Ex Parte 6469012 et al

Board of Patent Appeals and Interferences

Feb 12, 2010

90007478 (B.P.A.I. Feb. 12, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________________

Ex parte PFIZER, INC.,
Patent Owner and Appellant
____________________

Appeal 2009-004106
Merged Reexamination Control Nos.
90/006,617; 90/006,886;
90/007,110; and 90/007,478
Patent 6,469,012 B11
Technology Center 3900
____________________

Decided: February 12, 2010
____________________

Before EDWARD C. KIMLIN, CAROL A. SPIEGEL, and
ROMULO H. DELMENDO, Administrative Patent Judges.

SPIEGEL, Administrative Patent Judge.

DECISION ON APPEAL

1U.S. Patent No. 6,469,012 B1, Pyrazolopyrimidinones for the Treatment of
Impotence, issued 22 October 2002 to Ellis et al. (hereinafter "the 012
patent"), based on application 08/549,792, filed 4 March 1996, under 35
U.S.C. § 371 as the national phase of PCT/EP94/01580, filed 13 May 1994,
which claims benefit under 35 U.S.C. § 119 of GB application 9311920,
filed 9 June 1993. The real party in interest is PFIZER, INC. (Appeal Brief
filed 24 July 2006; Supplemental Appeal Brief filed 14 November 2008
(hereinafter "App. Br.") at 2).
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Appellant Pfizer, Inc. appeals under 35 U.S.C. §§ 134(b) and 306
from an Examiner's final rejection of claim 24. Claims 1-23, 25, and 26, the
only other pending claims, have been found patentable (App. Br. 2; Ans.2 2).
Oral arguments were heard June 3, 2009. We have jurisdiction under 35
U.S.C. §§ 134(b) and 306. We AFFIRM.
I. Statement of the Case
A. Background
The 012 patent issued on October 22, 2002. A first reexamination,
Control No. 90/006,617, was ordered by the Director of the Patent and
Trademark Office on September 29, 2003. A second request for
reexamination, Control No. 90/006,886, was filed by third party requester
Lilly ICOS LLC on December 15, 2003. Reexamination was ordered in the
'886 reexamination proceeding on February 6, 2004. A third request for
reexamination, Control No. 90/007,110, was filed by third party requester
Bayer AG and Bayer Pharmaceuticals Corporation on July 7, 2004.
Reexamination was ordered in the '110 reexamination proceeding on
September 13, 2004. A fourth request for reexamination, Control No.
90/007,478, was filed by third party Requester ICOS Corporation on March
23, 2005. Reexamination was ordered in the '478 reexamination proceeding
on May 16, 2005. A Patent Owner statement was filed with respect to the
first reexamination proceeding only. The '478 reexamination proceeding
was merged with the three previously merged '617, '886, and '110
reexamination proceedings. (See Decision Merging Reexamination

2 Examiner's Answer mailed 20 July 2007 (hereinafter "Ans.").
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Proceedings mailed August 19, 2005; App. Br. 63). A fifth request for
reexamination, Control NO. 90/007,614, was filed by third party requester
Lilly Corporation on July 5, 2005. This request was denied because it was
determined not to cite any new and different patents or printed publications
which would raise a new substantial new question not already of record in
the pending merged reexamination proceeding.4
There is also a pending litigation involving the 012 patent. The Patent
Owner sued Lilly ICOS, LLC, Eli Lilly & Company, and ICOS Corporation
for infringing the 012 patent by making the drug product Cialis®
(Complaint, Pfizer Inc., et al. v. Lilly ICOS LLC et al, Civil Action No. 02-
1561 (D. Del. Oct. 22, 2005))5.
We have fully considered the respective positions and arguments of
the Appellant and the Examiner, as well as all of the evidence submitted in
support thereof unless expressly noted otherwise.
B. The subject matter on appeal
The subject matter on appeal is directed to a method of treating male
erectile dysfunction (hereinafter "ED") by oral administration of a selective
inhibitor of a particular enzyme found in the penis, i.e., cyclic guanosine

3 The Appeal Brief incorrectly stated that the Decision Merging
Reexamination Proceedings was mailed 19 July 2005.
4 See Order Denying Request for Ex Parte Reexamination mailed 18 August
2005 and Decision Dismissing Petition mailed 8 November 2005 in
Reexamination 90/007,614.
5 Complaint filed 22 October 2002 in Pfizer Inc., Pfizer Limited, and Pfizer
Ireland Pharmaceuticals, Plaintiffs, v. Lilly ICOS LLC, Eli Lilly &
Company, and ICOS Corporation, Civil Action No. 02-1561 (JJF) (D. Del.)
attached to the Appeal Brief as Exhibit A (hereinafter "Complaint").
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3',5' monophosphate phosphodiesterase V, also referred to as "cGMP
PDEV," "PDEV," and "PDE5" (hereinafter "PDEV").
Claim 24, the only claim on appeal, reads (App. Br. Clm. App'x 1):
A method of treating erectile dysfunction in a male
human, comprising orally administering to a male
human in need of such treatment an effective
amount of a selective cGMP PDEV inhibitor, or a
pharmaceutically acceptable salt thereof, of [sic,
or] a pharmaceutical composition containing either
entity.
Claim 24 broadly encompasses treating ED by oral administration of
Pfizer's drug Viagra®, Lilly/ICOS LLC's drug Cialis®, and Bayer
Pharmaceuticals Corporation's drug Levitra® (Viagra Package Insert 12;6
Cialis Package Insert 9;7 Levitra Package Insert 108).
C. The rejections
The Examiner rejected claim 24 under 35 U.S.C. § 102(b) as
anticipated by any of Korenman,9 Bensky,10 Hsu,11 Chang,12 and Yin13 (Ans.

6 Viagra® package insert 69-5485-00-9, (Pfizer Labs Revised August 2003).
(Appeal Brief Exhibit F-12 (hereinafter "Viagra Package Insert").)
7 Cialis® package insert PV 3530 AMP, (Lilly ICOA LLC Issued November
2003). (Appeal Brief Exhibit F-9 (hereinafter "Cialis Package Insert").)
8 Levitra® package insert 08669034M (Bayer Pharmaceuticals Corporation
August 2003). (Appeal Brief Exhibit F-10 (hereinafter "Levitra Package
Insert").)
9 Stanley G. Korenman & Sharon P. Viosca, Treatment of Vasculogenic
Sexual Dysfunction with Pentoxyifylline, 41 J. Am. Geriatrics 363-366 (April
1993). (Appeal Brief Exhibit F-2 (hereinafter "Korenman").)
10 Chinese Herbal Medicine Materia Medica, 3-27, 490-92 (Dan Bensky &
Andrew Gamble with Ted Kaptchuk eds. and trans., Eastland Press 1986).
(Appeal Brief Exhibit J (hereinafter "Bensky").)
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4-5). The Examiner relied on Florio Declaration I,14 Florio Declaration II,15
and Iversen Declaration I16 to support the anticipation rejections.
The Examiner also rejected claim 24 under the judicially created
doctrine of obviousness-type double patenting over claim 1 of any of
Campbell 270,17 Campbell 511,18 and Campbell 94519 (Ans. 5-8).

11 Hong-Yen Hsu et al., Oriental Materia Medica: A Concise Guide, 563-65
(Oriental Healing Arts Institute 1986). (Appeal Brief Exhibit H (hereinafter
"Hsu").)
12 2 Pharmacology and Applications of Chinese Materia Medica, 1135-39
(Hson-Mou Chang & Paul Pui-Hay But eds., Shem Chang-Shing Yeung et
al. trans., World Scientific Publishing Co. Pte. Ltd. 1987). (Appeal Brief
Exhibit I (This decision cites to the English translation of Chang by Dennis
Goldwater) (hereinafter "Chang").)
13 Ai-Hua Yin et al., 50 Cases of Treating Male Impotence Using Powdered
YinYangHuo and TuSiZi, 10(6) Yunnan J. Traditional Chinese Med. 13
(1989). (Appeal Brief Exhibit G (hereinafter "Yin").)
14 Declaration under Rule 37 C.F.R. § 1.132 of Vincent Allen Florio, Ph.D.,
dated 12 December 2003. (Answer Exhibit G, Appeal Brief Exhibit UU-7
(hereinafter "Florio Decl. I").)
15 Declaration under Rule 37 C.F.R. § 1.132 of Vincent Allen Florio, Ph.D.,
dated 21 March 2005. (Answer Exhibit F (hereinafter "Florio Decl. II").)
16 Declaration under Rule 37 C.F.R. § 1.132 of Philip W. Iversen, Ph.D.,
dated 14 December 2003. (Answer Exhibit H, Appeal Brief Exhibit UU-8
(hereinafter "Iversen Decl. I").)
17 U.S. Patent 6,100,270, Bicyclic Heterocyclic Compounds for the Treatment
of Impotence, issued 8 August 2000, to Simon Fraser Campbell (hereinafter
"Campbell 270”). (Appeal Brief Exhibit L.)
18 U.S. Patent 6,534,511 B1, Bicyclic Heterocyclic Compounds for the
Treatment of Impotence, issued 18 March 2003, to Simon Fraser Campbell
(hereinafter "Campbell 511"). (Appeal Brief Exhibit M.)
19 U.S. Patent 6,656,945 B2, 6-Heterocyclyl Pyrazolo[3,4-D]Pyrimidin-4-one
cGMP-PDE Inhibitors for the Treatment of Erectile Dysfunction, issued 2
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II. The Anticipation Rejections
Claim 24 is rejected under 35 U.S.C. § 102(b) as anticipated by each
of Korenman, Bensky, Hsu, Chang, and Yin.
A. Anticipation based on Korenman
1. the Examiner's findings
The Examiner found that Korenman successfully treated ED in about
half a patient population by oral administration of pentoxifylline (Ans. 4).
Citing the Florio I and Iversen I declarations,20 the Examiner found that
selective PDEV inhibition is an inherent property of pentoxifylline (id.).
Thus, the Examiner found claim 24 to be anticipated by Korenman (id.).
2. Appellant's arguments
Appellant essentially argues that (i) Korenman does not provide any
meaningful data showing successful treatment of ED or disclose successful
treatment of ED by inhibition of PDEV, (ii) the evidence relied on by the
Examiner to show that pentoxifylline is necessarily a selective inhibitor of
PDEV is flawed and unreliable, and (iii) the Examiner improperly dismissed
rebuttal evidence showing that pentoxifylline is a nonselective PDEV
inhibitor as mere opinion lacking "hard factual evidence" (App. Br. 11-15).
In particular, Appellant argues that "data that lacks statistical significance

December 2003, to Campbell et al. (hereinafter "Campbell 945"). (Appeal
Brief Exhibit N.)
20 The Examiner directed attention to "all of page 38 and the table on page 39
and exhibits J and K" (Ans. 4). Exhibits J and K referred to in the Answer
are identical to Appeal Brief Exhibits UU7 and UU8, respectively.
However, the Examiner did not identify which exhibit contained the
referenced pages 38 and 39 and, therefore, these pages have not been
considered.
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cannot be relied upon to prove or even support a scientific assertion, in this
case that pentoxifylline is selective for PDEV" (App. Br. 41).
3. the issue
The dispositive issue is whether the preponderance of the evidence
establishes that pentoxifylline is inherently a selective PDEV inhibitor.
4. findings of fact
The following findings of fact (hereinafter "FF") are supported by a
preponderance of the evidence of record.
a. Korenman
[1] Korenman characterizes pentoxifylline as a drug which renders red
blood cells more deformable, thereby allowing them to pass more
readily through partially obstructed arterial channels (Korenman 363,
c. 1, ¶ 1).
[2] Korenman hypothesized that pentoxifylline would be similarly
effective in improving blood flow through the penis, thereby
facilitating erection in men with a vascular component of impotence
(Korenman 363, c. 1, ¶ 1).
[3] Study subjects were treated with either placebo or 400 mg tid of
pentoxifylline for twelve weeks (Korenman 364, c. 1, ¶ 3).
[4] Four of eight subjects receiving pentoxifylline initially and none of
ten subjects receiving placebo showed any improvement (Korenman
364, c. 2, ¶ 4), i.e., four of eight subjects receiving pentoxifylline
initially experienced successful intercourse.
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[5] When the ten subjects initially receiving placebo were subsequently
placed on pentoxifylline, five of them experienced successful
intercourse (Korenman 364, c. 2, ¶ 4).
[6] Korenman concluded that these preliminary results suggested a well
tolerated alternative therapy for ED in patients with mild to moderate
penile vascular disease (Korenman 363, abstract).
b. Florio I and Iversen I declarations
[7] Vincent Allen Florio, Ph.D., is a principal scientist and project leader
for phosphodiesterase research at ICOS Corporation and the research
leader for Cialis® on behalf of Lilly-ICOS (Florio Decl. I ¶ 2).
[8] Both Lilly ICOS and ICOS Corporation requested reexamination of
the 012 patent (see the requests for reexamination in Reexamination
Control Nos. 90/006,886 and 90/007,478).
[9] From late October 2003 through early November 2003, Dr. Florio
supervised testing to determine and compare pentoxifylline's IC5021
against PDEIA, PDEII, PDEIIIA, PDEIIIB, PDEIVB, and PDEV (Florio
Decl. I ¶¶ 9-11).
[10] The test protocol supervised by Dr. Florio was run in 8-strip cluster
tubes in a 96-well format, i.e., an 8 row (A-H) x 12 tube (well) matrix
and comprised

21 IC50 is the concentration of an inhibitor at which 50% inhibition of a target
response, such as enzyme activity, is seen. See e.g., International Patent
Publication WO 93/06104, Pyrazolopyrimidinone Antianginal Agents,
published 1 April 1993, at 7-8. (Appeal Brief Exhibit Z (hereinafter "WO
6104").)
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(i) adding 50 µl assay buffer into each well from A1 to H11 and
75 µl of 250 µM pentoxifylline into wells A12 to H12,
(ii) transferring 25 µl of wells A12 to H12 into wells A11 to
H11 with an 8-channel pipettor, mixing and serially repeating through
wells A3 to H3 to make a 1:3 serial dilution over 10 wells in each
row,
(iii) adding 100 µl 3H-cGMP substrate to each well in rows A to
D and 100 µl 3H-cAMP substrate to each well in rows E to H,
(iv) adding 50 µl enzyme to each well as follows to initiate the
enzyme reaction: PDEIA3 to row A, PDEIIA to row B, PDEVA to rows
C and D, PDEIIIA to rows E and F, PDEIIIB to row G, and PDEIVB2 to
row H, and
(v) measuring enzymatic cleavage products using a
scintillation counter (Florio Decl. I, Exhibit A, "Methology [sic]").
[11] Dr. Florio summarized his results as follows (Florio Decl. I ¶11):
PDEIA3 PDEIIA PDEIIIA PDEIIIB PDEIVB2 PDEVA
IC50 (in µM) 233 109 275 333 79.4 63.8
Selectivity Ratio 3.65 1.71 4.31 5.22 1.25 1.00

[12] Florio Declaration I did not contain any raw data.
[13] Phillip W. Iversen, Ph.D., is a statistician employed as a research
scientist by Lilly company (Iversen Decl. I ¶¶ 2-4).
[14] Dr. Iversen testified that he applied a 3-parameter logistic model fit to
analyze the data summarized in the table at paragraph 11 of Florio
Declaration I (Iversen Decl. I ¶¶ 6-7).
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[15] Dr. Iversen concluded that the selectivity ratios for PDEI through
PDEIV versus PDEVA "are statistically significantly different from a
ratio value of 1" (Iversen Decl. I ¶ 8).
c. Appellant's rebuttal evidence
[16] Martyn Frank Burslem, Ph.D., is a research biochemist for patentee
Pfizer (Burslem Decl.22 ¶¶ 2-6).
[17] Mr. Burslem testified that the "relative selectivity" of a compound can
be calculated by dividing the summary statistic for potency, typically
the IC50 of the compound, at a nontarget protein by the summary
statistic for potency at the target compound (Burslem Decl. ¶ 12).
[18] Specifically, Mr. Burslem testified that a compound could be
described as relatively selective for PDEV if the IC50 for PDEI, II, III, or IV
divided by the IC50 for PDEV is statistically greater than 1 (Burslem
Decl. ¶ 12), i.e., "the difference in potency of the drug at the two
enzymes must be greater than the variation occurring in the test
system" (id. ¶ 13).
[19] Ian Colin Marschner, Ph.D., is a statistician employed by Pfizer
Australia Pty. Limited as Director of its Asia Biometrics Centre
(Marschner Decl.23 ¶¶ 1-4).

22 First Declaration under 37 CFR 1.132 of Martyn Frank Burslem, dated 4
June 2005. (Appeal Brief Exhibit P (hereinafter "Burslem Decl.").) The
Burslem Declaration was submitted in Eli Lilly and Company v. Pfizer
Overseas Pharmaceuticals, Federal Court of Australia, Victoria District
Registry, and filed in Reexamination 90/006,886 (Burslem Decl. ¶ 18).
23 First Declaration under 37 CFR 1.132 by Ian Colin Marschner, dated 5
April 2005. (Appeal Brief Exhibit UU (hereinafter "Marschner Decl.").)
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[20] The dates, experimental protocol, and data summary described in
Florio Declaration I are identical to the dates, experimental protocol,
and data summary testified to by Lother Uher, a technical scientist at
ICOS, and by Dr. Florio as described in the Florio24 and Uher25
Affidavits attached to the Marschner Declaration (hereinafter "the
Florio PDE experiment") (see Florio Aff. ¶¶ 9-17 and attached ICOS
Corporation Laboratory Notebook No. 47057, Project 1410, 1-4; Uher
Aff. ¶¶ 4-8 and attached ICOS Corporation Laboratory Notebook No.
47057, Project 1410, 1-4; Florio II Decl. ¶ 13).
[21] The Florio Affidavit provided the raw data collected from the October
28, 2003 to November 18, 2003 PDE testing (Florio Aff. ICOS
Corporation Laboratory Notebook No. 47056, 103-138).
[22] According to Dr. Florio, the data files, including the raw data, were
sent to Dr. Iversen for statistical analysis (Florio Aff. ¶ 18).
[23] Dr. Burslem opined that the Florio PDE experiment was flawed for a
number of reasons including failure to account for expected
experimental variations, such as systemic bias and random

The Marschner Declaration was submitted in Eli Lilly and Company v.
Pfizer Overseas Pharmaceuticals, Federal Court of Australia, Victoria
District Registry, and filed in Reexamination 90/006,886 (Marschner Decl. ¶
6).
24 Affidavit of Vincent Allen Florio in Eli Lilly and Company v. Pfizer
Overseas Pharmaceuticals, Federal Court of Australia, Victoria District
Registry. (Appeal Brief Exhibit UU-2 (hereinafter "Florio Aff.").)
25 Affidavit of Lothar Josef Uher in Eli Lilly and Company v. Pfizer Overseas
Pharmaceuticals, Federal Court of Australia, Victoria District Registry.
(Appeal Brief Exhibit UU-3 (hereinafter "Uher Aff.").)
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experimental error, e.g., the Florio PDE experiment did not run
independent or replicate experiments using new enzyme, inhibitor,
and reagent solutions in order to differentiate meaningful data from
random effects of batch-to-batch enzyme, inhibitor, and reagent
solution or vary the positions of the test samples to account for
positional effects such as edge effects in a matrix plate format
(Burslem Decl. ¶¶ 8-10, 13, 19, and 25-29).
[24] Dr. Burslem reviewed the raw data from the Florio PDE experiment,
determined the intra- and inter-plate variation, and concluded that a
relative selectivity of between 1.2 and 2.2 was within experimental
error (Burslem Decl. ¶¶ 33-34).
[25] Dr. Burslem explained that (Burslem Decl. ¶ 36 (footnote omitted)),
[a]lthough . . . Uher never measured the variability that
arises from the enzyme and pentoxifylline preparations,
he did at least measure the variability that arises simply
from taking multiple measurements from the same
preparations. He measured the inhibition of the PDE
enzymes 4 times for PDE1A, PDE2, PDE3B and
PDE4B2 and 8 times for PDE3A and PDE5. This
variability that arises from taking multiple measurements
from the same experiment is generally less than the
variability that arises from independent experiments
because in the former the enzyme and inhibitor
preparations are the same for each measurement.
Nevertheless, even this degree of variability can be
significant to affect the validity of any analysis of the
data and must therefore be taken into account.

[26] According to Dr. Burslem, based on his own experience over 17
years, variations of 2 to 3.5 fold in IC50 values between replications of
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an experiment using different preparations of enzyme, inhibitor, and
reagent preparations were commonplace (Burslem Decl. ¶¶ 3 and 29).
[27] Dr. Iversen similarly stated that "[f]or many of the assays I have
consulted on, in my experience, the reproducibility of the IC50s is in
the range of 2 to 3" (Australian proceeding transcript26 754), and he
acknowledged that edge effect and single batch experiment problems
may raise concerns where it is critical to establish that a particular
selectivity ratio was a real effect (id. 752-756).
[28] Dr. Marschner faulted the Florio PDE experiment for failing to
include high enough concentrations of pentoxifylline to assess the
entire dose-response curve as well as for not including replicate
experiments to confirm the statistical validity of its conclusions in
view of known sources of experimental error, such as positional edge
effect (Marschner Decl. ¶¶ 6-25).
[29] Instead of analyzing the raw data per se, Dr. Iversen simply calculated
an average of the observed data across all of the runs conducted at
each concentration of a single PDE inhibition experiment and only
analyzed the difference between the averaged data and the theoretical

26 Transcript of proceedings in Eli Lilly and Co. v. Pfizer Research and
Development Co. and Bayer Aktiengesellschaft v. Pfizer Ireland
Pharmaceuticals, Federal Court of Australia, Victoria District Registry.
(Appeal Brief Exhibit Q-2 attached to Appeal Brief Exhibit Q, First
Declaration under 37 CFR 1.132 of Matthew Guy Swinn, dated 6 April 2005
(hereinafter "Australian proceeding transcript").)
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IC50 curve generated by software that fit a curve to the data (Burslem
Decl. ¶¶ 35-38; Iversen Aff.27 ¶¶ 6-8).
[30] It is well known that "no quantitative experimental result is of any
value unless it is accompanied by an estimate of the errors involved in
its measurement" (STATISTICS28 44).
[31] PDEV has been called the cGMP-specific PDE or the cGMP-binding
PDE (Beavo29 738, c. 1, ¶ 2).
[32] Pentoxifylline has been recognized as a cAMP PDE inhibitor or a
nonspecific PDE inhibitor in the scientific literature, e.g.,
Pentoxifylline "increased significantly the level of
cAMP" but "[n]o significant increase of the cGMP level
was observed . . ." (Vittone30 1090, c. 1, ¶ 3).

"[N]on-selective PDE inhibitors, . . . pentoxifylline . . ."
(Cortijo31 562, c. 1, ¶ 3).

27 Affidavit of Philip Iversen dated 29 September 2004. (Appeal Brief
Exhibit P-4 attached to the Burslem Declaration (hereinafter "Iversen
Aff.").)
28 J.C. Miller & J.N. Miller, Statistics for Analytical Chemistry ch. 2, 33-52
(Ellis Horwood ed., PTR Prentice Hall) (3d ed. 1993). (Appeal Brief
Exhibit P-9 attached to the Burslem Declaration (hereinafter
"STATISTICS").)
29 Joseph A. Beavo, Cyclic Nucleotide Phosphodiesterases: Functional
Implications of Multiple Isoforms, 75 Am. Physiology Soc’y 725-48 (1995).
(Appeal Exhibit F-3 (hereinafter "Beavo").)
30 Vittone et al., The Mechanical and Biochemical Effects of Pentoxifylline on
the Perfused Rat Heart, 36 Experientia 1088-90 (1980). (Appeal Brief
Exhibit F-6 (hereinafter "Vittone").)
31 Cortijo et al., Investigation into the Role of Phosphodiesterase IV in
Bronchorelaxation, Including Studies with Human Bronchus, 108 Brit. J.
Pharmacology 562-568 (1993). (Appeal Brief Exhibit F-17 (hereinafter
"Cortijo").)
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"As expected, . . . pentoxifylline (non-specific cAMP-
PDE inhibitor) increased cAMP levels without affecting
cGMP levels" (Valente32 229 abstract); "[T]he cAMP-
dependent PDE inhibitor, pentoxifylline . . . " (id. 234, c.
2, ¶ 2); and, "[T]he respective PDE5 and cAMP-
dependent PDE inhibitors, sildenafil and pentoxifylline . .
. " (id. 240, c. 2, ¶ 1).

"[A]n increase in cAMP but not cGMP during
pentoxifylline infusion . . . suggests that if pentoxifylline
exerts its actions as a PDE inhibitor, it is most likely to
inhibit the cAMP-specific PDE more than the other
PDEs" (Kruuse33 636, c. 2, ¶ 4).
Pentoxifylline "increased cAMP in a dose-dependent
manner . . . but not cGMP level" (Chen34 773 abstract).

[33] The Food and Drug Administration approved package insert for
Trental® (pentoxifylline) describes its mode of action as "improv[ing]
the flow properties of blood by decreasing its viscosity" and
"increas[ing] leukocyte deformability and . . . inhibit[ing] neutrophil

32 Valente et al., L-Arginine and Phosphodiesterase (PDE) Inhibitors
Counteract Fibrosis in the Peyronie's Fibrotic Plaque and Related
Fibroblast Cultures, 9 Nitrous Oxide 229-244 (2003). (Appeal Brief Exhibit
F-4 (hereinafter "Valente").)
33 Kruuse et al., Effects of the Non-selective Phosphodiesterase Inhibitor
Pentoxifylline on Regional Cerebral Blood Flow and Large Arteries in
Healthy Subjects, 7 Eur. J. Neurology 629-638 (2000). (Appeal Brief
Exhibit F-5 (hereinafter "Kruuse").)
34 Chen et al., Pentoxifylline Inhibits PDGF-induced Proliferation of and
TGF-ß-stimulated Collagen Synthesis by Vascular Smooth Muscle Cells, 31
J. Molecular & Cellular Cardiology 773-83 (1999). (Appeal Brief Exhibit F-
7 (hereinafter "Chen").)
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adhesion and activation" (Trental Package Insert35 c. 1 "Mode of
Action").
[34] Peter Ellis, Ph.D., co-inventor of the 012 patent, testified that
pentoxifylline's mode of action as described by Korenman and the
Trental Package Insert are "not indicative of the effects of PDEV
inhibition" (Ellis I Decl.36 ¶¶ 28-29).
d. Florio II declaration
[35] Dr. Florio disagreed that the Florio PDE experiment would have had
any material edge effect because a water bath was used to keep each
reaction well at a consistent and uniform temperature (Florio II Decl.
¶ 13).
[36] As to random experimental variation in the Florio PDE experiment,
Dr. Florio testified that the protocol specified in the 012 patent
describes a partial purification of PDE enzymes. It does
not describe an assay for PDE inhibitors, per se, but
rather, provides a method to measure phosphodiesterase
activity of the partially purified PDEs. As such, it is
decidedly imprecise regarding the nature of the PDEs
being tested, is silent regarding any need for use of
additional batches of substrate, and is also silent on the
other issues raised by Pfizer in Australia. [Florio II Decl.
¶ 14.]

Other findings of fact follow below.

35 Trental® package insert TRE-MAY03-F-A, (Aventis Pharmaceuticals
Revised May 2003). (Appeal Brief Exhibit F-14 (hereinafter "Trental
Package Insert").)
36 First Declaration under 37 CFR 1.132 of Peter Ellis, dated 29 March 2005.
(Appeal Brief Exhibit F (hereinafter "Ellis I Decl.").)
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5. legal principles
A reference anticipates a claim under § 102(b) when it discloses each
and every element of the claimed invention, either explicitly or inherently.
In re Gleave, 560 F.3d 1331, 1334 (Fed. Cir. 2009). "Inherency, however,
may not be established by probabilities or possibilities. The mere fact that a
certain thing may result from a given set of circumstances is not sufficient."
In re Oelrich, 666 F.2d 578, 581 (CCPA 1981). "If a prima facie case is
made in the first instance, and if the applicant comes forward with
reasonable rebuttal, whether buttressed by experiment, prior art references,
or argument, the entire merits of the matter are to be reweighed." In re
Hedges, 783 F.2d 1038, 1038 (Fed. Cir. 1986).
6. analysis
The Examiner's prima facie case of anticipation is based on his
finding that pentoxifylline treatment was successful in about half of patients
suffering from impotence and that pentoxifylline is necessarily a selective
cGMP PDEV inhibitor as shown in the Florio I and Iversen I declarations
(Ans. 4). Dr. Florio supervised an experiment, the Florio PDE experiment,
which determined the average IC50 of pentoxifylline for PDEIA, PDEIIA,
PDEIIIA, PDEIIIB, PDEIVB, and PDEVA as well as their respective "selectivity
ratio" vis-à-vis the IC50 for PDEVA (FF 9-11, 20, 29). Dr. Florio summarized
the results of the Florio PDE experiment as (FF 11):
PDEIA3 PDEIIA PDEIIIA PDEIIIB PDEIVB2 PDEVA
IC50 (in µM) 233 109 275 333 79.4 63.8
Selectivity Ratio 3.65 1.71 4.31 5.22 1.25 1.00

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Dr. Iversen evaluated the summary data and concluded that the selectivity
ratios for PDEI through PDEIV versus PDEVA were scientifically reliable, i.e.,
statistically and significantly different from a ratio value of 1 (FF 14, 15,
29).
In rebuttal, Appellant submitted testimony by Drs. Burslem and
Marschner attacking the scientific reliability of the Florio PDE experimental
data (FF 16-26, 28). According to Drs. Burslem and Marschner, the Florio
PDE experiment did not control for expected experimental variations, such
as systemic bias and random experimental error, e.g., by running
independent or replicate experiments using new enzyme, inhibitor, and
reagent solutions in order to differentiate meaningful data from random
effects of batch-to-batch enzyme, inhibitor, and reagent solution and by
varying the positions of the test samples to account for positional effects
such as edge effects in a matrix format (FF 23, 25, 28). Furthermore, both
Drs. Burslem and Iversen agreed, based on their own experiences, that it was
not unusual for the reproducibility of IC50s to be in the range of 2 to 3 or 3.5
(FF 26-27). Moreover, Dr. Iversen acknowledged that edge effect and single
batch experiment problems may raise concerns where it is critical to
establish that a particular selectivity ratio was credible (FF 27). Indeed, it is
well known that "no quantitative experimental result is of any value unless it
is accompanied by an estimate of the errors involved in its measurement"
(FF 30). Furthermore, Appellant submitted a sampling of scientific
literature which characterized pentoxifylline as a cAMP PDE inhibitor or as
a nonspecific PDE inhibitor (FF 32).
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According to the Examiner, the rebuttal "opinions are not hard factual
evidence" (Ans. 12) and "the experimental details stressed by the patent
owner . . . would be more pertinent before the FDA . . ." (id. 13; see also 14
("In other words, the analysis is more suitable for the FDA.")). The
Examiner complains that Appellant has been repeatedly invited to supply
evidence comparing the IC50s of pentoxifylline for PDEv and PDEIII using
the protocol described in the 012 patent under reexamination to determine if
pentoxifylline is a selective PDEV inhibitor, but Appellant has failed to do so
(Ans. 16 and 17). According to the Examiner, there is no need to respond to
Appellant's arguments regarding the experimental methodology and
statistical analysis of the Florio PDE experiment because the evidence
weighs heavily on the side of the declaration by Philip Iversen showing that
pentoxifylline is a selective PDEV inhibitor (Ans. 16).
We disagree. While the Florio I and Iversen I declarations appear to
support the contention that pentoxifylline is a selective PDEV inhibitor,
when Appellant comes forward with reasonable rebuttal, buttressed by prior
art references and argument, as is the case here, the entire merits of the
matter must be reweighed. In re Hedges, 783 F.2d at 1038. This the
Examiner has not done. Here, the weight of the evidence calls the reliability
of the relative selectivity ratios calculated from the Florio PDE experimental
data into question based on the expected systemic and random errors of the
experiment (FF 23, 25, 28). In our opinion, while Dr. Florio addressed the
edge effect systemic error (FF 35), he did not meaningfully address the
expected random errors in the Florio PDE experiment (FF 36), including
enzyme, inhibitor, and reagent batch-to-batch variations. Moreover, the
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expected random errors highlighted by Appellant are not all inclusive. For
example, the Florio PDE experiment serially diluted the pentoxifylline (FF
10). It is well known that transfer inaccuracies lead to less accurate and less
precise dispensing with each sequential serial dilution step, resulting in the
highest dilutions having the most inaccurate results. If the Florio PDE
experiment cannot meaningfully discriminate between an IC50 ratio of 1 or 2
or 3 or 3.5 because of systemic and/or random experimental errors, then a
ratio of 1.71 or 1.25 has the same statistical significance as a ratio of 1.00
and does not establish that pentoxifylline is necessarily a selective PDEV
inhibitor. Rather, it reasonably appears that the Florio I and Iversen I
declarations understated the actual variability measured and overstated the
statistical significance of the data from the Florio PDE experiment testing of
pentoxifylline. This conclusion is consistent with the characterization of
pentoxifylline as a cAMP PDE inhibitor or as a nonspecific PDE inhibitor in
the scientific literature (FF 32) and with the testimony of Dr. Ellis, a co-
inventor of the 012 patent, that the reported mode of action of pentoxifylline
is not indicative of the effects of PDEV inhibition (FF 1, 33, 34). In
summary, claim 24 recites treating ED by orally administering an effective
amount of a selective PDEV inhibitor and the Examiner has failed to
establish, by a preponderance of the evidence of record, that pentoxifylline is
inherently a selective PDEV inhibitor.
Furthermore, while the Examiner may suggest possible types of
rebuttal evidence, the Examiner must evaluate the rebuttal evidence
submitted by Appellant.

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7. conclusion
Based on the foregoing, we reverse the rejection of claim 24 under 35
U.S.C. § 102(b) as anticipated by Korenman. The preponderance of the
evidence of record establishes that pentoxifylline is not a selective PDEV
inhibitor.
B. Anticipation based on the Yin Yang Huo references: Bensky,
Hsu, Chang, and Yin

1. the Examiner's findings
The Examiner found that each of Bensky, Hsu, Chang, and Yin
(collectively "the Yin Yang Huo references") treats impotence by oral
administration of the herb Yin Yang Huo (Ans. 5). The Examiner found that
"[t]he Declarations of . . . Florio and . . . Iversen, clearly establish that icariin
is an ingredient of Yin Yang Huo and that icariin is a selective cGMP PDEV
inhibitor" (id.). Thus, the Examiner found claim 24 anticipated by each of
the Yin Yang Huo references (id. 5, 23).
2. Appellant's arguments
Appellant argues that there is no credible evidence that Yin Yang Huo
treats ED or any basis for concluding that the Yin Yang Huo references
disclose using an "effective amount" of a selective PDEV inhibitor to treat
ED (App. Br. 15-17). Specifically, Appellant argues that none of the Yin
Yang Huo references identify which compound in Yin Yang Huo is
responsible for efficacious treatment of impotence (App. Br. 15-17, 90-91,
and 98) and that the Examiner improperly credited evidence lacking
scientific credibility over substantial rebuttal evidence in the form
declarations by experts in Chinese herbal medicines and clinical trials (id.
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15-17 and 90-91). As to Yin in particular, Appellant argues that the
disclosed treatment comprises a mixture of Yin Yang Huo and Tu Si Zi, as
well as yellow rice wine, genital massage, rest, bathing in a herbal mixture,
and abstinence from intercourse and, therefore, does not establish that the
treatment effect was due to Yin Yang Huo alone (id. 16). Essentially,
Appellant argues that the Yin Yang Huo references are not enabled.
3. the issue
The dispositive issue is whether the Yin Yang Huo references
describe oral administration of the selective PDEV inhibitor icariin in an
amount effective to treat ED.
4. additional findings of fact
a. the Yin Yang Huo references
[37] The pharmaceutical name for Yin Yang Huo is "Herba Epimedii"
(Bensky 490; Yin 1), which includes the species E. sagittatum, E.
brevicornum, and E. macranthum (Chang 1135; Hsu 563)
[38] According to Bensky, Yin Yang Huo is "used for Deficient Kidney
Yang patterns with such symptoms as impotence, spermatorrhea,
frequent urination, forgetfulness, withdrawal, and painful cold lower
back and knees" (Bensky 490) and is combined with Wu Wei Zi, Gou
Qui Zi, and Sha Yuan Ji Li "for Deficient Kidney impotence and
infertility" (id. 491).
[39] Bensky lists icariin, benzene, sterols, tanin, palmitic acid, linolenic
acid, oleic acid, and vitamin E as the major known ingredients of Yin
Yang Huo (Bensky 491).
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[40] Bensky reports a dosage of 1-4 quian of Yin Yang Huo, i.e., 3 to 12 g
(Bensky 20, 491).
[41] According to Hsu, Yin Yang Huo is traditionally used to treat
impotence, weakness in the loins and knees, arthralgia due to wind,
cold, and damp, general paralysis (Hsu 564).
[42] Specifically, Hsu reports (Hsu 564) that Yin Yang Huo
has an aphrodisiac action mainly because it stimulates
secretion of semen, causing the filling up of the scrotum,
thereby stimulating the sensing nerves, and indirectly
promoting sexual desire. The leaf and the root are most
potent in this action, the fruit is intermediate, and the
stem is the least potent.

[43] Hsu lists the chemical constituents of the Yin Yang Huo root and
rhizome as O-methylicariin, magnoflorin, and vitamin E; and, of the
leaf and stem as icariin, olivil, and icariresinol (Hsu 564).
[44] Hsu reports a dosage of Yin Yang Huo of 6 to 12 g (Hsu 565).
[45] According to Chang, Yin Yang Huo "is used for impotence, atrophy
and weakness of the low-back and knee, numbness of limbs,
neurasthenia, amnesia and climacteric hypertension" (Chang 1135).
[46] Specifically, Chang reports (Chang 1135, footnotes omitted) that
[t]he aqueous extract of given to
dogs intragastrically did not cause erection (or mounting
behavior) though it promoted semen secretion. The rank
of potency of the various plant parts was leaf and root >
fruit > stem. [] The weight-increase experiment on
mouse prostate, seminal vesicle, and levator ani proved
that the injection of the extract 20-40 mg
was as efficacious as androgen 7.5 µg. [] A significant
rise in the mean 24-hour urinary 17-ketosteroids . . . but
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no significant change in the 24-hour 17-
hydroxycorticosteroid excretion was obtained. These
results suggest that has gonadotropic
effects [].

[47] According to Chang, the stem and leaf of E. sagittatum contain
icariin, des-O-methylicaritin, ß-anhydroicaritin, and magnoflorine,
while the underground part contains des-O-methyl-ß-anhydroicaritin,
icariins A, B, C, D, and E, and 4 kinds of lignan (Chang 1135).
[48] Chang does not report any specific regimen for treating impotence
using Yin Yang Huo.
[49] According to Yin, the authors have satisfactorily treated 50 cases of
male impotence with their own formulation of Yin Yang Huo and
TuSiZi (Yin 1).
[50] Yin describes a typical case involving a 27 year old male, Mr. Qi,
diagnosed with impotence caused by excessive sex who achieved an
erection after 10 days and was reported cured after 17 days of
treatment (Yin 2).
[51] Yin describes the method of treatment as follows (Yin 1):
Formula components: 15 grams each of YinYangHuo
and TuSiZi, powdered together and bottled in preparation
for use. Dosage: 5 grams per time, 3 times per day, taken
with huang-jiu [Chinese rice wine], for a period of 20
days as one course of treatment. Supplemental treatment:
1. Massage the area of the lower abdomen and the
perineum, 10 times, beginning from left to right followed
by from right to left. Do this for 1 minute each before
arising in the morning, before the noon nap, and before
going to bed in the evening. 2. Every evening boil 15
grams each of ChuanXiong (Radix Ligustici
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Chuanxiong) and XiXin (Herba cum Radice Asari) in
water and then sit in it for 20 minutes. Precautions:
Abstain from intercourse for 100 days, and avoid
becoming over-tired or exposed to cold.

[52] According to Yin, the formulation was taken for a minimum of 7 days
and a maximum of 4 courses of treatment, with an average of 48.5
days (Yin 1).
b. the Florio II declaration
[53] Dr. Florio testified that he supervised testing to determine and
compare the IC50s of icariin against PDEI through PDEV (Florio II
Decl. ¶ 9).
[54] According to Dr. Florio, the experimental protocol was largely
identical to that used to test pentoxifylline except that dimethyl
sulfoxide was used to help solubilize the icariin (Florio II Decl. ¶ 10).
[55] According to Dr. Florio, a first experiment was conducted using
0.00254 to 50 µM icariin and second and third experiments were
conducted using 0.01 to 200 µM icariin (Florio II Decl. ¶ 11 n.5).
[56] Dr. Florio summarized his results as follows (Florio II Decl. ¶11):
PDEIA3 PDEIIA PDEIIIA PDEIIIB PDEIVB2 PDEVA
IC50 (in µM) ± SE 312±71 203±48 1460±914 1228±375 159±33 1.08±0.16
Selectivity Ratio 289 188 1352 1137 147 1.00

[57] Appellant does not dispute that the experimental data shows the
selectivity of icariin for PDEV (App. Br. 51).

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c. Appellant's rebuttal evidence37
[58] Eric J. Lien, Ph.D., Emeritus Professor of Pharmaceutical Sciences at
the University of Southern California, reported that amounts of icariin
found in 67 different samples of Yin Yang Huo ranging from 0.00307
(sample #14) to 3.692 (sample #13) weight percent (Lien Decl.38 ¶¶ 1,
15; Lien Decl. Exhibits 6-11).
[59] Wu reported that as of 2003 the Epimedium genus reportedly
contained about sixty flavonoid glycosides, including icariin, nearly
thirty flavones, and around fifty icarisides (Wu39 27).
[60] Dr. Ellis testified that a 5 gram dose of Yin Yang Huo tid, such as
disclosed by Yin, is insufficient to treat ED through inhibition of
PDEV (Ellis II Decl.40 ¶ 4).
[61] Specifically, Dr. Ellis testified that the mere fact that a compound
administered to an impotent man contains some amount of a selective
PDEV inhibitor does not mean that the amount administered will
inhibit PDEV in the body sufficiently to produce any relief in the
treatment of ED (Ellis II Decl. ¶ 9).

37 We have not considered the Second Declaration under 37 CFR 1.132 of
Emilia Bagiella, Appeal Brief Exhibit VV, because it is not signed or dated.
38 First Declaration under 37 CFR 1.132 by Eric J. Lien, Ph.D., dated 11
November 2005. (Appeal Brief Exhibit AAA (hereinafter "Lien Decl.").)
39 Wu et al., Chemical and Pharmacological Investigations of Epimedium
Species: A Survey, 60 Progress in Drug Research 1-57 (2003). (Appeal
Brief Exhibit BBB (hereinafter "Wu").)
40 Second Declaration under 37 CFR 1.132 of Peter Ellis, dated 11 November
2005. (Appeal Brief Exhibit CCC (hereinafter "Ellis II Decl.").)
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[62] According to Dr. Ellis, the maximum plasma concentration (Cmax) of
icariin achieved following a 5 g oral dosing of Yin Yang Huo tid as
described by Yin is well below its IC50 for PDEV (Ellis II Decl. ¶ 11).
[63] Based on the average amounts of icariin in Yin Yang Huo reported by
Dr. Lien and the molecular weights and reported pharmacokinetic data
for Viagra®, Levitra®, Cialis®, and icariin in rats and/or man, Dr.
Ellis calculated the following comparative summary:
Brand name Viagra® Levitra® Cialis® Yin
Yang
Huo
Generic Name or Active Sildenafil
Citrate
Vardenafil
HCl
Tadalafil Icariin
Minimum effective clinical oral dose
of Viagra®, Levitra® and Cialis® vs.
Yin's dose of icariin in Yin Yang Huo

25 mg 5 mg 5 mg 25.4 mg
PDEV Inhibitor IC50 3.5 nM 0.14 nM 6.7 nM 1080
nM
Blood Plasma Free Drug Concentration
at Cmax
4.5 µg/L 0.225 µg/L 4.9 µg/L 7.8
µg/L
Percent Inhibition of PDEV at Cmax 73% 75% 62% 0.5%
(Ellis II Decl. ¶¶ 12-17; Ellis II Decl. Exhibit 1; Viagra Package Insert
19; Levitra Package Insert 10; Cialis Package Insert 10; Florio II
Decl.).
[64] Dr. Ellis further opined that, since the only observation Yin obtained
of any sexual capability during dosing with icariin is the erection
reported by Mr. Qi after taking the treatment for 10 days, any efficacy
Yin observed should be correlated with total drug exposure, not Cmax
(Ellis II Decl. ¶ 18).
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[65] Based on total drug exposure, Dr. Ellis calculated that Yin Yang Huo
would only inhibit 0.14% of PDEV at average blood levels of icariin
(Ellis Decl. II ¶¶ 19-20).
[66] Upon considering the 3 to 12 g dosage of Yin Yang Huo reported by
Bensky (FF 40), the 6-12 g dose of Yin Yang Huo reported by Hsu
(FF 44), and a description in Chang of using "small oral doses of the
herb maceration (60 g of herb in 1 liter of wine)" (Chang 1138), and
assuming dose proportionality, Dr. Ellis calculated that a 15 g dose of
Yin Yang Huo would correspond to 0.43% inhibition of PDEV at
average blood levels of icariin or to less than 1.5% inhibition at Cmax
(Ellis Decl. II ¶ 22; FF 40).
Other findings of fact follow below.
d. legal principles
A reference is anticipatory under § 102(b) when it (i) discloses each
and every element of the claimed invention, either explicitly or inherently,
and (ii) enables one of ordinary skill in the art to make the invention. In re
Gleave, 560 F.3d at 1334.
e. analysis
Claim 24 requires oral administration of a selective PDEV inhibitor in
an amount effective to treat ED.
As found by the Examiner (Ans. 5), each of the Yin Yang Huo
references treats impotence by administering herbal Yin Yang Huo (FF 38,
41, 45, 49). It is undisputed that the herb is orally administered (see e.g., FF
46, 51), that icariin is an active component of the herb (FF 39, 43, 47, 58)
and that icariin is a selective PDEV inhibitor (FF 57). Thus, the issue is
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whether the Yin Yang Huo references describe oral administration of the
selective PDEV inhibitor icariin in an amount effective to treat ED.
Bensky, Hsu, Chang, and Yin describe administering Yin Yang Huo
in dosages of 3-12 g (FF 40), 6 to 12 g (FF 44), 60 g/liter wine (FF 66) and
15 g (FF 51), respectively. Indeed, Dr. Ellis was able to calculate expected
plasma free icariin concentrations at Cmax and % PDEV inhibition levels
based on a daily dosage of icariin as described by the Yin Yang Huo
references (FF 62, 63, 65, 66). However, Yin Yang Huo is orally
administered in specific amounts over a period of time, not just in a single
dose, to treat impotence. For example, Yin describes taking Yin Yang Huo
for a minimum of 7 days and a maximum of 4 courses of treatment, with an
average of 48.5 days (FF 52). Appellant argues that a single dosage of Yin
Yang Huo fails to provide an amount of icariin sufficient to treat ED based
on a comparison of Dr. Ellis' calculated percent inhibition of PDEV of an
average amount of icariin present in a Yin Yang Huo dosage versus the
calculated percent inhibition provided by a single dose of Viagra®,
Levitra®, and Cialis®. However, the selective PDEV inhibitor of claim 24 is
not required to have a minimum % inhibition at its IC50 or a maximum Ki or
other enzyme kinetics inhibition value or other defined parameter that would
exclude Yin Yang Huo from the claimed method. Moreover, Yin Yang Huo
is not administered as a single daily dosage when treating ED. Yin
expressly defines one course of treatment as comprising administering 2.5
grams Yin Yang Huo 3 times per day for 20 days (FF 51). Therefore, this
rebuttal evidence is insufficient to establish by a preponderance of the
evidence that the Yin Yang Huo references fail to disclose oral
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administration of icariin in an amount effective to treat ED, particularly in
view of Yin's disclosed successful treatment of 50 cases of impotence (FF
49).
f. conclusion
Ergo, based on the foregoing, we sustain the rejections of claim 24
under 35 U.S.C. § 102(b) as anticipated by any of Bensky, Hsu, Chang, and
Yin. The Yin Yang Huo references disclose oral administration of a
selective PDEV inhibitor, i.e., icariin, in an amount effective to treat ED.
III. Obviousness-type Double Patenting Rejection
A. The Examiner's findings and conclusion
The Examiner found that claims 1 of Campbell 270, 945, and 511
each recite a method of treating male ED by administering a defined species
of selective PDEv inhibitor, while claim 24 on appeal treats male ED by oral
administration of any selective PDEv inhibitor (Ans. 5-8). The Examiner
concluded that it would have been obvious to administer the specific
selective PDEv inhibitor recited in claim 1 of Campbell 270, claim 1 of 945,
and claim 1 of 511 orally because oral administration is the easiest mode to
deliver the selective PDEv inhibitor and because the prior art applied in the
anticipation rejections, i.e., Korenman and the Yin Yang Huo references,
administered their respective ED treatment drug via the oral route or,
alternatively, because the Campbell 270, 945, and 511 patent specifications
make clear that oral administration is the preferred route of administration
(Ans. 8).

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B. Appellant's arguments
Appellant argues that Campbell 511 and 945 cannot be double
patenting references because they issued after the 012 patent (App. Br. 9, 17-
21; Reply Br. 41 1). Specifically, "the unusual circumstance created solely
by GATT result[ed] in terms of the '511 and '945 reference patents that are
entirely subsumed within the term of [the 012 patent]" (App. Br. 20).
Appellant further argues that the convenience of oral administration is
of no use if the drug does not work unless injected locally into the penis
(App. Br. 25). According to Appellant, the Examiner improperly relied on
the Campbell patent specifications to reach his conclusion of obviousness
and ignored the teachings of the prior art that the drugs administered in
method claims 1 of Campbell 270, 945, and 511 are known
antihypertensives and PDE inhibitors and that the systemic effects of orally
administered antihypertensives and PDE inhibitors may cause or worsen ED
(App. Br. 8, 21-27, 32-35; Reply Br. 1-7).
Appellant still further argues that the Examiner has failed to establish
that the drugs administered in method claims 1 of Campbell 270, 945, and
511 are selective PDEv inhibitors (App. Br. 27-28; Reply Br. 1 and 7-8).
According to Appellant, contrary to the Patent Office's statement, WO 6104
and WO 714942 only teach that the compounds used in method claims 1 of
Campbell 270 and 511, respectively, are selective for cGMP PDEs rather

41 Reply Brief for Appellant under 37 C.F.R. 41.37 filed 24 September 2007
(hereinafter "Reply Br.").
42International Patent Publication WO 93/07149, Pyrazolopyrimidinone
Antianginal Agents, published 15 April 1993. (Appeal Brief Exhibit AA
(hereinafter "WO 7149").)
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than cAMP PDEs, i.e., that the compounds are selective for PDEI or PDEV
(App. Br. 27-28). According to Appellant, neither WO 6104 nor WO 7149
teach that the Campbell compounds are selective PDEV inhibitors or are
useful for treating ED (App. Br. 28).
C. Issues
Therefore, at issue is
(i) whether patent term or patent issue date determines if a claim of
a patent issued based on a post-GATT application qualifies as a double
patenting reference against a claim of a patent issued based on a pre-GATT
application,
(ii) whether the Examiner reversibly erred in relying on the
specifications of Campbell 270, 511, and 945 to interpret the coverage of
"administering" as recited in their respective method claims 1, and
(iii) whether one of ordinary skill in the art would have had a
reasonable expectation of success of treating ED by orally administered the
specific compounds recited in method claims 1 of Campbell 270, 511, and
945.
D. Additional findings of fact
1. the Campbell patents
[67] Campbell 270 issued on August 8, 2000 based on application
08/836,671, which is the national phase filing under 35 U.S.C. § 371
of PCT application PCT/EP95/04065, filed October 16, 1995
(Campbell 270 front page).
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[68] Campbell 511 issued March 18, 2003 based on application
09/542,489, filed April 3, 2000, which is a division of application
08/836,671, which issued as Campbell 270.
[69] Claim 1 of Campbell 270 reads
A method of treating male erectile dysfunction
comprising administering to a male human in need
of such treatment an effective amount of a
compound of formula (I):

wherein
R1 is methyl or ethyl;
R2 is ethyl or n-propyl; and
R3 and R4 are each independently H, or C1-C6 alkyl
optionally substituted with C5-C7 cycloalkyl
or with morpholino; or a pharmaceutically
acceptable salt thereof, or a pharmaceutical
composition containing either entity.
[70] Claim 1 of Campbell 511 reads
A method of treating male erectile dysfunction,
comprising administering, to a male human in need
of said treatment an effective amount of a
compound of formula (II):
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wherein
R1 is C1-C6 alkyl;
R2 is H; methyl or ethyl;
R3 is C2-C4 alkyl;
R4 is H; [sic ,] C1-C4 alkyl optionally substituted
with NR5R6, CN, CONR5R6 or CO2R7; C2-
C4 alkenyl optionally substituted with CN,
CONR5R6 or CO2R7; C2-C4 alkanoyl
optionally substituted with NR5R6;
SO2NR5R6; CONR5R6; CO2R7 or halo;
R5 and R6 are each independently H or C1-C4
alkyl; or together with the nitrogen atom to
which they are attached, form a pyrrolidino,
piperidino, morpholino, 4-(NR8)-1-
piperazinyl or 1-imidazolyl group wherein
said group is optionally substituted with one
or two C1-C4 alkyl groups;
R7 is H or C1-C4 alkyl; and
R8 is H; C1-C3 alkyl or (hydroxy)C2-C3 alkyl;
or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition containing either
entity.
[71] According to Campbell 270 and 511, the compounds of claim 1 may
be administered orally and have a preferred dosage for a typical man
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of 5 to 75 mg tid (Campbell 270 1:66-67, 7:25-26; Campbell 511 2:1-
2, 7:54-55).
[72] Campbell 945 issued December 2, 2003 based on application
09/880,141 which is the national phase filing under 35 U.S.C. § 371
of PCT application PCT/EP95/04066, filed October 16, 1995
(Campbell 945 front page).
[73] Claim 1 of Campbell 945 reads
A method of treating erectile dysfunction in a male
animal, comprising administering to an animal in
need of said treatment an effective amount of a
compound of the Formula I:

wherein:
R1 is a hydrogen, alkyl, cycloalkyl, cycloalkyl
substituted by alkyl or hydroxyl; 2- or 3
tetrahydrofuranyl, 3-tetrahydrothienyl 1,1-
dioxide, cycloalkylalkyl, carboxyalkyl,
carbo-lower-alkoxy-alkyl,
dialkylaminoalkyl, phenyl-lower-alkyl,
phenyl-lower-alkyl in which the phenyl ring
is substituted in the 2,3, or 4-position by one
or two substituents, the same or different,
selected from the group consisting of amino,
halogen, alkyl, carboxyl, carbo-lower-
alkoxy, carbamoyl, NHSO2-(quinolinyl),
nitro and cyano;
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R3 is hydrogen, lower-alkyl, phenyl-lower-alkyl,
lower-alkoxyphenyl-lower-alkyl, dilower-
alkoxyphenyl-lower-alkyl, pyridyl-lower-
alkyl, cycloalkyl-lower-alkyl, phenylamino,
dialkylamino, halogen, trifluoromethyl,
lower-alkylthio, cyano or nitro; and
R6 is a five or six membered heterocyclic ring
having from one to two nitrogen atoms, or a
nine or ten membered bicyclic ring having
from one to two nitrogen atoms, or
optionally substituted at any available
carbon atom by one or two substituents, the
same or different, selected from the group
consisting of lower-alkyl, halogen, lower-
alkoxy, cycloalkyloxy, 4-morpholinyl-
lower-alkoxy-lower-alkoxy, hydroxyl,
imidazolyl, oxo and 4-morpholinyl-lower-
alkoxy; or at any available nitrogen atom by
lower-alkyl, lower alkanoyl, or
trifluoroacetyl; or a pharmaceutically
acceptable acid-addition salt thereof.
[74] According to Campbell 945, the compounds of claim 1 may be
administered orally or parenterally and have a preferred dosage for a
typical man of 5 to 75 mg daily (Campbell 945 4:55-59, 64-67).
[75] Appellant acknowledges that "'. . . Campbell claims broadly enough to
cover oral routes of administration'" (App. Br. 24).
2. the patent terms of the 012 and the Campbell patents
[76] The 012 patent under reexamination issued on October 22, 2002 based
on application 08/549,792, which is the national phase filing under 35
U.S.C. § 371 of PCT application PCT/EP94/01580, filed May 13,
1994 (012 patent front page).
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[77] The patent term of the 012 patent is seventeen years from date of
grant on October 22, 2002, since its parent PCT application was filed
before June 8, 1995, whereas the patent terms of Campbell 270, 511,
and 945 are all twenty years from their PCT filing dates on October
16, 1995, which are all after June 8, 1995. 35 U.S.C. § 154(c).
3. Appellant’s rebuttal evidence
a. common routes of drug administration
[78] Benet discusses common routes of drug administration, including
intravenous, subcutaneous, intramuscular, and oral ingestion (Benet43
6).
[79] Other known routes of drug administration include parenteral (Husa44
6:41-49), intracavital and intratumor injections (Burzynski45 11:35-
37), and intravesical administration (Deininger46 5:39-42).
[80] According to Benet, oral ingestion is the most convenient,
economical, and, usually, a safer route of drug administration, but the

43 Leslie Z. Benet & Lewis B. Sheiner, Pharmokinetics: Dynamics of Drug
Absorption, Distribution, and Elimination, in The Pharmacological Basis of
Therapeutics, ch. 1, 3-13 (Goodman & Gilman et al. eds., MacMillan
Publishing Co. (7th ed. 1985). (Appeal Brief Exhibit R, (hereinafter
"Benet").)
44 U.S. Patent 5,180,720, 2- And 3-Alkoxy or Hydroxy-8-Substituted-
Dibenz[B,F]-[1,4]Oxazepine-10(11H)-Carboxylic Acid, Substituted
Hydrazides and Methods for Treating Pain, issued 19 January 1993 to Husa
et al. (Appeal Brief Exhibit T (hereinafter "Husa").)
45 U.S. Patent 4,470,970, Purified Antineoplaston Fractions and Methods of
Treating Neoplastic Disease, issued 11 September 1984 to Stanislaw R.
Burzynski. (Appeal Brief Exhibit U (hereinafter "Burzynski").)
46 U.S. Patent 4,119,730, Treating Muscle Spasms, issued 10 October 1978 to
Deininger et al. (Appeal Brief Exhibit V (hereinafter "Deininger").)
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pattern of drug absorption is potentially erratic and incomplete for
drugs that are poorly soluble, slowly absorbed, unstable, or
extensively metabolized by the liver (Benet 6-8).
[81] In contrast, Benet states that parenteral injection provides more rapid
and predictable drug absorption in active form and more accurate
selection of the effective dose (Benet 6).
b. causes and prior art treatment of ED
[82] According to Goldstein,47 impotence has a diversity of possible
causes, including diabetes, radical pelvic surgery, peripheral vascular
disease, hypertension, hardening of the arteries, side effects from
drugs, and hormonal imbalance, and a number of suggested
treatments, including direct penile injection of certain vasodilators
and/or adrenergic blocking agents (Goldstein 1:34-38, 44-46, 56-60;
see also Krane48 1649-51 (Pathophysiology of Impotence) and 1654-
56 (Therapeutic Options)).
[83] Carrier classifies the causes of impotence as (i) psychogenic, (ii)
neurogenic, (iii) endocrinologic, (iv) arterial, (v) cavernosal (including
neurotransmitters), and (vi) other contributing factors, including drugs

47 U.S. Patent 4,931,445, Agents for Treatment of Male Impotence, issued 5
June 1990 to Goldstein et al. (Appeal Brief Exhibit S (hereinafter
"Goldstein").)
48 Krane et al., Medical Progress: Impotence, 321 New Eng. J. Med. 1648-58
(1989). (Appeal Brief Exhibit W (hereinafter "Krane").)
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(most commonly antihypertensive agents), Peyronie's disease, and
diabetes (Carrier49 468-476).
[84] Carrier describes (Carrier 468),
[p]enile erection [as] a complex neurovascular
phenomenon involving not only the coordination of three
hemodynamic events (increased arterial flow, sinusoidal
smooth muscle relaxation, and decreased venous
drainage) but also the interaction of nerves,
neurotransmitters, striated and smooth muscle, and the
tunica albuginea. . . . [N]itric oxide is believed to be the
principal neurotransmitter in smooth muscle relaxation.

[85] According to Carrier, nitric oxide elicits smooth muscle relaxation by
stimulating the formation of cGMP through activation of guanyl
cyclase (Carrier 474).
[86] Carrier theorizes that "defects in neurotransmitter production, release
or the presence of antagonists could cause inhibition of cavernosal
smooth muscle relaxation, resulting in inhibition of erection" (Carrier
474).
[87] According to Lerner, "nitric oxide is an important factor in the
modulation of corporeal smooth muscle tone" (Lerner50 1248).
[88] Indeed, Lerner reports that "recent findings indicated that nitrous [sic,
nitric51] oxide is involved in the nonadrenergic/noncholinergic

49 Carrier et al., Pathophysiology of Erectile Dysfunction, 42 Urology 468-
481 (October 1993) (Appeal Brief Exhibit HH (hereinafter "Carrier").)
50 Lerner et al., A Review of Erectile Dysfunction: New Insights and More
Questions, 149 J. Urology 1246-55 (1993). (Appeal Brief Exhibit BB
(hereinafter "Lerner").)
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mediated relaxation of human corporeal smooth muscle, and
suggested that defects in this pathway may cause some forms of
impotence.63" (Lerner 1251).
[89] Wein warns that when considering whether a particular drug is
responsible for an adverse effect on libido, erection, emission, or
ejaculation, one must consider whether the disease being treated is a
causative or contributory factor, the substrate with which the drug
interacts, and other factors, such as age, personal history, lifestyle, and
secondary drug interactions (Wein52 25).
[90] According to Weiss, sexual dysfunction is a potential side effect of
antihypertensives and has been most associated with potassium-
sparing diuretics, nonselective ß-blockers, and centrally acting
antihypertensive agents, but may also be due to underlying disease
states or psychogenic factors completely unrelated to drug therapy
(Weiss53 2079-81).
[91] Goldstein discloses treating ED by oral, rectal, or parenteral
administration of etoperidone (Goldstein 1:6-11; 2:60-67; 3:45-51).

51 Lerner footnote 63 cites to Raifer et al., Nitric oxide as a mediator of
relaxation of the corpus cavernosum in response to nonadrenergic,
noncholinergic neurotransmission, 326 New Eng. J. Med. 326:90 (1992).
Therefore, the recitation of "nitrous oxide" is an apparent typographical error
based on the words of the sentence and the title of the cited reference.
52 Alan J. Wein & Keith N. Van Arsdalen, Drug-Induced Male Sexual
Dysfunction, 15 Urologic Clinics N. Am. 23-31 (1988) (Appeal Brief
Exhibit NN (hereinafter "Wein").)
53 R. J. Weiss, Effects of Antihypertensive Agents on Sexual Function, 44
Am. Family Physician 2075-82 (1991). (Appeal Brief Exhibit PP
(hereinafter "Weiss").)
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[92] According to Goldstein (Goldstein 2:2:62-67),
[a]lthough oral administration of eptoperidone is a
preferred route of administration, being both effective
and harmless for most patients, nonetheless a parenteral
method of administration, direct injection into the penis,
is the most preferred route of administration . . . .

[93] In addition to intracavernosal injection of vasoactive drugs, such as
papaverine, Krane discloses oral, parenteral, and intramuscular
administration of testosterone to treat ED (Krane 1654-55).
[94] According to Krane, prostaglandin E1, alone or in combination with
papaverine and phentolamine, is a less frequently used intracavernosal
agent for treating ED (Krane 1655).
[95] According to Zentgraf, ED can be diagnosed and treated with
intracavernal injection of the opium alkaloid papaverine, alone or in
combination with the α-blocker phentolamine (Zentgraf54 65, 71).
[96] Specifically, Zentgraf discloses that patients with nonvascular ED
usually require low doses of papaverine alone or in combination with
phentolamine, whereas arterial ED requires a higher dosage, and
venous ED fails to respond at even higher doses (Zentgraf 71).
[97] However, Zentgraf cautions that possible localized side effects of
intracavernous injection of vasoactive agents include hematomas,
burning pain on injection, damage to the urethra, infection, fibrotic

54 Zentgraf et al., Diagnosis and Treatment of Erectile Dysfunction Using
Papaverine and Phentolamine, 43 Urology Int’l 65-75 (1982). (Appeal
Brief Exhibit O (hereinafter "Zentgraf").)
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changes, wearing off of the effect, and "above all, prolonged erection
and priapism" (Zentgraf 68).
[98] As to possible systemic reactions, Zentgraf reports that "[v]asodilatory
drugs such as papaverine and phentolamine can produce a fall in
blood pressure which may result in collapse" (Zentgraf 69).
[99] Zentgraf reports that one researcher recommended using a penis
clamp after 60 mg of papaverine to prevent systemic reactions, while
another researcher found no clinically significant changes in blood
pressure following intracavernous injection of papaverine combined
with phentolamine (Zentgraf 69, 71).
[100] Zentgraf concludes that "[c]onsidering the local and systemic side
effects following administration of papaverine, combination therapy
should be preferred to render treatment as safe as possible" (Zentgraf
72).
[101] According to Lerner, "intracavernous pharmacotherapy affects penile
rigidity independent of the cause of impotence, . . ." (Lerner 1246).
[102] In 1990, Foreman reported a lack of effective oral drug therapies for
the treatment of sexual dysfunction (Foreman55 111) (Accord Stief56
1390).

55 Mark M. Foreman & Joachim F. Wernicke, Approaches for the
Development of Oral Drug Therapies for Erectile Dysfunction, 8 Seminars
in Urology 107-112 (1990). (Appeal Brief Exhibit X (hereinafter
"Foreman").)
56 Stief et al., The Effect of the Specific Phosphodiesterase (PDE) Inhibitors
on Human and Rabbit Cavernous Tissue In Vitro and In Vivo, 159 J.
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[103] According to Foreman, oral medications based on vascular
pharmacologic approaches for treating ED "have not been attempted
primarily because of the systemic side effects of these agents", e.g.,
phentolamine, prostaglandin E1, and papaverine (Foreman 110).
[104] Foreman suggests creating a drug that has selectivity for penile tissue
responses in order to minimize or eliminate systemic side effects
(Foreman 110).
c. zaprinast
[105] Zaprinast is 2-α-propoxyphenyl-8-azapurin-6-one, i.e.,

(Trapani57 abstract).
[106] According to Trapani, data from intravenous infusion of zaprinast, a
relatively selective inhibitor of low Km cGMP PDE, suggests that
zaprinast preferentially dilates arterioles and has a less effect on the

Urology 1390-1393 (April 1998). (Appeal Brief Exhibit EE, (hereinafter
"Steif").)
57 Trapani et al., Hemodynamic Basis for the Depressor Activity of Zaprinast,
a Selective Cyclic GMP Phosphodiesterase Inhibitor, 258 J. Pharm. and
Experimental Therapeutics 269-74 (1991). (Appeal Brief Exhibit KK
(hereinafter "Trapani").)
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venous circulation (Trapani abstract, 271, 274) (Accord Lee58 132
(zaprinast IC50 of 300 nM against 0.2 µM cGMP-PDE), 138 (zaprinast
lowered or tended to lower pulmonary mean arterial pressure and
systemic vascular resistance)).
d. Campbell's compounds
[107] According to WO 6104, the compounds utilized in method claim 1 of
Campbell 270 are vasodilators useful for treating cardiovascular
disorders, including angina and hypertension, as well as selective
inhibitors of both cGMP PDEs, i.e., calcium/calmodulin-dependent
cGMP PDE (PDEI) and calcium/calmodulin-independent cGMP PDE
(PDEV) (WO 6104 abstract, 1-2, 7-8).
[108] According to WO 6104, "oral dosages of the compounds will
generally be in the range of from 4-800 mg daily for an average adult
patient . . ." (WO 6104 8-9).
[109] According to WO 7149, the compounds utilized in method claim 1 of
Campbell 511 are vasodilators useful for treating cardiovascular
disorders, including angina and hypertension, as well as selective
inhibitors of calcium/calmodulin-independent cGMP PDE (PDEV)
(WO 7149 abstract, 1-2, 14-15).

58 Lee et al., Comparative Hemodynamic and Renal Effects of the Low Km
cGMP Phosphodiesterase Inhibitors Cicletanine and Zaprinast in
Anesthetized Dogs, 23 Drug Dev. Res. 127-144 (1991). (Appeal Brief
Exhibit LL (hereinafter "Lee").)
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[110] According to WO 7149, "oral dosages of the compounds will
generally be in the range of from 4-800 mg daily for an average adult
patient . . ." (WO 71409 15).
[111] PDE catalyzes the hydrolysis and inactivation of intracellular cAMP
and cGMP (Beavo II59 3).
[112] According to Beavo, PDE comprises five isoenzyme families, i.e.,
calcium/calmodulin-dependent PDE or PDEI, cGMP stimulated PDE
or PDEII, cGMP-inhibited PDE or PDEIII, cAMP-specific PDE or
PDEIV, and cGMP-specific PDE or PDEV (Beavo II 6-11).
E. Legal principles
The PTO may consider double patenting in a reexamination. In re
Lonardo, 119 F.3d 960, 966 (Fed. Cir. 1997).
"[O]bviousness-type double patenting . . . is a judicially-created
doctrine that seeks to prevent the applicant from expanding the grant of the
patent right beyond the limits prescribed in Title 35." In re Dembiczak, 175
F.3d 994, 1001 (Fed. Cir. 1999). In other words, "[t]he rule against 'double
patenting' . . . is to prevent unjustified timewise extension of the right to
exclude granted by a patent no matter how the extension is brought about."
In re Schneller, 397 F.2d 350, 354 (CCPA 1968).
The level of ordinary skill in the art is evidenced by the references. In
re Oelrich, 579 F.2d 86, 91 (CCPA 1978) ("the PTO usually must evaluate
both the scope and content of the prior art and the level of ordinary skill

59 Joe Beavo , Cyclic Nucleotide Phosphodiesterases Structure, Regulation
and Drug Interaction ch. 1, 3-15 (Joe Beavo and Miles D. Houslay eds.,
John Wiley & Sons 1990). (Appeal Exhibit E (hereinafter "Beavo II").)
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solely on the cold words of the literature."); In re GPAC Inc., 57 F.3d 1573,
1579 (Fed. Cir. 1995) (the Board did not err in adopting the approach that
the level of skill in the art was best determined by the references of record).
"It is the claims, not the specification, that define an invention. . . .
And it is the claims that are compared when assessing double patenting."
Ortho Pharm.Corp. v. Smith, 959 F.2d 936, 943 (Fed. Cir. 1992). However,
this does not mean that the specification may not be used at all. In re Vogel,
422 F.2d 438, 441-42 (CCPA 1970). Indeed, our reviewing court reaffirmed
the holding in Vogel, stating that the disclosure may be used to learn the
meaning of terms and in "interpreting the coverage of [a] claim." Id. at 441.
It may also be used to answer the question whether the claims merely define
an obvious variation of what is earlier disclosed and claimed. The court
stated that the disclosure "sets forth at least one tangible embodiment within
the claim, and it is less difficult and more meaningful to judge whether
[something] has been modified in an obvious manner." Id. at 442. The
court further stated that "use of the disclosure is not in contravention of the
cases forbidding its use as prior art, nor is it applying the patent as a
reference under 35 U.S.C. § 103, since only the disclosure of the invention
claimed in the patent may be examined." Id. See also, In re Basell
Poliolefine Italia S.P.A., 547 F.3d 1371, 1378-79 (Fed. Cir. 2008).
The Longi court characterized an obviousness-type double patenting
rejection as “analogous” to a § 103 rejection. In re Longi, 759 F.2d 887, 892
n.4 (Fed. Cir. 1985). An obviousness determination requires that a skilled
artisan would have perceived a reasonable expectation of success in deriving
the claimed invention in light of the teachings of the prior art. In re Kubin,
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561 F.3d 1351, 1360 (Fed. Cir. 2009); see also In re Longi, 759 F.2d at 896–
97 (holding that a patent application was properly rejected for obviousness-
type double patenting where the prior art references indicated a reasonable
expectation of success). Only a reasonable expectation of success, not
absolute predictability, is necessary to show obviousness. In re Longi, 759
F.2d at 897. Furthermore, "[w]hen chemical compounds have 'very close'
structural similarities and similar utilities, without more a prima facie case
may be made." In re Grabiak, 769 F.2d 729, 731 (Fed. Cir. 1985).
F. Analysis
1. issue: does patent term or patent issue date determine if a
claim of a patent issued based on a post-GATT application
qualify as a double patenting reference against a claim of a
patent issued based on a pre-GATT application?

The rule against double patenting seeks to prevent unjustified
timewise extension of the right to exclude granted by a patent no matter how
the extension is brought about. In re Schneller, 397 F.2d at 354. Here,
Appellant argues that Campbell 511 and 945 cannot be double patenting
references because they issued after the 012 patent (App. Br. 9, 17-21; Reply
Br. 1). Although Appellant has cited to several cases which refer to double
patenting over a prior patent, none of these cases involve the unusual
circumstance created here by GATT.
The patent term of the 012 patent under reexamination is seventeen
years from its date of grant on October 22, 2002 (i.e., October 22, 2019),
whereas the patent term of both Campbell 511 and 945 is twenty years from
their October 16, 1995 filing date (i.e., October 16, 2015) (FF 77). Thus, as
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recognized by Appellant, the "terms of the '511 and '945 reference patents
are entirely subsumed by within the term of [the 012 patent]" (App. Br. 20).
Claims 1 of Campbell 511 and 945 each recite a method of treating
male ED by administering a defined species of selective PDEV inhibitor,
while claim 24 of the 012 patent recites a method of treating male ED by
oral administration of any selective PDEV inhibitor (FF 70, 73; App. Br.
Clm. App'x 1). According to Appellant, the 012 patent will not prevent the
public from using the Campbell compounds to treat ED through non-oral
routes of administration after Campbell 511 and 945 expire (App. Br. 20).
However, the 012 patent will extend Appellant's right to exclude the public
from practicing that portion of the Campbell 511 and 945 patent which treats
male ED by oral administration of their specific selective PDEV inhibitors
from October 16, 2015 to October 22, 2019. This is precisely what
obviousness-type double patenting was intended to prevent. Therefore,
under the circumstances of this case, it is the patent term and not the patent
issue date that determines if a claim of Campbell 511 or 945 qualifies as a
double patenting reference against a claim of the 012 patent.
2. issue: did the Examiner reversibly err in relying on the
specifications of Campbell 270, 511, and 945 to interpret
the coverage of "administering" as recited in their
respective claims 1?

As reaffirmed recently in In re Basell Poliolefine Italia S.P.A., 547
F.3d at 1378-79, the specification may be used to learn the meaning of terms
and in interpreting the coverage of a claim. Thus, we discern no reversible
error in the Examiner relying on the specifications of Campbell 270, 522,
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and 945 to interpret the coverage of the term "administering" as recited in
their respective claims 1.
3. issue: would one of ordinary skill in the art have had a
reasonable expectation of success of treating ED by
orally administered the specific compound recited in
method claims 1 of Campbell 270, 511, and 945?

We begin with a discussion of the prior art as disclosed in the rebuttal
evidence submitted by Appellant.
A number of routes of drug administration, including oral and
parenteral, are known (FF 78, 79). Oral administration is the most
convenient, economical, and usually, safest route of drug administration,
albeit not without drawbacks, such as potentially erratic and incomplete
absorption of poorly soluble, slowly absorbed, unstable, or extensively
metabolized drugs (FF 80). Alternatively, parenteral injection provides
more rapid and predictable drug absorption and more accurate selection of
the effective dosage (FF 81).
It is also known that diabetes, pelvic surgery, peripheral vascular
disease, hypertension, hormonal imbalances, side effects from drugs (most
commonly antihypertensives), and other factors contribute to ED (FF 82-83).
When considering whether a particular drug is responsible for ED, for
example, one must consider whether the disease being treated is a causative
or contributory factor, the substrate that the drug interacts with, and other
factors, including age, personal history, lifestyle, and secondary drug
interactions (FF 89-90). Thus, ED treatments vary with the causative and
contributory factors of the ED and the treatment approach taken. In other
words, not all ED treatments are created equal.
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Effective ED therapies include direct penile (intracavernal) injection
of certain vasodilators and/or adrenergic blocking agents (FF 82, 95); oral,
rectal, or parenteral administration of etoperidone (FF 91); and, oral,
parenteral, or intramuscular administration of testosterone (FF 93). While
"intracavernous pharmacotherapy affects penile rigidity independent of the
cause of impotence" (FF 101), the possible localized side effects, including
hematomas, pain, and "above all, prolonged erection and priapism" (FF 97)
are undesirable to say the least. Oral medications based on vascular
pharmacologic approaches for treating ED "have not been attempted
primarily because of the systemic side effects of these agents" (FF 103). For
example, vasoactive drugs such as papaverine and phentolamine can
produce a drop in blood pressure which may result in collapse (FF 98). One
researcher went so far as to recommend using a penile clamp after
intracavernous injection of 60 mg papaverine to prevent systemic reactions
(FF 99). Not surprisingly, the prior art suggests creating a drug that has
selectivity for penile tissue responses in order to minimize or eliminate
systemic side effects (FF 104).
Penile erection is a complex neurovascular phenomenon involving the
coordination of three hemodynamic events (increased arterial flow,
sinusoidal smooth muscle relaxation, and decreased venous drainage) as
well as the interactions of nerves, neurotransmitters, striated smooth muscle,
and the tunica albuginea (FF 83-84). Nitric oxide is the principal
neurotransmitter modulating smooth muscle tone by way of a
nonadrenergic/noncholinergic pathway (FF 84, 87, 88). Nitric oxide elicits
smooth muscle relaxation by stimulating the formation of cGMP (FF 85).
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cGMP levels are determined by two enzymes -- guanylate cyclase which
stimulates its formation and PDE which facilitates its degradation (FF 85,
111). Reports suggest that defects in this pathway may cause some forms of
impotence (FF 86, 88).
We now turn to the issue before us.
The Examiner maintains that oral administration would have been
obvious because it is the easiest mode of drug delivery, because Korenman
and the Yin Yang Huo references administered their respective ED
treatments orally, and because the specifications of Campbell 270, 945, and
511 make clear that oral administration is the preferred route of
administration (Ans. 8). The Examiner erred in relying on the disclosure in
Campbell 270, 945, and 511 that oral administration is a preferred route of
drug administration in order to conclude that it would have been obvious to
orally administer a selective PDEV inhibitor to treat ED. However, the
Examiner provided two alternative reasons for concluding that oral drug
administration would have been obvious -- ease of delivery and treatment of
ED in the prior art by oral drug/herbal remedy administration.
Appellant argues that the prior art teaches successful treatment of ED
by intracavernal injection of a drug and that the systemic effects of orally
administered antihypertensives and PDE inhibitors may cause or worsen ED
(App. Br. 8, 21-27, 32-35; Reply Br. 1-7). However, the prior art submitted
by Appellant, namely Goldstein and Krane (FF 91, 93), also teach successful
treatment of ED by orally administering a drug. The real issue is whether
one of ordinary skill in the art would have orally administered the specific
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compounds recited in method claims 1 of Campbell 270, 511, and 945 with a
reasonable expectation of success of treating ED.
Citing WO 6104, Appellant stated that "[i]n addition to being
antihypertensives, the Campbell compounds were known PDE inhibitors,
although . . . they were not know [sic] in the prior art as PDEV selective
inhibitors" (Reply Br. 6). Appellant argues that, contrary to the Patent
Office's statement, WO 6104 and WO 7149 only teach that the compounds
used in method claims 1 of Campbell 270 and 511, respectively, are
selective for cGMP PDEs rather than cAMP PDEs, i.e., that the compounds
are selective for PDEI or PDEV (App. Br. 27-28). Appellant further argues
that the ordinarily skilled artisan would not have treated ED with oral
administration of an antihypertensive because of known systemic effects
thereof (App. Br. 32-35).
However, WO 7149 discloses that the compounds of method claim 1
in Campbell 511 are not only antihypertensives, e.g., vasodilators useful for
treating hypertension, but also selective PDEV inhibitors, i.e., inhibitors of
calcium/calmodulin-independent cGMP PDE (FF 109, 111, 112).
Furthermore, WO 7149 discloses that the oral dosages of the compounds of
method claim 1 in Campbell 511 are generally within the range of 4-800 mg
daily for an average adult (FF 108), which encompasses the "effective
amount" recited in claim 1 of Campbell (5-75 mg tid or 15-255 mg daily for
a typical man (FF 71)). Therefore, we agree with the Examiner that it would
have been obvious to modify method claim 1 of Campbell 511 by orally
administering the specified compounds to treat ED because WO 7149
establishes that the specified compounds of Campbell 511 are selective
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PDEV inhibitors suitable for oral administration in the claimed "effective
amounts." Furthermore, given the very close, and in some cases
overlapping, chemical structures of the compounds of Campbell 511 and
Campbell 270,60 WO 6104 and WO 7149 provide the Examiner with a
reasonable basis for concluding that one of ordinary skill in the art would
have orally administered the specific compound recited in method claim 1 of
Campbell 270 with a reasonable expectation of success of treating ED (FF
71, 107-110; Ans. 11). In re Grabiak, 769 F.2d at 731.
Therefore, we sustain the rejection of claim 24 under the judicially
created doctrine of obviousness-type double patenting over claim 1 of either
Campbell 270 or Campbell 511.
For completeness, we note that the prior art suggests oral
administration of a drug that is selective for penile tissue responses in order
to minimize or eliminate systemic side effects (FF 104) and that a selective
PDEV inhibitor would prevent the degradation of cGMP formed in response
to the neurotransmitter nitric oxide when eliciting smooth muscle relaxation
during penile erection (FF 83-88, 111).
As to the obviousness-type double patenting rejection based on
method claim 1 of Campbell 945, the Examiner has failed to provide any
reasoned basis for concluding that one of ordinary skill in the art would have

60 For example, R1 of Campbell 270 and R2 of Campbell 511 can both be
methyl or ethyl, R1 of Campbell 511 can be methyl as shown in Campbell
270, R2 of Campbell 270 and R3 of Campbell 511 can both be ethyl or n-
propyl, and R4 of Campbell 511 and -SO2NR3R4 of Campbell 270 can both
be - SO2NR5/3R6/4 where R3/5 and R4/6 are each independently H, or C1-C4
alkyl.
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orally administered the recited compounds of Campbell 945 claim 1 with a
reasonable expectation of success of treating ED. We note that the selective
PDEV inhibitor Zaprinist and the compounds recited in claims 1 of Campbell
270 and 511 are all three ring structures (FFs 69, 70, 105), while the
compounds recited in claim 1 of Campbell 945 are two ring structures (FF
73). In addition, the preferred adult dosage of the compounds recited in
claim 1 of Campbell 945 is one third that of the compounds recited in claims
1 of Campbell 270 and 511. Therefore, we reverse the rejection of claim 24
under the judicially created doctrine of obviousness-type double patenting
over claim 1 of Campbell 945.
G. Conclusion
We sustain the rejection of claim 24 under the judicially created
doctrine of obviousness-type double patenting over claim 1 of either
Campbell 270 or Campbell 511, but reverse the rejection over claim 1 of
Campbell 945.
Under the circumstances of this case, it is the patent term and not the
patent issue date that determines if a claim of Campbell 511 or 945 qualify
as double patenting references against a claim of 012. The Examiner did not
err in relying on the specifications of Campbell 270, 511, and 945 to
interpret the coverage of the term "administering" as recited in their
respective claims 1. Based upon a preponderance of the evidence of record,
one of ordinary skill in the art would have had a reasonable expectation of
success of treating ED by orally administered the specific compound recited
in method claims 1 of either Campbell 270 or 511, but not Campbell 945.

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IV. Order
Upon consideration of the record, and for the reasons given, it is
ORDERED that the decision of the Examiner to reject claim 24 as
unpatentable under 35 U.S.C. § 102(b) as anticipated by Korenman is
REVERSED;
FURTHER ORDERED that the decision of the Examiner to reject
claim 24 as unpatentable under 35 U.S.C. § 102(b) as anticipated by any of
Bensky, Hsu, Chang, and Yin is AFFIRMED;
FURTHER ORDERED that the decision of the Examiner to reject
claim 24 as unpatentable under the judicially created doctrine of
obviousness-type double patenting over claim 1 of Campbell 945 is
REVERSED;
FURTHER ORDERED that the decision of the Examiner to reject
claim 24 as unpatentable under the judicially created doctrine of
obviousness-type double patenting over claim 1 of either Campbell 270 or
Campbell 511 is AFFIRMED; and,
FURTHER ORDERED that no time periods for taking any
subsequent action in connection with this appeal may be extended under 37
C.F.R. § 1.136(a)(1)(iv).
AFFIRMED

KMF

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Patent Owner:

Gregg C. Benson
PFIZER, INC.
Patent Department MS 4159
Eastern Point Road
Groton, CT 06340

1st Third Party Requester:

FINNEGAN, HENDERSON, FARABOW,
GARRETT & DUNNER, LLP
1300 I Street, N.W.
Suite 700
Washington, DC 20005

2nd Third Party Requester:

Larry S. Nixon
NIXON & VANDERHYE, P.C.
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Arlington, VA 22203

3rd Third Party Requester:

Douglas K. Norman
ELI LILLY AND COMPANY
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Indianapolis, MN 46206-6288