Ex Parte Nazzal et al

Patent Trial and Appeal Board

Jan 4, 2018

13656573 (P.T.A.B. Jan. 4, 2018)

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.
13/656,573 10/19/2012 Sami Mahmoud Nazzal 011.08 4963
107354 7590
Edel Patents LLC
8550 United Plaza Blvd., Suite 702
Baton Rouge, LA 70809
EXAMINER
BASQUILL, SEAN M
ART UNIT PAPER NUMBER
1613
NOTIFICATION DATE DELIVERY MODE
01/08/2018 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
following e-mail address(es):
j ohn @ edelpatents. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SAMI MAHMOUD NAZZAL,
PAUL W. SYLVESTER, and ALAADIN Y. ALAYOUBI
Appeal 2017-001371
Application 13/656,573
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
ROBERT A. POLLOCK, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a vitamin
E composition. The Examiner rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We affirm.
Statement of the Case
Background
“Vitamin E is a group of compounds having eight members . . .
Compounds and formulations disclosed herein have potential use as
1 Appellants identify the Real Party in Interest as First Tech International
Limited (see App. Br. 3).
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Application 13/656,573
pharmaceutical products and may be employed in the treatment of various
maladies including cancer and may specifically have uses in the treatment of
breast, colon and other related cancers” (Spec. ^ 2). The Specification
indicates that vitamin E compounds include a-tocopherol and a, y, and 5-
tochotrienols. (See id. at 42).
The Claims
Claims 56-75 are on appeal. Independent claim 56 is representative
and reads as follows:
56. A composition of matter comprising:
a. a quantity of vitamin E;
b. a glycerol ester; and
c. a polyoxyethylated triglyceride;
d. wherein the composition of matter is sufficiently
homogenized to perform as a self-emulsifying drug
delivery system;
e. wherein the quantity of vitamin E is at least 15 weight
percent of the composition of matter; and
f. wherein the quantity of vitamin E is at most 55 weight
percent of the composition of matter.
The Issue
The Examiner rejected claims 56-75 under 35 U.S.C. § 103(a) as
obvious over Ho2 and Lipari3 (Ans. 2-8).
The Examiner finds “Ho describes self-emulsifying formulations
(SEDDS) containing fat-soluble (ergo lipophilic or sparingly soluble in
water) drugs which form emulsions upon contact with gastrointestinal
2 Ho et al., US 6,596,306 Bl, issued July 22, 2003.
3 Lipari et al., US 2007/0104780 Al, published May 10, 2007.
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fluids” (Ans. 4). The Examiner finds Ho teaches “TOCOMIN tocotrienols
in 25%, each of either palm olein or soybean oil at 58.6%, LABRASOL at
14.5%, and TWEEN 80 at 2.2% of the composition” {id. at 5). The
Examiner finds that based on Ho, the “artisan can at once envisage the use of
tricaprylin caprylic/capric triglycerides in place of the other two particularly
embodied oily vehicles [palm oil or soybean oil] that comprise the total list
of suitable alternatives” {id. at 5).
The Examiner acknowledges “Ho does not recite the use of
polyethoxylated castor oil, ethanol, a glycerol ester, or the precise
triglyceride or tocotrienol concentrations claimed recited” (Ans. 6).
The Examiner finds Lipari teaches “that a combination of
phospholipid, solubilizing agent, and surfactant system each combine to
improve the solubilization of the sparingly soluble drug to be deliver” {Ans.
6). The Examiner finds Libari teaches “capric and caprylic acid
triglycerides exemplified by CAPTEC 355”; “ethanol” and “polyoxy 35
castor oil such as CREMOPHOR EL” {id.).
The Examiner finds Ho and Lipari teach the component
concentrations are “very important for establishing enhanced drug
absorption and self-emulsifying properties” (Ans. 6). The Examiner finds it
obvious
to have incorporated any, or indeed all, of the phospholipid,
ethanol, or polyoxy castor oil taught by Lipari as either
alternative surfactants, solubilizers, or adjuvants designed to
improve a SEDDS for the delivery of sparingly soluble
therapeutic active agents into the SEDDS taught by Ho as
useful for forming finely divided emulsions for delivering the
tocotrienol lipophilic active agent.
{Id. at 7).
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The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that Ho and Lipari render claim 56
obvious?
Findings of Fact
1. Ho teaches a “pharmaceutical formulation for oral
administration which comprises: (i) a fat-soluble drug; (ii) an appropriate
oil; and (iii) an appropriate surfactant system; the resulting formulation
which self-emulsifies under gentle agitation in the presence of an aqueous
medium” (Ho 2:46-52).
2. Ho teaches a “formulation of tocotrienols, in which the
tocotrienols are incorporated into a palm olein-surfactant system to form a
self-emulsifying system” (Ho 2:54-56).
3. Ho teaches
different surfactant systems at various ratio were tried out to get
a self-emulsifying drug delivery system (SEDDS). The aim of
this part of the study is to incorporate tocotrienols into a
suitable surfactant different surfactant systems at various ratio
were tried out to get a self-emulsifying drug delivery system
(SEDDS). The aim of this part of the study is to incorporate
tocotrienols into a suitable surfactant.
(Ho 3:64 to 4:3).
4. Ho teaches a table of the final formulation reproduced below:
IngredientsS-- Weight per capsule (mg)
Tocomrn ®50% 148.66
Palm olein/soybean oil 351,34
Labrasol 87.00
Tween 80 13,00
'Total weight 600.00
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(Ho 4:31-38).
5. Claim 1 of Ho teaches, in part, a
self-emulsifying drug delivery composition for use with oral
administration of fat-soluble drugs, said composition consisting
essentially of: fat-soluble drug selected from the group
consisting of tocotrienols, tocopherols ... an oil selected from
the group consisting of palm olein and soy bean oil... a
surfactant system comprised of a first component consisting of
caprylocaproyl macrogolglycerides and a second component
consisting of polyoxyethylene sorbitan monooleate
(Ho 6:26-38).
6. Claim 3 of Ho teaches, in part, the “composition of claim 1,
wherein the fat-soluble drug is about 24.8 weight percent of the
composition” (Ho 6:46^17).
7. Ho teaches
the studies had optimized three important formulation
variables to achieve a superior product with enhanced
bioavailability/absorption, namely
(i) use of palm olein and soybean oil as the vehicle for
fat-soluble drugs like tocotrienols, which help to enhance
absorption;
(ii) addition of a suitable combination of Labrasol and
Tween 80 into the drug/oil mixture to promote self­
emulsification and thus help to further increase the absorption
of tocotrienols; and
(iii) a suitable combination of surfactant system
(Labrasol and Tween 80) with the oil/drug mixture to optimize
drug absorption.
(Ho 2:28^10).
8. Lipari teaches “a drug-carrier system having a small-molecule
drug of low water solubility in solution in a substantially non-aqueous
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carrier that comprises (a) at least one phospholipid and (b) a
pharmaceutically acceptable solubilizing agent. The drug-carrier system,
when mixed with an aqueous phase, forms a non-gelling, substantially non­
transparent liquid dispersion” (Lipari ^ 15).
9. Lipari teaches
the carrier comprises two essential components: at least one
phospholipid, and a pharmaceutically acceptable solubilizing
agent for the at least one phospholipid. The solubilizing agent,
or the combination of solubilizing agent and phospholipid, also
solubilizes the drug, although other carrier ingredients such as a
surfactant optionally present in the carrier can in some
circumstances provide enhanced solubilization of the drug.
(Lipari ^ 79).
10. Lipari teaches in “one embodiment, the solubilizing agent
comprises . . . one or more glyceride materials” (Lipari 82).
11. Lipari teaches a “suitable example of a medium chain
triglyceride material is a caprylic/capric triglyceride product such as, for
example, Captex 355 EP” (Lipari 86) (see Spec. ^ 42 “triglycerides of
caprylic/capric acid sold as Captex® 355 and referred to herein as ‘Captex’
and C8/C10 polyglycolyzed glycerides from coconut oil sold as Labrasol®
referred to herein as ‘LabrasoT were provided by BASF.”)
12. Lipari teaches a
suitable total amount of glycerides is an amount effective to
solubilize the phospholipid and, in combination with other
components of the carrier, effective to maintain the drug in
solution. For example, glyceride materials such as medium
chain and/or long chain triglycerides can be present in a total
glyceride amount of about 5% to about 70%.
(Fipari 87).
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13. Lipari teaches “to select a suitable surfactant for use in the
composition ... a surfactant such as polysorbate 20 can be included in an
amount of 0% to about 25%” (Lipari 88).
14. Lipari teaches the use of “Cremophor EL™ of BASF: polyoxyl
castor oil” (Lipari 126) (see Spec. ^ 41 “self-emulsifying drug delivery
system (SEDDS) formulations described in Table 1 below were prepared
using Tween 80 or Cremophor EL as the primary surfactant”).
15. Lipari teaches
the drug must normally be formulated at a concentration below
its limit of solubility in the carrier. It will be understood that
the limit of solubility can be temperature-dependent, thus
selection of a suitable concentration should take into account
the range of temperatures to which the composition is likely to
be exposed.
(Lipari ^ 77).
Principles of Law
“[WJhere the general conditions of a claim are disclosed in the prior
art, it is not inventive to discover the optimum or workable ranges by routine
experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955).
“[T]he discovery of an optimum value of a variable in a known
process is usually obvious.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348,
1368 (Fed. Cir. 2007). The rationale for determining the optimal parameters
for prior art result effective variables “flows from the ‘normal desire of
scientists or artisans to improve upon what is already generally known.’” Id.
(quoting In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003).)
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Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Ans. 2-8; FF 1-15) and agree that the
claims are obvious over Ho and Fipari. We address Appellants’ arguments
below.
Appellants contend:
the rejection should be overturned because, that rejection does
not even allege that the proposed combination of prior art meets
the claimed emulsification characteristics. Applicant
anticipates that the present appeal may motivate a shift in the
nature of the rejection including an argument that all of claimed
emulsification characteristics are inherent in the combination of
Ho ’306 and Fip[]ari ’780. However, that rejection is not the
rejection being appealed.
(App. Br. 11).
We are not persuaded. Both Ho and Fipari are drawn to “a self-
emulsifying drug delivery system” (FF 3; cf. FF 8), directly rebutting
Appellants’ argument that the prior art fails to satisfy the recitation in claim
56 of a “self-emulsifying drug delivery system.” As Appellants
acknowledge in their argument, Appellants show no evidence4 of a
difference between the composition of claim 56 and the self-emulsifying
systems rendered obvious by the combination of Ho and Fipari.
Appellants contend there is “strong evidence rebutting the alleged
expectation of success which remains the only evidence of record on that
4 We note Appellants’ citation of Gursoya et al, Self-emulsifying drug
delivery systems (SEDDS) for improved oral delivery of lipophilic drugs, 58
Biomedicine & Pharmacotherapy 173 (2004)(Abstract), but this reference is
newly cited and not admissible after appeal (see 37 CFR § 41.33(d)(2)).
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issue” and the “record shows a series of prior attempts to create a Vitamin E
SEDDS composition with high Vitamin E loading that were unsuccessful”
(App. Br. 12). Appellants creates a table including data from Table 2 of Ali5
that shows certain formulations gave different degrees of turbidity,
indicating various degrees of self-emulsification (App. Br. 14; cfi Ali 106,
visual grading).
We find this argument unpersuasive because there is no requirement
that every possible composition functions, only that there is a reasonable
expectation of success based on the teachings of the prior art. “Obviousness
does not require absolute predictability of success ... all that is required is a
reasonable expectation of success.'''’ In re Kubin, 561 F.3d 1351, 1360 (Fed.
Cir. 2009). Here, Ho teaches a vitamin E formulation that self-emulsifies
(FF 4), and Lipari provides extensive guidance on formulations that self-
emulsify (see, e.g., Lipari 16-18, Table 1A).
Moreover, it is unclear that Ali supports the position Appellants
propound because it is unclear that Ali teaches any of the compositions of
Table 2 fail to form a self-emulsifying system. Ali teaches: “Within these
limits a homogenous transparent microemulsion pre-concentrate is
produced. Outside these limits a non-homogenous product or a turbid
microemulsion preconcentrate is formed” (Ali 105, col. 2). Thus, Ali is
reasonably understood as teaching that there is a turbidity difference, but Ali
never indicates that these compositions are not self-emulsifying. Indeed, Ali
5 Ali et al., Comparison between lipolysis and compendial dissolution as
alternative techniques for the in vitro characterization of a-tocopherol self-
emulsified drug delivery systems (SEDDS), 352 International J.
Pharmaceutics 104-114 (2008).
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teaches that formulation 8 that was graded as “milky” also had a Y4 value
(percentage of vitamin E dissolved in the dissolution medium) of 91.85, very
close to the 95.95 value for the translucent formula 1 (see Ali 106, table 2).
Thus, to the extent that Ali shows differences in vitamin E dissolution
for 25 different self-emulsifying compositions, that evidence supports the
Examiner’s obviousness rejection because each of the 25 compositions was
capable of self-emulsifying (see Ali 105, col. 2; “a turbid microemulsion
preconcentrate is formed”). In addition, the efficacy differences between the
25 compositions is not relevant to claim 56, because claim 56 imposes no
specific percentage of vitamin E that must be dissolved in the aqueous
dissolution media after self-emulsification occurs.
Appellants contend “there is some evidence that Examiner may
beli[e]ve Claim 3 of Ho suggests higher concentrations of Vitamin E than
otherwise described in Ho. Any indication that Claim 3 of Ho teaches a
SEDDS having 24.8% Vitamin E is a direct contradiction of the teachings of
Ho” (App. Br. 15; cf. Reply Br. 4). Appellants contend the “recited
limitations of Claim 3 of Ho track the ‘final master formulation’ precisely
down to the 10th of 1%. With Tocomin @50% being approximately 50%
Vitamin E the percentage of Vitamin E claimed in Ho[.] Claim 3 is no
different than the final master formulation, i.e. 12.4%” {id.).
We are not persuaded because Ho teaches the amount of tocotrienols
may be optimized, specifically teaching that one system “can incorporate a
bigger amount of tocotrienols” “compared to the other two systems” (FF 7),
reasonably suggesting the amount of vitamin E is a results-effective variable.
Moreover, Lipari teaches that drug concentrations may be optimized and
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teaches solubility and temperature are relevant to “selection of a suitable
concentration” of active agent (FF 15).
Finally, while we agree with Appellants that the master formulation
appears to be the descriptive source of the 24.8% value in claim 3 of Ho,
claim 3 broadly claims “wherein the fat-soluble drug is about 24.8 weight
percent” (FF 6). Appellants provide no evidence that this statement is not
enabled by Ho and it does represent a specifically described teaching of Ho.
“[DJuring patent prosecution, an examiner is entitled to reject claims as
anticipated by a prior art publication or patent without conducting an inquiry
into whether or not that prior art reference is enabling. . . . [T]he burden
shifts to the applicant to submit rebuttal evidence of nonenablement.” In re
Antor Media Corp., 689 F.3d 1282, 1289 (Fed. Cir. 2012). Appellants have
provided no evidence that the 24.8 weight percent value for fat-soluble drugs
taught by Ho would not have been enabled by Ho.
Appellants contend
that a mere identification of a compound that can dissolve some
quantity of Vitamin E among hundreds or thousands of
similarly capable [compounds] is of very little help in a
multivariate optimization that would be needed to achi[e]ve the
Optimization Objective. Accordingly, a mere identification of a
compound that can dissolve some quantity of Vitamin E does
not make that compound a result effective variable.
(App. Br. 17). Appellants further contend the Examiner has failed to
establish Labrasol, Cremophor, Captex, or Ethanol as result effective
variables (see App. Br. 18).
We find this argument unpersuasive. Ho teaches testing “different
surfactant systems at various ratio” (FF 3), and specifically teaches “studies
optimized three important formulation variables” including vehicle
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components, surfactant system, and combination of those components (FF
7). Lipari teaches to select “a suitable total amount of glycerides in an
amount effective to solubilize the phospholipid” (FF 12) and teaches
surfactant amounts can be selected within a range (FF 13).
Moreover, Ali, a prior art reference cited by Appellants, demonstrates
that the person of ordinary skill in the art, prior to the time of invention,
would have known that “[ajmong the critical factors that are frequently
considered for the optimal in vitro performance of SEDDS are the surfactant
concentration, oil to surfactant ratio, triglyceride and co-solvent content,
polarity of the emulsion, and droplet size” (Ali 104, col. 2). Ali further
teaches “optimizing the ratio of primary and secondary surfactants, and oil
are essential to produce SEDDS with desirable in vitro characteristics” (Ali
113, col. 1). Finally, Ali teaches “standard dissolution studies are suitable
for optimizing SEDDS formulations and for identifying critical formulation
variables” (Ali 113, col. 1). Thus, Ali evidences that the ordinary artisan
would have had assays to optimize SEDDS formulations and would have
optimized concentrations of components because these are critical
formulation variables. Appellants provide no evidence that such
optimization was anything other than routine.
Appellants contend they “developed a new SEDDS with
unprecedented vitamin E loading and shown it to have exceptional
emulsification performance” (Reply Br. 2).
We find this argument unpersuasive because Appellants identify no
evidence supporting any unexpected results. See In re Soni, 54 F.3d 746,
750 (Fed. Cir. 1995) (“It is well settled that unexpected results must be
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established by factual evidence. Mere argument or conclusory statements
. . . [do] not suffice.”)
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that Ho
and Lipari render claim 56 obvious.
SUMMARY
In summary, we affirm the rejection of claim 56 under 35 U.S.C.
§ 103(a) as obvious over Ho and Lipari. Claims 57-75 fall with claim 56.
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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