Biohaven Pharmaceutical Holding Company Limited (B

Patent Trials and Appeals Board

Oct 20, 2021

2021000716 (P.T.A.B. Oct. 20, 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.
15/100,160 05/27/2016 Vladimir Coric 1511731.102US9 1069
164621 7590 10/20/2021
Biohaven Pharmaceuticals, Inc.
215 Church Street
New Haven, CT 06510
EXAMINER
CRUZ, KATHRIEN ANN
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
10/20/2021 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):
dmitry.zuev@biohavenpharma.com
patents@biohavenpharma.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte VLADIMIR CORIC, ROBERT BERMAN,
RONALD S. VLADYKA, AMGAD SALEH, and DANNY YU

Appeal 2021-000716
Application 15/100,160
Technology Center 1600
____________

Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
ULRIKE W. JENKS, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
The Examiner rejected claims 1–3, 5, and 42–54 under 35 U.S.C.
§ 103 as obvious. Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from
the Examiner’s decision to reject the claims. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE and set forth a new ground of rejection.

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 Biohaven
Pharmaceutical Holding Company Ltd. Appeal Br. 3.
Appeal 2021-000716
Application 15/100,160

2
STATEMENT OF THE CASE
The Examiner rejected claims 1–3, 5, and 42–54 in the Final Action as
follows:
Claims 1–3, 42–47, and 49–54 under 35 U.S.C. § 103 as obvious in
view of Artico et al. (US 8,765,150 B2, issued July 1, 2014) (“Artico”),
Aubourg et al. (US 6,432,992 B1, issued Aug. 13, 2002) (“Aubourg”),
Yarwood et al. (US 5,837,287, issued Nov. 17, 1998) (“Yarwood”), and
Staniforth (US 2010/0159007 A1, published June 24, 2010) (“Staniforth”).
Ans. 4.
Claims 5 and 48 under 35 U.S.C. § 103 as obvious in view of Artico,
Aubourg, Yarwood, Staniforth, and Jager et al. (US 2002/0025366 A1,
published Feb. 28, 2002) (“Jager”). Ans. 8–9.
Claim 1 is representative and copied below (annotations added for
reference to the specific components of the claimed formulation):
1. A sublingual formulation in the form of a lyophilized,
tableted pharmaceutical composition that provides sublingual
absorption of riluzole comprising [1] a pharmaceutically
effective amount of riluzole or a pharmaceutically acceptable
salt thereof, said formulation further comprising [2] gelatin as a
tablet binder, [3] mannitol or sorbitol as a bulking agent, and
[4] docusate sodium as a solubilizing agent.

CLAIM 1
Claim 1 is directed to a “lyophilized, tableted pharmaceutical
composition” comprising: (1) a pharmaceutically effective amount of
riluzole or a pharmaceutically acceptable salt thereof; (2) gelatin as a tablet
binder; (3) mannitol or sorbitol as a bulking agent; and (4) docusate sodium
as a solubilizing agent.
Appeal 2021-000716
Application 15/100,160

3
The tablet formulation is recited in the claim to provide for sublingual
absorption of riluzole. We interpret this limitation as an intended use of the
tablet. There is no requirement in the claim that the tablet is used for
sublingual absorption of riluzole because the claim is directed to the
formulation, and not a method of administering it. Thus, the prior art
references do not have to disclose administering the claimed formulation;
instead, the claim limitation is met if the prior art discloses or suggests a
formulation that is capable of sublingual absorption when administered.
Each of components (2), (3), and (4) are stated in terms of their
function in the tablet, namely, as a tablet binder, as a bulking agent, and as a
solubilizing agent, respectively. These ingredients, with their associated
functions, appear to be conventional components of a pharmaceutical
composition. See Spec. 14:10–15:20. The cited prior art references do not
have to describe the components as having the recited function of a tablet
binder, bulking agent, and solubilizing agent, but these components must be
included in the tablet in such a way that they perform the recited function
when present in the tablet.
According to the Specification, riluzole is a neuropsychiatric drug
used for the treatment of amyotrophic lateral sclerosis (“ALS”). Spec. 1:12–
17. The Specification discloses that riluzole “has a very low solubility in
water, poor oral palatability, pH dependent chemical stability, and intense as
well as persistent numbness or burning sensation throughout the oral cavity.”
Spec. 1:26–28. The claimed riluzole formulation is described as addressing
these disadvantages. Spec. 3:27–30

Appeal 2021-000716
Application 15/100,160

4
REJECTIONS
The Examiner made the following findings with regard to the cited
prior art references. The numbers in parentheses refer to components (1) to
(4) of claim 1 as we have numbered them.
1. Artico discloses that (1) riluzole has a very low solubility in water.
Ans. 4.
2. Artico describes (4) docusate sodium as a preferred solubilizing
agent for riluzole. Ans. 4.
3. Aubourg describes an oral composition of (1) riluzole, (2) gelatin,
and (3) mannitol. Ans. 4–5.
4. Yarwood describes a composition comprising “domperidone free
base (which less soluble than domperidone maleate),” (2) gelatin, (3)
mannitol, aspartame, and peppermint” Ans. 5 (citing Example 2 of
Yarwood).
5. Staniforth describes a transmucosal composition “comprising
submicron particles comprising the active agent, wherein the active agent is
sparingly soluble or insoluble in water (e.g[.] low solubility).” Ans. 5.
6. Staniforth discloses that “the submicron particles of active agent are
embedded in one or more larger particles of inert material, the inert material
rapidly dissolves once it is wetted in the buccal cavity, thereby releasing
individual (0049).” Ans. 5–6.
7. Staniforth discloses riluzole in its composition. Ans. 6.
Based on these findings, the Examiner states it would have been
obvious to one of ordinary skill in the art to formulate a composition of (1)
riluzole, (2) gelatin, (3) mannitol, and (4) sodium docusate in a sublingual
tablet “because all are known in the art for the composition consisting of
Appeal 2021-000716
Application 15/100,160

5
riluzole with a binder (gelatin), mannitol,” sodium docusate as taught by
Artico and Aubourg. and “it is also known in the art that sublingual tablet
provides enhance transmucosal absorption into the systemic circulation and
any desired subsequent absorption into the CNS as taught by Staniforth with
a reasonable expectation of success.” Ans. 6.

Discussion
We begin with Yarwood. Yarwood, as found by the Examiner,
describes two examples of a rapidly disintegrating tablet comprising both (2)
gelatin and (3) mannitol, the same two ingredients required by claim 1.
Yarwood 5–6. The tablets contain loperamide and domperidone,
respectively. Id. Staniforth provides evidence that a rapidly disintegrating
tablet would at least show some transmucosal absorption and therefore be
capable of sublingual absorption.2
Yarwood, however, does not disclose (1) riluzole. But the Examiner
found it obvious to include it in Yarwood’s tablet.
Yarwood discloses that its “oral solid rapidly disintegrating dosage
form” is for “a pharmaceutically active substance which has an unacceptable
taste which does not only depend upon trying to mask the unacceptable taste
by the use of sweetening agents, flavouring agents and the like.” Yarwood

2 Staniforth ¶ 12: “Fast disintegrating systems such as those from tablets,
chewable tablets, wafers and the like have been developed, but these do not
provide optimal transmucosal absorption of the active agent because such
compositions are usually wetted substantially prior to contact with the oral
mucosal surfaces, thereby preventing efficient adhesion of the composition
and/or active agent to the mucosa and allowing a significant proportion of
the active agent to be swallowed.”
Appeal 2021-000716
Application 15/100,160

6
1:54–59. Loperamide and domperidone are disclosed as “pharmaceutically
active substances which have an unacceptable taste.” Id. at 4:42–55.
Appellant argues that Yarwood addresses the problem of drugs with
an unacceptable taste, but riluzole is not identified in Yarwood as a drug
having this property. Appeal Br. 7.
The Examiner responds that Yarwood is cited “to demonstrate that
gelatin, mannitol, aspartame and peppermint and freeze drying is known in
the art and that it would have been obvious to employ a known method of
preparing freeze dried composition to arrive at the instantly claimed
composition.” Ans. 10. The Examiner also states that “both riluzole and
domperidone have low solubility and the composition of Yarwood teaches
that the same inactive agents [with low solubility] are effective in freeze
drying in tablets with a reasonable expectation of success.” Ans. 11.
We agree with Appellant that the Examiner did not provide an
adequate reason to have used riluzole in Yarwood’s tablet.
As explained by Appellant, Yarwood does not teach an orally
disintegrating dosage form of a low solubility drug. Instead, Yarwood
discloses that “[t]he pharmaceutically active substance with [an]
unacceptable taste may be rendered less soluble by conversion of a salt to a
free acid or a free base, changing the salt form” (emphasis added). Yarwood
2:53–55. Thus, while Yarwood describes making a drug less soluble by
converting it to a free acid or free base, the drug itself is a drug with “an
unacceptable taste.” Id. The Examiner did not provide evidence that riluzole
is a drug with an unacceptable taste that would benefit from Yarwood’s
process.
Appeal 2021-000716
Application 15/100,160

7
The Examiner attempts to rehabilitate the rejection by stating that
Yarwood is only relied upon to show that gelatin and mannitol are used to
prepare freeze dried compositions. Ans. 10, 11, 15, 22. However, the
difficulty with this argument is that Yarwood’s description of a tablet
comprising gelatin and mannitol is for a pharmaceutical compound with an
unacceptable taste and the Examiner did not provide evidence that riluzole is
such a drug.
Because Yarwood is deficient, we turn to the remaining references
cited by the Examiner. The Examiner cited Aubourg’s disclosure of a tablet
containing riluzole and mannitol, providing a reason to have used mannitol
in a tablet comprising riluzole. Aubourg 5:45–60 (Example 2, Example A).
However, the Examiner’s reason to provide gelatin in a tablet is missing.
The Examiner cited three references as evidence of the obviousness of
using gelatin in a tablet. The first reference, Yarwood, we have already
explained is deficient because the gelatin is used as part of a tablet for drugs
which have an unacceptable taste. The second reference cited by the
Examiner is Aubourg. Ans. 4–5. However, as acknowledged by the
Examiner, the gelatin described by Aubourg is for a capsule that surrounds a
pharmaceutical composition. Aubourg 2:65–67; 5:65–66. Likewise, the third
reference, Artico, discloses a riluzole-based formulation in a hard gelatin
capsule. Artico 1:43–46. The Examiner has ignored the explicit limitation in
claim 1 that the gelatin is a “tablet binder” and therefore must be part of the
tablet, itself, not a coating that surrounds the pharmaceutical composition.
Neither Aubourg nor Artico provide gelatin as a tablet binder. The Examiner
therefore did not provide sufficient evidence that gelatin would be routinely
Appeal 2021-000716
Application 15/100,160

8
incorporated into a tablet, along with other conventional pharmaceutical
ingredients.
Staniforth is directed to a transmucosal composition, which contains a
long list of drugs that can be included in it, including riluzole. Staniforth
¶¶ 1, 67. But Staniforth does not describe either mannitol or gelatin in its
composition. The Examiner did not provide sufficient evidence of the
obvious of incorporating gelatin into Staniforth’s transmucosal composition.
The additionally cited Jager reference does not make up for the
deficiency in the rejection.
Because the Examiner did not meet the burden of establishing the
prima facie obviousness of the claimed formulation comprising gelatin,
mannitol, and docusate, we are constrained on this record to reverse the
rejections of claim 1 and claims 2, 3, 5, and 42–54, each of which require
mannitol and gelatin the pharmaceutical formulation.

NEW GROUND OF REJECTION
The rejection based on Artico, Aubourg, Yarwood, and Staniforth is
deficient because the evidence was insufficient to establish the obviousness
of providing gelatin in a tablet comprising riluzole. However, as explained in
more detail below, we find that Jones,3 a newly cited publication, teaches
that it was known prior to the application’s effective filing date that both
gelatin and mannitol were conventional constituents of an oral disintegrating

3 Jones et al., The Influence of Formulation and Manufacturing Process
Parameters on the Characteristics of Lyophilized Orally Disintegrating
Tablets, 3 Pharmaceutics 440–457 (2011). A copy of the reference is being
mailed with the Decision.
Appeal 2021-000716
Application 15/100,160

9
tablet. Consequently, pursuant to 37 C.F.R. § 41.50(b), a new ground of
rejection of claim 1 is set forth as follows:
Claim 1 is rejected under 35 U.S.C. § 103 as obvious in view of Jones,
Artico, Aubourg, and Staniforth.

Findings of Fact (“FF”)
The following findings of fact are pertinent to the rejection:
FF1. Staniforth describes compositions for transmucosal
administration. Staniforth ¶ 1. Staniforth describes the advantages of the
compositions:
the compositions enabling rapid and efficient uptake of a
therapeutically active agent to provide a rapid, effectively
durable, predictable and consistent therapeutic effect. In
particular, the compositions are intended for buccal and/or
sublingual delivery of the active agent. The invention is
particularly suitable for administering therapeutically active
agents which have an effect on the central nervous system and
even more particularly where rapid onset of this effect is
desired or beneficial. The invention is also particularly suitable
for administering active agents in low solubility base or acid
forms.
Staniforth ¶ 1.
FF2. Staniforth provides evidence that rapidly disintegrating tablets
would at least show some transmucosal absorption and therefore be capable
of sublingual absorption. Staniforth ¶ 12.
FF3. Riluzole is among a list of drugs disclosed by Staniforth that
would benefit from transmucosal absorption. Staniforth ¶ 67.
FF4. Artico describes oral riluzole for treatment of various diseases,
including ALS. Artico 1:15–27, 60–67.
Appeal 2021-000716
Application 15/100,160

10
FF5. Artico discloses that sodium docusate is an ionic surfactant used
in making stable riluzole compositions, the latter which has low solubility in
water. Artico 4:25–31; 1:58–60.
FF6. Jones discloses that orally disintegrating tablets (“ODT”) are
useful “for groups of the population who commonly have difficulty in
swallowing conventional solid dosage forms (e.g. conventional tablets and
capsules).” Jones 441.
FF7. Jones discloses that “ODTs manufactured using freeze-drying
have been the most successful commercially.” Jones 441.
FF8. Jones discloses that “[g]elatin and mannitol are both excipients
which are used in the formulation of freeze-dried ODTs.” Jones 441; see
also Jones 442 (“Gelatin was dissolved in double-distilled water at about
40°C, followed by the addition of mannitol to form a solution.”).
FF9. Aubourg discloses an oral tablet containing riluzole and
mannitol. Aubourg 5:45–60 (Example 2, Example A).
FF10. The Specification discloses that methods for preparing ODTs
were known in the art at the time of the invention, including “lyophilisation
by flash freezing and freeze drying.” Spec. 15:6–20.

Rejection
Artico and Aubourg describe orally administered riluzole, a drug used
to treat ALS and other disorders. FF4, FF9. Staniforth describes the
advantages of oral compositions for transmucosal administration, including
for sublingual administration. FF1. Staniforth discloses that an orally
disintegrating tablet would provide some transmucosal absorption. FF2.
Riluzole is among a list of drugs disclosed by Staniforth that would benefit
Appeal 2021-000716
Application 15/100,160

11
from transmucosal absorption. FF3. Jones also discloses the advantages of
orally disintegrating tablets. FF6. Thus, it would have been obvious to one of
ordinary skill in the art to formulate riluzole in an orally disintegrating tablet
for the advantages described by Staniforth and Jones.
Jones specifically discloses that gelatin and mannitol are used in
freeze-dried ODTs (FF8), providing an express reason for one of ordinary
skill in the art before the effective date of the application to have formulated
these components in combination with riluzole when preparing riluzole as an
oral pharmaceutical formulation. Jones establishes that these are predictable
and equivalent excipients and an “[e]xpress suggestion to substitute one
equivalent for another need not be present to render such substitution
obvious.” In re Fout, 675 F.2d 297, 301 (CCPA 1982). “If a person of
ordinary skill can implement a predictable variation, § 103 likely bars its
patentability.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007).
Aubourg also teaches mannitol in tablet form with riluzole, providing
an additional reason to have used it in Jones’s ODT. FF9.
With regard to the sodium docusate, Artico describes it as a useful
surfactant in oral formulations (FF5), a fact not challenged by Appellant in
the Appeal Brief.
It would have been reasonably expected that incorporating riluzole in
Jones’s ODT comprising gelatin and mannitol would be capable of
sublingual absorption because the same ingredients described by Jones are
also present in the claimed formulation. As held in In re Best, 562 F.2d 1252
(CCPA 1977):
Where, as here, the claimed and prior art products are identical
or substantially identical, or are produced by identical or
substantially identical processes, the PTO can require an
Appeal 2021-000716
Application 15/100,160

12
applicant to prove that the prior art products do not necessarily
or inherently possess the characteristics of his claimed product.
Whether the rejection is based on “inherency” under 35 U.S.C.
§ 102, on “prima facie obviousness” under 35 U.S.C. § 103,
jointly or alternatively, the burden of proof is the same, and its
fairness is evidenced by the PTO’s inability to manufacture
products or to obtain and compare prior art products.
Id. at 1255 (footnote omitted) (citation omitted).
For the foregoing reasons, a new ground of rejection of claim 1 is
made under the provisions of 37 C.F.R. § 41.50(b).
We have not reviewed the remaining claims 2, 3, 5, and 42–54 to
determine whether these claims are obvious over the combination of Jones,
Artico, Aubourg, Yarwood, Staniforth, Jager or other prior art references.
We leave it to the Examiner to determine the appropriateness of any further
rejections based on these or other references. Our decision not to enter a new
ground of rejection for claims 2, 3, 5, and 42–54 should not be considered as
an indication of the appropriateness of a further rejection or allowance of
these claims.
Appeal 2021-000716
Application 15/100,160

13

CONCLUSION
In summary:
Claim(s)
Rejected
35
U.S.C.
§
Reference(s)/Basis Affirmed Reversed New
Ground
1–3, 42–
47, 49–
54
103 Artico, Aubourg,
Yarwood,
Staniforth
1–3, 42–
47, 49–54

5, 48 103 Artico, Aubourg,
Yarwood,
Staniforth, Jager
5, 48
1 103 Jones, Artico,
Aubourg,
Staniforth
1
Overall
Outcome
1–3, 5,
42–54
1

TIME PERIOD FOR RESPONSE
This decision contains a new ground of rejection pursuant to
37 C.F.R. § 41.50(b). Section 41.50(b) provides “[a] new ground of rejection
pursuant to this paragraph shall not be considered final for judicial review.”
Section 41.50(b) also provides:
When the Board enters such a non-final decision, the appellant,
within two months from the date of the decision, must exercise
one of the following two options with respect to the new ground
of rejection to avoid termination of the appeal as to the rejected
claims:
(1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence relating
to the claims so rejected, or both, and have the matter
reconsidered by the examiner, in which event the prosecution
will be remanded to the examiner. The new ground of rejection
is binding upon the examiner unless an amendment or new
Appeal 2021-000716
Application 15/100,160

14
Evidence not previously of Record is made which, in the
opinion of the examiner, overcomes the new ground of rejection
designated in the decision. Should the examiner reject the
claims, appellant may again appeal to the Board pursuant to this
subpart.
(2) Request rehearing. Request that the proceeding be
reheard under §41.52 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.
Further guidance on responding to a new ground of rejection can be
found in the Manual of Patent Examining Procedure § 1214.01 (9th Ed., Rev.
10.2019, June 2020).
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv) (2019).

REVERSED; 37 C.F.R. § 41.50(b)