Eric First et al.

Patent Trials and Appeals Board

Jul 28, 2021

2020005932 (P.T.A.B. Jul. 28, 2021)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/387,977 05/11/2009 Eric R. First BHC 106001 US 6835
70224 7590 07/28/2021
Bayer HealthCare LLC
(Whippany)
1 Bayer Drive
Indianola, PA 15051
EXAMINER
GREENE, IVAN A
ART UNIT PAPER NUMBER
1619
NOTIFICATION DATE DELIVERY MODE
07/28/2021 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
uspoccs@bayer.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ERIC R. FIRST, ASHISH B. PATEL,
GUIDO SCHMITZ, STEPHANIE PETAWAY-HICKSON, and
HUNG-HUAR TONG
Appeal 2020-005932
Application 12/387,977
Technology Center 1600
Before JEFFREY N. FREDMAN, RACHEL H. TOWNSEND, and
CYNTHIA M. HARDMAN, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims directed to a compressed oral tablet of
acetylsalicylic acid as being obvious. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.

1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R.
§ 1.42(a). Appellant identifies the real party in interest as “Bayer
HealthCare LLC, the assignee of record, which is a subsidiary of Bayer
AG.” (Appeal Br. 4.)
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STATEMENT OF THE CASE
Appellant’s Specification states:
Solid dosage forms, such as capsules, tablets and caplets, are
very popular delivery mechanisms for doses of medicinal
compounds. . . . Unlike injections, solid dosage forms do not
require medical expertise for administration, so patients may
take the medicine at home.
(Spec. ¶ 2.) Appellant’s Specification further notes, however, that “[u]nlike
injections and other direct administration techniques that deliver the
medicinal compound directly to the bloodstream, solid dosage forms such as
tablets must be absorbed into the bloodstream through the gastrointestinal
tract.” (Id. ¶ 3.) One consequence of that requisite absorption is that “solid
dosage forms do not provide immediate medicinal benefits,” i.e., there is a
delayed onset of action. (Id. ¶ 5.) Some approaches to overcoming the
delayed onset of action problem have been to develop “effervescent tablets
that dissolve in a glass of water or powders carried in individual envelopes.”
(Id. ¶ 8.) However, “these approaches have drawbacks of their own.” (Id.)
In particular, Appellant’s Specification explains:
Effervescent tablets tend to be significantly larger than tablets
that are to be swallowed directly, and so can be less durable and
portable than smaller tablets. Powders generally do not taste
very good, and the large surface area of a powder, when
compared to a compressed tablet, at least, can ensure an
unpleasant taste experience for the patient.
(Id.) Quick dissolve tablets have also been tried. (Id. ¶ 9.) However, the
quick dissolve technology has similar
problems found with effervescent tablets and powders. Quick-
dissolve tablets are generally larger and not as highly
compressed as tablets, so they are not as durable as compressed
tablets, and, if the medicinal ingredient has a bad taste, the bad
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taste can still be detected while the quick-dissolve tablet is
being swallowed.
(Id.) Appellant’s invention is directed to an oral compressed tablet of
acetylsalicylic acid, i.e., aspirin.
Claims 31–33 are on appeal. Claim 31 reproduced below, is
illustrative of the claimed subject matter:
31. A compressed tablet for oral administration consisting
essentially of:
a. acetylsalicylic acid, and
b. sodium carbonate,
the acetylsalicylic acid having a d50 particle size prior to
tableting of less than about 40 microns measured by wet
dispersion laser diffraction, and wherein the weight ratio of
acetylsalicylic acid to sodium carbonate is about 3:1, the tablet
being 100% dissolvable after 2 minutes in 900 L of an acetate
buffer at pH 4.5 in a dissolution testing system in which a sample
basket is spun at 50 rpm and maintained at about 37°C.
(Appeal Br. 28.)

The prior art relied upon by the Examiner is:

Name Reference Date
Patel et al. US 2003/0180352 A1 Sept. 25, 2003
Bertelsen (Bertelsen
’688)
US 2005/0147688 A1 July 7, 2005
Bertelsen (Bertelsen
’128)
US 2007/0218128 A1 Sept. 20, 2007
D. Orton et al., Plasma Salicylate Levels After Soluble and Effervescent
Aspirin, 7 Br. J. Clin. Pharm. 410–12 (1979)
Lovorka Nikolic et al., Influence of ln Vitro Test Conditions on Release of
Aspirin from Commercial Tablets, 81 J. Pharm. Sciences 386–91 (1992)
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The following ground of rejection by the Examiner is before us on
review:
Claims 31–33 under 35 U.S.C. § 103(a) as unpatentable over
Bertelsen ’128, Bertelsen ’688, Patel, Orton, and Nikolic.
DISCUSSION
The Examiner found that Bertelsen ’128 teaches a quick release
pharmaceutical composition of water insoluble drugs (i.e., having a
solubility at room temperature of less than 0.1% w/v in 0.1 N hydrochloric
acid, such as acetylsalicylic acid (or aspirin), which is considered practically
insoluble in water and in 0.1 N HCl at room temperature) where the
formulation provides for a significant improvement in stability and longer
shelf life than “conventionally formulated and processed drugs.” (Non-Final
Action2 4–5 (citing, inter alia, Bertelsen ’128 Abstr., ¶ 83).) The Examiner
found that the formulation includes an alkaline substance as a dissolution
helper, such as salts of carbonic acid, e.g., di-sodium carbonate and/or
sodium carbonate, co-milled with the active ingredient without the addition
of a liquid. (Id. at 5–6 (citing Bertelsen ’128 ¶¶ 11, 16–21, 53, 110, 114, and
128).) The Examiner further found that the co-milling provides for the
active ingredient and alkaline substance to be in close physical contact and
in which the particle size of the co-milled pharmaceutical composition is
preferably less than about 40 microns, and where the mean particle size of
the alkaline substance, which the Examiner interprets as the d50 particle
size, is in the range of 1 to 400 microns. (Id. at 5 (citing Bertelsen ’128
¶¶ 11, 103, 128).) In addition, the Examiner found that Bertelsen ’128

2 The Non-Final Action is dated September 6, 2019.
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teaches the formulation is compressed into a tablet. (Id. (citing Bertelsen
’128 ¶¶ 16–21, 53).)
The Examiner also found that Bertelsen ’128 teaches that the
composition has a dissolution rate of active substance of at least 50% being
dissolved within the first 20 minutes at conditions simulating the gastric
fluid, and can be at least 95% dissolved. (Id. at 7 (citing Bertelsen ’128
¶¶ 14, 154).) The Examiner additionally found that, although Bertelsen ’128
does not limit the amount of alkaline substance in the formulation or teach
the weight ratio of active substance to sodium carbonate claimed, it does
teach that the amount of nonsteroidal anti-inflammatory drug can be
anywhere from about 1 mg to about 1600 mg. (Id. at 6.)
In finding the claimed tablet composition having the claimed ratio of
aspirin to sodium carbonate and the claimed dissolution rate obvious, the
Examiner turns to the teachings of Patel and Orton.3 In particular, the
Examiner found that Patel describes solid pharmaceutical formulations that
include alkaline materials as stabilization aids in from 54–500% by weight of
active ingredient or 10–100% by weight of active ingredient “having more
rapid dissolution upon administration to a patient” and “demonstrates the

3 The Examiner relied on Bertelsen ’688 only for its teaching of 500 mg of
an NSAID being a dosage that is generally known in the art that can be
present in a quick release composition. (Non-Final Action 8.) The
Examiner relied on Nikolic only for the fact that dissolution of tablets in pH
4.5 buffer solutions is faster than compared to artificial gastric juices which
suggests “that the compositions of Bertelsen [’128] would have had a faster
dissolution in acetate buffer at pH 4.5.” (Id. at 11.)
4 The Examiner indicates the ratio is 50–500%, which is an obvious
inadvertent error given the Examiner’s acknowledgement that the narrower
range disclosed by Patel is “preferably 10–100 %.” (Id. at 8.)
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high dissolution rate in the examples and Figures, though not with an
acetylsalicylic acid active agent.” (Non-Final Action 9 (citing Patel ¶ 11).)
The Examiner found that Patel teaches that the amount of alkaline material
included depends on the relative strength of that material. (Id. at 8.) The
Examiner found that Orton teaches a number of known aspirin formulations
in Table 1, one of which includes “Soluble aspirin B.P.” having 300 mg
aspirin, 100 mg calcium carbonate and 30 mg anhydrous citric acid, thus,
including about 33% carbonate based upon the weight of aspirin. (Id. at 9–
10 (citing Orton 411, col. 1).) The Examiner further found that Orton
teaches another known aspirin composition, an effervescent formulation,
included “Anhydrous sodium carbonate” that included 25 mg anhydrous
sodium carbonate and 300 mg aspirin. (Id.) The Examiner further noted
that Orton teaches the effervescent preparations “have been shown to give
higher blood levels within a shorter time than solid tablets” and that
“[s]oluble aspirin, has been shown to be absorbed more rapidly than
ordinary aspirin.” (Id. (citing Orton 410–11).)
In light of the foregoing teachings, the Examiner found that it would
have been obvious to one having ordinary skill in the art to have optimized
the amount of aspirin and carbonate ingredients “to achieve the shortened
dissolution as taught by BERTELSEN [’128], PATEL and ORTON, and
arrived at the instantly claimed invention” and produce an aspirin product
“having a significant improvement in stability and longer shelf life than
conventionally formulated and processed aspirin.” (Id. at 10–11, 12.) In
addition, regarding the claimed dissolution limitation, the Examiner found
that because the prior art suggests a “substantial[ly] identical aspirin
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product,” it would have had “the same properties as the claimed
compositions.” (Id. at 11, 14.)
We do not agree with the Examiner’s conclusion of obviousness as
will be discussed below. First, we note that Appellant’s claim is a
composition that consists essentially of two ingredients: a micronized aspirin
combined with sodium carbonate in a particular weight ratio. In addition,
the claim requires that the tablet composition achieves a particular
dissolution profile. “By using the term ‘consisting essentially of,’ the drafter
signals that the invention necessarily includes the listed ingredients and is
open to unlisted ingredients that do not materially affect the basic and novel
properties of the invention.” PPG Indus. v. Guardian Indus. Corp, 156 F.3d
1351, 1354 (Fed. Cir. 1998). Thus, the tablet formulation may include
unlisted ingredients but those cannot be responsible for affecting the
dissolution profile. We do not find the prior art references provide a
suggestion to arrive at a 3:1 ratio of micronized aspirin to sodium carbonate
in a tablet with a reasonable expectation of achieving a tablet that is 100%
dissolvable after 2 minutes in 900 L of an acetate buffer of pH 4.5 in the
testing system claimed.
Bertelsen ’128 specifically teaches a “typical” molar ratio between the
active drug substance and the alkaline substance is between 1:100 and 1:1,
and “preferably, the said molar ratio is 1:80, 1:60, 1:40 or 1 :30, most
preferably 1:20,” and further noting that a ratio of 1:10 may be appropriate.
(Bertelsen ’128 ¶ 107; see also id. Example 2 (8 mg lornoxicam to 78 mg of
trisodium phosphate), Example 3 (8 mg lornoxicam to 136.2 mg of sodium
carbonate decahydrate), Example 4 (2% lornoxicam to 18.7% arginine);
Example 5 (1.7% lornoxicam to 19% sodium carbonate), Example 9 (2.5%
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lornoxicam to 12.5% sodium bicarbonate).) In other words, Bertelsen ’128
generally teaches the use of an excess of alkaline substance in combination
with the drug product in order to achieve a tablet that has a fast dissolution
profile, at least 50% in 20 minutes, and a stable composition. We do not
agree with the Examiner that the prior art provides a reason to change that
ratio to arrive at the claimed 3:1 aspirin to sodium carbonate ratio, much less
with a reasonable expectation that the claimed 100% dissolution after
2 minutes under the claimed conditions would be achieved.
First, Patel is concerned with providing an active ingredient
formulation avoiding micronization of the active by providing the active in
combination with at least one surfactant and/or a solubilizer. (See, e.g., Patel
¶¶ 4, 5, 10, 30–35, 47–48, 359–361.) Although Patel discloses the
possibility of including a stabilization aid that is an alkaline material, such as
a basic inorganic salt, as well as providing that material in amounts from 5–
500% or 10–100% (id. ¶ 256), it does not provide any disclosure of having
particular ratios of active agent to stabilization aid. Thus, it does not provide
motivation to specifically select a ratio of an active agent to stabilization
agent (much less sodium carbonate), nor does it provide motivation to
specifically select such a ratio in which the stabilization agent is not present
in an excess of the active ingredient, much less of a specific ratio of active
agent to stabilization agent of 3:1.
Moreover, there is even less suggestion to combine aspirin and
sodium carbonate in that manner and without including additional
ingredients responsible for dissolution. As Appellant explains, Patel does
not disclose a composition that includes aspirin in combination with sodium
carbonate (Appeal Br. 13–14), much less without including surfactants
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and/or other solubilizing ingredients as taught to be part of the formulation
of Patel (see, e.g., Patel Abstr.).
Furthermore, Orton’s disclosure either alone or in combination with
Bertelsen ’128 and Patel does not provide a motivation to include a 3:1 ratio
of micronized aspirin and sodium carbonate in a tablet. That is because the
formulation that Orton teaches as including an aspirin to carbonate ratio of
3:1 (Orton, Table 1) is one that includes calcium carbonate. The only
formulation that includes sodium bicarbonate is the effervescent formulation
that includes bicarbonate at 435 mg with aspirin being present at 300 mg.
(Id.) However, not only does that effervescent formulation require a greater
amount of bicarbonate to aspirin (as in Bertelsen ’128), it also includes
sodium citrate at 134 mg. (Orton, Table 1.) Moreover, Orton teaches that
the effervescent formulation has been “shown to give higher blood levels of
drug within a shorter time than solid tablets.” (Id. at 410–11.) Thus, Orton
does not provide a suggestion that a tablet having more aspirin than sodium
carbonate would reasonably be expected to achieve a faster dissolution rate
than that already achieved by the formulation described in Bertelsen ’128.
In light of the foregoing, we do not agree with the Examiner that one
of ordinary skill in the art would have found a reason to “optimize” the ratio
of micronized aspirin to sodium carbonate of Bertelsen ’128 to arrive at the
claimed 3:1 ratio, much less to expect that such a ratio would have the
improved stability that Bertelsen ’128 teaches would be achieved by having
a ratio of drug to alkaline substance in the range of 1:100 to 1:1.
Notwithstanding the foregoing, we also agree with Appellant that the
evidence submitted establishes an unexpectedly better stability compared to
the closest prior art, i.e., Bertelsen ’128. In particular, Appellant submitted
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the Declaration of Harsh Mehta describing the preparation of formulations
according to the claimed invention, i.e., a 3:1 ratio of micronized aspirin to
sodium carbonate, and preparations having an excess or alkaline substance
to active ingredient as suggested in Bertelsen ’128. (See Appeal Br. 21;
Declaration of Harsh Mehta dated January 25, 2019.) As Appellant
explains, Bertelsen Example 9 describes a compressed tablet in which the
active ingredient, lornoxican, to sodium bicarbonate ratio is 1:5, and
Bertelsen Example 3 describes a tablet in which the active ingredient,
lornoxican, to sodium carbonate ratio is 1:17. (Appeal Br. 21 (citing
Bertelsen ’128 ¶¶ 221, 254).).
The Mehta Declaration describes the preparation of four aspirin
compositions with aspirin (milled grade with particle size D50 < 40
microns) having been co-mixed with sodium carbonate, anhydrous, in
selected ratios by bin blending, roller compacting the blend to form ribbons,
milling the ribbons to granules, and compressing the granules into tablets.
(Mehta Declaration ¶¶ 5–6.) The four compositions had aspirin to sodium
carbonate ratios of 1:5, 1:10, 1:15 and 3:1. (Id. ¶¶ 5, 7.) The 1:5, 1:10, and
1:15 ratios were weight ratios in the range of excess alkaline to active
ingredient ratios exemplified in Bertelsen ’128 by Examples 3 and 9.
Stability tests were run on each of the four different aspirin tablet
groups. (Mehta Declaration ¶¶ 8–9.) The tableted formulations were placed
in a vial (20 tablets to a vial) and put in a temperature controlled oven at
50 °C and ambient humidity and a sample from the vials was tested at day 0,
day 6, and day 11 with HPLC for the presence of % free salicylic acid
(FSA), a degradation product. (Id.) The results demonstrated that the tablet
having a 3:1 ratio of aspirin to sodium carbonate had significantly lower
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percentages of FSA compared to the other formulations having an excess of
alkaline compared to aspirin. (Id. ¶¶ 10–11 (Table II and Figure 1).) Such a
result was not predictable from the disclosure of Bertelsen ’128, which
teaches stability is achieved where the alkaline substance, which also serves
as the dissolution helper, is achieved with a 1:100 to 1:1 ratio of aspirin to
alkaline substance, not an excess of active ingredient compared to alkaline
substance. Thus, we disagree with the Examiner’s assertion that “the results
demonstrated by Appellants are in the same direction using the same
techniques of BERTELSEN” (Ans. 17).
The Examiner also dismissed the Declaration evidence because the
Declaration showing %FSA of 1.48 initial %FSA is much higher than the
results shown in testing in the Specification for a 3:1 ratio (75% to 25%)
(Table 3). (Ans. 16.) Appellant’s Declaration evidence, however, clearly
demonstrates a significant stability difference between tablets suggested by
Bertelsen ’128 and the claimed tablet. The Declaration evidence indicates
that tablets according to the claimed invention and as suggested by Bertelsen
’128 were subjected to the same processing steps and degradation testing.
The results are set forth in the table below.

The table above provides the percentage FSA initially, i.e., prior to being
subjected to oven-controlled temperature at 50 ºC, and at 6 days and 11 days
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after being subjected to oven-controlled temperature at 50 ºC. The tablet
according to the invention had 3.6% FSA after 11 days of being subjected to
an oven-controlled temperature of 50 ºC, whereas tablets having a ratio of
micronized aspirin to sodium carbonate of (a) 1:5 had 14.77% FSA, (b) 1:10
had 23.4% FSA, and (c) 1:15 had 34.31% FSA. The %FSA of formulations
suggested by Bertelsen ’128 are an order of magnitude greater than that for
the tablet having the claimed ratio of micronized aspirin to sodium carbonate
of 3:1. There can be no doubt of the statistical significance of such a
difference.
Thus, for the foregoing reasons, we reverse the Examiner’s rejection
of claims 31–33 under 35 U.S.C. § 103(a) as being unpatentable over
Bertelsen ’128, Bertelsen ’688, Patel, Orton, and Nikolic.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
31–33 103(a) Bertelsen ’128,
Bertelsen ’688,
Patel, Orton,
Nikolic
31–33

REVERSED