MERCK PATENT GMBH

Patent Trials and Appeals Board

Oct 27, 2021

2021000577 (P.T.A.B. Oct. 27, 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.
15/645,436 07/10/2017 Hiltrud LINDENBLATT MERCK-4275-C01 4360
23599 7590 10/27/2021
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON, VA 22201
EXAMINER
SHIN, MONICA A
ART UNIT PAPER NUMBER
1616
NOTIFICATION DATE DELIVERY MODE
10/27/2021 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):
docketing@mwzb.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HILTRUD LINDENBLATT, THOMAS T. FRANK, and
REINER VONDERSCHMITT
Appeal 2021-000577
Application 15/645,436
Technology Center 1600
Before DONALD E. ADAMS, ULRIKE W. JENKS, and
RACHEL H. TOWNSEND, 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 to a solid pharmaceutical preparation of
levothyroxine sodium and methods of making such a composition 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. Appellant identifies the real party in interest as Merck Patent GmbH.
(Appeal Br. 1.)
Appeal 2021-000577
Application 15/645,436

2
STATEMENT OF THE CASE
Levothyroxine sodium is used to treat thyroid hormone deficiency.
(Spec. 1.) Storage stability of pharmaceutical preparations of this compound
is important to avoid dosage variations. (Id.) Appellant’s invention is
directed to a solid pharmaceutical preparation of levothyroxine sodium
having improved stability. (Id.)
Claims 1–10, 12–17, 20, and 21 are on appeal. Claims 1 and 13,
reproduced below, are illustrative of the claimed subject matter:
1. A solid pharmaceutical preparation comprising levothyroxine
sodium, 2-10% by weight based on the preparation of gelatine,
0.2 to 3% by weight based on the preparation of citric acid, and
a filler that is 50 to 80% by weight, based on the preparation, of
mannitol, sucrose or lactose, and 10 to 30% by weight, based on
the preparation, of maize starch.
13. A process for the production of a solid pharmaceutical
preparation according to Claim 7, comprising suspending
(a) levothyroxine sodium and optionally liothyronine sodium in
an aqueous gelatin solution,
(b) spraying the suspension obtained in (a) onto the filler in a
fluidized bed granulation and drying to form granules, citric
acid being either dissolved in the aqueous gelatine solution or
admixed with the granules,
(c) collecting the granules obtained in (b) and optionally,
(d) mixing a disintegrant and optionally a lubricant with the
granules obtained in (c), and (e) compressing a mixture
obtained in (d) to give tablets.
(Appeal Br. 9–10.)

Appeal 2021-000577
Application 15/645,436

3
The prior art relied upon by the Examiner is:
Name Reference Date
Kahn WO 95/20954 Aug. 10, 1995
Kun et al. US 6,017,958 Jan. 25, 2000
Schreder et al. US 6,646,007 B1 Nov. 11, 2003
Hanshew, JR et al. US 2004/0013725 A1 Jan. 22, 2004

The following grounds of rejection by the Examiner are before us on
review:
Claims 1–4, 6–10, 13, 14, 16, 17, and 21 under 35 U.S.C. § 103(a) as
unpatentable over Khan and Schreder.
Claim 15 under 35 U.S.C. § 103(a) as unpatentable over Khan,
Schreder, and Kun.
Claims 5, 12, and 20 under 35 U.S.C. § 103(a) as unpatentable over
Khan, Schreder, and Hanshew.
DISCUSSION
The Examiner found that Khan teaches a solid pharmaceutical
composition that includes the ingredients and the ranges recited in claim 1,
where Khan calls the sugar or sugar alcohol a diluent instead of a filler, and
citric acid is provided as a flavoring agent. (Final Action 4 (citing Khan,
2:24–33, 3:40–4:4, 5:19–32, 9 (Example 1), 6:7–25.) The Examiner
recognized, however, that the use of gelatin as a binder is only suggested as
among the possible “suitable additional pharmaceutically acceptable
ingredients” in a tablet formulation. (Final Action 4–5.)
The Examiner relied on Schreder “for the motivation to specifically
select and use gelatin in Khan’s tablets.” (Id. at 5.) In particular, the
Examiner found that Schreder discloses levothyroxine sodium tablets that
Appeal 2021-000577
Application 15/645,436

4
comprise gelatin and fillers and also discloses that when gelatin is used as a
binder, the “preparation has a surprising stability.” (Id. (citing Schreder
1:66–67, 4:15–29 (Example 3)).) The Examiner found that one of ordinary
skill in the art would have had a reasonable expectation of success given that
“both Khan and Schreder are directed to levothyroxine sodium tablets and
Khan discloses that binders such as gelatin are suitable for inclusion in their
tablets.” (Id. at 6.)
The Examiner further found that Schreder teaches a process for
producing the pharmaceutical preparation as substantially set forth in claim
13. (Id. at 5–6 (citing Schreder 2:27–43, 3:11–37).) The Examiner found
that one of ordinary skill in the art would have found it obvious to use
Schreder’s method to make the levothyroxine sodium tablets including
gelatin. (Id. at 6.) The Examiner explained that
One of ordinary skill in the art would have been motivated with
a reasonable expectation of success in doing so as both Schreder
and Khan are directed to levothyroxine sodium tablets; Khan
discloses generally mixing all of the components together before
compressing the mixture into a tablet; and Schreder generally
discloses that ingredients outside of gelatin, active agent, and
filler(s) are mixed in with the formed granules prior to
compressing the mixture into a tablet.
(Id.)
We agree that the Examiner set out a prima facie case of obviousness
in the initial rejection of the claims. However, we conclude that Appellant
has provided evidence of unexpected results sufficient to establish the non-
obviousness of the claimed invention. In re Soni, 54 F.3d 746, 750 (Fed.
Cir. 1995) (“One way for a patent applicant to rebut a prima facie case of
obviousness is to make a showing of ‘unexpected results,’ i.e., to show that
the claimed invention exhibits some superior property or advantage that a
Appeal 2021-000577
Application 15/645,436

5
person of ordinary skill in the relevant art would have found surprising or
unexpected.”)
Appellant’s argument that one of ordinary skill in the art would not
have added a stability-inducing agent such as gelatin to Kahn because the
goal of Khan is to produce an essentially unstable tablet that can dissolve in
the mouth (Appeal Br. 2–3, 5) is not persuasive. In particular, while Kahn is
concerned with a composition that can easily dissolve in the mouth, such
does not indicate that Kahn is not interested in a product that has a stable
shelf life until inserted into the mouth of a patient. Schreder suggests such
stability can be provided by gelatin (Schreder 1:66–67), and Kahn does
teach that binders such as “starch, gelatin or natural and synthetic gums” are
pharmaceutically acceptable ingredients that “[t]he solid oral dosage forms
of the invention may further comprise.” (Kahn 6:7–11.)
Despite the foregoing, however, Appellant has provided evidence
demonstrating that at the time the invention was made, it was known that
citric acid (and tartaric acid) is a pH modifier that reduces the stability of
levothyroxine sodium pentahydrate in tablets. (Appeal Br. 4 (citing Patel2).)
Patel describes tablet formulations of levothyroxine sodium pentahydrate
including 10% pH modifier and the diluent dibasic calcium phosphate.
(Patel 38, 41.) Formulations that included basic pH modifiers provided
greater storage stability of the levothyroxine sodium pentahydrate in the
tablets than did citric acid. (Id. at 41 (Table 3).) And formulations that
included no pH modifiers provided greater storage stability of levothyroxine

2 Himanshu Patel et al., The effect of excipients on the stability of
levothyroxine sodium pentahydrate tablets, 264 Int’l J Pharm. 35–43, 41
(Table 3) (2003).
Appeal 2021-000577
Application 15/645,436

6
sodium pentahydrate in tablets than the formulations that included citric
acid. (Id.) In addition, Appellant has provided testing results demonstrating
the instability of levothyroxine sodium tablets that include 1.5 % by weight
citric acid, which is within range recited in claim 1. (Id. (citing 2018
Declaration3).) The Storage and Stability Testing data provided in the 2018
Declaration demonstrates that the stability of levothyroxine sodium in a
composition that includes 1.5% by weight citric acid is worse than the
stability of levothyroxine sodium in a composition that does not include
citric acid. (2018 Declaration 4 (15 tablets of each group were subjected to
assay/purity determination)4.) Thus, Appellant’s data indicates that even
with lower percentages of citric acid than was used in the Patel formulations,
the same negative impact on stability arises.
The 2018 Declaration also provided data showing the stability of
levothyroxine sodium in a tablet composition that includes 1.5% by weight
citric acid together with 5% by weight gelatin. (Id.) Appellant provided
additional data showing the stability of levothyroxine sodium in a tablet
composition that includes gelatin but no citric acid. (Appeal Br. 4 (citing
2020 Declaration5).) The data provided in the 2020 Declaration included

3 Declaration Under 37 C.F.R. § 1.132 of Daniel Schwartz, dated November
27, 2017, and submitted by Appellant to the Office in 2018.
4 Thus, even though there is only a single assay result reported each for 7,
14, and 28 days storage, that data point is based on a number of tablets
having been tested. As such, we do not find the Examiner’s concern
regarding the absence of margin of error (Ans. 9) to be an appropriate reason
to discount Appellant’s data.
5 Declaration Under 37 C.F.R. § 1.132 of Daniel Schwartz, dated April 16,
2020. The 2020 Declaration is not paginated, we assume the first page is
page 1, and number the remaining pages consecutively.
Appeal 2021-000577
Application 15/645,436

7
stability results for the Comparison Example 1 composition described in
Appellant’s Specification. (2020 Declaration 2–3.) The Specification
discloses that Comparison Example 1 is a tablet formulation that includes
5% by weight gelatin and no citric acid. (Spec. 17.) The 2020 Declaration
demonstrates that the levothyroxine sodium in a tablet composition that
includes no citric acid and 5% by weight gelatin is more stable than the
tablet composition that has no gelatin and no citric acid, both of which are
more stable than the tablet composition that has 1.5% citric acid and no
gelatin. (2020 Declaration 3 (20 tablets of Comparison Example 1 were
used in the assay determination).) The 2020 Declaration also shows that the
levothyroxine sodium in a tablet composition that includes 1.5% citric acid
and 5% by weight gelatin is more stable than the tablet composition that has
5% gelatin and no citric acid. We agree with Appellant that the stability
results observed with the combination of gelatin and citric acid would not
have been expected by one having ordinary skill in the art because citric acid
by itself has been reported in the literature, and shown by Appellant, to
negatively affect the stabilization of levothyroxine sodium in a tablet. That
is, one of ordinary skill in the art would not have expected the combination
of citric acid and gelatin to provide better stabilization of levothyroxine
sodium in a tablet composition than the stabilization provided by gelatin
alone, “citric acid not being recognized as having any stability-
enhancing ability.” (Appeal Br. 4.) Contrary to the Examiner’s apparent
position (Ans. 9) that synergy must be established to rebut the Examiner’s
prima facie case, “it is well settled that comparative test data showing an
unexpected result will rebut a prima facie case of obviousness.” In re Fenn,
639 F.2d 762, 765 (CCPA 1981).
Appeal 2021-000577
Application 15/645,436

8
For the foregoing reasons, we do not affirm the Examiner’s rejection
of claims 1–4, 6–10, 12, 13, 14, 16, 17, and 21 as being obvious from Khan
and Schreder.
The Examiner’s reliance on Kun and Hanshew to address dependent
claim limitations does not address the data supporting unexpected results of
better storage stability of the levothyroxine sodium in a tablet that includes
both gelatin and citric acid than in gelatin alone. Thus, we reverse the
Examiner’s rejection of claim 15 as being obvious from Khan, Schreder, and
Kun and of claims 5, 12, and 20 as being obvious from Khan, Schreder, and
Hanshew.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
References/Basis Affirmed Reversed
1–4, 6–10,
13, 14, 16,
17, 21
103(a) Khan, Schreder 1–4, 6–10,
13, 14, 16,
17, 21
15 103(a) Khan, Schreder,
Kun
15
5, 12, 20 103(a) Khan, Schreder,
Hanshew
5, 12, 20
Overall
Outcome
1–10, 12–
17, 20, 21

REVERSED