PHARMATHEN S.A.

Patent Trials and Appeals Board

Nov 23, 2021

2020005284 (P.T.A.B. Nov. 23, 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.
15/326,767 01/17/2017 EVANGELOS KARAVAS PHARMA-132 9218
27769 7590 11/23/2021
AKC PATENTS
215 GROVE ST.
NEWTON, MA 02466
EXAMINER
BROWE, DAVID
ART UNIT PAPER NUMBER
1617
NOTIFICATION DATE DELIVERY MODE
11/23/2021 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):
acollins@akcpatents.com
aliki@alum.mit.edu
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte EVANGELOS KARAVAS, EFTHYMIOS KOUTRIS,
VASILIKI SAMARA, IOANNA KOUTRI, ANASTASIA KALASKANI,
LIDA KALANTZI, ANDREAS KAKOURIS, AMALIA DIAKIDOU,
GEORGE GOTZAMANIS, ZAHARIAS GEORGOUSIS, and
LOUIZA KONSTANTI
Appeal 2020-005284
Application 15/326,767
Technology Center 1600

Before ULRIKE W. JENKS, JOHN G. NEW, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

Opinion for the Board filed by Administrative Patent Judge JENKS.

Opinion Dissenting filed by Administrative Patent Judge TOWNSEND.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s
decision to reject claims directed to a water dispersible minitablet as
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 Pharmathen S.A.
Appeal Br. 2.
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STATEMENT OF THE CASE
Enalapril is an angiotensin-converting enzyme (ACE) prodrug
inhibitor. “It is rapidly hydrolyzed in the liver to Enalaprilat following oral
administration and is excreted primarily by renal excretion. In addition to
treating hypertension, Enalapril has been used for treatment of symptomatic
heart failure and assyptomatic [sic] left ventricular dysfunction.” Spec. 3:16–
19. The Specification explains that there is
a need to manufacture a dosage form [of Enalapril] for the
treatment of hypertension in a pediatric population from 0 to 18
years of age that is easy to swallow, it has no risk of choking
and/or aspiration, it has a pleasant taste and therefore it has
increased compliance compared to other dosage forms targeting
adult populations and is has an easy and cost effective
manufacturing process.
Id. at 4:32–5:1.
CLAIMED SUBJECT MATTER
The claims 1–7 are directed to a water dispersible minitablet. Claim 1,
reproduced below, is illustrative of the claimed subject matter:
1. A water-dispersible minitablet comprising:
Enalapril or pharmaceutically acceptable salts thereof as
an active ingredient, a disintegrant, a diluent, a lubricant and a
glidant;
wherein the active ingredient is distributed evenly in the
minitablet;
wherein the minitablet has a diameter of 3mm;
wherein the disintegrant comprises Crospovidone; and
wherein the minitablet disintegrates in less than 15
seconds in water.
Appeal Br. 13 (Claims App.).
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REJECTION
Appellant requests review of Examiner’s rejection of claims 1–7 as
obvious over Patel2 in view of Thomson,3 Momma,4 and Uzunovic.5
OPINION
The issue before us is whether the preponderance of evidence of
record supports Examiner’s conclusion that an enalapril containing water
dispersible minitablet using crospovidone as a disintegrant is obvious.
Examiner finds that Patel teaches an oral, water-dispersible tablet
comprising enalapril, mannitol, “2–6 wt% disintegrant, e.g., crospovidone,”
talc, magnesium stearate, aspartame and camphor, where the tablet “can
exhibit a dispersion time in water of less than 15 seconds.” Final Act. 5.
Examiner acknowledges that Patel teaches enalapril formulations with 2–6%
Kyron t314 as the disintegrant, as well as enalapril formulations with 2–6%
sodium starch glycolate as the disintegrant. Ans. 5. Examiner also
acknowledges that Patel discloses that batch “A2” containing Kyron t314
had the lowest disintegration time among the batches A1–A6 tested. Id.
However, Examiner finds that “Table 6 simply does not properly establish
that Kyron t314 is significantly superior to either crospovidone or to sodium
starch glycolate in producing a faster MDT disintegration time” because (1)

2 Patel et al., Formulation and Evaluation of Mouth Dissolving Tablet for
Anti-Hypertensive Drug, 1 PHARMAGENE 10–21 (2013) (“Patel”).
3 Thomson et al., Minitablets: New Modality to Deliver Medicines to
Preschool-Aged Children, 123 PEDIATRICS e235-8 (2009) (“Thomson”).
4 Momma, ACE Inhibitors in Pediatric Patients with Heart Failure, 8
PAEDIATR. DRUGS (2006) (Abstract only).
5 Uzunovic & Vranic, Effects of Magnesium Stearate Concentration on
Dissolution Properties of Ranitidine Hydrochloride Coated Tablets,
7 BOSNIAN J. BASIC MED. SCI. 279–283 (2007) (“Uzunovic”).
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Patel does not disclose the composition for each of the 6 batches A1–A6 in
table 6, which is a table reporting disintegration time of screening
formulations, (2) nine screening formulations were made (Kyron t314 (2, 4,
6 %), crospovidone (2, 4, 6%), and sodium starch glycolate (2, 4, 6%)), yet
only 6 batches are shown in table 6, and (3) while “Figure 1 compares the
several superdisintegrants, . . .the graph is so illegible as to be inconclusive
as well.” Ans. 5–6.
Examiner finds that “Patel teaches that camphor is a results-effective
variable. Increasing the amount of camphor will significantly decrease the
disintegration time for any given concentration of superdisintegrant
employed.” Final Act. 8. Based on these teachings of Patel, Examiner
concludes that “one of ordinary skill in the art would find it just as obvious
to select crospovidone as Kyron t 314 as the superdisintegrant, and to
optimize the formulation with the combined amounts of both the
superdisintegrant and the camphor to achieve the desired disintegration
time.” Id.
Appellant contends, and we agree, that Patel does not provide a reason
to select crospovidone as the starting disintegrant for further optimizing the
disintegration time of the mouth dissolving tablets (MDTs). Appeal Br. 6.
(“Patel teaches away from using Crospovidone as a disintegrant for
Enalapril tablets that would require a disintegration time of less than
15 sec.”).
“[E]xaminer bears the initial burden, on review of the prior art or on
any other ground, of presenting a prima facie case of unpatentability.” In re
Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). In satisfying this initial
burden, “[i]t is impermissible to use the claimed invention as an instruction
manual or ‘template’ to piece together the teachings of the prior art so that
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the claimed invention is rendered obvious.” In re Fritch, 972 F.2d 1260,
1266 (Fed. Cir. 1992). Stated differently, to establish obviousness, there
must be “an apparent reason to combine the known elements in the fashion”
recited in the claims. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418
(2007).
Patel teaches that mouth dissolving tablets (“MDTs”) are particularly
useful in the pediatric and elderly patient population. Patel 10–11. Mouth
dissolving tablets offer substantial advantages like rapid onset of action,
beneficial for patients having difficulties in swallowing and in conditions
where access to water is difficult. Patel Abstr. With MDTs the goal is to
minimize the disintegration time and to provide fast drug release. Id.
Patel teaches that “MDTs having of Kyron t 314, crosspovidone &
sodium starch glycholate were prepared separately as batches Al to A6 in
2%, 4%, [and] 6% concentration.” Patel 11. According to Patel “batch A2
showed lowest disintegration time (13 [s]ec), so [K]yron t 314 was taken as
main super-disintegrating agent in further factorial design.” Patel 14, see
also id. at Table 6, Fig. 1. Both Examiner and Appellant, however, agree that
Patel does not provide a list of the components in the screening formulations
A1–A6 other than identifying that A2 contains Kyron t 314 as the
disintegrant.6 See Appeal Br. 7; Final Act. 7–8. Based on Patel’s disclosure,

6 The Dissent agrees that Patel is not clear whether any of the screening
formulations A1 and A3–A6 contain crospovidone. See Dissent 10–11 (“It is
not clear which of, or if any of A1 or A3–A6 contained crospovidone, but, it
is not inconceivable that A1 did include the super-disintegrant crospovidone,
which formulation disintegrated in 30 seconds. . . . If 30 seconds was a
screening result from crospovidone, a reduction of 17 seconds would bring
the composition within the claimed disintegration time.”) Admittedly, the
interpretation that A1 contains crospovidone is conceivable. Speculation,
however, is not a sufficient basis for a prima facie case of obviousness. See
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there is also no reason to believe that the formulations contained mixtures of
the listed disintegrates. See Patel Table 2.
Thomson, Momma, and Uzunovic relied upon by Examiner are
directed at tablet size, suitable enalapril concentration for pediatric
application, and magnesium stearate as a lubricant. None of these references
discuss crospovidone as a disintegrant, or provide a reason to include
crospovidone in a MDT tablet.
Based on the combined references, we find that Examiner has not
provided a sufficiently articulated rationale based on evidence in this record
that would suggest selecting crospovidone as a reasonable starting
disintegrant for optimization based on the teachings of Patel. Examiner has
also not advanced a reasonable alternative rationale explaining why an
ordinary artisan would have added crospovidone to a Kyron t 314 containing
MDT. Accordingly, we are not persuaded that the Examiner has made out a
prima facie case of obviousness as to claim 1.
CONCLUSION
Examiner has not pointed to any teaching in Patel that would have led
the ordinary artisan to select crospovidone as the disintegrant for
optimization. We, therefore, reverse the rejection of claims 1–7 under
35 U.S.C. § 103 based on Patel, Thomson, Momma, and Uzunovic.

In re Warner, 379 F.2d 1011, 1017 (CCPA 1967); In re Sporck, 301 F.2d
686, 690 (CCPA 1962) (“We are unwilling to substitute speculation and
hindsight appraisal of the prior art for such factual data.”).
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DECISION SUMMARY
In summary:
Claim(s)
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1–7 103 Patel, Thomson,
Momma, Uzunovic
1–7

REVERSED

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TOWNSEND, Administrative Patent Judge, dissenting.
I respectfully dissent from the decision to overturn the Examiner’s
rejection.
Claim 1, reproduced below, is illustrative of the claimed subject
matter:
1. A water-dispersible minitablet comprising:
Enalapril or pharmaceutically acceptable salts thereof as
an active ingredient, a disintegrant, a diluent, a lubricant and a
glidant;
wherein the active ingredient is distributed evenly in the
minitablet;
wherein the minitablet has a diameter of 3mm;
wherein the disintegrant comprises Crospovidone; and
wherein the minitablet disintegrates in less than 15
seconds in water.
Appeal Br. 13 (Claims App.).
Notably, the composition claimed does not recite any required or
limiting amounts of any of the recited ingredients. Moreover, the claim
includes the open-ended transition phrase “comprising,” “which means that
the named elements are essential, but other elements may be added and still
form a construct within the scope of the claim.” Genentech, Inc. v. Chiron
Corp., 112 F.3d 495, 501 (Fed. Cir. 1997). Thus, for example, camphor is
not excluded from being part of the composition.
Patel reports on research work “to develop a mouth dissolving tablet
[(MDT)] of Enalapril maleate prepared with kyronT-314, camphor and D(-)
mannitol . . . selected on the basis of pre formulation studies.” (Patel Abstr.)
Patel explains that a “screening study” using 3 different super disintegrants
was carried out; the super disintegrants were Kyron t 314, crospovidone and
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sodium starch glycolate. (Patel 11, 14.) Patel states that “MDTs having
Kyron t 314, cros[]povidone & sodium starch glyc[]olate were prepared
separately as Batches A1 to A6 in 2%, 4%, & 6% concentration.” (Id. at
11.)
As the Examiner noted in the rejection, Patel does not explain what
the formulations of A1–A6 are. It is agreed by Appellant, that the only thing
that is known from the reference regarding the screening compositions is
that A2 included Kyron t 314 and had a disintegration time that was lowest
(13 seconds) of the six screening formulations A1–A6. (Id. at 14, and Table
6.) Based on that disintegration time further formulations with Kyron t 314
were studied. (Id. at 14.) Patel states “factorial design was applied to
develop an optimized formulation” where “the concentration of kyron t 314
(X1) and concentration of camphor (X2) were selected as independent
variables.” (Id. at 11.) The formulations tested in the factorial design are set
forth in Table 2. (Id. at 12.)
I note that in the factorial design, not only was camphor and Kyron t
314 modified, but so was mannitol. (See id. Table 2.) As the amounts of
these ingredients were modified, the disintegration time changed. (See id. at
Table 2 and Table 9.) In F1-F3 Kyron t 314 was used in 2%, 4%, and 6%
respectively, and mannitol was present at 82%, 80%, and 78%, respectively,
but camphor was held constant at 5%. (Id.) The in vitro disintegration was
highest in F1 (about 27 seconds) and decreased 3 seconds in F2 and 3 more
seconds in F3. (Id.) When camphor was increased to 10% and mannitol
was further decreased, the disintegration times were reduced even further.
(Id.) F4 disintegration was about 7 seconds less than F1, both of which
contained 2% Kyron t 314. F6 which had 6% Kyron t 314, 10% camphor
and 73% mannitol disintegrated about 10 seconds faster than F1. (Id.)
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Similarly, when camphor was increased to 15% and mannitol was further
decreased, the disintegration times were reduced even further. (Id.) F9
which had 6% Kyron t 314, 15% camphor, and 68% mannitol disintegrated
about 17 seconds faster than F1, (10 seconds). (Id.) Furthermore, F7 which
also had 15% camphor, but only 2% Kyron t 314 and 72% mannitol
disintegrated in just about 15 seconds, and F8 which had 15% camphor, but
4% Kyron t 314, and 70% mannitol disintegrated in 12 seconds.
There is nothing in Patel that suggests the results observed with Kyron
t 314 would not be observed when combining a different super-disintegrant
with camphor. All that Patel indicates with respect to the selection of Kyron
t 314 as the super disintegrant was a decision to pursue MDT compositions
with it based on studying screening formulations that included 2, 4, or 6% of
Kyron t 314 or starch glycolate or crospovidone. The remaining contents of
the screening formulation are unknown though presumably it included
Enalapril. It is not clear which of, or if any of A1 or A3–A6 contained
crospovidone, but, it is not inconceivable that A1 did include the super-
disintegrant crospovidone, which formulation disintegrated in 30 seconds.
But even if A1 did not include crospovidone, I find that what one of
ordinary skill in the art would reasonably take away from Patel is that the
percentage of super-disintegrant, the percentage of camphor, and the
percentage of mannitol in the composition are known results effective
variables and that increasing the super-disintegrant and camphor percentages
in the composition while also decreasing the mannitol percentages would
reasonably have been expected to decrease the disintegrating time. Patel
teaches that it was able to reduce disintegration times up to 17 seconds by
manipulating those variables. Applying that knowledge, one of ordinary
skill in the art would have reasonably concluded that formulations of
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crospovidone with camphor and mannitol and enalapril could be arrived at
and achieve similar reductions in disintegration time, if not more given the
additional teachings discussed below regarding size of tablet and effects of
magnesium stearate. “[D]iscovery of an optimum value of a result effective
variable in a known process is ordinarily within the skill of the art.” In re
Boesch, 617 F.2d 272, 276 (CCPA 1980). As to the specific disintegration
time of less than 15 seconds, one of ordinary skill in the art would have
understood from Patel that less than 15 seconds was the desirable target
range, and would have found it obvious to optimize the percentages of
crospovidone with camphor and mannitol to arrive at this disintegration
limit.
If 30 seconds was a screening result from crospovidone, a reduction of
17 seconds would bring the composition within the claimed disintegration
time. But, as noted, even assuming A1 was not a formulation including
crospovidone, the teachings of Patel are sufficient regarding the fact that
percentages of super-distintegrant and camphor and mannitol are results
effective variables that can be manipulated to significantly reduce the
disintegration time of the screening compositions. Moreover, selecting
crospovidone as the super-disintegrant instead of Kyron t 314 for use in the
combination would have been an obvious substitution of one known super-
disintegrant for another. Appellant’s claim “recites a combination of
elements that were all known in the prior art, and all that was required to
obtain that combination was to substitute one well-known . . . agent for
another.” Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356,
1364 (Fed. Cir. 2012). While it might be true that Patel did not describe “the
combination of Enalapril with Crospovidone . . . result[ing] in disintegration
time of less than 15 sec” (Appeal Br. 6), that is not dispositive of whether a
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composition that would achieve that disintegration time would have been
obvious from all of the teachings of Patel and particularly in view of the
additional references the Examiner relied upon regarding dosage amounts of
active in a minitablet for pediatric use.
The Examiner provided evidence that for pediatric patients, a much
lower amount of enalapril can be used than the amount in the Patel tablet
(100 mg tablets (Patel 11) with 5% being enalapril (i.e., 5 mg) (Patel 12)).
(Momma (once or twice a day doses ranging from 0.1 to 0.5 mg/kg).) Thus,
one of ordinary skill in the art would reasonably have been motivated to
develop a pediatric MDT formulation of Enalapril and would have
consequently, found it obvious to reduce the active ingredient amount.
Additionally, the Examiner provided further evidence that at the time
the invention was made minitablet formulations for young children were
being developed (3 mm). (See Thomson.) That tablet size is half the size of
what was tested in Patel. (Patel 11 (6 mm tablets).) One of ordinary skill in
the art would have had motivation to prepare smaller MDT tablets of
Enalapril for pediatric patients, which had less active agent than taught in
Patel, and which one would have reasonably expected to necessarily dissolve
in less time than the tablets described in Patel.
Furthermore, the Examiner also provided evidence that it was known
at the time the invention was made that magnesium stearate which is used as
a lubricant for tablet formulation, could form a film on tablet excipients and
lead to prolonged liberation time of the active. (Uzonovic 280.) This is an
ingredient in the Patel tablets. I agree with the Examiner that one of
ordinary skill in the art would reasonably have been motivated from the
prior art to develop a pediatric MDT formulation and would have sought to
limit the amount of magnesium stearate in the formulation disclosed in Patel.
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And in doing so, one of ordinary skill in the art would have understood that
ingredient to be another results effective variable that if lowered would
reasonably be expected to assist in decreasing disintegration times.
Thus, I would find that the combination of teachings of the prior art
supports the Examiner’s conclusion that given all the results-effective
variables known in the art that would be expected to be able to be
manipulated to reduce the disintegration time of an MDT tablet of enalapril,
i.e., the amounts of crospovidone, camphor, mannitol, talc and magnesium
stearate, and size of the tablet, the invention recited by claim 1 would have
been obvious. Based on the foregoing, I would have affirmed the
Examiner’s obviousness rejection.