Ex Parte Wilhelm et al

Patent Trial and Appeal Board

Sep 11, 2018

14061578 (P.T.A.B. Sep. 11, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/061,578 10/23/2013 Rudolf Wilhelm
31496 7590 09/13/2018
SMITH PA TENT
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
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EXAMINER
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ART UNIT PAPER NUMBER
1616
NOTIFICATION DATE DELIVERY MODE
09/13/2018 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
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte RUDOLF WILHELM and MARKUS PRO ELS 1
Appeal2017-008582
Application 14/061,578
Technology Center 1600
Before ULRIKE W. JENKS, JOHN G. NEW, and RYAN H. FLAX,
Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellants state that the real party-in-interest is Dr. Falk Pharma GmbH.
App. Br. 1.
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Application 14/061,578
SUMMARY
Appellants file this appeal under 35 U.S.C. § I34(a) from the
Examiner's Final Rejection of claims 1-33. Specifically, claims 1-18, 23,
24, 26, 31, and 32 stand rejected as unpatentable under 35 U.S.C. § I03(a) as
being obvious over the combination of Rau (US 2007 /0071817 Al, March
29, 2007) ("Rau"), Yang et al. (US 2006/0013873 Al, January 19, 2006)
("Yang"), S. Elad et al., Budesonide: A novel treatment for oral chronic
graft versus host disease, 95(3) ORAL SURGERY ORAL MED. ORAL PATROL.
ORAL RADIOL. ENDOD. 308-11 (2003) ("Elad"), Hill et al. (US
2007/0191323 Al, August 16, 2007) ("Hill"), Ubeda Perez et al. (WO
2009/043844 A2, April 9, 2009) ("Ubeda Perez"), Appellants' admissions,
and Magic Mouthwash 23(230703) Pharmacist's Letter/Prescriber's Letter
1-5 (2007) ("MM").
Claims 18-33 stand rejected as unpatentable under 35 U.S.C. § I03(a)
as being obvious over the combination of Rau, Yang, Elad, Hill, Ubeda
Perez, and Appellants' alleged admissions as applied to claims 1--4, 6-10,
12-16, 18, 23, 26, and 31, and MM.
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to an effervescent tablet for
preparing a mouth-rinsing solution, wherein the effervescent tablet exhibits a
high release rate ofbudesonide. Spec. Abstr.
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REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
1. A solid pharmaceutical composition comprising a
therapeutically effective amount of budesonide in combination
with an effervescent mixture of a pharmaceutically acceptable
acid in solid form and a compound containing carbonate and/or
hydrogen carbonate, wherein said composition is formulated to
rapidly dissolve in a specific volume of liquid so as to generate
an orally-administrable mouth rinsing solution comprising a
therapeutically effective amount of dissolved budesonide
suitable for the treatment of inflammatory changes in the upper
digestive tract.
App. Br. 29.
ISSUES AND ANALYSES
We are persuaded by, and expressly adopt, the Examiner's findings,
reasoning, and conclusion that Appellants' claims are primafacie obvious
over the combined cited prior art. We address the arguments raised by
Appellants below.
Issue 1
Appellants argue the Examiner erred because there is no guidance in
the prior art that would motivate a person of ordinary skill in the art to
combine the prior art teachings with a reasonable expectation of success.
App. Br. 15.
Analysis
The Examiner finds that Rau teaches effervescent oral care
compositions, such as mouthwashes, wherein solid compositions, i.e.,
tablets, comprising an edible acid and a carbonate for effervescence, which
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can be dissolved in a specific volume of water (15-25 ml) to form a mouth
rinsing solution which is then contacted/orally administered to the oral
tissues of a user, or the tablet itself can be placed directly into the oral cavity
of a user and allowed to dissolve and effervesce in the oral cavity. Final
Act. 4 (citing Rau, e.g., Abstr., ,r,r 9-10, 16, 18, 44). The Examiner finds
that Rau also teaches these tablets can carry active agents, such as
prescription medications (which broadly includes corticosteroids such as
budesonide) and antimicrobial agents, as well as binders/fillers/etc.,
specifically polyvinylpyrrolidone, and anhydrous surfactants, specifically
ducosate sodium ( dioctyl sodium sulfosuccinate ), and flavorants. Id. ( citing
Rau, e.g., ,r,r 20, 21, 23, 26, 32, 34, 25, Examples, claim 10).
The Examiner finds that Rau does not expressly teach a tablet
comprising budesonide as an active agent which is present in the recited
range. Final Act. 5. The Examiner finds that Rau also does not teach that
the mouthwash solution formed from the effervescent tablet is used to treat
inflammatory changes in the upper digestive tract. Id.
The Examiner finds that Ubeda Perez teaches orodispersible
formulations of corticosteroids (budesonide is a known corticosteroid),
which can comprise effervescent agents, specifically edible acids and
carbonates, e.g., sodium carbonate or potassium carbonate. Final Act. 5
(citing Ubeda Perez, e.g., 9, 6, 11, claims 11, 14).
The Examiner finds that Elad teaches that budesonide is suggested as
an alternative treatment for chronic oral graft versus host disease ("GVHD")
and has a clinical advantage over other treatments for oral GVHD. Final
Act. 6 (citing Elad, e.g., Abstr., 308, 309). The Examiner also finds that
Elad teaches methods of administering the budesonide to the upper digestive
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tract in which budesonide tablets are crushed and dissolved in water to form
a solution used as a mouthwash to treat the upper digestive tract. Id.
The Examiner finds that Yang teaches bioadhesive steroid
nanoparticle compositions in the form of a tablet that rapidly disintegrates in
the oral cavity and adheres to the periodontal pocket and oral mucosa to
deliver the steroid. Final Act. 6. The Examiner finds that the compositions
of Yang comprise: (1) a bioadhesive polymer surrounding the steroid and
having an average particle size of 1,000 nm or less, (2) a surfactant; (3) a
disintegrant; and (4) an effervescent agent. Id. (citing Yang title; Abstr.,
,r,r 2, 15-16). The Examiner finds that Yang teaches that many steroids are
anti-inflammatory agents and have poor water solubility. Id. (citing Yang
,r,r 4, 15). The Examiner finds that Yang also teaches that suitable
effervescent agents include citric acid/ sodium carbonate, tartaric
acid/sodium carbonate or tartaric acid/sodium citrate. Id. ( citing Yang ,r 20).
The Examiner finds that Yang's formulations result in enhanced dissolution
of the steroid which include steroids suitable to remedy an oral disease, e.g.,
triamcinolone acetonide. Id. ( citing Yang ,r,r 2, 25, claims 2, 11 ).
The Examiner concludes that it would have been prima facie obvious
to a person of ordinary skill in the art to select budesonide as a steroid for
use in the formulations of Rau because budesonide is well known in the art
as being suitable for treating oral diseases, such as chronic oral GVHD, as
taught by Elad. Final Act. 7. The Examiner further concludes that a person
of ordinary skill in the art would have had a reasonable expectation of
successfully including budesonide in Rau's formulations, because Yang
teaches formulations which are designed to increase the dissolution of
steroids with poor water solubility, such as budesonide. Id. at 7-8. The
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Examiner concludes that Yang teaches that its compositions comprise
effervescent agents, and specifically the same effervescent agents taught by
Rau, that these are readily taken up in the oral cavity for treatment of an oral
disease. Id. at 8.
Appellants argue that Rau teaches a large array of effervescent oral
care compositions that constitutes a "laundry list" of functional ingredients
that may be incorporated into the solid composition and thus carried to oral
cavity. App. Br. 15-16. According to Appellants, a particular objective of
Rau is to provide a solid effervescent oral care composition that is "pleasing
to the user" and "substantially free of insoluble particulate material,"
particularly "material that can impart a gritty feeling to the composition."
Id. at 16 (quoting Rau ,r,r 8, 15). In addition, assert Appellants, Rau
expressly restricts the compositions to those having osmolality values of 310
mOsm/kg (millimoles per 5 kg water) or less, as osmolality values in excess
of this threshold "can result in damage due to cell dehydration when
contacted with the oral tissues." Id. (citing Rau ,r 38, claim 1). Appellants
therefore contend that a person of ordinary skill in the art would expect the
composition to be restricted to stable, water-soluble components. Id.
However, Appellants argue, budesonide is not only difficult to
dissolve in water, but tends to be highly unstable in its dissolved form,
particularly in the absence of precise pH, preservatives, and further
stabilizers, or in the absence of careful manufacture in a mixing vessel under
oxygen-depleted conditions. App. Br. 16-17 (citing Declaration of Dr.
Rudolf Wilhelm 11 (the "Wilhelm Declaration"), Declaration of Prof. Dr.
Sharon Elad (the "Elad Declaration"), Hill ,r 5, Fig. 1 ). Appellants assert
that, even assuming, arguendo, that a person of ordinary skill in the art were
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to contemplate the modification of Rau's compositions to include steroids,
such a skilled artisan would not reasonably expect budesonide to be suitable.
Id. at 17.
Appellants point out that, none of the additional references cited by
the Examiner teach or suggest a solid soluble formulation of budesonide.
App. Br. 17. Furthermore, argue Appellants, only two of these references
(Elad and Hill) mention budesonide per se and both references establish the
difficulties associated with formulating budesonide. Id. Therefore,
Appellants contend, none of the secondary references, alone or in
combination, provide the requisite motivation and reasonable expectation of
success necessary to support the Examiner's prima facie conclusion of
obviousness. Id.
With respect to Yang, Appellants argue that, whereas the Rau
formulation is designed to wholly disintegrate and dissolve, thereby yielding
a solution (acknowledged by Appellants as having an osmolality of 310
mOsm/kg), the solid matrix of the Yang formulations ( which "comprises a
disintegrant, an effervescent agent and an excipient" are designed to
disintegrate and thereby release a suspension of chitosan-coated steroid-
surfactant micelles (i.e., the "steroid nanoparticles") so that they will adhere
to the tissue of interest ( e.g., the periodontal pocket and oral mucosa). App.
Br. 17 ( citing Yang claim 1 ,r,r 16, 22, 24 ). According to Appellants,
because the bioadhesive dosage form taught by Yang, and the effervescent
tablet taught by Rau are structurally divergent, arising from divergent
manufacturing processes and having significantly different modes of action
and administration, a person of ordinary skill in the art would not have
looked to Yang for ways to modify and/or improve Rau so as to allow for
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the inclusion of the poorly soluble budesonide. Id. at 17-18. Nor, argue
Appellants, would such an artisan have had any reasonable expectation that
such a combination would lead to successful result. Id. at 18.
Furthermore, assert Appellants, were an ordinary artisan to attempt to
modify the Rau effervescent formulation to include Yang's bioadhesive
steroid nanoparticle construction, such a tablet would not rapidly dissolve in
a specific volume of water to generate an orally-administrable mouth rinsing
solution comprising a therapeutically effective amount of dissolved
budesonide as recited in the claims on appeal. Id.
With respect to Ubeda Perez, Appellants assert that the object of the
reference is to "provide an orodispersible [i.e., orally disintegrating] tablet
which can be dissolved quickly in the oral cavity, which presents good
palatability properties, and that can be obtained by conventional processes,
such as direct compression." App. Br. 18 (quoting Ubeda Perez 4).
Appellants contend that the orally disintegrating tablet taught by Ubeda
Perez is preferably formed from direct compression of a homogeneous dry
powdered mixture comprised of calcium silicate, a generic diluent, a generic
disintegrant, and a generic active ingredient, and optionally a generic
effervescent component. Id. ( citing Ubeda Perez 5---6, line 7). Appellants
assert that Ubeda Perez, like Rau, teaches an extensive laundry lists of
options for each component; as such, the disclosed genus necessarily gives
rise to innumerable combinations. Id. Therefore, Appellants argue, one
must look to the express guidance and illustrative examples of Ubeda Perez
to determine whether one of ordinary in the art would have been motivated
to select the claimed species or subgenus. Id. Appellants assert that whereas
Ubeda Perez expresses a preference for crospovidone ( a polymer of
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vinylpyrrolidone) as a disintegrant, there is no mention of docusate sodium
or budesonide. Id. Appellants acknowledge that, whereas corticosteroids as
an active agent are generically referenced, amid a Markush group of more
than 30 other categories of pharmaceutical, ranging from analgesics to
antidepressants to antihistamines, none of the six formulations taught by the
Examples of Ubeda Perez includes an anti-inflammatory, much less a
corticosteroid. Id. ( citing Ubeda Perez 9). Therefore, argue Appellants,
nothing in the teachings of Ubeda Perez may be fairly characterized as
guiding one skilled in the art toward or rendering obvious the selection of
the budesonide. Id.
Furthermore, Appellants argue, Ubeda Perez expressly teaches that
non-water soluble components be "considerably minimized," so as to ensure
a positive organoleptic sensation. Id. ( citing Ubeda Perez 6). Appellants
assert that these teachings "suggest away" from the inclusion of an only
sparingly soluble active ingredient such a budesonide and would necessarily
undermine any expectation for success. Id.
With respect to Elad, Appellants argue that reference does not teach a
solution or a homogeneous mixture of budesonide fully dissolved in water,
as recited in the claim. App. Br. 19. Appellants point to the Wilhelm
Declaration, in which Dr. Wilhelm states that when he attempted to replicate
the Elad protocol, he found that: "[i]ndependent from the level of crushing
reached, there is no development of a stable and homogenous suspension of
active ingredient, let alone a solution," but rather, that most of the capsule
components remained as "insoluble powder," a "solid fraction," or
"sediment" in the sample. Id. ( quoting Wilhelm Deel. 9, ,r 2). Appellants
contend that Dr. Wilhelm states that further testing revealed that the
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percentage of the 3 mg dosage of budesonide capsules dissolved in 10 ml
sample of water provided a mean value range of from 0.15% to 1.9%. Id.
( citing Wilhelm Deel. Table 1 ).
Therefore, Appellants argue, although the Elad reference may teach
the utility of a budesonide mouthwash, the use of the budesonide capsules to
form the mouthwash in Elad does not give rise to a solution as recited in the
claims on appeal. Id.
Appellants argue further that Elad is not enabling in that it does not
teach how to make and use a solid composition or tablet using the
budesonide capsules, which can subsequently be used to generate an orally-
administrable mouth rinsing solution. App. Br. 19. Appellants point again
to the Wilhelm Declaration, in which Dr. Wilhelm states, following the
teachings of Elad, he was unable to formulate a solid composition or tablet
using crushed budesonide capsules, which could be used to generate an
orally-administrable mouth rinsing solution, as recited in the claims. Id.
Appellants also argue that the claims require that the "composition is
formulated to rapidly dissolve in a specific volume of liquid." App. Br. 19-
20. Appellants argue that this limitation requires the complete dissolution of
the tablet within a period of time of less than two minutes. Id. at 20.
Appellants assert that the Wilhelm Declaration states that the Elad crushed
capsules do not result in either a rapid or complete dissolution of the
budesonide in water, and that the Wilhelm Declaration further states that
only O .15-1. 9% dissolution of budesonide. Id. Moreover, Appellants argue,
the Wilhelm Declaration further states that the teachings of Elad are "wholly
unsuitable to provide a sufficient dose of active ingredient when
administering the mouth rinse solution." Id.
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With respect to Hill, Appellants argue that the reference is not
directed to the formulation of a solid pharmaceutical composition or tablet
comprising budesonide, as recited in the claims. App. Br. 20. According to
Appellants, the "solubility enhancer" is intended to be mixed with the
corticosteroid and water under oxygen-depleted conditions in order to
increase the solubility of the aqueous solution and increase the stability of
the corticosteroid in solution. Id. Therefore, argue Appellants, a person of
ordinary skill in the art would not have been motivated to utilize the
components intended for an aqueous solution to formulate a solid
composition or tablet, nor would an artisan be motivated to combine the
teachings of Hill with the effervescent solutions taught by Rau. Id. at 20-21.
Appellants argue further that the teachings of Hill would not have
motivated a skilled artisan to specifically select PVP or docusate sodium.
App. Br. 21. According to Appellants, Hill sets forth large "laundry lists" of
"optional additional ingredients" including at least 50 possible "solubility
enhancers." Id. (citing Hill ,r 34). Appellants note that neither PVP nor
docusate sodium comes within the first 40, nor is either highlighted or
exemplified. Id. Instead, contend Appellants, Hill focuses on cyclodextrin
solubility enhancers, such as sulfoalkyl ether cyclodextrin (SAE-CD)
derivatives, especially SBE7-beta-CD. Id. Therefore, Appellants assert, a
skilled artisan would have had to judiciously choose from among the wide
array of possible combinations, selecting components that are neither
extensively analyzed nor highlighted as particularly preferred. Id. ( citing
Wilhelm Deel. ,r 5(c)).
Appellants note that Dr. Wilhelm concludes that "one of skill in the
art would not have looked to Hill for ways and means to modify and/or
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improve Rau so as to allow for the inclusion of the hardly soluble
budesonide. Nor would the skilled artisan have had any reasonable
expectation that such a combination would lead to successful results."2,3 Id.
With respect to Magic Mouthwash, Appellants argue that the
reference, like Rau, Yang, and Ubeda Perez, Pather provides no teaching of
budesonide or docusate sodium, and provides only a passing reference to
"crospovidone" ( a polymer of polyvinylpyrrolidone) in the context of
optional "noneffervescent disintegration agents" that may be employed to
aid in the dispersion of the drug in the gastrointestinal tract." App. Br. 21-
22.
Appellants summarize their arguments, asserting that only Elad and
Hill teach the use ofbudesonide. App. Br. 22. According to Appellants,
although Elad teaches a mouthwash made from budesonide capsules, these
2 Dr. Rudolf Wilhelm, the declarant, received his Dr. rer. nat. (Ph.D.) in
1996 and is presently Head of the Pharmaceutical Development
Department at Dr. Falk Pharma Gmbh, a position he has held since 2005.
See Wilhelm Deel. ,r,r 2-3. He has extensive experience in the
development of novel immediate-release, delayed-release, and modified-
release oral solid dosage formulations of new and already existing drugs.
Id. at ,r 3. We find that Dr. Falk is qualified to render an expert opinion,
and we also note that he is one of the co-inventors of the claimed
invention.
3 We note that the Wilhelm Declaration, while convincingly documenting
Dr. Wilhelm's scientific expertise, provides no evidence or statement that
Dr. Wilhelm has any training in the law or, specifically, that Dr. Wilhelm,
a citizen of Germany, has any training in U.S. patent law, or is a member
of the patent bar. We therefore do not recognize Dr. Wilhelm's
qualification to express a legal conclusion in this regard and we disregard
this conclusion.
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teachings would not motivate a skilled artisan to modify Rau to include
anything other than crushed budesonide capsules in its formulations. Id.
However, Appellants argue, Dr. Wilhelm, following the teachings of Elad,
was unable to make a budesonide solid composition or tablet that would
rapidly dissolve in a specific volume of liquid to generate an orally-
administrable mouth rinsing solution comprising a therapeutically effective
amount of dissolved budesonide to treat inflammatory changes in the upper
digestive tract, as recited in the claims. Id.
Furthermore, contend Appellants, the teachings of Hill are directed to
improving the stability of budesonide in aqueous solutions, not in the
formulation of solid compositions or tablets that can subsequently be used to
generate mouth rinsing solutions. Id. at 22-23. Therefore, Appellants
assert, none of the references that actually describe budesonide provide the
requisite motivation for a person of ordinary skill in the art to modify Rau to
formulate the composition recited in the claims on appeal. Id. at 23.
Finally, Appellants argue, with respect to claims 2, 3, 8, 9, 14, and 15,
that Rau neither highlights nor exemplifies the use of PVP or docusate
sodium. App. Br. 23 ( citing Rau Table 1 ). Appellants point to Table 1 of
Rau, which, Appellants assert, recommends PEG over PVP and sodium
lauryl sulfate over docusate sodium. Id. Appellants further assert that none
of the illustrative embodiments include any of the claimed components
much less two or more in combination. Id.
We are not persuaded by Appellants' arguments. As an initial matter,
we remind Appellants that: "one cannot show non-obviousness by attacking
references individually where ... the rejections are based on combinations of
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references," which is what Appellants have primarily done, as discussed
above. In re Keller, 642 F.2d 413,426 (C.C.P.A. 1981).
We agree with the Examiner's findings, reasoning, and conclusion.
Specifically, we agree with the Examiner that Rau teaches, generally, a solid
pharmaceutical composition, comprising an effervescent mixture of a
pharmaceutically acceptable acid in solid form and a compound containing
carbonate and/or hydrogen carbonate, in which "composition is formulated
to rapidly dissolve in a specific volume of liquid." Furthermore, Yang and
Ubeda Perez teach similar compositions, indicating that such compositions
are well known in the art. The issue before us then, is whether a person of
ordinary skill in the art would have been motivated to combine the teachings
of the cited references with a reasonable expectation of success in arriving at
Appellants' claimed invention.
As we see it, the dispositive issues, according to Appellants'
arguments, are twofold. The first is, given the generally poor solubility of
budesonide, would the combination of references give a person of ordinary
skill in the art a reasonable expectation of success in using budesonide in the
dissolvable effervescent compositions taught by Rau? The second is
whether Yang teaches a "solution" as recited in the claims using the
construction of that term that Appellants urge us to adopt.
We address the latter issue first. Appellants' Specification provides
no express definition of the claim term "solution." Consequently, we adopt
the broadest reasonable interpretation of the term consistent with Appellants'
Specification as it would be interpreted by a person of ordinary skill in the
art. Cuozzo Speed Tech., LLCv. Lee, 136 S. Ct. 2131, 2145 (2016); Phillips
v. AWH Corp., 415 F.3d 1303, 1316 (Fed. Cir. 2005).
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Appellants urge us to construe the claim term "solution" as meaning a
homogeneous mixture of solvent and dissolved substance (solute) in which
the solute does not exist as a solid. App. Br. 6. Appellants contend that the
dictionary definition of solution is a type of homogeneous, mixture that is
made up of two or more substances. Id. (citing Study.com, What is a
Solution in Science? -Definition & Examples - Video & Lesson Transcript I
(2016), available at: https://study.com/academy/lesson/what-is-a-solution-
in-science-definition-examples.html, last visited August 13, 2018).
Appellants assert that a homogeneous mixture is a type of mixture with a
uniform composition, and that this means that the substances cannot be
distinguished easily from one another. Id. at 6-7.
Appellants' Specification provides no express definition of the claim
term "solution." However, the Specification discloses an example of the
size distribution of the particles of budesonide that are dispersed in the
specific volume of liquid recited in the claims. According to Appellants'
Specification:
Micronised budesonide is preferably used. The size of the
budesonide particles plays an essential part in the dissolution rate
and the resorbability. Budesonide is preferably used in which
the particle size distribution is adjusted such that at least 90% of
the particles have a diameter of less than 20 µm, preferably less
than 10 µm. In a particularly preferred embodiment, 100% of the
particles have a diameter ofless than 10 µm, 95% of the particles
have a diameter of less than 5 µm and 80% of the particles have
a diameter ofless than 3 µm. The particle diameter is determined
by conventional measuring methods.
Spec. 3/3.
Yang teaches that the bioadhesive steroid nanoparticles have a
bioadhesive polymer surrounding the steroid nanoparticles and with an
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average diameter of less than 1000 nm. Yang Abstr. Yang further teaches
that the steroid/polymer nanoparticles are added to an effervescent matrix
that rapidly dissolves into a suspension of nanoparticles which can adhere to
tissues of the upper digestive tract. Id. at ,r,r 24--25.
We agree with the Examiner that a homogeneously dispersed
suspension of particles of less than 1000 nm would be understood by a
person of ordinary skill in the art, applying the broadest reasonable
interpretation, to constitute: "an orally-administrable mouth rinsing
solution," as recited in the claims. Although the claims do not recite
bioadhesive polymers, the claims recite, "[a] solid pharmaceutical
composition comprising ... ," meaning that the scope of the claims does not
exclude additional components. See Crystal Semiconductor Corp. v.
TriTech Microelectronics Int'!, Inc., 246 F.3d 1336, 1348 (Fed. Cir. 2001)
(Use of the transition "comprising" in the language of a claim "creates a
presumption ... that the claim does not exclude additional, unrecited
elements"). Rau and Hill similarly teach that sodium ducosate is known in
the art as a component of effervescent solutions and can act as a solubility
enhancer.
Appellants' second issue is whether, given the poor solubility of
budesonide, the combination of references cited by the Examiner give a
person of ordinary skill in the art a reasonable expectation of success in
using budesonide in the dissolvable effervescent compositions taught by
Rau.
Appellants' Specification discloses that: "Surprisingly, it was found
that the solubility of budesonide effervescent tablets is significantly
increased by the addition of polyvinylpyrrolidone (PVP) and ducosate
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sodium." Spec. 6. However, we agree with the Examiner that both Rau and,
particularly Hill teach that, at the time of Appellants' claimed invention, it
was well known in the art that polyvinylpyrrolidone can be used to enhance
the solubility of corticosteroids, such as budesonide. See Rau ,r,r 7, 23; Hill
,r,r 34--36 (listing polyvinylpyrrolidone as a "solubility enhancer" and stating
that:
A "solubility enhancer," as used herein, includes one or more
compounds which increase the solubility of corticosteroid in the
aqueous phase of the corticosteroid mixture. In general the
solubility enhancer increases the solubility of the corticosteroid
in water without chemically changing the corticosteroid. In
particular, the solubility enhancer increases the solubility of
corticosteroid without substantially decreasing, and in some
embodiments increasing, the activity of the corticosteroid.
Hill ,r 36. Hill continues: "Solubility enhancers are known in the art and are
described in, e.g., U.S. Pat. Nos. 5,134,127, 5,145,684, 5,376,645, 6,241,969
and U.S. Pub. Appl. Nos. 2005/0244339 and 2005/0008707, each of which
is specifically incorporated by reference herein." Id. at ,r 37. Importantly,
Hill does not teach that the solubility enhancers are useful for enhancing
solubility only in the low-oxygen protocols taught by Hill for the synthesis
of corticosteroid solutions with long-term stability.
We therefore agree with the Examiner that the combined references
teach that polyvinylpyrrolidone was well known in the art as an ingredient in
effervescent solutions and could be used to increase the solubility of
corticosteroids in aqueous solutions.
Appellants contend that the "solubility enhancer" of Hill is intended to
be mixed with the corticosteroid and water under oxygen-depleted
conditions in order to increase the solubility of the aqueous solution and
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increase the stability of the corticosteroid in solution. See App. Br. 20.
Therefore, argue Appellants, a person of ordinary skill in the art would not
have been motivated to utilize the components intended for an aqueous
solution to formulate a solid composition or tablet, nor would an artisan be
motivated to combine the teachings of Hill with the effervescent solutions
taught by Rau. Id. at 20-21.
We are not persuaded. First, Rau expressly teaches that
polyvinylpyrrolidone is well known as a component of effervescent
solutions. See Rau ,r,r 7, 23. Although we acknowledge Appellants' point
that the procedures taught by Hill are directed to the preservation of long-
term solubility in solutions, we agree with the Examiner that the
combination of the teachings of Yang, Rau, and Hill would give a person of
ordinary skill in the art a reasonable expectation of success, for the reasons
we have explained, in making an effervescent composition with a soluble
budesonide component.
Issue 2
Appellants argue that the Examiner erred because the combined cited
references do not adequately render the presently claimed invention
"obvious to try." App. Br. 23.
Analysis
Appellants argue that, because none of the references cited by the
Examiner describe or suggest a solid soluble formulation ofbudesonide, the
Examiner's position is that the formulation would have been "obvious to
try" i.e., it would have been obvious to a person of ordinary skill to modify
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the Rau compositions to include solid budesonide. App. Br. 23. Appellants
argue that, the Examiner's findings and conclusion notwithstanding, the
potential pathways for modification are neither finite nor identified nor
predictable and, therefore, for this additional reason, the invention of the
pending claims may not be fairly characterized as obvious. Id. at 23-24.
Appellants largely repeat their arguments from the previous section of
this decision. Appellants assert that a person of ordinary skill could not have
readily extracted or synthesized from these teachings the requisite small
number of easily traversed options or identifiable predictable solutions
required to support a conclusion of "obvious to try." Appellants point to our
reviewing court's holding in Sanofi-Aventis Deutsch/and GmbH v. Glenmark
Pharmaceuticals Inc., USA, 748 F.3d 1354 (Fed. Cir. 2014) that, when there
are potentially hundreds of possible combinations and the prior art gives
"either no indication of which parameters [are] critical or no direction as to
which of many possible choices is likely to be successful," modification may
not be fairly characterized as "obvious to try." Id. at 24 (citing Glenmark,
748 F.3d at 1360 (citing In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir.
1988)).
Appellants argue further that "impermissible hindsight must be
avoided and the legal conclusion must be reached on the basis of the facts
gleaned from the prior art," as opposed to the cited prior art. App. Br. 24
( quoting MPEP § 2142). Appellants allege that the Examiner impermissibly
employed hindsight reasoning, asserting that, in this appeal, the references
that the Examiner concludes teaches the invention of the claims on appeal
are even more tangential and farther removed than those applied in
Glenmark, etc.
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We are not persuaded by Appellants' arguments. The test for
obviousness is: "what the combined teachings of the references would have
suggested to those of ordinary skill in the art." Keller, 642 F.2d at 425. We
agree with the Examiner that the combined prior art teaches or suggests the
combined invention. Specifically, Rau generally teaches effervescent
compositions that can be used to deliver medicaments. Ubeda Perez
similarly teaches effervescent compositions for drug delivery, including
those containing corticosteroids. See Ubeda Perez claims 11 and 14. Yang
and Hill teach that corticosteroids in general, and budesonide in particular,
are poorly soluble, and Yang teaches methods by which corticosteroid
solubility can be improved in an effervescent solution that is within the
scope of the claims, and is combinable with the teachings of Ubeda Perez
and Rau. See Yang ,r,r 7, 8, 15-16. Both Rau and Hill teach the use of
polyvinylpyrrolidone in their compositions, with Hill teaching that
polyvinylpyrrolidone is a solubility enhancing agent for corticosteroids, of
which budesonide is one such. See Hill ,r,r 34--36; Rau ,r 23.
The ... "obvious to try" [ error typically occurs in one of
two contexts: (1) when it] would have been "obvious to try" ...
to vary all parameters or try each of numerous possible choices
until one possibly arrived at a successful result, where the prior
art gave either no indication of which parameters were critical or
no direction as to which of many possible choices is likely to be
successful[; or (2)] to explore a new technology or general
approach that seemed to be a promising field of experimentation,
where the prior art gave only general guidance as to the particular
form of the claimed invention or how to achieve it.
In re O'Farrell, 853 F.2d at 903. We do not think either criterion applies to
the references cited by the Examiner. Rau and Ubeda Perez teach general
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effervescent compositions, including polyvinylpyrrolidone, which Hill
teaches enhances corticosteroid solubility. Yang and Hill both teach that
cortical steroid solubility in solutions is known in the art to be a problem,
and provide methods by which the solubility can be increased. Elad teaches
that oral compositions containing budesonide, in particular, is helpful in
treating "inflammatory changes in the upper digestive tract," as recited in the
claims. We consequently agree with the Examiner that the teachings and
suggestions of the combined cited prior art teach the limitations of the
claims, and that a person of ordinary skill would have had a reasonable
expectation of success in combining the references.
With respect to Appellants' argument that the Examiner improperly
applied hindsight reasoning:
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level of
ordinary skill at the time the claimed invention was made and
does not include knowledge gleaned only from applicant's
disclosure, such a reconstruction is proper.
In re McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A. 1971). Appellants point
to no evidence of record that the Examiner relies on information or
knowledge that can be gleaned solely from Appellants' Specification and
makes only the mere assertion that the Examiner relied on hindsight
reasoning. Such attorney argument is not persuasive. See In re Geisler, 116
F.3d 1465, 1470 (Fed. Cir. 1997) (holding that attorney arguments and
conclusory statements that are unsupported by factual evidence are entitled
to little probative value).
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Issue 3
Appellants argue the Examiner erred because the Examiner's
conclusion that the claims are obvious is rebutted by the unexpected results
of record. App. Br. 25.
Analysis
Appellants argue that they have developed a novel effervescent
budesonide tablet configured for the creation of a single-dose, user-prepared
mouth rinsing solution that affords significant advantages with regard to
long-time stability of the drug, as well as delivering a simple and accurate
dosage. App. Br. 25. Appellants assert that, in contrast to Yang's
bioadhesive tablets that rely exclusively on saliva to disperse through the
mouth, Appellant's effervescent tablet-generated mouth rinsing solution
provides better dispersion, contacting more tissues (i.e., more volume=
greater tissue contact). Id. Appellants claim that their effervescent tablets
also avoid the need for precise pH adjustment, preservatives and stabilizers
associated with liquid formulations of the prior art such as those disclosed
by Hill and Elad. Id. Moreover, argue Appellants, the claimed composition
demonstrates an unexpected superiority over the exemplary Elad
formulations. Appellants point to the Elad Declaration which, contend
Appellants, not only characterizes embodiments of the present invention as
showing "superior results" and a "superior design" but further attests that
"one of skill in the art would consider the present invention to constitute a
significant improvement over the prior art alternatives including those
described in [the Elad reference]." Id. at 25-26 (citing Elad Deel. ,r,r 8, 11,
12) ( emphasis omitted).
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Appellants point to the Wilhelm Declaration as similarly stating that
the superior results achieved by the present invention as compared to the
prior art "could not have been predicted a priori, are not disclosed or
suggested in the prior art, and are, therefore, quite unexpected and
surprising." App. Br. 26.
We do not find Appellants' arguments to be persuasive. "[W]hen
unexpected results are used as evidence of nonobviousness, the results must
be shown to be unexpected compared with the closest prior art." In re
Baxter Travenol Labs., 952 F.2d 388,392 (Fed. Cir. 1991).
As evidence of the unexpected properties of their claimed
composition, Appellants point to the Elad and Wilhelm Declarations. Both
declarants point to the Elad references as closely-related prior art with which
to compare the claimed composition. See Wilhelm Deel. ,r 7, App 'x A; Elad
Deel. ,r 11.
Elad teaches results of a clinical trial employing budesonide in the
treatment of chronic oral graft versus host disease ("GVHD"). Elad teaches
that the method employed consisted of having patients crush a budesonide
capsule, dissolve it in 5 mls of water, and rinse for 15 minutes 2 or 3 times
daily, then expectorate the solution. Elad 309. Elad teaches that an
objective response to budesonide mouthwashes was observed in all patients
and that all patients reported subjective improvement. Id. at 310.
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Dr. Elad4 attests that the Phase III clinical trial of Appellants' claimed
composition disclosed in the Elad Declaration has a superior design
compared to the initial study taught by the Elad reference. Elad Deel. ,r 11.
Dr. Elad states that the reasons for the superiority of the design of the
clinical trial are based upon the lack of a placebo in the Elad reference study,
the larger sample size of the clinical trial, and the extent of data collection in
the clinical trial. Id. Dr. Elad opines that, for these reasons, the Phase III
clinical trial has a superior design as compared to the study in the Elad
reference. Id. Dr. Elad further opines that one of skill in the art would
consider the Appellants' invention to constitute a significant improvement
over prior art alternatives including those described in the Elad reference.
Id. at 12.
Dr. Wilhelm identifies the Elad reference as the closest prior art.
Wilhelm Deel. App 'x A at 8. Appendix A of the Wilhelm Declaration
relates how Dr. Wilhelm attempted to replicate the study taught by Elad. Id.
at 10. The Wilhelm Declaration then compares the results of the replicated
Elad study to a similar study using Appellants' claimed composition. Id. at
15. Dr. Wilhelm opines that: "The effervescent tablet according to the
present invention allows for the routine and reproducible production of an
orally applicable mouth rinse solution that cannot be achieved using the
4 Dr. Sharon Elad is professor of dentistry and a professor of oncology at the
University of Rochester where I am Chair of the Division of Oral Medicine
at the Eastman Institute for Oral Health (EIOH). Elad Deel. ,r 3. Dr.
Sharon is the first author of the Elad reference and has published
extensively in the field of oral medicine. We find Dr. Elad qualified to
render an expert opinion.
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product and techniques of the prior art. Moreover, the effervescent tablets
show surprising, advantageous effects over the prior art." Id. at 16.
As an initial matter, we are not persuaded that Elad is the closest prior
art to Appellants' claimed invention. The composition of the budesonide
administered in Elad is not directly comparable to that of Appellants'
effervescent tablet and contains none of the other ingredients recited in
Appellants' claims, e.g., an effervescent mixture of a pharmaceutically
acceptable acid in solid form and a compound containing carbonate and/or
hydrogen carbonate, polyvinylpyrrolidone. Rather, 3 mg budesonide
capsules are simply crushed and mixed with water. Corticosteroids in
effervescent compositions are cited in both Rau and Ubeda Perez, and
methods of increasing the solubility of corticosteroids were also known in
the art. See, e.g., Hill ,r 3.
We also note that Dr. Elad's opinion that the superiority of the Phase
III clinical trial disclosed in the Elad Declaration refers to the superiority of
the design of the Phase III clinical trial to that of the Elad reference. Dr.
Elad does not offer an opinion as to the superiority of the composition, other
than to state that: "that one of skill in the art would consider the
[Appellants'] invention to constitute a significant improvement over prior art
alternatives including those described in [the Elad reference,]" although Dr.
Elad does not offer a specific opinion as to the properties of other,
corticosteroid effervescent compositions. See Elad Deel. ,r 12.
With respect to the comparative study disclosed by the Wilhelm
Declaration, we find the data persuasive of the superiority of Appellants'
claimed composition, however, as we have explained supra, we are not
persuaded that Elad represents close prior art due to the differences of the
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composition taught by Elad and that of Appellants' claims. On balance then,
we do not find that Appellants' argument claiming unexpected results
outweighs the other evidence of record that the claims are prima facie
obvious over the combined cited prior art. See also Pfizer, Inc. v. Apotex,
Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007) (unexpected results are not
sufficient to outweigh a stronger showing of obviousness).
Issue 4
Finally, Appellants dispute the Examiner's finding that Appellants'
argument of unexpected results are "not necessarily unexpected." App. Br.
26 ( emphasis omitted).
Analysis
Appellants contend that the Examiner rejected their argument that the
claimed compositions exhibit unexpected properties because: (1) Pather et
al. (US 6,641,838 B2, November 4, 2003) ("Pather") teaches the inclusion of
"effervescent agents into drugs to increase the dissolution of the drug and
thereby increase its biovailability"; and (2) "[Ubeda Perez] and Hill already
recognized that PVP and/or docusate sodium increased the dissolution of the
steroid active agents (i.e., budesonide)." App. Br. 26 (quoting Non-Final
Act., 15-16, August 13, 2015). Appellants assert that these findings by the
Examiner have no support in law. Id. (citing In re Piasecki, 745 F.2d 1468
(Fed. Cir. 1984)). Appellants rely upon Piasecki 's holding that: "If rebuttal
evidence of adequate weight is produced, the holding of prima facie
obviousness, being but a legal inference from previously uncontradicted
evidence, is dissipated. Regardless of whether the prima facie case could
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have been characterized as strong or weak, the examiner must consider all of
the evidence anew." Id. at 26 (emphasis omitted) (citing Piasecki, 745 F.2d
at 1472). According to Appellants, Piasecki stands for the proposition that it
is wholly improper for an earlier decision to be considered as "set in
concrete" with Appellants' rebuttal evidence evaluated only on its
"knockdown ability," and therefore that "[f]acts established by rebuttal
evidence must be evaluated along with the facts on which the earlier
conclusion was reached, not against the conclusion itself." Id. at 26-27
(citing Piasecki, 745 F.2d at 1472).
Appellants therefore allege that the Examiner has ignored the facts
provided by both Dr. Wilhelm and Dr. Elad. App. Br. 27. Appellants point
to the Wilhelm Declaration's statement that a person of ordinary skill in the
art would not "reasonably expect the stability achieved by Hill under such
high regulated conditions to extend and/or translate to the effervescent-based
mouthwashes of Rau." Id. (quoting Wilhelm Deel. ,r 5). Appellants argue
that Dr. Wilhelm does not consider Hill's recitation of a "vast laundry list of
'optional additional ingredients' including at least 50 possible 'solubility
enhancers"' to give rise to the expectation found by the Examiner, viz., that
"the addition of docusate sodium and PVP ... would increase the solubility
and bioavailability of the drug in the mouth." Id. ( citing Final Act. 18).
Appellants assert that the Examiner is not free to simply disregard this
testimony in the Wilhelm Declaration. Id.
Appellants therefore argue that, given that:
nothing in the references of record may be fairly characterized as
clearly teaching the use of PVP and/or docusate sodium to
increase the dissolution of budesonide in the context of
effervescent tablet formulations as presently claimed, it must
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Id.
therefore be accepted as fact that the superior results achieved by
the present invention could not have been predicted a priori, are
not disclosed or suggested in the prior art, and are, therefore quite
unexpected and surprising.
We are not persuaded. As an initial matter, we do not agree that the
Examiner simply ignored the disclosures and opinions of the Wilhelm and
Elad Declarations. The Examiner discusses, in the Final Office Action, both
Declarations at some length, but does not find the arguments raised in the
Declarations sufficient to overcome the Examiner's conclusion that the
claims are prima facie obvious over the prior art. See Final Act 18-20; see
also Ans. 9-11.
As we have explained in the previous section, we agree with the
Examiner's reasoning that Appellants have not provided comparison data
which shows that their solubility results are in fact unexpected as have been
asserted. See Ans. 9-10. We have also explained why we find that Elad is
not sufficiently close prior art to support an argument that the allegedly
unexpected results are sufficient to overcome the Examiner's conclusion that
the claims are prima facie obvious over the combined cited prior art. We
consequently affirm the Examiner's rejection of the claims.
DECISION
The Examiner's rejection of claims 1-33 under 35 U.S.C. § 103(a) is
affirmed.
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No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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