037. 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.
Sef
/SUSAN E. FERNANDEZ/ Examiner, Art Unit 1651
Prosecution Insights