Ex Parte 6440457 et al

Board of Patent Appeals and Interferences

Nov 18, 2010

90008142 (B.P.A.I. Nov. 18, 2010)

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.
90/008,142 09/06/2006 6440457 0002717-00264 6540
23122 7590 12/08/2010
RATNERPRESTIA
P.O. BOX 980
VALLEY FORGE, PA 19482
EXAMINER
TURNER, SHARON L
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
12/08/2010 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte ALZA CORP.
Patent Owner and Appellant
____________

Appeal 2010-007626
Reexamination Control 90/008,142
Technology Center 3900
Patent No. 6,440,457
____________

Before ROMULO H. DELMENDO, RICHARD M. LEBOVITZ, and
JEFFREY B. ROBERTSON, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL1
This is a decision on the appeal by the Patent Owner of U.S. Patent
No. 6,440,457 B1 from the Patent Examiner’s rejection of claim 1 in an Ex

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
shown on the PTOL-90A cover letter attached to this decision.
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Parte Reexamination proceeding. The Board’s jurisdiction in this appeal is
based on 35 U.S.C. §§ 6(b), 134, and 306. We reverse the Examiner.

STATEMENT OF THE CASE
U.S. Patent No. 6,440,457 (hereinafter “the ‘457 patent”) issued
August 27, 2002. The named inventors are David E. Edgren, Gurdish K.
Bhatti, Zahedeh Hatamkhani, and Patrick S.L. Wong. The patent owner
(“assignee”) is Alza Corporation (App. Br. 1, dated Jan. 13, 2009)
(hereinafter, “Alza”). A Request for Ex Parte Reexamination of claims 1 of
the ‘457 patent was filed by Third-Party Requester (“Requester”) on July 28,
2006, pursuant to 35 U.S.C. §§ 302-307 and 37 C.F.R § 1.510 (“Req.”).
Reexamination was sought on the basis, inter alia, that the Examiner did not
consider US Patent 4,111,201 (issued Sep. 5, 1978; hereinafter “the ‘201
patent” or “the ‘201 Theeuwes patent”) during prosecution of the ‘457 patent
(Req. 20).
Reexamination was granted by the Examiner in response to the
Request (Order Granting Request for Reexamination mailed Oct. 5, 2006).
In a Final Rejection dated February 13, 2008, patented claim 1 was rejected.
The final rejection was appealed by the patent owner, who is the Appellant
in this proceeding (hereinafter, “Alza”). Oral arguments by Alza were heard
on September 22, 2010. A written transcript of the oral arguments will be
entered into the electronic record in due course.
A petition by Alza under 37 C.F.R. § 1.181 is pending before the PTO
regarding the propriety of the Examiner’s refusal to enter the Reply Brief
(Petition to the Director, dated May 14, 2010). An Administrative Remand
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was made to the Examiner on November 18, 2010 to decide the petition.
However, because we have decided this appeal in favor of Alza, we consider
the issue moot and vacate the remand.
Claim 1 stands rejected under 35 U.S.C. § 103(a) in view of
Husbands,2 Montgomery,3 Gupta,4, Longer5 and the ‘201 Theeuwes patent.
Claim 1, on appeal and as it appeared in the ‘457 patent, reads as
follows:
1. A method for administering a drug to the
gastrointestinal tract of a human, wherein the method
comprises:
(a) admitting orally into the human a dosage form
comprising a drug of the formula:

which drug possess antidepressant therapy and the dosage form
comprises a member selected from the group consisting of a
sustained-release dosage form and a controlled-release dosage
form; and,

2 U.S. Patent No. 4,761,501, issued Aug. 2, 1988.
3 Stuart A. Montgomery, Venlafaxine: A New Dimension in Antidepressant
Pharmacotherapy, 54 J. Clinical Psychiatry, 119-126 (1993).
4 Pardeep K. Gupta & Joseph R. Robinson, Oral Controlled-Release
Delivery, in Treatise on Controlled Drug Delivery: Fundamentals,
Optimization, Applications 255 (Agis Kydonieus ed., 1992).
5 Mark A. Longer & Joseph R. Robinson, Sustained-Release Drug Delivery
Systems, in Pharmaceutical Sciences 1644 (1985).
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(b) administering the drug from the dosage form over an
extended period of time in a therapeutically responsive dose to
produce the antidepressant therapy.

CLAIM INTERPRETATION
Issue
Whether the claimed method, when given its broadest reasonable
interpretation, is limited to a dosage form that provides once a day, oral
administration of venlafaxine “over an extended period of time in a
therapeutically responsive dose to produce the antidepressant therapy.”

Legal Principles
The “Board gives claim language its broadest reasonable
interpretation consistent with the specification.” In re Buszard, 504 F.3d
1364, 1368 (Fed. Cir. 2007). During patent examination proceedings, claim
terms are given “the broadest reasonable meaning . . . in their ordinary usage
as they would be understood by one of ordinary skill in the art, taking into
account whatever enlightenment by way of definitions or otherwise that may
be afforded by the written description contained in the applicant’s
specification.” In re Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997). This
mode of claim construction applies even in reexaminations. In re Translogic
Tech., Inc., 504 F.3d 1249, 1256 (Fed. Cir. 2007); In re Am. Acad. of Sci.
Tech Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004).
“[W]hile it is true that claims are to be interpreted in light of the
specification and with a view to ascertaining the invention, it does not follow
that limitations from the specification may be read into the claims.” Sjolund
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v. Musland, 847 F.2d 1573, 1581 (Fed. Cir. 1988). See Texas Digital Sys.,
Inc. v. Telegenix, Inc., 308 F.3d 1193, 1204 (Fed. Cir. 2002).
“Absent an express definition in their specification, the fact that
appellants can point to definitions or usages that conform to their
interpretation does not make the PTO's definition unreasonable when the
PTO can point to other sources that support its interpretation.” In re Morris,
127 F.3d at 1056.
“An essential purpose of patent examination is to fashion claims that
are precise, clear, correct, and unambiguous. Only in this way can
uncertainties of claim scope be removed, as much as possible, during the
administrative process.” In re Zletz, 893 F.2d 319, 322 (Fed. Cir. 1989).

Findings of Fact (FF)
1. “The primary goal of drug administration is to provide a therapeutic dose
of drug in the body to achieve a desired blood concentration, and then
maintain the desired drug blood concentration.” (‘457 patent, col. 1, ll. 24-
27.)
2.
One dosage program consists of a single dosing of the drug
from a conventional capsule or tablet that produced a rapid rise
followed by an immediate decline of the drug blood level
versus time. The single dosing does not maintain the drug
within a therapeutic range for an extended period of time, but
exhibits of a short duration of action due to the inability of the
conventional dosage form to provide drug delivery over time.
(Id. at col. 1, ll. 29-36.)
3.
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Another prior art dosing program used to obtain and to achieve
drug blood levels consists in administering the drug repetitively
using conventional dosage forms at various dosing intervals, as
in multiple-dose therapy. . . . There are, however, several
potential problems inherent in multiple dose therapy. For
example, if the dosing interval is not appropriate for the
biological half-life of the drug, large peaks and valleys may
result in the drug blood levels.
(Id. at col. 1, ll. 37-47.)
4.
A critical need exists for a controlled-rate dosage form for
administering the drug of the formula: [showing a genus of
chemical structures which includes venlafaxine] which drug is
presently administered in conventional dosage forms including
tablets, capsules, elixirs and suspensions. These conventional
dosage forms produce the peaks and valleys drug pattern
presented above and they do not provide for controlled-rate
therapy over an extended period of time. The drug of the
formula is dosed twice or thrice a day now because of its
elimination half-life of three to five hours. This pattern of
dosing indicates the need for a controlled-release dosage form
that can administer the drug at a controlled rate over an
extended time to provide constant therapy and thereby eliminate
the need for multiple dosing.
(Id. at col. 2, ll. 1-24.)
5. The “Objects of the Invention” in paragraphs 1, 2, 4, 5, 7, and 9, refer to
“controlled release delivery,” “controlled-rate dose in a therapeutic range
over a prolonger period of time,” “controlled-release system that can deliver
a drug for maintaining constant drug levels in the blood thereby functioning
as a prolonged release system,” “slow release of the drug over an extended
period of time optionally in a therapeutic range,” an improvement which
“comprises delivering the drug in a controlled-release rate from the dosage
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form for improved and known therapy,” and “orally administering the drug
in a controlled rate dose per unit dose over an extended time.” (Id. at col. 3,
ll. 1-37).
6. Paragraph 8 of the “Objects of the Invention” reads: “Another object of
the invention is to provide a once-a-day controlled-release dosage form to
deliver the drug of the structural formula orally to a patent in need of
therapy.” (Id. at col. 3, ll. 31-33.)
7. ‘457 patent states:
The dosage form 10 of drawing FIG. 1 illustrates a controlled-
release dosage form manufactured as an osmotic dosage form
that delivers a drug by osmotic action over an extended period
of time. The dosage form comprising controlled-release
properties embraced by this invention are successful at
maintaining substantially constant drug levels in the blood or in
a tissue.
(Id. at col. 4, ll. 21-27.)
8. ‘457 patent states:
The dosage forms within the mode and manner of this invention
comprises also sustained-release dosage forms. The sustained-
release dosage forms releases the drug and provide drug levels
in the blood or target tissue within a therapeutic range over an
extended period of time.
(Id. at col. 4, ll. 28-33.)
9. The ‘457 patent, in reference to venlafaxine (compound shown at col. 6,
ll. 23-30) states: “The therapeutic amount of drug 16 in dosage form 10 is
0.5 mg to 750 mg, with individual dosage forms comprising 2, 5, 10, 25, 40,
50, 75, 100, 150, 250, 300, 500, and 600 mg of drug 16 for administering in
a single dose or in more then one dose over an extended period of 24 hours.”
(Id. at col. 6, ll. 40-45.)
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10. In the “Detailed Disclosure of Examples of the Invention,” the examples
are said to be “merely illustrative of the present invention and they should
not be considered as limiting the scope of the invention in any way” (id. at
col. 11, ll. 26-29).
11. Examples 1, 2, 3, and 4 of the “Detailed Disclosure of Examples of the
Invention” show dosage forms that deliver venlafaxine in simulated fluid
(Ex. 1) or artificial intestinal fluid (Ex. 2-4) for 15 hours, 16 hours, 15 hours,
and 20 hours, respectively (id. at cols. 11-13).
12. The ‘457 patent describes prior art control release formulation, but
states that drugs of the formula recited at column 2, lines 3-13, which
include venlafaxine, “possess properties such as a high solubility of 570 mg
per ml at a body temperature of 37ºC. that can lead to a premature release of
the drug from the dosage form.” (Id. at col. 2, ll. 44-48.)
13. An object of the invention is stated to be: “to provide a dosage form
that can deliver the drug of the formula essentially-free of a premature
release from the dosage form.” (Id. at col. 3, ll. 8-10.)

Gupta
14. “Sustained-release systems are those that allow at least a twofold
reduction in dosing frequency when compared to the same drug in
conventional dosage form.” (Gupta, p. 277.)
15. “Dose dumping is a phenomenon where a large amount of drug is
released in a short period of time, resulting in undesired high plasma levels
and potential toxicity.” (Id. at 256.)

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Analysis
Claim 1 comprises administering venlafaxine in a “sustained-release
dosage form” or a “controlled-release dosage form” and “over an extended
period of time in a therapeutically responsive dose to produce the
antidepressant therapy.”
Alza contends that “sustained-release” and “controlled-release”
dosage forms would be interpreted by one of ordinary skill in the art to
mean dosage forms that “allow[ ] for once a day oral administration of
venlafaxine” (App. Br. 15). In support of this position, Alza asserts:
• “To persons skilled in the art in 1993,” the terms “sustained-release”
dosage form and “controlled-release” dosage form “required that the dosage
forms allow for reduced dosing frequency as compared with the prior art.”
(Id.)
• Gupta “sets forth the definition of a sustained-release dosage form as
one that allows ‘at least a twofold reduction’ in dosing frequency as
compared to conventional dosing frequency using immediate-release dosage
forms” (id. at 19).
• “In 1993, for the treatment of depression, it was known that
immediate-release venlafaxine should be dosed twice-a-day (id.).
• Examples 1-4 describe dosage forms that allow for once-daily
dosing (id. at 21).
The Examiner contends that the claims are not limited to once-a-day
administration. The Examiner found that administration of an immediate-
release form as in the Montgomery publication would be “sufficient to meet
the ‘sustained-release dosage form and a controlled-release dosage form’ as
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the treatment notes administration of a constant amount of drug, for example
at 75-375 mg/day t.i.d[.], which is maintained within the therapeutic range
and over an extended period of time” (Answer 8-9). The Examiner also
found that the immediate-release release Effexor was within the scope of the
claim because it was administered over an extended period of time (id.).

Gupta
Appellant contends that Gupta compels a narrower interpretation of
claim 1 because it defines the “sustained-release dosage form” to mean at
least a two-fold reduction in dosage as compared to the conventional dosage
form, which in light of the known immediate-release dosages of venlafaxine,
would be understood to mean a 24-hour or once-a-day formulation.6
In his review article, Gupta stated that “Sustained-release systems are
those that allow at least a twofold reduction in dosing frequency when
compared to the same drug in conventional dosage form.” (FF14.) While
this may be a plausible definition of the term “sustained-released,” there is
insufficient evidence that this was the definition adopted by the inventors of
the ‘457 patent in describing the subject matter of claim 1. The evidence of
record does not show that this “definition” is the “ordinary meaning” of the
claim term as it would have been understood by persons of ordinary skill in
the art. To the contrary, the ‘457 patent describes the sustained-release

6 This argument only applies to the claimed “sustained-release dosage form.”
However, claim 1 comprises “admitting orally” either a “sustained-release
dosage form” or a “controlled-release dosage form.” Thus, even if Alza is
correct that, based on Gupta, the “sustained-release dosage form” is limited
to at least once a day dosing, this interpretation would not apply to the
claimed “controlled-release dosage form.”
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dosage form more broadly as one which “releases the drug and provide drug
levels in the blood or target tissue within a therapeutic range over an
extended period of time” (FF8), without requiring a specific reduction in
dosing frequency.
Dr. Donald R. Paul, an expert in the design of controlled-release and
sustained release drug delivery systems for oral administration to the human
gastrointestinal tract, testified in a declaration on behalf of Alza that “in the
context of venlafaxine, under the definition of Gupta, a sustained-release
dosage form would be one that can be administered to a human with a
twofold reduction of the twice or thrice daily, i.e., just once-a-day.” (Paul
Dec. ¶ 31)
Claim terms are read in light of the specification to determine their
meaning as they would be understood by persons of ordinary skill in the art.
In re Morris, 127 F.3d at 1054. Dr. Paul explained how “sustained-release”
would be understood in view of Gupta, but not in the context of the ‘457
patent’s written description. While the prior art definition of Gupta might be
consistent with Appellant’s definition as set forth in their Brief, this is not
the proper standard upon which to base claim interpretation. Rather, the
issue is how the terms are employed in the ‘457 written description, an
inquiry which must begin by reading the patent.
In this case, the ‘457 patent describes its invention as controlled-rate
dosage forms to achieve and maintain a desired blood concentration in
contrast to dosage forms in which there is a rapid rise and decline of drug
levels, leading to “large peaks and valleys” in drug blood levels (FF1-FF5).
The ‘457 patent expressly recognized a “critical need” for controlled rate
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delivery forms that do not “produce the peaks and valleys” and which
provide “constant [drug] therapy” over an extended period of time (FF4). In
seven paragraphs of the ‘457 patent which state the “Objects of the
Invention,” six (1, 2, 4, 5, 7, and 9) refer to “controlled” and “slow” release”
formulations (FF5), but only one paragraph (8) refers to “once-a-day”
dosage forms (FF6). Thus, “once-a-day” formulations are described in the
‘457 patent, but they appear to be a narrower embodiment of the more
general invention of controlled and slow release formulations.
Consistently, at column 4 of the ‘457 patent, a controlled release
dosage form is described as one which has properties that “are successful at
maintaining substantially constant drug levels in the blood or in a tissue.”
(FF7.) A sustained-release dosage form is described as one which “releases
the drug and provide[s] drug levels in the blood or target tissue within a
therapeutic range over an extended period of time.” (FF8). In neither case,
do the descriptions restrict the dosage forms to ones which require the
extended release to last for 24 hours. Yet, the inventors recognized 24-hour,
once-a-day formulations as a part of the invention, describing them
explicitly in two sections (FF6 & FF9), but in other sections of the patents,
characterized the invention more broadly. Plainly, the once-a-day
formulation is a species of the broader genus of controlled-release dosage
forms.
There are additional terms in the claim which lead to this broader
interpretation. Claim 1 recites “administering the drug from the dosage form
over an extended period of time in a therapeutically responsive dose to
produce the antidepressant therapy.” We interpret this to mean that the
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administered dosage form has the property of delivering the drug in a
therapeutic amount for an extended period of time. As indicated at column
6, lines 40-45, the amount of venlafaxine in a dosage form can vary over a
wide range, from small to large amounts and can be administered “in more
than one dose” (FF9). Since claim 1 is not limited to a particular amount of
venlafaxine, it is not reasonable to read the claimed sustained- and
controlled-release formulations as delivering therapeutic amounts for 24
hours. That is, when smaller amounts of venlafaxine are placed in the
dosage form, these amounts may be insufficient to achieve therapy over the
full 24 hour period.

Examples
Alza contends:
the ‘457 patent discloses that the invention of claim 1 solves the
problems associated with multiple daily dosing and provides a
method of dosing venlafaxine “once-a-day.” (Tab 106, ‘457
patent at col. 3, ll. 31-33; see also col. 2, ll. 21-24.) In addition,
the four numbered examples in the ‘457 patent each disclose
dosage forms that allow for once daily dosing of venlafaxine.
(App. Br. 16)
The ‘457 patent expressly states that the examples are not to limit the
scope of the invention in any way (FF10). Consequently, it is inconsistent
with the inventors’ own words to read the claims as limited to the dosage
forms described in the examples.

Summary
By statute, claims must “particularly point[ ] out and distinctly
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claim[ ] the subject matter which the applicant regards as his invention.” 35
U.S.C. § 112, second paragraph. It is therefore the purpose of the claims,
not the patent specification to point out the subject matter which is regarded
as the invention. Accordingly, while claims must be read in view of the
specification, limitations from the specification are not imported into the
claims. Texas Digital Sys., 308 F.3d at 1204. Rather, the patent applicant
has the burden of writing claims which are precise, clear, and free as much
uncertainty as possible regarding their scope. In re Zletz, 893 F.2d at 322.
In our opinion, the claims do not precisely and clearly limit the dosage forms
to those which require at least one a day dosing.
We agree that one problem the ‘457 patent addresses is multiple drug
dosing and provides a once-a-day dosage form as a solution. However, the
patent more generally and explicitly describes the invention as controlled
release dosage forms that deliver drugs for an extended period of time
without the peaks and valleys (FF4 & FF5). The express descriptions in the
patent of the claimed sustained- and controlled-release drug formulations
(FF7 & FF8) do not limit them to 24-hour formulations. Thus, while 24-
hour formulations are exemplified in the ‘457 patent, absent express
limitations in the claim, we will not interpret the claims more narrowly than
the claim language mandates.

Immediate-release and dose-dumping
The Examiner appeared to interpret the claims to cover immediate-
release formulations which were administered over an extended period of
time to produce an extended therapeutic effect (Answer 12 & 23). This
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interpretation is incorrect because it ignores the explicit limitation in the
claim that the “dosage form” is “a sustained-release dosage form” or “a
controlled-release dosage form.” The ‘457 patent, as discussed above,
defined the dosage form itself as responsible delivering the drug over an
extended period of time to achieve the therapeutic effect (FF7 & FF8).
The ‘457 patent also expressly distinguishes its invention over prior
art dosing regimes which are of short duration (i.e., immediate release),
characterized by “peaks and valleys”, and which prematurely release drug –
a phenomenon known as “dose dumping” (FF2, FF3, FF4, FF11, FF12,
FF13, & FF15). This is reflected in the claim language which requires the
dosage form be administered “over an extended period of time in a
therapeutically responsive dose to produce the antidepressant therapy.”
Immediate-release and dose dumping dosage forms would not possess this
claimed characteristic because neither would administer a therapeutically
responsive dose over an extended period of time. Consequently, we
interpret the claims to exclude immediate-release and dose dumping dosage
forms (FF12 & FF13), the precise problems addressed by the claimed
sustained- and controlled-release dosage forms.

Conclusion
The claimed “sustained-release dosage form” and “controlled-release
dosage form” are not limited to dosage forms which administer therapeutic
amounts for at least a 24-hour period to produce the antidepressant therapy.
However, we interpret these dosage forms which administer “the drug from
the dosage form over an extended period of time in a therapeutically
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responsive dose to produce the antidepressant therapy” to exclude dosage
forms which are immediate-release or which experience dose dumping.

OBVIOUSNESS
Issue
Whether the combination of Gupta, Longer, and the ‘201 Theeuwes
patent, coupled with the knowledge of a person of ordinary skill in the art,
would have enabled the claimed method of “administering” “sustained-
release” or “controlled-release” dosage forms “over an extended period of
time in a therapeutically responsive dose to produce the antidepressant
therapy.”
Legal Principles
“References relied upon to support a rejection under 35 USC 103
must provide an enabling disclosure, i.e., they must place the claimed
invention in the possession of the public.” In re Payne, 606 F.2d 303, 314
(CCPA 1979).
“Thus, upon careful reconsideration it is our view that if the prior art
of record fails to disclose or render obvious a method for making a claimed
compound, at the time the invention was made, it may not be legally
concluded that the compound itself is in the possession of the public.
[footnote omitted].” In re Hoeksema, 399 F.2d 269, 274 (CCPA 1968).

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Findings of Fact
Edgren Declaration
16. David E. Edgren, is one of the named inventors of the ‘457 patent and
an employee of Alza, the owner of the ‘457 patent (Edgren Dec. ¶¶ 1 & 2;
date stamped Mar. 19, 2007).
17. Mr. Edgren testified that he “had significant experience with sustained-
release and controlled-release dosages forms” and had “worked with
elementary osmotic pump (‘EOP’) dosage forms (e.g., the dosage form
disclosed in the ‘899 patent) and push pull (‘push-pull’) dosage forms (e.g.,
the dosage form disclosed in the ‘725[7] patent).” (Id. at ¶ 10).
18. Mr. Edgren testified that the EOP is a basic design of the osmotic drug
delivery system and “is still tested in the initial stages of making an osmotic
dosage form and, if it successfully operates, it is an acceptable, cost effective
and feasible design.” (Id. at ¶ 14.)
19. According to Mr. Edgren, an “EOP is suited for a drug with a solubility
between 200 and 400 mg/ml.” (Id. at ¶ 15.)
20. The ‘201 patent, Mr. Edgren testified, describes another type of osmotic
drug delivery system that “was a preliminary step in the development of
push-pull dosage forms.” (Id. at ¶ 16.)
21. Mr. Edgren testified that the push-pull technology in the ‘201 patent
started with the same basic structure as the EOP “and then added a coated
delivery member(s) interspersed within” the drug composition which helps
to push the drug composition out of the device (id. at ¶ 17).
22. Mr. Edgren stated:

7 US Patent 4,327,725.
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The specific push-pull system described in the ‘201 patent was
not a feasible design due to its complexity. After further
development of push-pull technology that resulted in the ‘725
patent, the push-pull osmotic system disclosed in the '201
patent was essentially abandoned as a platform for osmotic drug
delivery at Alza. To the best of my knowledge, the push-pull
osmotic system of the ‘201 patent was never a feasible or
practical design. Indeed, although as noted above, I worked in
this field in Alza beginning in 1975, I was unaware of the ‘201
patent which issued in 1978 until recently when it was cited by
PTO Examiners in connection with the prosecution of
applications for which I am listed as an inventor.
(Id. at ¶ 18.)
23. Mr. Edgren described the push-pull device described in the ‘725 patent
as an improvement over the device described in the ‘201 patent:
Unlike the coated delivery members disclosed in the ‘201
patent, the ‘725 patent teaches an uncoated, single layer of an
expandable driving member formed of a water swellable
hydrogel that absorbs fluid imbibed into the dosage form and
can expand from a compressed to an expanded state . . . [,]
pushing more drug composition from the dosage form . . . Such
push-pull osmotic systems have been commercialized . . ..
(Id. at ¶ 19.)
24. Mr. Edgren testified that he “managed and directed a project at Alza
Corporation to place venlafaxine in a new dosage form.” (Id. at ¶ 20.)
25. After preliminary testing, Mr. Edgren testified “we began our in vitro
experiments with our standard procedure of creating drug compositions and
putting them in both an EOP and push-pull.” (Id. at ¶ 27.)
26. Mr. Edgren testified that he was also working with the push-pull dosage
form in the ‘725 patent because the “push-pull design in the ‘201 patent was
not feasible or practical” (id. at ¶ 30).
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27. Mr. Edgren described various problems experienced in making a
venlafaxine dosage form (id. at ¶¶ 30-34).
& 31).
28. However, Mr. Edgren stated that they were “rapidly approaching a
deadline for having a usable dosage form” of venlafaxine and while “we did
not yet have a feasible and practical dosage form, we selected our best
current experimental dosage form for use in the bioavailability study.” (Id.
at ¶ 34).
29. During the fabrication and testing of the clinical batch for the
bioavailability study, Mr. Edgren identified problems that arose, the “most
troubling problem was that the dosage form exhibited dose dumping,”
characterized as “a premature release of the drug from the dosage form.”
(Id. at ¶ 35.)
30. Mr. Edgren testified that he was “surprised to see this problem with
venlafaxine” and had “never personally experienced this problem with any
prior drugs” he had worked on. (Id. at ¶ 35.)
31. Mr. Edgren provided evidence from the laboratory notebook of one
member of his team showing the dosage dumping observed with the
venlafaxine dosage form (id. at ¶¶ 36 & 37).
32. He concluded: “Such a premature and uncontrolled release of the drug
was unacceptable for a dosage form of venlafaxine that would be given to
humans.” (Id. at ¶ 37.)
33. Mr. Edgren testified:
Adding to the complexity of the problem was that the dose
dumping observed in vitro was pH dependent, contrary to our
initial testing of venlafaxine in which we saw no pH
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dependence. The pH dependence of solubility is relevant to how
the drug is released from the dosage form as it travels from the
stomach (pH is acidic) to the colon (pH is neutral). Our
preliminary tests had showed that the solubility of venlafaxine
was not pH dependent; however, surprisingly, the release rate
profiles on our best current experimental dosage form showed
dose dumping of venlafaxine in artificial intestinal fluid
(“AIF”) (pH is neutral, like the colon) when compared to
artificial gastral fluid (“AGF”) (pH is acidic, like the stomach).
(Id. at ¶ 38.)
34. Mr. Edgren provided a figure showing evidence of this pH dependence,
stating that “[w]e had no idea why a drug with a solubility that we
understood to be pH independent demonstrated drastic differences between a
release in AGF versus AIF” and stated that this “added to the complexity of
the problem because we would have to correct the dose dumping problem in
AIF without changing the release profile in AGF.” (Id.)
35. Finally, Mr. Edgren stated:
As of early 1993, I was not aware of any literature or other
publication that explained how to solve the problem of dose
dumping of a highly soluble drug. Therefore, using our known
procedures for putting a drug in the push-pull osmotic
technology still failed to produce an acceptable sustained-
release or controlled-release dosage form.
(Id. at ¶ 39.)
36. Mr. Edgren testified that through “further extensive experimentation”
they were able to solve the dose dumping problem and that the results of the
successful dosage form are shown in the examples of the ‘457 patent. (Id. at
¶ 40.)

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Paul Declaration
37. Testimony in the form of a declaration was provided by Donald R. Paul,
Ph.D., a scientist and professor at University of Texas, with extensive
experience in the design of controlled-release and sustained release drug
delivery systems for oral administration to the human gastrointestinal tract
(Paul Dec. ¶ 1, 4, & 5).
38. Dr. Paul stated that he “talked with David Edgren about the work
conducted at Alza that led to the ‘457 patent” and “reviewed notebooks that
memorialize that work.” (Id. at ¶ 60).
39. Consistent with Mr. Edgren’s testimony, Dr. Paul stated that, when
working with the push-pull dosage form, the inventors of the ‘457 patent
“observed dose-dumping; that is, venlafaxine was prematurely and
uncontrollably released from the dosage form.” (Id. at ¶ 62.)
40. According to Dr. Paul, the ‘201 patent “does not contain any disclosure
indicating recognition of the problem of dose dumping, nor does it propose
any solution for preventing dose dumping.” (Id.).
41. Furthermore, Dr. Paul testified: “I am not aware of any reference prior
to the filing date of the application leading to the ‘457 patent that explained
a method for solving the problem of dose dumping in an osmotic dosage
form.” (Id.)
42. Dr. Paul acknowledged that the experiments at Alza did not include the
dosage form described in the ‘201 patent, but he testified that “one skilled in
the art would have expected dose dumping with the ‘201 dosage form with
venlafaxine” and that “the distinctions between the designs [of the ‘201 and
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‘725 push-pull dosage forms] are irrelevant to the issue of dose dumping.”
(Id. at ¶ 63.)
43. Dr. Paul explained the basis for his opinion as to why dose dumping
would have been expected with venlafaxine in the dosage form of the ‘201
patent:
As can be seen in Figure 7 [of the ‘201 patent], the release rate
in the first two hours of the test is significantly higher than the
on-going release rate in the time period from 4-7 hours. This
initial release rate in Figure 7 suggests a large amount of drug
prematurely released in a short period of time which Gupta
refers to as dose dumping. (See Tab 203, Gupta at 256). The
delivery profile in Figure 7 for procainamide appears to be
similar to profiles that the inventors of the ‘457 patent deemed
unacceptable due to dose dumping. (See, e.g., Lab Notebook
3296, pages 24, 28, cited hereinafter as Tab 206, 3296:24, 28).
Moreover, I note that procainamide is less soluble than
venlafaxine and therefore one of ordinary skill in the art would
have concluded, based on the difference in solubility and the
effect of that solubility difference on the osmotic pressure, that
dose dumping would have been a more significant problem
with venlafaxine.
(Id. at 64.)
Analysis
Obviousness
The Examiner found that each of Montgomery and Husbands
described administration of venlafaxine to treat depression (Answer 6-8).
The Examiner found that the difference between Montgomery and Husbands
and claim 1 was that the latter publications did not describe “administering
the drug from “a sustained-release dosage form” or “a controlled-release
dosage form . . . over an extended period of time in a therapeutically
responsive dose to produce the antidepressant therapy” as recited in the
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claim. However, the Examiner found that the ‘201 Theeuwes patent
described sustained- and controlled-release delivery systems and that
persons of ordinary skill in the art would have had reason to use the
Theeuwes system for its recognized advantage in achieving controlled drug
release (id. at 10-11). To establish that persons of ordinary skill in the art
were familiar with controlled and sustained release delivery systems, the
Examiner cited Gupta and Longer (id. at 3-5.)
Alza contends that there is a “complete lack of a proper prima facie
case of obviousness because of the lack of any reasonable expectation of
success.” (App. Br. 6). As evidence of this, Alza relied upon testimony co-
inventor David Edgren (FF16) and drug delivery system expert Dr. Donald
R. Paul (FF37).

Dose dumping
Mr. Edgren testified in his declaration about the experiments which
led to the filing of the application that gave rise to the ‘457 Patent. Mr.
Edgren testified that his team selected their “best experimental dosage form
for use in” a bioavailability study of venlafaxine (FF28). This dosage form
was based on the ‘725 patent disclosure, not the cited ‘201 Theeuwes patent
(FF17-25). During the fabrication and testing of the clinical batch for the
bioavailability study of venlafaxine, Mr. Edgren identified problems that
arose, the “most troubling problem was that the dosage form exhibited dose
dumping,” characterized as a premature and uncontrollable release of the
drug from the dosage form (FF29). Mr. Edgren testified that he was
“surprised to see this problem with venlafaxine” and had “never personally
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experienced this problem with any prior drugs” he had worked on (FF30).
Mr. Edgren provided a figure from the laboratory notebook of one member
of his team showing the dosage dumping (FF15) observed with the
venlafaxine dosage form (FF31). He concluded: “Such a premature and
uncontrolled release of the drug was unacceptable for a dosage form of
venlafaxine that would be given to humans.” (FF32.)
Mr. Edgren stated that the complexity of this problem was enhanced
because while the solubility of venlafaxine was shown not to be pH
dependent in preliminary tests, the dose dumping surprisingly was pH
dependent (FF33 & FF34).
Dr. Paul confirmed that dose-dumping of venlafaxine had been
observed in Mr. Edgren’s experiments (FF38 & FF39). Dr. Paul testified
that the ‘201 Theeuwes patent showed a release profile of procainamide that
suggested dose-dumping, a similar unacceptable profile observed by the
inventors for venlafaxine using a dosage form based on the ‘725 patent
(FF43). As venlafaxine was even more soluble than procainamide, Dr. Paul
stated that “one of ordinary skill in the art would have concluded, based on
the difference in solubility and the effect of that solubility difference on the
osmotic pressure, that dose dumping would have been a more significant
problem with venlafaxine.” (Id.)
Based on the results observed with procainamide (FF43), Dr. Paul
testified that “one skilled in the art would have expected dose dumping with
the ‘201 Theeuwes dosage form with venlafaxine” and that “the distinctions
between the designs [of the ‘201 and ‘725 push-pull dosage forms] are
irrelevant to the issue of dose dumping.” (FF42). Both Mr. Edgren and Dr.
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Paul stated they were not aware of publications that explained how to solve
the problem of does-dumping observed with a soluble drug (FF35, FF40, &
FF41). Mr. Edgren, however, testified that the ‘457 patent showed how to
solve the problem (FF36).
The Examiner contends that the dose-dumping evidence is
unpersuasive since the ‘201 Theeuwes patent explicitly taught that its device
would work with “very soluble drugs.” (Answer 21; ‘201 patent, col. 2, ll.
59-60.)
It is true that the ‘201 patent taught that its delivery device is effective
to deliver very soluble drugs. However, the evidence – which the Examiner
did not rebut – showed that procainamide (Figure 7 of the ‘201 patent) and
venlafaxine (FF31, FF39, & FF43) experienced dose-dumping, a result
which is excluded from the scope of claim 1 (see Claim Interpretation
section, beginning on page 4). Thus, while the ‘201 patent may be enabling
for osmotic drug delivery devices, Alza provided persuasive evidence that it
did not enable a device formulated with venlafaxine in the absence of dose-
dumping.
Obviousness requires that the prior art, coupled with the knowledge of
a persons of ordinary skill in the art, enable a person of ordinary skill in the
art to make the claimed invention. In re Payne, 606 F.2d at 314; In re
Hoeksema, 399 F.2d at 274. In this case, persuasive evidence was provided
by Alza that it would have required undue experimentation to have made the
claimed sustained- and controlled- release dosage forms. Evidence was
presented that, when the ‘201 dosage form was formulated with venlafaxine,
dose-dumping would have been expected to occur (FF43). Consistently,
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when venlafaxine was combined with the ‘725 dosage form dose-dumping
was observed (FF31 & FF39). Although the ‘725 patent was not the cited in
the obviousness rejection, Dr. Paul testified that, with respect to dose-
dumping, there was no distinction between the designs of the ‘201 and ‘725
push-pull dosage forms (FF42 & FF43). Thus, actual failure with the ‘725
push-pull device would have predicted failure with the ‘201 device. Both
inventor Edgren and Dr. Paul testified that they were not aware of literature,
prior to the filing date of the application which matured into the ‘457 patent,
that taught how to solve the dose-dumping problem (FF35, FF40, & FF41).
Absent such guidance, we conclude that the cited prior art, coupled with the
knowledge of the skilled worker, did not enable a person of ordinary skill in
the art to have made the claimed invention.

SUMMARY
The obviousness rejection of claim 1 is reversed.

TIME PERIOD FOR RESPONSE
Requests for extensions of time in this ex parte reexamination
proceeding are governed by 37 C.F.R. § 1.550(c). See 37 C.F.R. § 41.50(f).

REVERSED

saw
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