Ex Parte Zerbe et al

Patent Trial and Appeal Board

Feb 21, 2019

12963132 (P.T.A.B. Feb. 21, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/963,132 12/08/2010
35684 7590
BUTZEL LONG, P.C.
IP DEPARTMENT
41000 Woodward A venue
Stoneridge West
Bloomfield Hills, MI 48304
02/25/2019
FIRST NAMED INVENTOR
Horst Zerbe
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
Intelgenx 143939-8 2242
EXAMINER
TOWNSLEY, SARA ELIZABETH
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
02/25/2019 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):
PA TENT@BUTZEL.COM
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HORST ZERBE, NADINE P AIEMENT, ANGELA ANGUS TI,
and CORMAC LONG 1
Appeal 2018-000638
Application 12/963, 132
Technology Center 1600
Before TA WEN CHANG, JOHN E. SCHNEIDER, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
SCHNEIDER, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal2 under 35 U.S.C. § 134 from the Examiner's
rejection of a claim to a method for administering an active agent which
have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b ).
We AFFIRM.
1 Appellants identify the Real Party in Interest as Intelgenx Corporation. Br.
3.
2 We have considered and herein refer to the Specification of Dec. 8, 2010
("Spec."); Final Office Action of June 16, 2016 ("Final Act."); Advisory
Action of Aug. 22, 2016 ("Advisory Act."); Appeal Brief of Nov. 10, 2016
("Appeal Br."); Examiner's Answer of Aug. 25, 2017 ("Ans."); and Reply
Brief filed Oct. 24, 2017 ("Reply Br.").
Appeal 2018-00063 8
Application 12/963, 132
STATEMENT OF THE CASE
Oral films are a solid oral dosage form that permits the administration
of a pharmaceutical, nutritional and/or cosmetic ingredient without water.
Spec. ,r 3. It is often used to ensure compliance for patients who have
difficulty swallowing oral drugs. Id. Oral films are formulated to "exhibit
instant hydration followed by a rapid dissolution/disintegration upon
administration into the oral cavity." Spec. ,r 4. The Specification describes
an oral film for delivery of pharmaceutical, nutraceutical, or cosmetic
ingredients. Spec. ,r 12.
Claim 42 is on appeal and reads as follows:
42. A method of administering a therapeutically effective
amount of at least one active ingredient present as an effectively
stabilized plurality of particles in an oral film dosage form,
compnsmg:
disposing a pharmaceutically active ingredient in the
form of particles that is capable of existing in both amorphous
and crystalline forms into a suitable liquid medium containing
at least one primary crystallization inhibitor present in an
amount that inhibits growth and/or agglomeration of the
particles of the pharmaceutically active ingredient, at least one
liquid crystallization inhibitor selected from glyceryl
monooleate and propylene glycol caprylate, and present in an
amount that enhances inhibition of crystallization and/or
agglomeration of the particles of the pharmaceutically active
ingredient, and at least one plasticizer present in an amount that
is effective to increase flexibility and elasticity of the film
dosage form;
casting and drying the composition to make a solid oral
dosage form;
applying the dosage form in a subject's mouth and
having the subject maintain the dosage form in the subject's
mouth until an effective quantity of the dosage form has
dissolved, whereby a therapeutic effect is achieved.
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Application 12/963, 132
Claims 42 has been rejected under 35 U.S.C. § I03(a) as unpatentable
over Bangalore3 as evidenced by Sajja4 and in view of Scott5 and Strickley. 6
DISCUSSION
Issue
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner's conclusion that the subject matter of
the claims would have been obvious over Bangalore combined with Scott
and Strickley.
The Examiner finds that Bangalore teaches "flexible, edible, polymer-
based oral film dosage forms containing one of three active agents for
treating erectile dysfunction, including the elected active agent, tadalafil."
Final Act. 2. The Examiner finds that Sajja teaches that tadalafil exists in
both amorphous and crystalline forms. Id.
3 Bangalore, US 2009/0047330 Al, published Feb. 19, 2009 ("Bangalore").
4 Sajja et al., US 2009/0131667 Al, published May 21, 2009 ("Sajja").
5 Scott et al., US 6,887,307 Bl, issued May 3, 2005 ("Scott").
6 R. Strickley, Solubilizing Excipients in Oral and Injectable Formulations,
21 Pharmaceutical Res. 201 (2004) ("Strickley"). While the Examiner has
not cited Strickely as part of the formal rejection of claims 42, it is clear
from the Advisory Action and the Examiner's Answer that the Examiner
relies on Strickley to support the rejection. Advisory Act. 2; Ans. 7 and 9-
10. In addition. Appellants have presented substantive arguments regarding
the teachings of Strickely. Appeal Br. 12-13; Reply Br. 5-6. To avoid
piecemeal examination, we elect to treat the rejection as including Strickley.
See MPEP § 707 .07 (g) ("Piecemeal examination should be avoided as much
as possible.")
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Application 12/963, 132
The Examiner finds that Bangalore teaches the use of emulsifiers such
as TWEEN® 80 (also known as polysorbate 80), a polyoxyethylene sorbitan
fatty ester. Final Act. 8. The Examiner finds that the present Specification
teaches that polyoxyethylene sorbitan fatty esters act as crystallization
inhibitors. Id. The Examiner finds that the amounts of TWEEN® 80 taught
in Bangalore overlap with the range taught in the present Specification as the
amount needed to inhibit crystallization. Id. The Examiner finds that use of
TWEEN® 80 in the films of Bangalore would inherently inhibit
crystallization of tadalafil. Id.
The Examiner finds that while Bangalore does not disclose the use of
glyceryl monooleate, Scott teaches that both glyceryl monooleate and
polyoxyethylene sorbitan esters can act as surfactants in pharmaceutical
compositions. Id. The Examiner finds that Strickley teaches that both
polysorbate 80 and glyceryl monooleate are solubilizing excipients used in
oral pharmaceutical compositions. Advisory Act. 2, Ans. 7.
The Examiner concludes
it would have been prima facie obvious to one of ordinary skill
in the art at the time the invention was made to substitute
polysorbates as the emulsifier or surfactant in the compositions
of Bangalore with glyceryl monooleate, as taught by Scott et
al., with a reasonable expectation of success, because, as
recognized by MPEP §2144.06, it is primafacie obvious to
substitute art-recognized equivalents, and an express suggestion
to substitute one equivalent component or process for another is
not necessary to render such substitution obvious.
Final Act. 9 ( emphasis in the original); see also Ans. 7-8.
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Principles of Law
[T]he examiner bears the initial burden, on review of the
prior art or on any other ground, of presenting a prima facie
case ofunpatentability. If that burden is met, the burden of
coming forward with evidence or argument shifts to the
applicant.
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
"[W]hen a patent claims a structure already known in the prior art that
is altered by the mere substitution of one element for another known in the
field, the combination must do more than yield a predictable result." KSR
Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007), citing United States v.
Adams, 383 U.S. 39, 50-51 (1966).
"In determining whether the subject matter of a patent claim is
obvious, neither the particular motivation nor the avowed purpose of the
patentee controls. . . . [ A ]ny need or problem known in the field of endeavor
at the time of invention and addressed by the patent can provide a reason for
combining the elements in the manner claimed." Id. at 419--20
"[F]amiliar items may have obvious uses beyond their primary
purposes, and in many cases a person of ordinary skill will be able to fit the
teachings of multiple patents together like pieces of a puzzle." Id.
"The consistent criterion for determination of obviousness is whether
the prior art would have suggested to one of ordinary skill in the art that this
process should be carried out and would have a reasonable likelihood of
success, viewed in the light of the prior art. Both the suggestion and the
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Appeal 2018-00063 8
Application 12/963, 132
expectation of success must be founded in the prior art, not in the applicant's
disclosure." In re Dow Chemical Co., 837 F.2d 469, 473 (Fed. Cir. 1988)
( citations omitted).
"Obviousness does not require absolute predictability of success ....
For obviousness under§ 103, all that is required is a reasonable expectation
of success." In re O 'Farrell, 853 F.2d 894, 903---04 (Fed. Cir. 1988).
"Where ... the claimed and prior art products are identical or
substantially identical ... the PTO can require an 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." In re Best, 562 F.2d 1252, 1255 (CCPA 1977)
( citations and footnote omitted).
Analysis
We adopt the Examiner's findings of fact, reasoning on scope and
content of the prior art, and conclusions set out in the Final Action and
Answer regarding this rejection. Final Act. 3-9; Ans. 2-8. We find the
Examiner has established that the subject matter recited by claim 42 would
have been obvious to one of ordinary skill in the art at the time the invention
was made over Bangalore combined with Scott and Strickley. Appellants
have not produced evidence showing, or persuasively argued, that the
Examiner's determinations on obviousness are incorrect. Only those
arguments timely made by Appellants in the Briefs have been considered in
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Application 12/963, 132
this Decision. Arguments not presented in the Briefs are waived. See 37
C.F.R. § 4I.37(c)(l)(iv) (2015). We address Appellants' arguments below.
Appellants contend that the references do not teach or suggest a
method which employs an oral film containing a crystallization inhibitor
selected from either glyceryl monooleate or propylene glycol caprylate.
Appeal Br. 7. Appellants contend that one skilled in the art would not have
a reasonable expectation that polysorbate 80 and glyceryl monooleate would
perform the same in the films of Bangalore. Id. Appellants contend that
Strickley does not address this deficiency. Id.
We are not persuaded by Appellants' arguments. Bangalore teaches
that, as part of the film making process, the active agent is "either dissolved
or dispersed in water of a hydroalcoholic mixture" and then added to a
polymer solution. Bangalore ,r 46. Bangalore also teaches that in a
preferred embodiment, the films contain 0.01 % to 10% of an emulsifying
agent. Bangalore ,r 45. Bangalore also teaches the films of the invention are
designed to enhance dissolution or absorption of poorly soluble drugs at
higher concentrations. Bangalore ,r 29. We find that one skilled in the art
reading Bangalore would understand that the addition of an emulsifier would
lead to better dispersion of the active agent throughout the film and improve
dissolution. This conclusion is borne out by the examples in Bangalore.
Example 1 of Bangalore, which uses TWEEN® 80, resulted in films that
were uniform in appearance and dissolved rapidly. Bangalore ,r 54. In
example 3, cited by Appellants, TWEEN® 80 was omitted to try to improve
the film. Bangalore i-f56. The resulting films were "[s]trong and slightly
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brittle" but "dissolved slightly slower than the previous films [ containing
TWEEN® 80] in the mouth." Id.
The equivalence of polysorbate 80 and glyceryl monooleate is shown
by Scott and Strickley. Scott teaches that both glyceryl monooleate and
polyoxyethylene sorbitan sugar esters are surfactants that can be used in oral
film forming formulations. Scott col. 6, 11. 31--41. Strickley teaches that
polysorbate 80 and glyceryl monooleate are solubilizing excipients
commonly used in oral drug formulations. Strickley Table III. We agree
with the Examiner that it would have been obvious to substitute glyceryl
monooleate for polysorbate 80 as both perform as surfactants and are used as
solubilizing agents in drug compositions. Ans. 12-13. We find that one
skilled in the art would have had a reasonable expectation of success in
making the substitution in that the art teaches that the compounds exhibit
similar behavior- acting as a surfactant and solubilizing.
Appellants contend that one skilled in the art would not have had a
reasonable expectation of success in substituting glyceryl monooleate for
polysorbate 80. Appeal Br. 11. Appellants argue that the fact that Strickley
lists polysorbate 80 and glyceryl monooleate as solubilizing agents does not
mean that they are interchangeable. Appeal Br. 11-12. Appellants point to
the teachings of Strickley where a formulation containing polysorbate 80
was withdrawn from the market because the active agent tended to
recrystallize over time. Id. The drug composition was reintroduced using
different solubilizing agents. Id. Appellants argue that "all [ solubilizing]
excipients are not equivalent and that it would not be obvious to merely
substitute one for another." Id.
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Application 12/963, 132
Appellants' argument is unpersuasive. While Appellants' intended
use of the glyceryl monooleate is as a crystallization inhibitor that enhances
inhibition of crystallization and/or agglomeration, Appellants' intended use
does not preclude a finding of obviousness even if the prior art does not
teach the compound to be used for Appellants' reasons. "In determining
whether the subject matter of a patent claim is obvious, neither the particular
motivation nor the avowed purpose of the patentee controls. . . . [ A ]ny need
or problem known in the field of endeavor at the time of invention and
addressed by the patent can provide a reason for combining the elements in
the manner claimed." KSR, 550 U.S. at 419-20. In this instance, one skilled
in the art would be motivated to use glycerol monooleate in lieu of
polysorbate 80 as a dissolution enhancer. That is because Bangalore teaches
the inclusion of polysorbate 80 to improve dissolution, Bangalore ,r 29, and
Strickley teaches that both polysorbate 80 and glycerol monooleate can be
used as solubilizers for pharmaceutical products. Strickley Table III. We do
not find Strickley's discussion that an amorphous semi-solid dispersion of
ritonavir in a hard gelatin capsule formulation with polysorbate 80
recrystallized to an insoluble crystal form during storage to evidence non-
equivalence of polysorbate 80 and glycerol monooleate as solubilizers, much
less in all pharmaceutical formulations where an active ingredient is capable
of existing in both amorphous and crystalline forms. 7
7 Moreover, even regarding crystallization inhibition, Bangalore teaches a
dissolving film not a hard gelatin capsule formulation, and Appellants have
not established that a skilled artisan would understand that the ritonavir
formulation problems discussed in Strickley for a hard gelatin capsule
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Appellants point out that the present claims call for the use of a
crystallization inhibitor to prevent crystallization or agglomeration of
particles of the active agent. Appeal Br. 8. Appellants contend that the
references do not teach or suggest the inhibition of agglomeration or
crystallization. Id. Appellants argue that while Bangalore may teach using
polysorbate 80 in amounts of from 0.01 % to 10%, there is nothing in
Bangalore that would lead one skilled in the art to use the same amount of
either glyceryl monooleate or propylene glycol caprylate. Br. 9.
We have considered Appellants' argument and are unpersuaded. As
noted above, while Appellants use the recited compounds as crystallization
inhibitors, this is not controlling on the question of the obviousness to use
glyceryl monooleate or propylene glycol caprylate in the Bangalore
composition. One skilled in the art would understand Bangalore to teach
using an emulsifier such as polysorbate 80 to improve distribution of the
active agent within the film and to improve dissolution. With this purpose in
mind, we agree with the Examiner that it would have been obvious to one
skilled in the art to make the proposed emulsifier substitution. Ans. 12. The
next question is whether the emulsifier would also be "present" in the oral
film dosage form "in an amount that enhances inhibition of crystallization
and/or agglomeration of the particles of the pharmaceutically active
ingredient" as required by the claim. We conclude that the Examiner has
established a prima facie case that such would be the case in light of the
amount of an emulsifier that Bangalore teaches to be used in the oral film
formulation would be the same in such a film formulation and with a
different drug.
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dosage form. In particular, Bangalore teaches using .01 to 10% of an
emulsifier. Bangalore ,r 45. We find that this teaching in Bangalore would
suggest to one skilled in the art to use an amount of glyceryl monooleate-a
functional emulsifying equivalent of polysorbate 80, as discussed above-
falling within that range. As the Examiner points out, this range overlaps
with the range taught to be an effective amount to inhibit crystallization.
Final Act. 8; Original claim 36 ( crystallization inhibitor present in an
amount of from 1 % to 19%). "[E]ven a slight overlap in range establishes a
prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1329 (Fed.
Cir. 2003). Thus, while we agree with Appellants that none of the
references teach any specific amounts of glyceryl monooleate, we find that
the functional amount claimed to provide the enhanced inhibition would
have been obvious.
The Examiner has established that the art teaches a composition with
the same or similar components as that recited in the claims. As such one
would expect the composition taught by the art to have the same property-
crystallization inhibition - as Appellants' composition, absent evidence to
the contrary. In re Best, 562 F.2d at 1255. Here Appellants have not offered
any persuasive evidence that the composition taught by the art would not
have the same properties.
Appellants argue that Bangalore teaches that emulsifiers are not
needed and that the presence of surfactants can result in a less desirable film.
Reply Br. 4. Appellants point to the teaching in Bangalore that better films
can be produced by removing surfactants, specifically TWEEN® 80. Id.
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We are not persuaded by this argument. The paragraph cited by
Appellants reads in part: "In this formulation the surfactant Tween 80 was
removed to obtain better films. Strong and slightly brittle dissolvable films
which dissolved slightly slower than previous films in the mouth."
Bangalore ,r 56 ( emphasis added). At least one prior example that used
TWEEN® 80 (i.e., Example 1) reported that the films produced "were
uniform in appearance and able to dissolve rapidly." Id. at ,r 54. In the other
Example using TWEEN® 80, the film "dissolved instantly." Id. at ,r 55.
When the statement cited by Appellants is read in context, it is clear that
while it was expected that removing TWEEN® 80 would improve the film
properties, the results of the experiment did not actually show an
improvement over the examples using TWEEN® 80.
Conclusion of Law
We conclude that a preponderance of the evidence supports the
Examiner's conclusion that the subject matter of claim 42 would have been
obvious over Bangalore combined with Scott and Strickley.
SUMMARY
We affirm the rejection under 35 U.S.C. § 103(a).
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
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