PATHEON SOFTGELS INC

Patent Trials and Appeals Board

May 24, 2021

2020005453 (P.T.A.B. May. 24, 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.
16/012,961 06/20/2018 Nachiappan Chidambaram 215336-9003-US07 6347
149398 7590 05/24/2021
Michael Best & Friedrich LLP (Patheon)
790 N WATER ST
SUITE 2500
MILWAUKEE, WI 53202
EXAMINER
VU, JAKE MINH
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
05/24/2021 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):
beth.obrien@thermofisher.com
mkeipdocket@michaelbest.com
pair_thermofisher@firsttofile.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte NACHIAPPAN CHIDAMBARAM and
AQEEL A. FATMI
Appeal 2020-005453
Application 16/012,961
Technology Center 1600
Before JOHN G. NEW, TAWEN CHANG, 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 liquid dosage form of sodium
naproxen as being obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

1 We use the term “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as Patheon
Softgels Inc., which is wholly owned by Thermo Fisher Scientific Inc.
(Appeal Br. 3.)
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STATEMENT OF THE CASE
Soft gelatin capsules (softgels) are used to encapsulate vitamins and
pharmaceuticals in a liquid vehicle or carrier. (Spec. 1.) However, “[n]ot all
liquids may be enclosed in softgels.” (Id.) For example, “[h]ighly acidic
liquids may hydrolyze the gelatin, resulting in leaks, while basic liquids may
tan the gelatin, resulting in decreased solubility of the gelatin shell.” (Id.)
Moreover, “solvents such as propylene glycol, glycerin, low molecular
weight alcohols, ketones, acids, amines, and esters all tend to degrade or
dissolve the gelatin shell to some extent.” (Id.) And, “water tends to
dissolve the gelatin shell” so “[l]iquids containing more than about 20%
water by weight are generally not enclosed in soft gels.” (Id.)
“Suitable softgel solutions . . . must . . . have sufficient solvating
power to dissolve a large amount of the pharmaceutical agent to produce a
concentrated solution” but include solvent volumes small enough to produce
a softgel capsule that is a size that can be taken by patients, and do “not
dissolve, hydrolyze or tan the gelatin shell.” (Id. at 2.) Appellant’s
invention is directed to liquid dosage forms of sodium naproxen for softgels.
(Id.)
Claims 1–10 and 13–22 are on appeal. Claim 1, reproduced below, is
illustrative of the claimed subject matter:
1. A soft gelatin capsule comprising a fill material comprising:
(a) a naproxen salt;
(b) a deionizing agent comprising acetic acid, propionic acid,
pyruvic acid, or lactic acid in an amount of from 0.2 to 1.0 mole
equivalents per mole of naproxen salt;
(c) polyethylene glycol; and
(d) one or more solubilizers.
(Appeal Br. 24.)
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REFERENCES
The prior art relied upon by the Examiner is:
Name Reference Date
Yu et al. US 5,360,615 Nov. 1, 1994
Ulloa et al. US 2003/0216423 A1 Nov. 20, 2003
Popp US 2005/0158377 A1 July 21, 2005
Tanner et al. US 2006/0099246 A1 May 11, 2006
REJECTION
The following rejection by the Examiner is before us for review:
Claims 1–10 and 13–22 are rejected under pre-AIA 35 U.S.C.
§ 103(a) as being unpatentable over Yu, Tanner, Popp, and Ulloa.
DISCUSSION
The Examiner finds that Yu teaches enhancing the solubility of
pharmaceuticals for encapsulation in soft capsules where the pharmaceutical
composition includes “a basic pharmaceutical agent,” “0.2–1.0 mole
equivalent of hydrogen species . . . such as fumaric or citric acid,”
polyethylene glycol, and “solubilizers, such as propylene glycol and
polyvinylpyrrolidone.” (Non-Final Action 3, 4.) According to the
Examiner, “YU does not teach using a specific basic pharmaceutical drug,
such as naproxen sodium; or using a specific organic acid, such as lactic
acid.” (Id. at 3.) However, the Examiner finds that doing so would have
been obvious from the teachings of Tanner, Popp, and Ulloa. (Id. at 4–5.)
The Examiner finds that Tanner teaches encapsulated liquid
medications in soft gels like Yu, and that “the prior art had known naproxen
sodium salt (see [0067]), which is alkaline and would be a basic drug (see
abstract), wherein naproxen sodium is typically administered in place of
naproxen, which is an acidic drug (see [0067]).” (Id. at 4.) The Examiner
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further finds that Tanner teaches “[t]he typical formulation for naproxen
sodium is disclosed with water and polyethylene glycol in Table XIV (see
[0068]).” (Id.)
The Examiner relies on Popp as teaching that fumaric and lactic acid
were known organic acids that “are functional equivalents,” and Ulloa for
the teaching that naproxen was known in the art to treat pain. (Id. at 4–5.)
The Examiner concludes that, in view of the foregoing references, it
would have been obvious to one having ordinary skill in the art to include
“naproxen sodium as the basic pharmaceutical in YU’s composition” as well
as use lactic acid, instead of fumaric acid, and include a solubilizer “as
taught by YU.” (Id. at 4.) According to the Examiner, one would have been
motivated to do so “because it would enhance the solubility of the naproxen
sodium salt to further prevent precipitation or allow a higher drug dosage if
needed.” (Id.)
We do not agree with the Examiner’s conclusion of obviousness for
the reasons that follow.
Yu teaches that naproxen is an acidic pharmaceutical agent, and that
“the present solvent system enhances the solubility of acidic pharmaceutical
agents in polyethylene glycol by increasing the number of species of the
acidic agent (ionized and unionized) that are available to go into solution
and by providing adequate solvation for each species.” (7:1–6.) Yu teaches
that polyethylene glycol has both hydrophobic and hydrophilic binding sites
and that solubility of acidic pharmaceutical agents is increased when
nonionized species are present as well as ionized species because both
binding sites of polyethylene glycol are used. (Id. at 7:6–10.) Thus,
hydroxide ion is added to the free acid agent to ensure deprotonation of the
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acidic drug such that an ionized species of naproxen (i.e., the free acid) is
present along with a nonionized species (i.e., the deprotonated free acid) to
take full advantage of the hydrophobic and hydrophilic binding sites of the
polyethylene glycol. (Id. at 7:16–26.) The Declaration of Dr. Kaspar van
den Dries2 supports the foregoing. (Van den Dries Declaration ¶¶ 12, 14.)
It is true that Yu teaches a similar concept for basic pharmaceutical
agents. (Id. at 9:35–46; Van den Dries Declaration ¶ 17.) However, Yu
refers not to salts of pharmaceutical agents that are basic agents, but to an
agent that is basic in its ionized form. (See, e.g., Yu at 9–10 (describing the
invention with respect to thioridazine, cimetidine); Van den Dries
Declaration ¶ 17.)
As Dr. van den Dries explains, Yu’s “general formulation concept” is
to neutralize an acidic pharmaceutical agent or a basic pharmaceutical agent
to create the pharmaceutical salt, which salt is a deprotonated form of the
free acid, i.e., neutralized, and thus is nonionic. (Id. ¶ 17.)
Yu explains that one can add the salt of the pharmaceutical agent
directly to the free pharmaceutical agent and “[i]n this way, the use of
ionizing agents such as hydroxide or hydrogen ion to produce the desired
ratio of ionization (neutralization) of the pharmaceutical is avoided or
minimized.” (Yu 10: 39–48.)
In view of these teachings of Yu, we do not agree with the Examiner
that one of ordinary skill in the art would have added naproxen sodium to

2 Declaration of Dr. Kaspar van den Dries dated August 7, 2019. (Van den
Dries Declaration at 9.) Dr. van den Dries is the “Senior Director of Science
and Innovation, Softgels, Patheon Softgels Inc., a subsidiary of
ThermoFisher Scientific Inc.” (Id. ¶ 4.)
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the Yu composition and would have also included an acid “in an amount of
from 0.2 to 1.0 mole equivalents per mole of naproxen salt” as required by
Appellant’s claim 1. As Dr. van den Dries explains, doing so would be
“completely contradictory” to Yu because it would shift the salt form, which
Yu teaches to form in order to balance the ionized naproxen free acid, from
the salt form back to the protonated state, thereby upsetting the balance and
creating more naproxen free acid, which is much less soluble than the ionic
salt form. (Van den Dries Declaration ¶ 17.)
This is true even in light of the Yu’s Example VIII, which is a
composition of diclofenac sodium that includes hydrochloric acid (Yu
12:30–45), which the Examiner suggest supports the conclusion that Yu
suggests inclusion of an acid in combination with a basic salt pharmaceutical
agent. (Non-final Action 18.) According to the Examiner, “Yu teaches the
solubility can be increased further even for basic salt compounds, such as
diclofenac sodium . . . using hydrogen ions from HCl.” (See Appeal Br. 16
(referring to a prior Final Office Action dated April 24, 2019).) We disagree
with the Examiner’s interpretation of Yu. As Appellant notes (Appeal Br.
16), Yu does not state that the hydrogen ions further increased the solubility
of diclofenac sodium. There is no comparison in Yu to a diclofenac free
acid formulation or to a diclofenac sodium composition without HCl; rather,
there is simply an indication that the formulation made with the sodium
diclofenac, polyethylene glycol, water, and HCl had 20% by weight
concentration of diclofenac. (Yu 12:35; Appeal. Br. 16.)
Furthermore, as Dr. Van den Dries explained “naproxen sodium is
already highly soluble in aqueous and PEG solutions.” (Van den Dries
Declaration ¶ 20.) Dr. Van den Dries notes that “[n]aproxen sodium has a
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solubility of 108 mM whereas “naproxen free acid has a water solubility of
69 μM. (Id. ¶ 19.) As Appellant notes, Yu discloses a formulation of
naproxen free acid, potassium hydroxide, and polyethylene glycol 600 that
has a 35.9% by weight concentration of naproxen. (Appeal Br. 17 (citing
Yu 11:42–54 (Example IV)).) In addition, Dr. Van den Dries explains that
naproxen sodium is twice as soluble as sodium diclofenac. (Id. ¶ 19.) Thus,
even if it might be the case that HCl assisted in further solubilizing sodium
diclofenac (which the current evidence of record does not suggest is the
case), given the fact that naproxen and naproxen sodium have a significantly
different solubility in water than diclofenac and diclofenac sodium and a
significantly different chemical structure, there does not appear to be a
reason suggested by Yu or any of the other cited references why it would be
reasonable to add HCl to a fill formulation for a softgel that includes
naproxen sodium.
And even beyond that, as Appellant further explains regarding the
claimed use of a weak acid as the “deionizing agent,” such as lactic acid:
Strong acids like HCl are fully ionized (deprotonated) in
solution, whereas weak acids do not completely ionize
(deprotonate) in solution. Therefore, the purported effect [by
the Examiner] of HCl on the solubility of diclofenac sodium,
which is minimal (~4% as calculated by Appellant), is entirely
incongruent with the potential and unknown effect of an
organic acid on the solubility of naproxen sodium.
(Reply Br. 9.)3

3 We note that the about 4% increase calculation arises from the difference
between Yu’s identification of a 20% by weight concentrated composition
compared to diclofenac sodium solubility in water of 15.91 mg/ml (e.g.,
about 15% by weight). (See Van den Dries Declaration ¶ 19 (noting the
“Sodium salt [of diclofenac free acid] solubility: 15.91 mg/ml (54 mM)”).)
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In view of all of the foregoing, we find that one of ordinary skill in the
art would not have found it obvious to have made softgel fill composition
that includes sodium naproxen and a weak acid such as lactic acid in the
mole equivalent range claimed based on the teachings of Yu example VIII
with a reasonable expectation of success.
We conclude the foregoing is true even considering the teachings of
the remaining prior art the Examiner relied upon.
Tanner simply teaches that naproxen is a free acid that is typically
administered as naproxen sodium salt, and describes a fill formulation for
use in a soft gel that includes naproxen sodium water and polyethylene
glycol. (Tanner ¶¶ 66–68.) Tanner does not in any way suggest adding an
acid to a naproxen salt formulation.
Popp teaches that lactic acid is interchangeably used with fumaric acid
in forming salts of active compounds. (Popp ¶ 58) That fact provides no
suggestion to combine lactic acid (or fumaric acid for that matter) with a
naproxen salt for any reason. Ulloa is of no consequence on the issue of the
obviousness of including an acid in combination with a naproxen salt, as it
merely mentions that naproxen can be added to pharmaceutical formulations
of a non-sedating antihistamine combined with a nasal decongestant in order
to address pain relief. (Ulloa ¶ 157, Abstract.)
Thus, for the foregoing reasons, we do not affirm the Examiner’s
rejection of claim 1 as being obvious from Yu, Tanner, Popp, and Ulloa.
For the same reasons, we also do not affirm the Examiner’s rejection of
independent claim 13 as being obvious from Yu, Tanner, Popp, and Ulloa,
which claim requires naproxen sodium rather than simply a naproxen salt as
in claim 1, as well as specifying particular solubilizers. The remaining
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claims are dependent claims on either claim 1 or claim 13. Thus, we do not
affirm the Examiner’s rejection of those claims as being obvious from Yu,
Tanner, Popp, and Ulloa. In re Fine, 837 F.2d 1071, 1076 (Fed. Cir. 1988)
(“Dependent claims are nonobvious under section 103 if the independent
claims from which they depend are nonobvious.”).
DECISION SUMMARY
Claim(s)
Rejected
35
U.S.C. §
Reference(s)/Basis Affirmed Reversed
1–10, 13–22 103(a) Yu, Tanner, Popp,
Ulloa
1–10, 13–22

REVERSED