ELI LILLY AND COMPANY et al v. PERRIGO COMPANY et al
Filing
462
FINDINGS OF FACT AND CONCLUSIONS OF LAW AND FINAL JUDGMENT ; *** PLEASE SEE ORDER ***. Signed by Judge Sarah Evans Barker on 8/22/2016.(CKM) Copies Mailed.
UNITED STATES DISTRICT COURT
SOUTHERN DISTRICT OF INDIANA
INDIANAPOLIS DIVISION
ELI LILLY AND COMPANY,
ELI LILLY EXPORT S.A.,
ACRUX DDS PTY LTD.,
Plaintiffs,
vs.
PERRIGO COMPANY,
PERRIGO ISRAEL
PHARMACEUTICALS LTD.,
ACTAVIS LABORATORIES UT, INC.
formerly known as WATSON
LABORATORIES INC.,
AMNEAL PHARMACEUTICALS LLC,
LUPIN PHARMACEUTICALS, INC., and
LUPIN LTD.,
Defendants.
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1:13-cv-00851-SEB-DKL
FINDINGS OF FACT AND CONCLUSIONS OF LAW AND FINAL JUDGMENT
BASED THEREON
This matter is before the Court for decision on the issues of validity,
enforceability, and infringement of three patents owned by Plaintiff Acrux DDS PTY
Ltd. (“Acrux”). Plaintiff Eli Lilly Export S.A. is the exclusive worldwide licensee of the
patents at issue in this litigation and has licensed its rights in the United States to Plaintiff
Eli Lilly and Company (“Lilly”). Plaintiffs hold an approved New Drug Application
(“NDA”) No. 022504 for the manufacture and sale of testosterone metered transdermal
solution, 30 mg/1.5mL used to treat males for conditions associated with a deficiency or
absence of endogenous testosterone. Lilly markets the product disclosed in NDA No.
1
022504 under the tradename Axiron®. Axiron® was approved by the Food and Drug
Administration (“FDA”) on November 23, 2010. In connection with the NDA, Lilly
listed nine patents in the Orange Book, including: U.S. Patent Nos. 6,299,900 (“the ‘900
patent”); 6,818,226 (“the ‘226 patent); 6,923,983 (“the ‘983 patent”); 8,071,075 (“the
‘075 patent”); 8,419,307 (“the ‘307 patent); 8,435,944 (“the ‘944 patent”); 8,177,449 (the
‘449 patent”); 8,807,861 (“the ‘861 patent”); and 8,993,520 (“the ‘520 patent”).
This action arises out of the Abbreviated New Drug Applications (“ANDA”) for
the commercial manufacture, use, and sale of generic versions of Axiron® filed by
Defendants Perrigo Company and Perrigo Israel Pharmaceuticals Ltd. (collectively,
“Perrigo”); Actavis Laboratories UT, Inc. (“Actavis”); Amneal Pharmaceuticals LLC
(“Amneal”); and Lupin Pharmaceuticals, Inc. and Lupin Ltd. (collectively, “Lupin”),
respectively. As will be described in more detail below, each Defendant sought FDA
approval to market its generic transdermal testosterone product before expiration of the
patents Lilly listed in the Orange Book, and, pursuant to 21 U.S.C. §
355(j)(2)(A)(vii)(IV), each ANDA includes a “paragraph IV certification” to Plaintiffs’
patents, in which each Defendant has certified that certain patents are invalid and/or
would not be infringed by Defendants’ manufacture, use, or sale, of their generic
testosterone products.
Plaintiffs proceeded to trial on the following representative patent claims: claim 13
of the ‘075 “formula” patent against Actavis; claim 20 of the ‘944 “axilla” patent against
all defendants; and claims 9 and 10 of the ‘861 “applicator” patent against all defendants.
Defendants contend that their proposed ANDA products would not infringe the asserted
2
claims of the ‘861 patent and that each of the asserted claims of the ‘861 patent and the
‘944 patent are invalid. Actavis also contends that the asserted claim of the ‘075 patent is
invalid.
A bench trial on these issues was conducted over nine (9) days, the first eight of
which ran from June 16, 2016 to/through June 28, 2016, and a final day of trial occurred
on July 21, 2016. Having now considered the evidence adduced at trial and the parties’
post-trial submissions, we hold, for the reasons set forth in detail below, as follows: (1)
claim 13 of the ‘075 patent is invalid for lack of written description and enablement; (2)
claim 20 of the ‘944 patent is invalid for obviousness; (3) the asserted claims of the ‘861
patent are not infringed by Actavis’s, Perrigo’s or Lupin’s accused products; (4) claims 9
and 10 of the ‘861 patent are neither anticipated nor obvious and are therefore valid and
enforceable; and (5) Amneal’s applicator product and/or its use will directly and
indirectly infringe the asserted claims of the ‘861 patent.
Findings of Fact
I.
The Parties
A.
Plaintiffs
Lilly is an Indiana corporation that has its corporate offices and principal place of
business in Indianapolis, Indiana. Lilly is engaged in the business of research,
development, manufacture, and sale of pharmaceutical products throughout the world.
Eli Lilly Export S.A. is a Swiss corporation and wholly-owned subsidiary of Lilly. Its
corporate offices and principal place of business are located at 16 Chemin des
Coquelicots, The Air Centre, 1214 Vernier/Geneva, Switzerland. Acrux is an Australian
3
corporation and its corporate offices and principal place of business are located at 103113 Stanley Street, West Melbourne VIC 3003, Australia. Acrux is engaged in the
development and commercialization of pharmaceutical products.
B.
Defendants
Perrigo Company is a Michigan corporation with its principal place of business in
Allegan, Michigan. Perrigo Israel Pharamceuticals is an Israeli corporation with a
principal place of business at 29 Lehi Street, Bnei Brak 51200, Israel. The Perrigo
Defendants are engaged in the business of making and selling generic drugs, which they
distribute in Indiana and throughout the United States. On April 3, 2012, Perrigo Israel
submitted ANDA No. 204255, pursuant to 21 U.S.C. § 355(j), seeking approval from the
FDA to sell “Testosterone Metered Transdermal Solution, 30 mg/1.5 mL.” By letter
dated October 16, 2015, the FDA informed the Perrigo Defendants of its tentative
approval of ANDA No. 204255.
Actavis (formerly known as Watson Laboratories, Inc.) is a Delaware corporation
with its principal place of business in Salt Lake City, Utah. Actavis is engaged in the
business of making and selling generic drugs, which it distributes in Indiana and
throughout the United States. On January 29, 2013, Actavis filed ANDA No. 205328,
pursuant to 21 U.S.C. § 355(j), seeking approval from the FDA to sell “Testosterone
Topical Solution, for Topical Use, 30 mg of Testosterone per Pump Actuation.” By letter
dated July 29, 2015, the FDA informed Actavis of its tentative approval of ANDA No.
205328.
4
Amneal is a Delaware corporation with its principal place of business in
Bridgewater, New Jersey. Amneal is engaged in the business of making and selling
generic drugs, which it distributes in Indiana and throughout the United States. On
March 14, 2014, pursuant to 21 U.S.C. § 355(j), Amneal filed ANDA No. 206998,
seeking approval from the FDA to sell “Testosterone Topical Solution, 30 mg/1.5 mL.”
Lupin Pharmaceuticals is a Delaware corporation with its principal place of
business in Baltimore, Maryland. Lupin Ltd. is an Indian corporation with its principal
place of business located at B/4 Laxmi Towers, Bandra-Kurla Complex, Bandra (E),
Mumbai 400 051, India. Lupin Pharmaceuticals is a wholly-owned subsidiary of Lupin
Ltd. The Lupin Defendants are engaged in the business of making and selling generic
drugs, which they distribute in Indiana and throughout the United States. On April 13,
2015, Lupin submitted ANDA No. 208061, pursuant to 21 U.S.C. § 355(j), seeking
approval from the FDA to sell “Testosterone Topical Solution, 30 mg/1.5 mL.”
Each of Defendants’ ANDA filings references Plaintiffs’ NDA No. 022504 for
Axiron® (testosterone) Metered Transdermal Solution 30 mg/1.5 mL as the referenced
listed drug.
II.
The Patents-In-Suit
A.
The ‘075 Patent
U.S. Patent No. 8,071,075, entitled “Dermal penetration enhancers and drug
delivery systems involving the same,” issued on December 6, 2011, to named inventors
Barry Leonard Reed, Timothy Mathias Morgan, and Barrie Charles Finnin. PTX-1 at 2.
The ’075 patent was assigned to Acrux DDS Pty Ltd. upon issuance. Id.
5
The ‘075 patent issued from U.S. Patent Application No. 11/905,926 filed on
October 5, 2007. PTX-1 at 2. The ’926 application is a continuation of U.S. Patent
Application No. 10/759,303 filed on January 20, 2004, which issued as U.S. Patent No.
7,438,203. Id. The ’303 application is a continuation-in-part of U.S. Patent Application
No. 09/910,780 filed on July 24, 2001, which issued as U.S. Patent No. 6,818,226. Id.
The ’780 application is a divisional of U.S. Patent Application No. 09/125,436, which
was filed as International Patent Application No. PCT/AU97/00091, filed on February
19, 1997, which issued as U.S. Patent No. 6,299,900. Id. The ’075 penetration enhancer
patent claims priority to Australian Provisional Patent Application No. 8144 filed on
February 19, 1996. 1 Id.
Plaintiffs are asserting claim 13 of the ‘075 patent against Actavis. 2 Claim 13
depends from claims 1, 5, 9, 10, and 11. Claim 13 and the claims from which it depends
recite as follows:
1.
A transdermal drug delivery system comprising:
(a) a therapeutically effective amount of testosterone;
1
Plaintiffs contend that the ‘075 patent is entitled to priority back to the Australian provisional
application filed in February 1996. Actavis initially challenged the priority date of 1996, but
conceded that if the priority date were February 19, 1997, the date of the PCT filing and the date
Actavis contends is the priority date, the prior art would remain the same. This dispute was
mainly relevant for purposes of Actavis’s obviousness challenge to the ‘075 patent, which it
withdrew before the bench trial commenced. Accordingly, we need not make a definitive
determination on this issue and will assume only for purposes of this ruling that the priority date
is February 19, 2006, as it does not affect our written description and enablement analysis, which
are the only two validity issues remaining in dispute.
2
Plaintiffs asserted claims 1-13 of the ‘075 patent against Actavis. By stipulation, the parties
proceeded to trial only on claim 13 of the ‘075 patent. They agree that disposition of claim 13
controls the disposition of the remaining asserted claims.
6
(b) at least one dermal penetration enhancer present in an
amount of from 10 to 10,000 wt % based on the weight of the
testosterone; wherein the dermal penetration enhancer is at least one
ester of formula (I):
wherein R1 is hydrogen, lower alkyl, lower alkoxy, halide, hydroxy or
NR3R4; R2 is a C8 to C18 alkyl; R3 and R4 are each independently
hydrogen, lower alkyl or R3 and R4 together with the nitrogen atom to
which they are attached form a 5- or 6-membered heterocyclic ring; n
is 0 or 1, and q is 1 or 2, wherein, when n is 0 and R1 is NR3R4, then
NR3R4 is para-substituted; and
(c) at least one volatile liquid present in an amount to act as a
vehicle for the testosterone and penetration enhancer.
5.
A method for the treatment of a testosterone deficient
hypogonadal man which comprises administering to a dermal surface
of said man in need of such treatment a therapeutically effective
amount of the drug delivery system according to claim 1.
9.
The method according to claim 5, wherein said ester is a C8 to
C18 alkyl para-aminobenzoate, C8 to C18 alkyl dimethyl-paraaminobenzoate, C8 to C18 alkyl cinnamate, C8 to C18 alkyl
methoxycinnamate or C8 to C18 alkyl salicylate.
10.
The method according to claim 9, wherein said ester is octyl
dimethyl-para-aminobenzoate, octyl para-methoxycinnamate, or
octyl salicylate.
11.
The method according to claim 10, wherein said ester is octyl
salicylate.
13.
The method according to claim 11, wherein said volatile liquid
is selected from the group consisting of ethanol, isopropanol, and a
mixture thereof.
7
PTX-1 at 27.
Actavis has stipulated that it infringes the ‘075 patent, if the patent is upheld as
valid. Dkt. 264 at ¶¶ 1-3.
B.
The ‘944 Patent
U.S. Patent No. 8,435,944, entitled “Method and composition for transdermal drug
delivery,” issued on May 7, 2013, to named inventors Tony Dipietro, Andrew
Humberstone, Igor Gonda, Adam Watkinson, Kerrie Setiawan, and Nina Wilkins. PTX-4
at 2. The ’944 patent was assigned to Acrux DDS Pty Ltd. upon issuance. Id.
The ’944 patent issued from U.S. Patent Application No. 11/445,463 filed on June
2, 2006. PTX-4 at 2. The ’944 patent claims priority to U.S. Provisional Application No.
60/752,884 filed on December 23, 2005, and Australian Application No. 2005902902
filed on June 3, 2005. Id. The earliest date to which the ’944 patent may claim priority is
June 3, 2005. Id.; Hadgraft Tr. 359:23-25.
Plaintiffs assert that defendants Perrigo, Actavis, Amneal, and Lupin infringe
asserted claim 20 of the ’944 patent. 3 Hadgraft Tr. 355:2-9. The asserted claim of the
’944 axilla patent and the claims to which it depends recite as follows:
13.
A method of increasing the testosterone blood level of an adult male
subject in need thereof comprising applying to at least one axilla of the
subject, without occlusion by a patch device, a non-occlusive transdermal
drug delivery composition consisting of: (a) a pharmaceutically effective
amount of testosterone; (b) one or more lower alkyl alcohols, wherein the
combined volume of the lower alkyl alcohol(s) is more than 60% (v/v) of the
3
Plaintiffs asserted claims 1-10 and 12-21 of the ‘944 patent and claims 1-19 of the ‘520 patent
against Defendants. By agreement, the parties proceeded to trial only on claim 20 of the ‘944
patent as a representative claim for the asserted claims of these two patents. They agree that
disposition of claim 20 controls the disposition of the remaining asserted claims.
8
composition; (c) one or more penetration enhancers selected from the group
consisting of octisalate, octyldimethyl-para-aminobenzoate and octyl paramethoxycinnamate; (d) one or more viscosity modulating agents, in an
amount effective to increase the viscosity of the composition to within the
range of from greater than the viscosity of water to less than 300 centipoise;
and (e) optionally, water, wherein the composition is applied in an amount
effective to achieve a testosterone blood level in the subject of at least 200
ng/dL.
14.
The method of claim 13 wherein the penetration enhancer is present
in an amount of from 0.01% to 15% (w/v) of the composition.
15.
The method of claim 14 wherein the penetration enhancer is
octisalate.
16.
The method of claim 15, wherein the lower alkyl alcohol is selected
from the group consisting of ethanol, isopropanol, and mixtures thereof.
17.
The method of claim 16 wherein the combined volume of lower alkyl
alcohol(s) is more than 70% (v/v).
18.
The method of claim 17 wherein the combined volume of lower alkyl
alcohols(s) is more than 80% (v/v).
19.
The method of claim 18 wherein the viscosity modulating agent is
polyvinyl pyrrolidone.
20.
The method of claim 19 wherein the polyvinyl pyrrolidone is present
in an amount of from 1% to 3% (w/v) of the composition.
PTX-4 at 18.
Defendants stipulate that they infringe the ’944 patent, if the patent is
upheld as valid. Dkt. 263, Joint Stipulation Between Plaintiffs and Perrigo
Defendants, at ¶¶ 1-3; Dkt. 264, Joint Stipulation Between Plaintiffs and
Defendant Actavis, at ¶¶ 1-3; Dkt. 272, Joint Stipulation Between Plaintiffs and
Lupin Defendants as to U.S. Patent Nos. 8,435,944, 8,993,520, 8,177,449, and
9
8,419,307, at ¶ 13; Dkt. 284, Joint Stipulation Between Plaintiffs and Amneal as to
U.S. Patent Nos. 8,435,944, 8,993,520, 8,177,449, and 8,419,307, at ¶¶ 1-3.
The use of Axiron® is an embodiment of claim 20 of the ‘944 patent.
C.
The ‘861 Patent
U.S. Patent Application No. 13/836,056 was filed on March 15, 2013, as a
continuation of application No. 13/464,556 (now the ’307 patent) and issued as the
’861 patent,” entitled “Spreading Implement,” on August 19, 2014. PTX-5, ’861
patent, at 2. The ’861 patent names Peter Bayly, Mark Simon Bayly, Magnus
Ahlstrom, and Adam Charles Watkinson as inventors. PTX-5, ’861 patent, at 2;
Dkt. 359, Stipulated Facts, at ¶ 16.
The ’861 patent issued from U.S. Patent App. No. 13/836,056, filed on
March 15, 2013, which is a continuation of U.S. Patent App. No. 13/464,556 filed
on May 4, 2012, which is a continuation of U.S. Patent App. No. 11/678,673, filed
on February 26, 2007, which claims priority to U.S. Provisional App. No.
60/884,482, filed on January 11, 2007.
Plaintiffs contend that Defendants’ applicators infringe dependent claims 9
and 10 of the ’861 patent. 4 These claims (and those from which they depend)
recite as follows:
4
Plaintiffs asserted against Perrigo the following claims: 1, 10, 17-20, 23, and 25 of the ‘449
patent; 1-4 and 6-23 of the ‘307 patent; and 1, 9-11 and 19 of the ‘861 patent. Plaintiffs asserted
against Actavis and Amneal claims 1 and 9-11 of the ‘861 patent and claims 1 and 9-10 of the
‘861 patent against Lupin. By agreement, the parties proceeded to trial on claims 9 and 10 of the
‘861 patent as the representative claims for the asserted Applicator Patents. Disposition of
10
1.
A system for transdermal administration of a physiologically
active agent from a liquid composition, the system including a
container containing the liquid composition including the
physiologically active agent, a dispensing device for delivering liquid
composition from the container; and an applicator for applying the
liquid to an area of skin for transdermal administration said applicator
including a support detachably contactable to the dispensing device or
container being adapted to detach to permit said dispensing device to
deliver said liquid composition, a receptacle mounted on the support
defining a reservoir space which receives a volume of the liquid
composition from the container, the receptacle having a base and a
resiliently deformable wall, the wall being substantially transverse to
the base and having a working surface that is used to spread the liquid
composition over the area of the skin surface, the base having a
surface such that the liquid composition cannot pass through the base.
9. A method of transdermal administration of a physiologically active
agent to a subject including providing a system according to claim 1;
applying the liquid composition including the physiologically active
agent to the reservoir space; and deforming the wall of the receptacle
containing the liquid composition against the skin of the subject and
spreading the liquid composition over the area of the skin surface in
at least one axilla.
10.
A system according to claim 1 wherein the receptacle defining
the reservoir space has an open top being configured to receive the
liquid composition from the dispensing device through the open top.
(Id. at claims 1, 9, 10.)
claims 9 and 10 of the ‘861 patent controls the disposition of the remaining asserted claims. See,
e.g., Scanner Techs. Corp. v. ICOS Visions Sys. Corp., 528 F.3d 1365, 1383-84 (Fed. Cir. 2008).
11
III.
The Experts
A.
Plaintiffs’ Experts
At trial, Plaintiffs offered the testimony of the following experts: (1) Dr. Jonathan
Hadgraft, an expert in transdermal formulation and skin barrier function; (2) Dr. Irwin
Goldstein, an expert in urology and hypogonadism; and (3) Dr. Alexander Slocum, an
expert in the field of mechanical engineering and the design of medical devices.
Jonathan Hadgraft, D.Sc.
Dr. Jonathan Hadgraft, Plaintiffs’ transdermal formulation and skin barrier
function expert, has worked in the field of dermal and transdermal drug delivery for more
than thirty-five years. Dr. Hadraft testified that in his opinion the asserted claims of the
‘075 and ‘944 patents are valid.
In 1973, Dr. Hadgraft received a B.A. and M.A. in Chemistry, with an emphasis
on Chemical Pharmacology, from the University of Oxford. In 1975, he earned a
doctorate in Physical Chemistry from the University of Oxford. In 1992, he was awarded
a D.Sc. from the Faculty of Medicine at the University of Oxford in recognition of his
12
research in dermal drug delivery. PTX-220; Hadgraft 102:2-104:17, 106:12-114:22,
116:20-123:23, 126:24-127:21.
Dr. Hadgraft founded the Prediction of Percutaneous Penetration Conference and
Skin Forum, which is comprised of multiple academic and industrial research groups. In
recognition of his contributions, he was named a Fellow of the American Association of
Pharmaceutical Scientists, Academy of Pharmaceutical Sciences, and the Controlled
Release Society. PTX-220; PDX-3001; Hadgraft 102:2-104:17, 106:12-114:22, 116:20123:23, 126:24-127:21.
Dr. Hadgraft has conducted research, lectured extensively on skin barrier function
and dermal and transdermal drug delivery, and published more than 500 peer-reviewed
articles. Dr. Hadgraft currently holds the rank of Emeritus Professor of Biophysical
Chemistry at the School of Pharmacy, the University of London. Prior to assuming
Emeritus status, Dr. Hadgraft was a full-time Professor of Biophysical Chemistry at the
School of Pharmacy. Since the 1980s, Dr. Hadgraft has served as an industry consultant
for SmithKline Beecham, Eastman Kodak, Shire and others on formulations for dermal
and transdermal therapies. Dr. Hadgraft worked on approved transdermal products, such
as nitroglycerin, clonidine, estradiol, fentanyl, and nicotine. PTX-220; PDX-3000; PDX3002; Hadgraft 102:2-104:17, 106:12-114:22, 116:20-123:23, 126:24-127:21; 142:25143:5. However, he has never been the lead formulator of a transdermal product that has
been approved by the FDA and has never worked on any actual experiments with
13
testosterone or conducted any research and development of a transdermal testosterone
product. Hadgraft 306:10-12, 307:23-308:6.
Irwin Goldstein, M.D.
Dr. Irwin Goldstein is a Board-certified urologist. The field of urology focuses on
the organs associated with the urinary system and male reproduction. At trial, Dr.
Goldstein opined that the asserted claim of the ‘944 patent would not have been obvious.
Dr. Goldstein received his M.D.C.M. from McGill University Faculty of Medicine
in 1975. He served as a surgical resident and fellow at University Hospital in Boston. In
1982, Dr. Goldstein joined the faculty of Boston University School of Medicine, teaching
courses in urology and gynecology until 2005. PDX-7000; PDX-7001; Goldstein 604:9610:10.
14
Dr. Alexander Slocum is an expert in the field of mechanical engineering. He
conducts research, has published in excess of 100 academic peer-reviewed journal
papers, and lectures extensively in the field. PTX-222 at 2, 4-5; Slocum 525:22-24,
526:21-527:11, 532:3-8. Dr. Slocum opined at trial that the asserted claims of the ‘861
patent are valid and infringed by Defendants’ products.
15
Dr. Slocum has been awarded more than 100 patents and has developed an
important precision alignment standard for the semiconductor industry. PTX-222 at 1;
Slocum 533:10-535:12. He has helped to create eleven products that have been awarded
“R&D 100” awards, each for being one of the one hundred most technologically
significant new products of the year. PTX-222 at 2-3; Slocum 533:1-8.
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20
21
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IV.
The ‘075 Formula Patent
The ‘075 formula patent claims a transdermal drug delivery system comprising a
therapeutically effective amount of testosterone and at least one dermal penetration
5
By stipulation, in lieu of live testimony from Mr. Plank at trial, the parties admitted the Expert
Report of Hermann Plank MSc., dated February 19, 2016 (“Plank Report”), including Exhibits 1
and 2 of the Plank Report as his direct testimony. See ECF No. 411. Mr. Plank’s report was
admitted as DTX-2082.
23
enhancer selected from safe ester sunscreens. PTX-1 at 2. The drug delivery system
claimed in the ‘075 patent is used to treat various medical conditions, including
testosterone deficiency in hypogonadal men. Id. at col. 28, ll. 32-26.
Definition of a Person of Ordinary Skill in the Art for the ‘075 Patent
A person of ordinary skill in the art (“POSA”) for the ‘075 formula patent would
have been a pharmaceutical formulator with a doctorate or master’s degree and with at
least two years of experience in transdermal or topical formulation, working together
with, or able to rely on, the expertise of a clinician or physician. Hadgraft 250:23-251:5;
251:14-16. Both sides’ experts agree that their opinions on validity of the ‘075 patent are
the same regardless of which expert’s precise POSA definition is adopted. Hadgraft
219:1-5; Potts 1309:17-1310:9.
Hypogonadism
Hypogonadism is the medical term for the physical condition of low levels of
testosterone in men. Goldstein 616:14-19. Testosterone is a 19 carbon sex-steroid that is
a male hormone circulating in human blood that affects male androgen dependent tissues,
e.g., the prostate, scrotum, and apocrine glands. PDX-7003; Goldstein 613:15-614:8.
Testosterone also forms and develops secondary sex characteristics such as facial hair,
muscle strength, deepening of the voice, bone growth, sperm maturation, and sexual
desire. Goldstein 614:9-14. There are several organs involved in the production and
secretion of testosterone, including the hypothalamus, pituitary gland, and testicles.
PDX-7003; Goldstein 615:8-616:13.
24
Hypogonadism is generally classified as primary or secondary hypogonadism.
Primary hypogonadism is a lack of function of the testes; anorchism, orchitis, cancer of
the testicles, and Klinefelter syndrome are examples. PTX-390 at 1; PDX-7004;
Goldstein 617:3-12. Secondary hypogonadism involves a breakdown of the regulatory
system that governs the hypothalamus and pituitary glands which regulates the
production of testosterone. Tumors, diabetes, hypertension, high cholesterol, and HIV
exemplify conditions that can lead to secondary hypogonadism and interfere with or limit
testosterone production. PDX-7006; Goldstein 618:5-22.
A hypogonadal male may suffer physical, metabolic, cognitive, psychological, and
sexual symptoms, e.g., decreased bone density, impaired memory, and reduced libido.
PDX-7007; Goldstein 619:8-620:15. In 2005, it was estimated that approximately 13
million men were hypogonadal. Goldstein 621:1-15.
The Invention and ‘075 Patent
In the 1980s, Drs. Reed and Finnin, professors in Melbourne, Australia, were
engaged in transdermal formulation research, studying formulations containing
25
hydroquinone, a compound that causes depigmentation in the skin. Because they were
concerned that the effects of sun exposure on skin would interfere with the effects of the
hydroquinone formulations, they decided to add a sunscreen agent to the formulation.
Upon adding the sunscreen agent, they were surprised to observe that a formulation
without the normal penetration enhancer but with sunscreen substantially enhanced
transdermal penetration of hydroquinone. PTX-1 at co. 11:41-45 (“Additionally the
group of compounds of the invention surprisingly exhibited appreciable penetration into
and substantivity for the outer layers of the skin, namely the stratum corneum which has
previously presented a formidable barrier to percutaneous drug absorption.”).
Following this discovery, Drs. Reed and Finnin continued their research with Tim
Morgan, then a Ph.D. student. Together, these inventors of the ‘075 patent discovered
that sunscreen compounds in combination with testosterone showed a significant
improvement in skin penetration, and that the penetration enhancer, octyl salicylate, in
particular, showed a substantial improvement in testosterone absorption through the skin.
PTX-1 at col. 23, ll. 15-41; Hadgraft 165:14-24.
In 1998, the inventors of the ‘075 patent along with a small group of founding
members formed the company Acrux to develop pharmaceutical treatment based on their
discovery. Their development work led to FDA approval of two products that include
octyl salicylate as the dermal penetration enhancer – Evamist®, an estrogen product sold
26
in the United States, and Axiron®, which is a transdermal testosterone formulation used
to treat hypogonadal men. Axiron® is the product at issue in this litigation. 6
Contemporaneous Transdermal Drug Formulations
6
Each metered dose of Axiron® contains 30 mg of testosterone in 1.5 mL of solution. PTX-44 at
8. The solution is 2% w/v testosterone (2.44% w/w); 5% w/v octisalate (6.1% w/w); 2% w/v
povidone (2.44% w/w); 30% v/v isopropyl alcohol (28.76% w/w); and the remainder is ethanol
alcohol (60.25% w/w). PTX-75 at 211.
27
7
This range is greatly expanded from that disclosed in the Australian provisional application.
The disclosed range of penetration enhancer in the Australian provisional application was an
amount of up to only 1,000% weight percent based on the weight of the active agent, which
equates to 10 times more penetration enhancer than active. In the ‘075 patent, the 10,000 weight
percent is claimed. We discuss this expansion in detail below.
28
The specification contains five examples disclosing transdermal formulations with
testosterone, and all five have 12% w/v testosterone and 8% v/v of penetration
enhancer—including Example 10 reciting 12% w/v testosterone and 8% v/v of octyl
salicylate. PTX-1 at Examples 6, 10, 12, 13, and 15; Potts 1320:8-17, 1321:11-1322:6;
Hadgraft 348:5-8; DDX 212. This ratio in all of the testosterone examples corresponds to
approximately 0.67-times (or 67%) of the penetration enhancer by weight of testosterone.
Potts 1320:18-1321:10. Accordingly, the examples illustrate that a formulation
comprising less octyl salicylate than testosterone is effective. There is no other indication
29
in the specification that testosterone is an active ingredient that may require 10,000% of
penetration enhancer. Id. at 1319:10-1322:6.
30
31
32
V.
The ‘944 Axilla Patent
The ‘944 axilla patent claims a method of treating hypogonadism by application of
a non-occlusive (non-patch) transdermal testosterone formulation to the axilla. PTX-4 at
claims 13-20. The relative time period for the validity analysis of the ‘944 patent is June
2005.
Definition of a Person of Ordinary Skill in the Art for the ‘944 Patent
A person of ordinary skill in the art (“POSA”) for the ‘944 axilla patent would
have been a pharmaceutical formulator with a doctorate or master’s degree in
pharmaceutical sciences or a similar degree and with at least two years of experience in
transdermal or topical pharmaceutical formulation, working together with, or able to rely
33
on, the expertise of a clinician or physician. Hadgraft 250:23-251:5; 251:14-16. Both
sides’ experts agree that their opinions on validity of the ‘944 patent are the same
regardless of which expert’s specific POSA definition is adopted. Hadgraft 219:1-5;
Potts 1339:14-1340:13; Chambliss 1538:22-1540:12.
General Background of the Invention
As of 2005, there were two types of transdermal testosterone replacement
therapies on the market: patches and gels. The patches were associated with skin
irritation, and the scrotal patch in particular was associated with elevated
dihydrotestosterone (“DHT”) levels. PTX-511 at 3; PTX-92 at 4; PTX-93 at 33; PTX264; PTX-587; Hadgraft 197:19-22; Goldstein 622:20-23, 623:1-8, 635:9-636:22.
Elevated DHT levels were associated with an increased risk of developing prostate cancer
or enlarged prostate and because of the chronic or long-term nature of testosterone
replacement therapy, such elevated DHT levels were of particular concern. PTX-511 at
3; PTX-92 at 4; Hadgraft 197:19-22; Goldstein 622:20-23; 636:23-637:16. The scrotal
patch was withdrawn from the market in 2002 at least in part because of these concerns.
PTX-587 at 4; Goldstein 623:12-15. The gels were applied to large areas, such as the
upper arms, back, abdomen, thighs, buttocks, or shoulders. PDX-2064. Although gels
were not associated with elevated DHT levels, it was reported that there was a risk of
inadvertent transfer to a spouse or child by patients using the gels. Hadgraft 209:14-17.
Acrux sought to develop an improved testosterone replacement therapy with its
sunscreen penetration enhancer formulation. In 2004, Acrux began clinical trials to
34
assess the safety, efficacy, and feasibility of administering testosterone through the axilla.
See, e.g., PTX-96; PTX-100; PTX-154; DTX-69; PTX-4, col. 20, ll. 32-67; Goldstein
668:23-669:20. The initial pilot study was conducted in women, and the follow-up study
was conducted in healthy men with compressed testosterone. PTX-4 at 16, col. 20, l. 32col. 23, l. 9; PTX-96; PTX-117. The results of the studies showed that applying
testosterone to the axilla was effective at increasing testosterone blood levels and did not
lead to abnormally high DHT levels or increase sweat or odor despite the increased
perspiration usually associated with the use of testosterone. Hadgraft 296:10-300:15;
Goldstein 612:17-613:8, 671:3-674:25, 682:17-683:17; PTX-4 at col. 22, l. 65-col. 23, l.
8. Based on the results of these studies, the inventors conceived of treating
hypogonadism by application of transdermal testosterone to the axilla, which is the
invention of the ‘944 patent. PTX-1109 at 3.
Claim 20 of the ‘944 Patent
Asserted claim 20 of the ‘944 patent depends upon independent claim 13 and each
of dependent claims 14-19. PTX-4 at Claims 13-20. The chart below maps each of the
limitations of asserted claim 20, including each of the limitations of the claims from
which it depends. Id.; Potts 1347:8-1348:24 (discussing demonstratives DDX 234-36);
see also PDX 2022.
35
Claim 13 of the Axilla Patent
Dependent Claims 14-20
of the Axilla Patent
Compilation of Claim 20 of
the Axilla Patent
A method of increasing the
testosterone blood level of an
adult male subject in need
thereof comprising applying
to at least one axilla of the
subject, without occlusion by
a patch device, a nonocclusive transdermal drug
delivery composition
consisting of:
A method of increasing the
testosterone blood level of an
adult male subject in need
thereof comprising applying
to at least one axilla of the
subject, without occlusion by
a patch device, a nonocclusive transdermal drug
delivery composition
consisting of:
(a) a pharmaceutically
effective amount of
testosterone;
(a) a pharmaceutically
effective amount of
testosterone;
(b) one or more lower alkyl
alcohols, wherein the
combined volume of the
lower alkyl alcohol(s) is more
than 60% (v/v) of the
composition;
’944 claim 16 – The method
of claim 15, wherein the
lower alkyl alcohol is
selected from a group
consisting of ethanol,
isopropanol, and mixtures
thereof.
’944 claim 17 – The method
of claim 16, wherein the
combined volume of lower
alkyl alcohol(s) is more than
70% (v/v).
(b) one or more lower alkyl
alcohols selected from a
group consisting of ethanol,
isopropanol, and mixtures
thereof, wherein the
combined volume of the
lower alkyl alcohol(s) is more
than 80% (v/v) of the
composition;
’944 claim 18 – The method
of claim 17, wherein the
combined volume of lower
alkyl alcohol(s) is more than
80% (v/v).
(c) one or more penetration
enhancers selected from the
group consisting of octisalate,
octyldimethyl-paraaminobenzoate and octyl
para-methoxycinnamate;
’944 claim 14 – The method
of claim 13 wherein the
penetration enhancer is
present in an amount of from
0.01% to 15% (w/v)
’944 claim 15 – The method
of claim 14 wherein the
penetration enhancer is
octisalate.
36
(c) the penetration enhancer
octisalate in an amount of
from 0.01% to 15% (w/v)
Claim 13 of the Axilla Patent
(d) one or more viscosity
modulating agents, in an
amount effective to increase
the viscosity of the
composition to within the
range of from greater than the
viscosity of water to less than
300 centipoise; and
Dependent Claims 14-20
of the Axilla Patent
’944 claim 19 – The method
of claim 18 wherein the
viscosity modulating agent is
polyvinyl pyrrolidone.
’944 claim 20 – The method
claim 19 wherein the
polyvinyl pyrrolidone is
present in an amount from
1% to 3% (w/v) of the
composition.
Compilation of Claim 20 of
the Axilla Patent
(d) the viscosity modulating
agent polyvinyl pyrrolidone
present in an amount from
1% to 3% (w/v) of the
composition, in an amount
effective to increase the
viscosity of the composition
to within the range of from
greater than the viscosity of
water to less than 300
centipoise
(e) optionally, water
(e) optionally, water
wherein the composition is
applied in an amount effective
to achieve a testosterone
blood level in the subject of at
least 200 ng/dL.
wherein the composition is
applied in an amount
effective to achieve a
testosterone blood level in the
subject of at least 200 ng/dL.
Occlusive and Non-Occlusive Transdermal Testosterone Treatments for
Hypogonadism Were Well-Known in the Prior Art
By June 2005, a number of transdermal testosterone products were commercially
available in the United States as testosterone therapies to treat males experiencing a
deficiency or absence of endogenous testosterone, as characterized by the condition
known as hypogonadism. Snyder 915:19-917:22. Such products included occlusive
(patch) treatments Testoderm® (PTX-511) and Androderm® (PTX-512), and nonocclusive (non-patch) treatments AndroGel® (PTX-1059), and Testim® (PTX-641).
Other transdermal testosterone formulations were disclosed in the prior art literature,
including U.S. Patent Application Publication No. 2004/0028725 (“Morgan ‘725
Publication”) (PTX-483); U.S. Patent No. 6,299,900 (“Reed ‘900 Patent”) (PTX-19);
37
U.S. Patent No. 6,211,250 (“Tomlinson ‘250 Patent”) (PTX-592); U.S. Patent No.
6,319,913 (“Mak ‘913 Patent”) (PTX-453); and U.S. Patent Application Publication No.
2005/0042268 (“Aschkenasy ‘268 Publication”) (PTX-243). These products and
formulations are all § 102(b) prior art to the ‘944 axilla patent. We describe each in
greater detail below:
A.
Testoderm®
Testoderm® was first approved by the FDA in 1993 and was commercially sold in
the United States prior to June 2005. PTX-511 at 2. Testoderm® was a commercially
available patch for the transdermal delivery of testosterone for testosterone replacement
therapy in hypogonadal men. Id. at 3. The Testoderm® system is a thin film about the
size of a business card containing testosterone that was designed to be worn on the
scrotum for 22 to 24 hours daily. Id.; Hadgraft 197:19-22; Goldstein 622:20-23.
Testoderm® was later withdrawn from the market because of concerns related to elevated
DHT levels associated with use of the product. Goldstein 623:12-15.
B.
Androderm®
Androderm®, another transdermal testosterone patch product, was first approved
by the FDA in 1995 and was commercially sold in the United States prior to June 2005.
PTX-512 at 2. Androderm® is a commercially available testosterone patch for
testosterone replacement therapy in men with conditions associated with a deficiency or
absence of endogenous testosterone, such as hypogonadism. Id. at 3. The suggested
38
starting dosage is two Androderm® patches applied to the back, abdomen, upper arm, or
thigh, providing a total dose of 5 mg/day of testosterone. Id. at 4.
C.
AndroGel® and U.S. Patent No. 6,503,894
AndroGel® was first approved by the FDA in 2000 and was commercially sold in
the United States prior to June 2005. PTX-1059 at 1; Potts 1342:6-12. AndroGel® is
§ 102(b) prior art to the axilla patent. AndroGel® is a non-occlusive hydroalcoholic gel
containing 1% testosterone as the active ingredient. PTX-1059 at 1. AndroGel® is a
testosterone replacement therapy for males with a deficiency or absence of endogenous
testosterone, as characterized by the condition known as hypogonadism. Id. at 11-12. An
appropriate starting dosage of AndroGel® 1% is 5 grams applied once daily to clean, dry,
intact skin of (i) the shoulders and upper arms (ii) and/or abdomen. Id. at 22.
U.S. Patent No. 6,503,894 (“Dudley ‘894 patent”) (PTX-319), entitled
“Pharmaceutical composition and method for treating hypogonadism,” issued on January
7, 2003. PTX-319 at 1; Potts 1342:6-12. The Dudley ’894 patent is § 102(b) prior art to
the axilla patent. The Dudley ’894 patent discloses the AndroGel® composition and
teaches a method for treating hypogonadism by applying the AndroGel® composition to
the skin. PTX-319 at Abstract, col. 13, ll. 22-35, col. 14, ll. 25-28.
D.
Testim® and International Patent Application Publication No. WO
2003/088974
Testim® was first approved by the FDA in 2002 and was commercially sold in the
United States prior to June 2005. PTX-641 at 1, 18; Potts Tr. 1342:6-12. Testim® is §
39
102(b) prior art to the axilla patent. Testim® is a non-occlusive hydroalcoholic gel
containing 1% testosterone as the active ingredient. PTX-641 at 1. Testim® is a
testosterone replacement therapy for males with a deficiency or absence of endogenous
testosterone, as characterized by the condition known as hypogonadism. Id. at 10. The
recommended starting dosage of Testim® is “5 g of gel (one tube) containing 50 mg of
testosterone applied once daily (preferably in the morning) to clean, dry intact skin of the
shoulders and/or upper arms.” Id. at 17.
International Patent Application Publication No. WO 2003/088974 (“Gyurik ’974
publication”) (PTX-382), entitled “Pharmaceutical Composition,” was published on
October 30, 2003. PTX-382 at 1; Potts 1342:6-12. Gyurik ’974 publication is § 102(b)
prior art to the axilla patent. Gyurik ’974 publication discloses a variation of the
Testim® formulation and teaches a method for treating hypogonadism by applying the
formulation to the skin. PTX-382 at Abstract, Example 1, Comparative Example C-1.
E.
Morgan ‘725 Publication
U.S. Patent Application Publication No. US 2004/0028725 (“the Morgan ’725
publication”), entitled “Transdermal Delivery Of Hormones,” is a patent application that
was filed by Morgan, et al., no later than May 2, 2003, and was published on February
12, 2004. PTX-483. The Morgan ’725 publication issued as the Morgan ’983 patent.
PTX-21.
The Morgan ’725 publication teaches a method of increasing testosterone blood
levels of an adult male subject in need thereof. Potts 1349:4-23. The Morgan ’725
40
publication discloses a “transdermal drug delivery system which comprises: a
therapeutically effective amount of a hormone; at least one dermal penetration enhancer,
which is a safe skin-tolerant ester sunscreen ester; and at least one volatile liquid.” PTX483 at Abstract. It further provides “a method for administering at least one systemic
acting hormone to an animal which comprises applying an effective amount of the
hormone in the form of the drug delivery system of the present invention.” Id.
Specifically, it teaches that the transdermal drug delivery system may be used as “male
hormone therapy in testosterone deficient hypogonadal men.” Id. at [0057].
A POSA would understand that the Morgan ’725 publication’s teaching that its
transdermal drug delivery system may be used as male hormone therapy in testosterone
deficient hypogonadal men inherently discloses raising the testosterone blood levels of
that hypogonadal male to at least 200 ng/dL. Potts 1349:4-23; Chambliss 1559:201560:17. By June 2005, methods for treating hypogonadal adult males by applying a
non-occlusive transdermal testosterone composition with the objective of increasing
testosterone blood levels to normal physiologic ranges were well-known in the art. Potts
1341:22-1342:12. For instance, AndroGel® and Testim® were FDA-approved
transdermal testosterone compositions used to treat hypogonadism in adult males by
transdermally delivering testosterone to maintain therapeutically effective testosterone
blood levels. PTX-1059 at 11-12; PTX-641 at 10. AndroGel® and Testim® deliver a
therapeutically effective amount of testosterone across the skin to produce testosterone
blood levels that approximate normal adult male blood levels of about 300 ng/dL to 1000
41
ng/dL. PTX-1059 at 2; PTX-641 at 1; Snyder 913:22-914:6. A POSA would have
sought to return the testosterone blood levels of a hypogonadal man to the normal adult
male levels, which is greater than 200 ng/dL. Id.; Chambliss 1559:20-1560:17.
Composition 13A of the Morgan ’725 publication expressly teaches a nonocclusive transdermal drug delivery composition consisting of: (a) testosterone in an
amount of 1% w/v, (b) 90% w/v aqueous ethanol, (c) the penetration enhancer octyl
salicylate in an amount of 2.5% w/v, and (d) the viscosity modulating agent hydroxyl
propyl cellulose in an amount of 1.5% w/v. PTX-483 at Example 13. Composition 13B
of the Morgan ‘725 publication discloses a similar formulation containing the viscosity
modulating agent ethyl cellulose in an amount of 1.5% w/v. Id. The Morgan ’725
publication teaches that the viscosity modulating agents in Compositions 13A and 13B
are interchangeable with the claimed viscosity modulating agent polyvinyl pyrrolidone
(also known as povidone). PTX-483 at [0024]; Potts 1350:23-1352:6. The Morgan ‘725
publication also discloses that the preferred range of the thickening agent in such
formulations is 0.5 to 5%. PTX-483 at [0027].
The Morgan ‘725 publication also states that “[p]referably the drug delivery
system is applied to the skin of the animal covering a delivery surface area between about
10 and 800 cm2, more preferably between about 10 and 400 cm2, and most preferably
between about 10 and 200 cm2.” PTX-483 ¶¶ 23, 30, 58; id. at claims 17-19.
The
Morgan ‘725 publication further discloses that the claimed transdermal testosterone
42
formulation may be applied to an area of the body on which it would be useful to use an
applicator. PTX-483 ¶ 58; Chambliss 1564:11-1565:1.
F.
Morgan ‘983 Patent
U.S. Patent No. 6, 923, 983 (“Morgan ‘983 patent”), entitled “Transdermal
Delivery Of Hormones,” issued to Morgan, et al., on August 2, 2005, from an application
filed no later than May 2, 2003. PTX-21. The Morgan ‘983 patent is prior art to the
axilla patent under 35 U.S.C. § 102(e). Dkt. 208, ¶ 19. The Morgan ‘983 patent issued
from the Morgan ‘725 publication and contains the same disclosures. See, e.g., Hadgraft
282:13-283:19, 486:10-16; Chambliss 1541:1-1542:8. 8
G.
Reed ‘900 Patent
The Reed ’900 patent, entitled “Dermal penetration enhancers and drug delivery
systems involving same,” issued on October 9, 2001. PTX-19 at 1. The Reed ’900
patent is the grandparent of the ’075 penetration enhancer patent. Hadgraft Tr. 271:1820. The Reed ’900 patent teaches a testosterone transdermal formulation. Potts 1342:161343:16; PTX-19 at Abstract, col. 4, ll. 20-45, col. 7, ll. 1-5, Example 15.
H.
Tomlinson ‘250 Patent
The Tomlinson ’250 patent, entitled “Percutaneous delivery system,” issued on
April 3, 2001. PTX-592 at 1. The Tomlinson ’250 patent teaches a testosterone
8
Because the disclosure of the Morgan ‘983 patent is the same as the Morgan ‘725 publication,
we will hereinafter refer only to the ‘725 publication. However, reference to that publication
incorporates the same disclosures of the ‘983 patent.
43
transdermal formulation. Potts 1342:16-1343:16; PTX-592 at Abstract, col. 4, ll. 39-48,
col. 5, ll. 35-40, col. 6, ll. 39-40.
I.
Mak ‘913 Patent
The Mak ’913 patent, entitled “Penetration enhancing and irritation reducing
systems,” issued on November 20, 2001. PTX-453 at 1. The Mak ’913 patent teaches a
testosterone transdermal formulation. Potts 1342:16-1343:16; PTX-453 at col. 2, ll. 4045, col. 4, ll. 1-9, Example 9.
J.
Aschkenasy ‘268 Publication
The Aschkenasy ’268 publication, entitled “Pharmaceutical composition and
method for transdermal drug delivery,” was published on February 24, 2005, from U.S.
Patent Application No. 10/891,489 filed on July 15, 2004. PTX-243 at 1. The
Aschkenasy ’268 publication is § 102(a) and (e) prior art to the ’944 axilla patent. See
Dkt. 208 ¶ 31.
The Aschkenasy ’268 publication teaches a testosterone transdermal formulation.
Potts 1364:13-1366:6. The Aschkenasy ’268 publication discloses “[a] pharmaceutical
composition for transdermal administration of a hormone (e.g., testosterone), which
includes urea and/or a derivative thereof as a penetration enhancer, and methods utilizing
same for treating medical conditions in which elevating a hormone serum level is
beneficial.” Id.; PTX-243 at Abstract.
44
The Aschkenasy ’268 publication teaches that applying the pharmaceutical
composition, such as testosterone and a penetration enhancer, to a biological surface can
“elevat[e] a blood serum concentration of the hormone in the subject from a subpotent
concentration to a potent concentration within about 24 hours after application. For
testosterone, in a human male, a potent concentration ranges between about 300 ng/dl and
1100 ng/dl in serum.” PTX-243 at [0065]; Potts 1365:6-15.
The PT considered the Aschkenasy ‘268 publication prior to allowance of the ‘944
patent. PTX-4 at 2.
Based on at least these afore-mentioned prior art references, a POSA would have
understood that transdermal testosterone formulas to treat hypogonadal men were welldisclosed in the prior art to the ‘944 axilla patent.
Characteristics of the Axilla
The axilla is the area of the body commonly referred to as the “armpit.” Hadgraft
362:8-10. The axilla is a region located under the shoulder joint that forms a depressed
or hollow region, i.e., a bowl, that contains, inter alia, apocrine and eccrine glands,
lymph nodes, fat, loose connective tissue, skin folds, and the brachial plexus. There are
both hairy and non-hairy portions of the axilla. Hadgraft 362:14-17; 364:17-365:5. The
axilla is known to be sweaty and is often treated with antiperspirants and deodorants to
offset odors. Hadgraft 177:23-25, 178:1-5.
Known Permeability Studies of Various Anatomical Sites, Including the Axilla
45
By June 2005, it was well-known in the art that the speed and extent of
transdermal drug delivery varies by the surface area of application, the anatomical site
upon which the drug formulation is applied, as well as the nature of the compound being
applied to the skin. Potts 1355:20-1358:1; 1505:6-10; Hadgraft 136:22-24; 229:22-230:6,
236:17-237:6, 499:10-501:7. In studies comparing the relative permeability of different
areas of skin for transdermal drug delivery, such as Feldmann (1967) and Maibach
(1971), the axilla was consistently found to be a site of high permeability for various
compounds in comparison to other potential application sites, including the back,
shoulders, abdomen, and forearms. Potts 1354:16-1355:4; PTX-340; PTX 449. At the
time of the invention of the ‘944 patent, the axilla was also known to have reduced
barrier properties. PTX-607 at 1; see Potts 1361:18-22.
A.
Feldmann (1967)
Feldmann et al., Regional Variation in Percutaneous Penetration of 14C Cortisol
in Man, The Journal of Investigative Dermatology, 48(2):181-83 (1967) (“Feldmann
(1967)”) was published in 1967. PTX-340 at 1. Feldmann (1967) is § 102(b) prior art to
the axilla patent.
Feldmann (1967) conducted a study that “quantitates the effect of regional
variation on percutaneous penetration of hydrocortisone.” PTX-340 at 1; Potts 1355:2023. The study authors delineated a 13 cm2 area on different skin sites for application of
hydrocortisone and measured the amount of drug delivery per unit area. PTX-340 at 1;
Potts 1355:24-1356:18. By pre-marking the exact size of the application site, the
46
Feldmann study accurately determined the amount of drug delivery per unit area. Id. As
shown in table 1 of Feldmann (1967), the absorption of hydrocortisone is 3.6-fold greater
across the axilla than the forearm (ventral). PTX-340 at 2; Potts 1356:19-1357:2;
Hadgraft 228:9-229:2. The permeability of the axilla was the second greatest among the
sites tested, with the scrotum having the highest permeability, which was 42 times more
permeable than the forearm. 9
The PTO considered Feldmann (1967) prior to allowing the ‘944 patent. PTX-4 at
3.
B.
Maibach (1971)
Maibach HI et al., Regional Variation in Percutaneous Penetration in Man, Arch
Environ Health, 23:208-211 (1971) (“Maibach (1971)”) was published in 1971. PTX449 at 2. Maibach (1971) is § 102(b) prior art to the axilla patent.
Maibach (1971) conducted a study of the systemic absorption of the pesticides
parathion and malathion when topically applied to different anatomical regions. PTX449 at 3-4. As shown in Tables 1-3 of Maibach (1971), the axilla demonstrated greater
absorption than many of the anatomical regions tested, including a 7.4-fold greater
absorption of parathion than the forearm and a 4.2-fold greater absorption of malathion
than the forearm. Id. at Tables 1-3; Potts 1357:3-20; Hadgraft 231:20-232:4.
9
A later study conducted by Feldmann and Maibach comparing absorption of steroids across the
skin of the forearm demonstrated that testosterone was better absorbed at that site than
hydrocortisone. DTX-188 at 2; Hadgraft 473:20-475:15.
47
Maibach (1971) was considered by the PTO prior to allowance of the ‘944 patent.
PTX-4 at 2-3.
C.
Watkinson (2002)
Watkinson A et al., Reduced Barrier Efficiency in Axillary Stratum Corneum,
International Journal of Cosmetic Science 24:151-161 (2002) (“Watkinson 2000”) was
published in 2002. PTX-607 at 1. Watkinson (2002) is § 102(b) prior art to the axilla
patent.
Watkinson (2002) reports a study to characterize the axillary skin and evaluate its
composition and function, particularly its barrier properties, as compared to other body
sites. PTX-607 at 2. Watkinson (2002) conducted a study of transepidermal water loss
(“TEWL”), which is a measure of how rapidly water is released from the skin and reflects
the strength of the skin site to act as a barrier to drug delivery. Id.; Potts 1360:15-25. As
illustrated in Figure 1 of Watkinson (2002), in a head-to-head comparison of the same
subjects serving as their own control, the “axillary TEWL measurements were
significantly greater than those of the volar forearm (Fig. 1).” PTX-607 at 5; Potts
1361:1-13. Watkinson (2002) ultimately concluded that the study “revealed a reduced
barrier function in the axilla.” PTX-607 at 1.
Watkinson (2002) also described the axilla as a “major recipient tissue for sweat
secretion,” a factor in providing the “ideal growth conditions for the commensal skin
bacteria.” PTX-607 at 2. Watkinson (2002) further reported that “we know virtually
48
nothing about axillary skin or how antiperspirant (AP) use impacts upon it.” PTX-607 at
1.
D.
Berti (1995)
Citing the data from Feldmann (1967) and Maibach (1971), Berti et al.,
Transcutaneous Drug Delivery: A Practical Review, Mayo. Clin. Proc., Vol. 70:581-586
(1995) (“Berti 1995”), reported that the axilla is approximately four times more
permeable than the forearm to transcutaneous absorption of the active ingredient
hydrocortisone. PTX-264 at Fig. 3. Berti (1995) further reported that “[a]lthough not all
drugs have the same degree of absorption as hydrocortisone, the relative ratio of
absorption at various skin sites (Fig. 3) is likely similar and correlates with the thickness
and lipid content of the stratum corneum.” PTX-264 at Fig. 3. Berti (1995) also noted
that “the areas of greatest transcutaneous absorption” (including the axilla) were “also
those subjected to the greatest application of cosmetics, antiperspirants, and deodorants.”
PTX-264 at 4.
Berti (1995) was considered by the USPTO prior to allowance of the ‘520 patent
(related to the ‘944 patent). PTX-6 at 4.
Potential Application Sites for Transdermal Testosterone Formulations Known in the
Art
In June 2005, there were no transdermal testosterone products that were applied to
the axilla. Rather, transdermal treatments as of 2005 were applied to the following sites:
(1) scrotum (Testoderm®); (2) upper buttocks, upper arms, back (Testoderm® TTS); (3)
49
abdomen, upper arms, back, thighs (Androderm®); (4) abdomen, shoulders, upper arms
(AndroGel®); (5) shoulders, upper arms, upper torso (Testim®); and (6) abdomen and
trunk (Percutacrine Androgenique Forte (“PAF”)). Axiron® is currently still the only
transdermal testosterone product that is applied through the axilla. Hadgraft 218:1-9.
The armpit or axillary area was, however, recognized as a potential application site
for transdermal testosterone treatment in the prior art, and as of June 2005 a POSA would
have been aware of the following references that teach administration of testosterone to
the axilla for delivery of testosterone into the systemic bloodstream:
A.
Aschkenasy ‘268 Publication
As discussed above, the Aschkenasy ’268 publication discloses pharmaceutical
compositions for transdermal drug delivery, including testosterone. Potts 1365:2-15.
The Aschkenasy ’268 publication is directed to “a pharmaceutical composition for topical
application, which comprises a pharmaceutically active ingredient, a penetration
enhancer, and a pharmaceutically acceptable carrier, wherein the pharmaceutically active
ingredient is a hormone, and the penetration enhancer is urea and/or a derivative thereof.”
PTX-243 at [0048]. This transdermal drug delivery composition may be used to deliver a
therapeutically effective amount of testosterone across a biological surface of the subject
to raise testosterone blood levels within the normal adult male range of 300-1100 ng/dL
testosterone:
[0065] The pharmaceutical composition of the present
invention is capable, upon application of an amount of the
composition onto at least one biological surface of a subject, of
50
elevating a blood serum concentration of the hormone in the
subject from a subpotent concentration to a potent
concentration within about 24 hours after application. For
testosterone, in a human male, a potent concentration ranges
between about 300 ng/dl and 1100 ng/dl in serum.
Id. at [0065]; Hadgraft 431:2-18. One of the express objectives of the Aschkenasy ’268
publication is the topical administration of a testosterone gel for use in hormone
replacement therapy in hypogonadal males. Hadgraft Tr. 428:4-429:2, 429:23-431:1;
PTX-243 at [0024]-[0027], [0047], [0057].
The Aschkenasy ’268 publication further teaches that its topical formulations
(which include testosterone formulations) may be applied to one of seven biological
surfaces of the skin, including the armpit:
[0066] The biological surface can be, for example, the
abdomen, an armpit, an inside arm, the back, a thigh, a
shoulder, or the scrotum.
PTX-243 at [0066] (emphasis added); Hadgraft 431:19-432:4, 447:5-12. The
Aschkenasy ’268 publication also claims application of the testosterone formulation to
only these seven biological surfaces. PTX-243 at claims 88, 93, 113, 142, 147, 167. A
POSA would understand that the Aschkenasy ’268 publication teaches application of
testosterone to the axilla for transdermal drug delivery. Potts 1365:2-1366:6.
A POSA would understand that the Aschkenasy ‘268 publication provides a
curated list of appropriate sites for transdermal delivery of testosterone. Potts 1365:21366:6. A POSA also would have known that the FDA-approved testosterone products
prior to June 2005 were applied to several of the biological surfaces listed in Aschkenasy
51
’268 publication—namely, the abdomen (Androderm® and AndroGel®), an inside arm
(AndroGel® and Testim®), the back (Androderm®), a thigh (Androderm®), a shoulder
(AndroGel® and Testim®), or the scrotum (Testoderm®). Hadgraft 447:5-452:16
(discussing DDX 1001). If a POSA wanted to apply a testosterone topical formulation to
a biological surface listed in Aschkenasy ‘268 publication that would be commercially
differentiated from the FDA-approved transdermal testosterone products, as Drs. Potts
and Chambliss explained that a POSA would have been motivated to do, the only choice
for application site would have been the armpit. Hadgraft 452:11-16; see Potts 1473:514; Chambliss 1611:10-1612:10.
The Aschkenasy ‘268 publication further teaches that the topical testosterone
formulation may contain additional additives, including humectants, deodorant agents,
antiperspirants, pH adjusting agents, preservatives, emulsifiers, occlusive agents,
solubilizing agents, colorants, and surfactants. PTX-243 at [0139]. The axilla patent
identifies these same inactive ingredients in the same order as the Aschkenasy ‘268
publication. PTX-243 at [0139]; PTX-4 at col. 18, ll. 14-23; Hadgraft 438:19-439:4. The
Aschkenasy ‘268 publication also provides an extensive list of deodorant agents and
antiperspirants (agents that are commonly applied to the axilla) for addition to the topical
testosterone formulation. PTX-243 at [0141], [0142]; Hadgraft 433:10-434:18.
The Aschkenasy ‘268 publication was considered by the PTO prior to allowance
of the ‘944 patent. PTX-4, ’944 patent, at 2; PDX-3031, Aschkenasy ’268 Publication
(2005); PTX-243; Hadgraft 267:24-268:1.
52
B.
Cutter (2000)
Cutter CB, Compounded Testosterone Gels: A Guide for Clinicians and
Pharmacists, Int’l J. of Pharm. Compounding, 4(6):432-437 (2000) (“Cutter 2000”)
published in 2000. PTX-301 at 3. Cutter (2000) is § 102(b) prior art to the axilla patent.
Cutter (2000) reviews the role of compounding pharmacists in developing
testosterone replacement therapies for the care of patients with hypogonadism. PTX-301
at 3. Cutter (2000) teaches that when administering testosterone gel for transdermal
delivery, “the choice of the application site is quite important.” Id. at 6. Cutter (2000)
recommends administering testosterone replacement therapies to the trunk or “axillary
area” to provide the normal physiologic balance of testosterone, DHT, and estradiol:
When the gel is applied to the trunk or axillary area, the resulting
balance of testosterone, DHT, and E2 will be very much in the normal
physiologic range. However, when the gel is applied to the scrotum,
the level of DHT becomes much higher because of the presence of a
much higher level of the enzyme 5-alpha reductase.
Id. A POSA would understand that Cutter (2000)’s discussion of the axillary area is a
reference to a part of the axilla. Potts 1380:21-1381:22, 1486:12-1487:25; 1489:5-17;
Chambliss 1569:6-17, 1614:4-24.
C.
Cutter (2001)
Cutter CB, Compounded Percutaneous Testosterone Gel: Use and Effects in
Hypogonadal Men, J. of the Am. Board of Family Practice, 14(1):22-32 (2001) (“Cutter
2001”) was published in 2001. (PTX-302 at 1.) Cutter (2001) is § 102(b) prior art to the
axilla patent.
53
Cutter (2001) reports the results from administering compounded percutaneous
testosterone gel to ten hypogonadal men (characterized as “a testosterone level of less
than 300 ng/dL on repeat morning serum testing”). PTX-302 at 1, 4. Patients were
provided a “testosterone gel in a dosing syringe and instructed on administration, the site
of application (either the upper inner arm or chest near the axilla or the inner thigh and
scrotum), and the amount of gel (1-3 mL).” Id. at 3. A POSA would understand that Dr.
Cutter is describing application of the testosterone gel to a portion of the axilla as one of
the sites of application. Potts 1367:21-1368:24; Snyder 966:20-967:7. A POSA would
understand that the armpit or axilla includes areas above and below the hairline of the
axilla. Chambliss 1614:4-1615:19; see also Hadgraft 419:1-420:9. A POSA would
understand that Dr. Cutter’s site of application represents the non-hairy area of the axilla.
Id. Indeed, consistent with his description of the study design, Dr. Cutter later identifies
the site of application as the “axilla” when presenting the results from the study. PTX302 at 4; Potts 1367:21-1368:24, 1487:3-25; Chambliss 1569:12-17.
Cutter (2001) further explains that he has “treated many men since the beginning
of this study.” PTX-302 at 9. In describing his clinical practice beyond the ten men
treated in his study, Dr. Cutter recommends that “the most useful starting dose for most
men is a 6% gel, 2.5 mL applied to the nonhairy area of the axilla.” Id.; Hadgraft
420:18-421:4. A POSA would understand that the axilla has both hairy and nonhairy
areas. Hadgraft 362:14-17. The nonhairy area of the axilla, where Dr. Cutter
54
recommends administering testosterone gel based on his clinical practice, is a part of the
axilla. Potts 1368:25-1369:20; Snyder 938:14-17; Chambliss 1614:4-1615:19.
Cutter (2001) further warns that “inadvertent transmission of the gels could occur
if the patient did not exercise caution in application and usage.” PTX-302 at 10.
Inadvertent transmission of testosterone is a particular concern for any children, sexual
partners, or pregnant women who may come into contact with the patient. Id. Cutter
(2001) recommends that “[b]y using the gel in the axillary area, at bedtime, transmission
can be avoided.” Id. (emphasis added). A POSA would understand that Cutter (2001)
teaches administration of testosterone gel to the remote area of the axilla to avoid
inadvertent transmission of testosterone to others. Potts 1376:1-14.
Cutter (2001) was considered by the PTO prior to allowance of the ’944 patent.
PTX-4, ’944 patent, at 2; PDX-3037, Cutter (2001): PTX-302; Hadgraft 255:17-18.
D.
Chein ‘790 Patent
U.S. Patent No. 6,562,790 (“Chein ‘790 patent”), entitled “Hormone therapy
methods and hormone products for abating coronary artery blockage,” issued on May 13,
2003. (PTX-283 at 1.) The Chein ’790 patent is § 102(b) prior art to the axilla patent.
The Chein ’790 patent discloses “methods and products to abate coronary artery
blockage in men and in women” by “administering a combination of natural hormones,
including human growth hormone or recombinant human growth hormone, one or more
sex hormones, such as testosterone, estrogen or progesterone and other naturally
occurring hormones, as appropriate.” PTX-283 at col. 1, ll. 5-11. For those men “with
below optimal testosterone levels, these methods call for administering natural
55
testosterone in gel form, preferably applied topically to under arm pits.” Id. at col. 1, ll.
22-25. A POSA would understand the Chein ‘790 patent’s instruction to apply the
testosterone composition to the “under arm pits” to refer to application to the axilla. Potts
1371:2-21.
The Chein ‘790 patent was considered by the USPTO prior to allowance of the
related ’520 axilla patent. PTX-6, ‘520 patent, at 2; PDX-3034, Chein ’790 Patent
(2003): PTX-283.
E.
Ben-Galim (1980)
Ben-Galim E et al., Topically Applied Testosterone And Phallic Growth, Am. J.
Dis. Child, Vol. 134:296-298 (1980) (“Ben-Galim (1980)”) was published in 1980.
(PTX-263 at 1.) Ben-Galim (1980) is § 102(b) prior art to the axilla patent.
Ben-Galim (1980) reports the results of a study of “the effect of topical application
of testosterone cream in five boys with micropenis and hypopituitarism.” PTX-263 at 1.
In this study, “all subjects were treated with 5% testosterone propionate in hydrophilic
ointment USP. Average dosage was between 2.5 and 4.0 mg of testosterone (50 to 75 mg
of ointment) applied three times a day for three weeks, on an approximate area of 9 sq
cm. In four patients (1 through 4), the ointment was applied directly to the phallus, and
in one patient (5) to his right axilla.” Id. For the patient that administered the
testosterone propionate to his right axilla, the total plasma testosterone increased from <
20 ng/dL before treatment to 573 ng/dL on the last day of treatment. Id. at 2. A POSA
would understand that Ben-Galim (1980) reports an example of administering
56
testosterone to the skin of the axilla to elevate systemic testosterone blood levels. Potts
1372:5-18; Hadgraft 403:25-404:21, 405:7-25, 407:9-15, 408:4-16.
Ben-Galim (1980) was considered by the PTO prior to allowance of the ‘944
patent. PTX-4, ’944 patent, at 3; Hadgraft 225:23-226:1.
F.
Papa (1967)
Papa CM et al., Effect of Topical Hormones on Aging Human Skin, Journal of the
Society of Cosmetic Chemists, 18(8):549-62 (1967) was published in 1967 (“Papa
(1967)”). PTX-502 at 1. Papa (1967) is § 102(b) prior art to the axilla patent.
Papa (1967) reviews the effect of administering topical hormones, including
testosterone propionate (a testosterone derivative) to aging human skin. PTX-502 at 1-2.
Papa (1967) applied the topical hormones to the “face, extensor forearm, and back of the
hand” and “axilla,” using “hydrophilic ointment base or alcoholic solution” formulations.
Id. at 2. Papa (1967) found that administering testosterone propionate to the axilla of
elderly men and women had a noticeable rejuvenating effect on the appearance of the
axilla skin. Id. at 3-5.
Papa (1967) is directed to studying the effectiveness of hormones, like testosterone
propionate, “to ameliorate the degradative changes” in aging human skin. PTX-502 at
12. Papa (1967) explains that the observed rejuvenating effect is limited to the local
areas of the skin topically treated with hormones, and that the systemic administration of
hormones (i.e., drug delivery to the entire body through the bloodstream) has been found
to be ineffective in rejuvenating the appearance of aging skin. Id. Papa (1967) does not
suggest that transdermal delivery of testosterone into systemic circulation would be
57
ineffectual through the axilla, however. Id. Instead, a POSA would have known that to
even have a local rejuvenating effect on the skin, the testosterone propionate must bypass
the stratum corneum (the main barrier to transdermal drug delivery) to reach the deeper
layers of the skin—in other words, it must penetrate the skin. Potts Tr. 1373:3-21) A
POSA would understand that topical administration of testosterone propionate to the
axilla was effective in delivering the drug across the skin for a local effect and would
have expected that applying a greater amount of testosterone propionate would have
increased the amount of testosterone delivered into the bloodstream. Id.
Papa (1967) was considered by the PTO during prosecution of the ‘944 patent.
Known Concern Regarding Inadvertent Transference of Testosterone
By June 2005, the inadvertent transference of testosterone was a known risk
associated with transdermal testosterone formulations. Both the AndroGel® and
Testim® labels cautioned that pregnant and nursing women should avoid skin contact
with the testosterone gels and warned of the risk of inadvertent transference of
testosterone. PTX-1059 at 12; PTX-641 at 10; Potts 1376:15-1377:8. Cutter (2001)
further warned that inadvertent transmission of the testosterone gels could occur if
patients did not exercise caution in application and usage. PTX-302 at 10; Potts 1375:231376:14; Hadgraft 421:23-422:22. A 2-year old boy experienced serious virilization
symptoms after coming into contact with his father who was using a testosterone gel on
his arms and back. Id. Cutter (2001) recommended that “by using the gel in the axillary
area, at bedtime, transmission can be avoided.” Id. A POSA would have understood that
58
application of a testosterone gel to the axilla—an area that infrequently comes into
contact with others—would avoid inadvertent transference of testosterone from the user
to other individuals. Id.
Elevated DHT Levels Associated With Transdermal Testosterone Treatment Applied to
Scrotum
Testosterone is converted in the body to DHT via the enzyme 5-alpha reductase.
Goldstein 626:11-13; PDX-7010. The metabolite, DHT, is a potent androgen that targets
androgen-dependent tissues: testes, prostate, apocrine glands, and hair follicles. Goldstein
627:3-629:24. The enzyme 5-alpha reductase catalyzes the conversion of testosterone to
DHT. The relevant measurement is the DHT-to-T (DHT to testosterone) ratio. Goldstein
628:15-629:24.
Exogenous testosterone permeating across the skin is metabolized to DHT prior to
reaching the dermal capillaries. PTX-464 at 12; Goldstein 627:3-12, 629:17-24. Once
reaching the dermal capillaries, DHT travels to the prostate via systemic circulation.
PTX-462 at 5; Goldstein 629:17-24; Snyder 965:13-18. The prior art recognized that
elevated DHT levels were found in men using scrotal patches. It was theorized in the
prior art that exogenous application of testosterone to a site rich in 5-alpha reductase
activity, like the scrotum, was what caused the abnormally high DHT levels. PDX-7013;
Goldstein 632:4-15. The prior art further recognized a concern regarding the possible
link between elevated DHT and DHT-to-T levels and negative side effects such as benign
prostatic hypertrophy (“BPH”) (enlargement of the prostate that can lead to kidney failure
and morbidity) and prostate cancer. Goldstein 628:21-629:16.
59
Despite the prior art recognizing a concern regarding elevated DHT levels
associated with transdermal application of testosterone to the scrotum, the FDA approved
the Testoderm® scrotal patch in 1993 as safe and effective for replacement therapy in
males for conditions associated with a deficiency or absence of endogenous testosterone.
Id. at 622:20-623:8; PTX-511 at 3. The FDA approved Testoderm® even though the
literature prior to 1993 (which Dr. Goldstein relied on) reported that administration of the
scrotal patch resulted in elevated DHT levels. Goldstein Tr. 635:9-636:14. Even after
the Testoderm® patch was discontinued, 10 the prior art still recommended administration
of testosterone to the scrotum for transdermal drug delivery. See, e.g., PTX-431 (“Kryger
‘448 patent”) at col. 4, ll. 36-50 (patent issued on June 1, 2004, teaching the application
of a testosterone formulation “to the scrotal skin” in order to “achieve a serum
testosterone level of from about 600 ng/dl to about 1200 ng/dl”); PTX-243 (Aschkenasy
’268 publication, which published on February 24, 2005, teaching topical administration
of a testosterone composition to the scrotum to achieve potent testosterone compositions
in men.). Indeed, the ’944 axilla patent itself lists the scrotum as a preferred area of skin
where the claimed composition may be applied; nowhere states to avoid application of
the disclosed formulation to the scrotum; and nowhere purports to solve any alleged
problem with DHT levels. PTX-4 at col. 7, ll. 39-42.
10
Dr. Goldstein suggested that the Testoderm® patch was discontinued in 2002 due to DHT
concerns. Goldstein 623:12-15, 716:3-15. But he presents no evidence that DHT levels had any
bearing on the manufacturer’s decision to discontinue production. Id. Indeed, the manufacturer
had developed a follow-on Testoderm® TTS product. Id. at 623:16-21. Further by 2002, two
additional non-patch testosterone products, AndroGel® and Testim®, became commercially
available in the United States. Id. at 624:1-14 (discussing PDX-7008).
60
At most, by June 2005, the clinical significance of elevated DHT levels on the
prostate gland was the subject of debate among physicians. Snyder 921:6-22. In its
normal function, the prostate converts testosterone taken from the bloodstream to DHT.
Id. There is a distinction between DHT levels in the prostate and DHT blood levels, with
levels in the prostate gland being far higher than those in the bloodstream. Id. Diseases
of the prostate, like BPH, depend on the conversion of testosterone to DHT that occurred
in the prostate. Id. To a physician in 2005, therefore, there was no particular reason to
believe that the blood concentrations of DHT had any clinical effect or medical
significance on prostate disease. Id.
The teachings of the prior art relevant to elevated DHT levels associated with
transdermal testosterone treatment applied to the scrotal skin are summarized below.
Each of the references cited is prior art to the ‘944 patent.
A.
Ahmed (1988)
Ahmed et al., “Transdermal Testosterone Therapy in the Treatment of Male
Hypogonadism,” J. Clin. Endocrin. & Metab., Vol. 66(3):546-51 (1988) (“Ahmed
(1988)”) reported on a study testing the efficacy of using a testosterone patch on the
scrotal skin. PTX-235 at Abstract. Ahmed (1988) found a “disproportionate increase in
serum DHT levels” which “probably resulted from the conversion of testosterone to DHT
in the scrotal skin” related to 5α-reductase activity known to be present there. Id. at 6-7.
Ahmed (1988) recognized that while short-term DHT elevations were not known to be
related to adverse clinical effects, “the effects of chronically elevated serum DHT
61
concentrations coupled with normal serum testosterone levels are unknown.” Id. at 7.
Although Ahmed (1988) noted that the long-term effects of increased serum DHT
concentrations on the prostate “need to be systematically studied,” the authors concluded
that transdermal testosterone therapy using a scrotal patch was “an effective long term
treatment for hypogonadism in men.” Id. at 7-8.
B.
Findlay (1989)
Like Ahmed (1988), Findlay et al., “Treatment of Primary Hypogonadism in Men
by the Transdermal Administration of Testosterone,” J. Clin. Endocrin. & Metab., Vol.
68(2):369-73 (1989) (“Findlay (1989)”) reported on a study testing the efficacy of using a
scrotal patch for the long term treatment of hypogondadal men. PTX-343 at Abstract.
Findley (1989) stated that an “unexpected finding” following the study was “the increase
in the serum [DHT] concentration in each of the 10 men from subnormal or low normal
to supranormal during transdermal testosterone administration.” Id. at 7. Findlay (1989)
speculated that “the reason for this increase is the high concentration in the scrotal skin of
5α-reductase, the enzyme that catalyzes the conversion of testosterone to [DHT].” Id.
Findlay (1989) recognized that such abnormally high levels of DHT “raise the issue as to
whether transdermal administration of testosterone would be more likely than other
methods of replacement to accelerate the development of [BPH], since BPH is probably
dependent on [DHT] formation.” Id. However, Findlay (1989) observed that the DHT
upon which BPH is dependent “is normally formed within prostatic cells from
testosterone taken up from the systemic circulation.” Id. Findlay (1989) advised that in
62
the absence of definitive information about the “hormonal mechanisms of BPH
development,” prostatic examination of subjects should be performed before starting and
annually during transdermal testosterone treatment. Findlay (1989) nonetheless
concluded that the transdermal administration of testosterone via scrotal patch “is an
effective means of treating testosterone deficiency in hypogonadal men, except in those
who have a very small or irregular scrotal surface.” Id.
C.
McClure (1991)
McClure et al., “Hypogonadal Impotence Treated by Transdermal Testosterone,”
Urology, Vol. 37(3):224-28 (1991) (“McClure (1991)”) reported the results of a clinical
study of Testoderm® with four men in which the DHT:T ratio was more than double the
upper value in normal men. PTX-468. McClure concluded that high concentration of 5alpha reductase in scrotal skin was likely the reason for this increase. However, despite
observing elevated DHT levels, McClure (1991) reported that “[n]one of our patients, 2
of whom were older than fifty-five, had any subjective evidence of changes in urine flow
or frequency or an increase in the size of the prostate.” Id. at 4. McClure (1991) noted
that the “etiology of the supposed large increases in DHT in BPH became a major focus
of research during the last decade,” and that, following that research, “[t]oday, less
credence is given to the simple concept that elevated DHT levels may be a factor in BPH
….” Id. McClure (1991) concluded that transdermal testosterone therapy applied to the
scrotal skin “is convenient, reliable, and more closely mimics normal physiology than do
conventional methods of testosterone replacement for hypogondal men.” Id. at 5.
63
D.
Confrancesco (1996)
Confrancesco & Dobs., “Transdermal Testosterone Delivery Systems,” The
Endocrinologist 6(3): 207-13 (1996) (“Confrancesco (1996)”) compares studies of
patients using the Testoderm® and Androderm® transdermal testosterone patches. PTX290. Confrancesco (1996) reports that patients using Testoderm® (applied to the scrotal
skin), unlike patients using Adroderm® (applied to nonscrotal skin), were found to have
elevated serum DHT levels following treatment. Confrancesco (1996) concluded this
was “likely due to the high level of 5 α-reductase activity in scrotal skin,” noting that
“[t]he clinical significance of the increased DHT is unknown.” Id. at 3.
E.
Amory (1998)
Amory & Matsumoto, “The therapeutic potential of testosterone patches.” Exp.
Opin. Invest. Drugs 7(11) (1998) (“Amory (1998)”) is a review of various transdermal
testosterone patches. PTX-238. Amory (1998) reported that in a study of Testoderm®
treatment for an extended period of time DHT-to-T ratios were elevated but
“[i]mportantly, there were no adverse effects such as gynaecomastia, prostatic
hypertrophy, or oedema.” Id. at 4 (emphasis added).
F.
Cutter (2001)
Cutter 2001 reported that long-term studies with Testoderm® do not support the
concerns that DHT may be linked to increased prostate growth:
The published findings on the long-term use of the scrotal application of the
Testoderm patch (ALZA Corporation, Palo Alto, California) indicate that the
64
level of DHT was several-fold higher in subjects who used the patch than it
was in those treated with nonscrotal patches. However, the incidence of
prostate problems in those who wore scrotal patches was no greater than
that in subjects given placebo. Additional studies have indicated a 15%
decrease in size of the prostate in men treated with pure DHT gels, probably
as a result of an inhibition of the normal production of DHT and E2 that
occurs in the prostate itself.
PTX-301 at 7 (emphasis added).
Prior Art Related to Connection Between Application of Testosterone to the Axilla and
Elevated DHT Levels
As discussed above, the prior art attributed the elevated DHT levels and DHT:T
ratio associated with use of transdermal testosterone treatments applied to scrotal skin to
the high 5-alpha reductase activity in that area. It was known at the time of the invention
of the ‘944 patent that high concentrations of 5-alpha reductase are predominately found
in skin where there are apocrine sweat glands, such as the scrotum and axilla. Goldstein
632:16-634:17, 711:16-25. Apocrine glands have highly regionalized locations and are
found only in the axillae (armpits), in anogenital regions, and around the nipples. 11
Goldstein 625:15-626:7; Potts 1481:8-1482:6.
Dr. Goldstein opined that the prior art taught away from the application of
testosterone to the axilla due to concerns of increases in DHT levels and increased DHTto-T ratios to above supraphysiologic levels. Goldstein 632:4-15. Yet, in arriving at his
11
Dr. Snyder, Defendants’ expert endocrinologist and only medical expert, did not contest Dr.
Goldstein’s testimony regarding high concentrations of 5-alpha reductase in apocrine glands in
the axilla. Dr. Snyder did not know whether apocrine glands are predominant in the axilla.
Snyder 946:1-948:9. Dr. Snyder also had no knowledge of whether apocrine glands produce 5alpha reductase. Snyder 948:22-25.
65
opinion, Dr. Goldstein relied on no prior art data showing that the administration of
testosterone to the axilla actually resulted in elevated DHT levels or elevated DHT-to-T
ratios. Id. at 692:11-693:5. Nor did he rely on any prior art reference describing that
administration of testosterone to the axilla would result in elevated DHT levels. Id. at
694:3-11. To the contrary, the Cutter (2000) and Cutter (2001) references disclose that
application of testosterone to the “axillary area” did not result in elevated DHT levels.
PTX-301 at 6; PTX-302 at 4.
Likewise, Dr. Goldstein presented no data or experimental results showing that
administration of testosterone to the axilla would result in increased risk of prostate
cancer. Id. at 694:12-22. Dr. Goldstein conceded that for his opinion on teaching away
he did not rely on any prior art reference that actually criticizes the administration of
testosterone to the axilla. Id. at 703:1-5. He is not aware of any prior art literature stating
that the axilla would not be a good site for transdermal delivery of testosterone. Id. at
701:4-20.
In the absence of any prior art reference that actually criticizes the administration
of testosterone to the axilla due to concerns of elevated DHT levels (Goldstein 703:1-5),
Dr. Goldstein’s opinion relied upon only one study that concerned axilla skin —the in
vitro study described in Takayasu (1980). Id. at 705:13-15. None of the studies Dr.
Goldstein relied on studied application of testosterone to the axilla of a living human.
Goldstein 704:11-24. None of the other prior art references that Dr. Goldstein relied
upon for his opinion studied or otherwise discussed DHT levels after application of
66
testosterone to the axilla of a human, or activity of the enzyme 5α-reductase in the axilla.
Id. at 726:14-24 (referring to demonstrative PDX 7013).
The prior art relevant to this issue includes the following references:
A.
Takayasu (1980)
Takayasu S. et al., Activity of Testosterone 5α-Reductase in Various Tissues of
Human Skin, Journal of Investigative Dermatology, 74:187-91 (1980) reports a study of
5α-reductase activity—the enzyme involved with converting testosterone to DHT—in
various skin components derived from various human skin sites. PTX-583 at 1. In this
study, samples of skin were collected from surgery and the authors collected a 5 mm
punch biopsy. Potts 1389:16-1390:7; PTX-583 at 1. The punch biopsy was further
dissected under a microscope into separate components—i.e., glands, hair follicles,
dermis, and epidermis. Id. Each individual component (but not the whole, intact skin
samples) was tested for 5α-reductase activity. Id. In total, Dr. Takayasu evaluated
components of axillary skin taken from two patients—Subject I, a 22-year-old female and
Subject J, a 41-year-old female. Potts Tr. 1391:8-22; PTX-583 at 4. No skin samples
were collected from any anatomical region other than the axilla for these two patients.
Id. Table II of Takayasu (1980) reports that the 5α-reductase activity of the sebaceous
glands or the dermis obtained from the axilla was in about the middle of the range for
these components obtained from other skin samples of other patients, whereas the 5αreductase activity of the sweat gland obtained from the axilla was higher than the sweat
67
glands obtained from the scalp and forehead of other patients. Potts Tr. 1391:23-1392:5;
Watkinson Dep. Tr. 152:10-24; PTX-583 at 4.
In the Takayasu study, only two subjects provided axillary skin samples, and no
skin samples from other anatomic regions from these subjects were studied. Potts
1391:8-22; PTX-583 at 4. The study collected a 5 mm punch biopsy from the skin
samples, which is about the diameter of a pencil eraser, representing less than 0.1% of the
total area of the axilla. Potts Tr. 1389:16-1390:7; PTX-583 at 1. The 5α-reductase
activity, as reported by Dr. Takayasu, was then adjusted by dry weight of the sample of
the component studied. PTX-583 at 2, 4. Dr. Takayasu does not provide data regarding
the relative abundance of the components in the skin samples—i.e., how much sweat
gland was in the skin sample relative to the total amount of all components in the punch
biopsy. Potts 1392:6-16; Goldstein 715:24-716:2. In the absence of this information, a
POSA would not be able to determine the level of 5α-reductase activity in the entire
axillary skin sample. Id. Dr. Goldstein attempts to fill in this missing information
regarding the composition of the skin by offering his opinion that the “majority” of the
skin of the axilla is comprised of sweat glands, but this opinion was not included in his
expert report nor did it rely upon any prior art for corroboration. Goldstein 711:16-712:4,
715:9-23.
Takayasu (1980) is the only prior art reference upon which Dr. Goldstein relied for
his opinion regarding the level of 5α-reductase activity in the axilla. Goldstein Tr.
705:13-15. Dr. Goldstein’s opinion assumes that the axilla has similar 5α-reductase
68
activity as the scrotum. Id. at 701:21-702:14; 717:8-13, 723:9-19. Takayasu (1980) did
not measure the 5α-reductase activity of the scrotum, however. Potts 1396:10-14;
Goldstein 706:17-21. Instead, Takayasu (1980) discloses that “[o]ur knowledge of the
localization of 5α-reductase activity in the skin largely depends upon indirect evidence
obtainable from a study with whole skin: the activity is high in genital [2] and axillary
skin [4].” PTX-583 at 2; Potts 1480:5-1481:3. Takayasu (1980) plainly cites to one
study for genital skin and another study for axillary skin. See PTX-583 at 2. Dr. Potts is
not aware of any reference that directly compares the 5α-reductase activity of the axilla
and that of the scrotum. Potts at 1397:6-25. Dr. Goldstein also is not aware of any data
in the prior art literature that directly compares the 5α-reductase activity of the axilla and
that of the scrotum. Goldstein 702:16-20; see also Watkinson Dep Tr. 161:6-10, 161:1214, 161:22-162:3.
Since there is no study directly comparing those two skin sites, there is no way to
evaluate what “high” activity in genital skin means versus in axillary skin. Potts 1480:51481:3. Indeed, Dr. Takayasu warned against drawing this parallel between 5α-reductase
activity of the axilla and scrotum from two different studies. Id.; PTX-583 at 2.
Specifically, he stated that, “in addition to complexity of the skin constituents, different
experimental conditions used in these studies, which may possibly have affected the in
vitro testosterone metabolism, does not permit us to draw a parallel between various
components of the skin from different regions or those in diseased state in terms of 5αreductase activity. PTX-583 at 2 (emphasis added).) A POSA would understand that Dr.
69
Takayasu cautions against making comparisons between two studies because of these
methodological difficulties. Potts 1480:5-1481:3.
B.
Scheuplein (1971)
Takayasu (1980) does not address whether the 5α-reductase activity of isolated
axillary sweat glands is representative of the 5α-reductase activity of intact living human
axilla. As Dr. Potts explained with Scheuplein & Blank, “Permeability of the Skin,”
Physiological Reviews, Vol. 51 (1971) (“Scheuplein (1971)”) and his demonstrative
exhibit DDX 248 (which was admitted into evidence), there are different routes of drug
transport through the skin, including drug delivery directly through the outermost layer of
skin (the stratum corneum) and through skin appendages that pierce the stratum corneum
(the hair follicles and sweat ducts).
70
Id. at 1393:7-20, 1394:18-1395:13 (referring to demonstrative DDX 248); Watkinson
Dep Tr. 154:9-15, 156:1-9, 156:16-21; PTX-563 at 7.) For a drug applied to the top of
the skin to reach the sweat glands in intact skin, the drug must go through the skin
appendage route by diffusing through a sweat pore and down the sweat duct to reach the
sweat gland. Id. As was well-known, drug delivery through the skin appendages is
minimal due to the relatively small total surface area of these appendages, with total
transport through the sweat glands and hair follicles on the order of about 10-3 (0.1%). Id.
Scheuplein (1971) in Table 6 compared the fractional diffusional volume of these
separate pathways as reported in the literature. Potts 1393:21-1394:10; PTX-563 at 22.
There are about 200-250 sweat ducts/cm2 of the skin and the fractional diffusion volume
of the collective sweat ducts is about 3-5 x 10-4 (0.03-0.05%) of the skin. Id. Even
71
accounting for regional variations of areas of high sweat—such as the palms of the hands
and soles of the feet that have about two to four times greater the amount of sweat ducts
than the average body surface—the fractional diffusion volume of the collective sweat
ducts in these areas of high sweat remains small. Potts 1483:21-1484:12; PTX-563 at 22.
A POSA with an understanding of the structure of the skin and the routes of drug
delivery through the skin would not extrapolate the data reported in Takayasu (1980) for
individual components of the skin to draw conclusions about the 5α-reductase activity of
intact living human axilla. Potts Tr. 1395:14-1396:22. Dr. Takayasu harvested
individual sweat glands away from the skin. Id. at 1395:14-21. His study was not
designed to take into account the amount of testosterone that would follow the narrow
pathway through the sweat pores and sweat ducts to reach the sweat glands. Id. at
1396:3-22. A POSA would know that drug delivery through the sweat ducts into the
sweat glands comprises a minor fraction of the total volume and is not a major route for
drug delivery through the skin. Id. at 1394:11-17; see also Hadgraft Tr. 183:6-184:10
(explaining that drug delivery through the hair follicle is “really insignificant”).
C.
Cutter (2000) and Cutter (2001)
Cutter (2000) teaches a POSA that applying a testosterone gel to the axillary area,
unlike the scrotum, will result in a balance of testosterone, DHT, and estradiol that is very
much in the normal physiologic range:
The choice of application site is quite important. When the gel is applied to
the trunk or axillary area, the resulting balance of testosterone, DHT, and
E2 will be very much in the normal physiologic range. However, when the
72
gel is applied to the scrotum, the level of DHT becomes much higher because
of the presence of a much higher level of the enzyme 5-alpha reductase.
PTX-301 at 6 (emphasis added); Potts 1380:17-1381:7. A POSA would understand that
Dr. Cutter’s reference to the “axillary area” would by definition include the axilla. Id. at
1381:16-22.
Cutter (2001) further presents clinical data demonstrating that administration of
testosterone to the axilla as an application site did not result in elevated DHT levels.
Potts 1381:23-1383:7. In Table 2 of Cutter (2001), reproduced below, Dr. Cutter
provided measurements of the DHT levels of ten patients, which included seven patients
administering testosterone gel to the scrotum and three patients administering
testosterone gel to the axilla. PTX-302 at 4. Each of the three subjects who had the drug
administered to the axilla demonstrated DHT levels within the normal physiological
range of 30-100 ng/dL, whereas each of the seven subjects who had the drug
administered to the scrotum demonstrated DHT levels above 100 ng/dL. Id.
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PTX-302 at 4. A POSA would understand that Dr. Cutter’s description of the “axilla” as
the site of application in Table 2 to refer to part of the axilla. Potts 1381:23-1383:7; see
Chambliss 1614:4-24. Cutter (2001) therefore teaches that it would be appropriate to
apply a testosterone gel to the axilla and that elevated DHT levels would not be expected.
Potts 1382:4-1383:7.
Internal Acrux Correspondence Related to DHT and the Axilla
In internal documents from 2004, Acrux noted certain concerns regarding
application of testosterone to the axilla. For example, in a March 2004 email, Acrux
recognized: “[T]here is still concern re DHT levels, even after application, because DHT
is a 5-fold more potent androgen than [testosterone]. Need to make sure this is measured
in any [pharmacokinetic] studies that Acrux completes.” PTX-1033, March 9, 2004, Email from Charman, at 1. Acrux meeting minutes from December 2004 also reflect
discussion of potential concerns regarding applying testosterone to the axilla, including
increased hair growth, increased sweating or smell, increased 5-alpha reductase and
DHT:T ratio, and interaction from shaving and cosmetics. PTX-657, Acrux Dec. 15,
2004, Meeting Minutes, at 1.
However, in an April 26, 2006 email from Ms. Paulina Hall (Acrux’s FDA
consultant) to Acrux recounting a conversation she had had with Mr. John Kim (the
FDA’s representative) occurring earlier that day, Ms. Hall clearly states that the FDA was
“not concern[ed] with using the axilla as the application site for the proposed IND study.”
PTX-1035 at 1. In his direct testimony, Dr. Goldstein offered an opinion as to why the
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FDA would have had no concern with selecting the axilla as an application site,
(Goldstein 670:8-23), stating that the FDA was at first concerned about DHT levels, but
that the FDA was subsequently convinced that there were no concerns, because “data
shown to [the FDA of any earlier Acrux clinical study] did not show elevations in DHT
when a testosterone formulation was applied to a region with high 5-alpha reductase
activity, the axilla.” Id. However, the email correspondence from Ms. Hall does not state
that the FDA ever had had any concerns with elevated DHT levels from application of
testosterone to the axilla. PTX-1035 at 1. Nor does Ms. Hall explain the reason the FDA
had had no concerns. Id.
Further, the premise of Dr. Goldstein’s opinion on the FDA correspondence is that
the FDA had reviewed the data from Acrux clinical study MTE04 in evaluating whether
there was any concern with applying testosterone to the axilla. Goldstein 670:8-23. But
it is not clear whether the FDA had actually reviewed the data at the point it expressed no
concern regarding application of testosterone to the axilla. In the April 11, 2006
correspondence, Ms. Hall inquired of the FDA as to whether it had “any concerns about
the use of the axilla as the proposed application site, potentially the levels of DHT.” Id.
at 664:17-23, 668:5-22; PTX-1034 at 1. Ms. Hall attached to her letter a protocol for
clinical study MTE04 (PTX-1034 at 1), noting that “the results from this study will be
available at the end of April/06” and asking whether the FDA would “recommend Acrux
to submit the results from study MTE04 for review prior to submitting the IND.” PTX1034 at 1. In the later April 26, 2006 email, when Ms. Hill reported that the FDA had no
concern, she did not state that the FDA had reviewed any patient data from MTE04.
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PTX-1035 at 1. Rather, in response to Acrux’s earlier question as to when the FDA
recommended that Acrux submit the results from the study, Ms. Hall reported that the
“[r]esults from study MTE04 will be included in the initial IND for review.” Id. In fact,
the clinical study dates for MTE04 extended to May 5, 2006 (subsequent to the April 26,
2006 email from Ms. Hall) and the final report was dated April 20, 2007. PTX-100,
MTE04 Clinical Study Report at 5. Thus, it is not clear whether, at the time of the April
26, 2006 email from Ms. Hall, the FDA had received the clinical study MTE04 data or if
that data impacted the FDA’s opinion regarding whether the axilla was expected to raise
DHT levels.
Impact of the Axilla’s Characteristics on Its Suitability as an Application Site for
Transdermal Drug Delivery
Plaintiffs maintain that a POSA in June 2005 would have been discouraged from
administering a transdermal drug to the axilla because of concerns regarding hair, creases
and folds in the skin, sweat, bacteria, and interference with deodorants and
antiperspirants that are regularly applied to the area. However, the prior art does not
support either this contention or these concerns and does not teach away from the axilla
as an application site for non-occlusive testosterone formulations based on any of these
concerns.
Prior Art Related to the Presence of Hair and Creases and Folds of the Skin
A.
Berti (1995)
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Dr. Hadgraft relied on a set of guidelines for transdermally delivered drugs
described in Berti (1995) to support his opinion that the prior art taught away from
topical administration to a hairy area of the skin. Hadgraft 189:8-190:10; PTX-264 at 5.
Berti (1995) states that “[t]he device should be applied to a region that has the least
amount of hair possible; otherwise, hair may be clipped rather than shaved.” Hadgraft
457:18-22; PTX-264 at 5. As Dr. Hadgraft conceded on cross-examination, however, a
POSA would have understood that the guidelines referencing a “device” is specific to
transdermal patch products, where the presence of hair may limit the ability of the patch
device to adhere to the skin and maintain contact for drug delivery. Hadgraft 458:10459:5; see also Snyder 915:16-916:6. By contrast, the claimed transdermal testosterone
formulations are limited to formulations that are applied to the skin “without occlusion by
a patch device.” PTX-4 at Claim 13, 20; Potts 1402:18-21.
B.
Tomlinson ‘250 Patent
These known disadvantages of transdermal patch products are consistent with the
teachings of the Tomlinson ’250 patent. Potts 1401:1-1402:17. The Tomlinson ’250
patent is a second reference upon which Dr. Hadgraft relied for his opinion that the prior
art teaches away from transdermal drug delivery to areas of the skin with hair and
significant creasing and folding. Hadgraft 276:10-20; PTX-592. However, the
Tomlinson ’250 patent teaches that these factors are the limitations of the prior art
relating to adhesive patches which may be applied to only “a non-hairy area of the skin
that is substantially free of wrinkles, creases, and folds.” PTX-592 at col. 2, ll. 7-16;
77
Potts Tr. 1401:1-22. The Tomlinson ’250 patent further teaches that for non-occlusive
compositions, “the presence of hair does not create as significant a problem as is the case
with adhesive patches” and “the presence of wrinkles, creases and folds in the skin are
not an impediment to the application of the composition of the invention to a particular
area of the body.” PTX-592 at col. 2, ll. 25-32, col. 2, l. 63 – col. 3, l. 5; Potts 1401:231402:11. A POSA would understand from the Tomlinson ’250 patent that, since the
claimed testosterone formulations are applied without occlusion by a patch device, the
presence of hair or creases and folds in the skin would not present a significant problem.
Potts Tr. 1402:12-17.)
C.
AndroGel® and Testim®
The two prior art non-occlusive testosterone gels, AndroGel® and Testim®, are
also applied to skin sites where men often grow hair such as the shoulders, upper arms,
and abdomen. Potts 1400:1-15. Unlike with patches, the presence of hair does not
present an obstacle for testosterone gels or solutions, which can flow past the hair and be
absorbed through the axilla skin. Snyder 931:7-14.
Prior Art Related to Sweat and Bacteria in Axilla
Dr. Hadgraft further opined that a POSA would have been discouraged from
application of testosterone to the axilla due to the presence of sweat. Hadgraft 176:1778
177:8, 178:10-14, 179:22-180:10, 279:13-280:13. But Dr. Hadgraft testified on direct
examination that the impact of sweat on transdermal drug delivery is “unpredictable.” Id.
at 279:13-280:13. Further, he does not identify any prior art reference that discusses any
adverse effect of sweat on transdermal delivery of testosterone. See id. at 176:17-177:8,
178:10-14, 179:22-180:10, 279:13-280:13.
Dr. Hadgraft also opined that “if you have bacteria in the armpit, then you have
the potential for breaking down any active . . . [and] then it will never get through to the
skin in the systemic blood supply. Hadgraft 122:2-13; see also id. at 177:23-178:1,
180:22-181:3. However, he failed to identify any specific bacteria that had been shown
to have this effect or any prior art reference discussing the effect of skin bacteria on the
transdermal delivery of testosterone. Id.
Even if this were a real concern regarding sweat or bacteria in the axilla, the prior
art testosterone gels, AndroGel® and Testim®, recommended application of the
testosterone product to “intact, clean, dry skin.” PTX-1059 at 1; PTX-641 at 1. These
instructions to wash and dry the skin prior to application of a testosterone product would
likely avoid any issues with the presence of excessive sweat or bacteria on the skin. Potts
1404:11-22. Axiron® includes a similar instruction to apply the testosterone composition
when the axilla is clean, dry, and intact. PTX-633 at 1; PTX-1061 at 1.
Prior Art Related to Presence of Deodorants and Antiperspirants
Dr. Hadgraft further opined that a POSA would have been discouraged from
application of testosterone to the axilla which is repeatedly treated with both deodorants
79
and antiperspirants. Hadgraft 176:8-177:8, 188:24-189:7, 279:9-280:13. Likewise, Dr.
Goldstein opined that a physician would expect that the presence of antiperspirants and
deodorants would affect testosterone blood levels. Goldstein 675:11-676:13. But Drs.
Hadgraft and Goldstein did not identify any specific deodorant or antiperspirant agent
that has been shown to interact or counteract with testosterone or otherwise impede
transdermal drug delivery. Id. Nor did Dr. Hadgraft rely on any prior art reference
warning that deodorants and antiperspirants were expected to affect transdermal delivery
of testosterone. Id. To the contrary, the prior art contemplates adding deodorants and
antiperspirants to transdermal testosterone formulations, as shown below.
A.
Aschkenasy ‘268 Publication
The Aschkenasy ’268 publication, for example, anticipates that deodorants and
antiperspirants may be added to its transdermal testosterone composition. PTX-243 at
[0139]. Specifically, the Aschkenasy ’268 publication, like the axilla patent, teaches that
the testosterone composition may comprise additives, including deodorants and
antiperspirants. Hadgraft 437:22-439:4; PTX-243 at [0139], PTX-4 at col. 18, ll. 14-23.
The Aschkenasy ’268 publication provides an extensive list of deodorant agents and
antiperspirants—agents that are commonly applied to the axilla—for addition to the
topical testosterone formulation. PTX-243 at [0141], [0142]; Hadgraft 433:10-434:18.
B.
AndroGel® and Testim®
As discussed above, the prior art testosterone gels, AndroGel® and Testim®
recommended application of the testosterone product to “intact, clean, dry skin.” PTX80
1059 at 1; PTX-641 at 1. These instructions to wash and dry the skin prior to application
of a testosterone product avoid the issues that might present with a deodorant agent or
antiperspirant on the skin. Potts 1404:11-22. Axiron® includes a similar instruction to
apply the testosterone composition when the axilla is clean, dry, and intact. PTX-633 at
1; PTX-1061 at 1.
Acrux’s Clinical Studies Applying Its Transdermal Testosterone Formulation to the
Axilla
In 2004, Acrux began clinical trials to assess the safety, efficacy, and feasibility of
transdermal testosterone application to the axilla. The initial pilot study was conducted in
women, and the follow-up study was conducted in healthy men with compressed
testosterone. PTX-4 at 16, col. 20, l. 32-col. 23, l. 9; PTX-96; PTX-117. The results of
the studies showed that applying testosterone to the axilla was effective at increasing
testosterone blood levels and did not lead to abnormally high DHT levels or increase
sweat or odor despite the increased perspiration usually associated with the use of
testosterone. Hadgraft 296:10-300:15; Goldstein 612:17-613:8, 671:3-674:25, 682:17683:17; PTX-4 at col. 22, l. 65-col. 23, l. 8.
One of Acrux’s initial studies, Clinical Trial No. DDS16, showed efficacy without
elevated DHT levels following application to the axilla. PTX-14; PTX-96; PTX-133;
PDX-7032; PDX-7033; Goldstein 669:15-20, 676:23-677:9. In fact, the reported DHT
levels were lower than those seen in the forearm. Goldstein 669:13-20; PTX-133 at 46
(“Whilst the inner arm treatment showed no significant change in T:DHT ratio over the
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72 hour time course, the average ratio of 5:1 was significantly higher than the average
ratio for the axilla treatment (3.7)”).) Later studies by Acrux confirmed this finding,
including, for example, Clinical Trial No. MTE04 (mean DHT:T ratio within the normal
physiological range). PTX-14; PTX-100 at 76; PDX-7032; PDX-7033; Goldstein
677:10-14.
Alleged Unexpected and Surprising Results of the Method Claimed in the ‘944 Patent
No Increased Sweating
Dr. Goldstein opined that a POSA would expect that testosterone increases the
activity of the apocrine glands and should result in increased sweating and odor in the
axilla. It therefore was surprising that application of testosterone to the axilla in
Plaintiffs’ clinical studies did not increase sweat or odor. 12 Goldstein 675:11-676:13.
However, because a hypogonadal man has decreased testosterone blood levels, a
physician would expect that his sweating would also be less than normal. Snyder 930:123. If testosterone replacement therapy returns a hypogonadal man to normal physiologic
12
Dr. Goldstein relies on a study reported in Example 4 of the axilla patent to support his
opinion that administration of testosterone surprisingly resulted in “no increased sweating.”
Goldstein 680:4-18; PTX-4 at Example 4. However, this study did not directly measure the
amount of sweating following application of testosterone, so there is no evidence that the men
who received it did not sweat or that they sweated less than usual in Example 4. PTX-4 at
Example 4. Instead, the study participants were instructed that they could “apply deodorant if
they were distressed with symptoms of sweating,” and that they should report any such
application. Id. None of the 16 subjects reported the need to apply deodorant or antiperspirant.
Id. Thus, the only conclusion that can be reasonably drawn from this study is that none of the
study participants felt particularly distressed enough to need the use of a deodorant or
antiperspirant. Snyder 930:24-931:6.
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ranges, a physician would then expect the amount of sweating to increase to normal
levels. Id. A physician would further understand that perspiration is a systemic effect of
testosterone. Id. Increased testosterone blood levels increases sweating in all areas
where men normally perspire. Id. Sweating does not increase just at the local site of
application of testosterone. Id. Regardless of the site of application, a physician would
expect that returning testosterone blood levels to normal physiologic ranges would result
in normal amounts of sweating. Id.
Seven-Fold Increase in Permeability Across the Axilla
Dr. Hadgraft opined that it was unexpected that drug delivery across the axilla
provided a seven-fold greater absorption of testosterone per unit surface area of the skin
than that of the forearm. Hadgraft 514:5-515:4. Dr. Hadgraft’s opinion relied upon the
results from plaintiff Acrux’s Clinical Study DDS16 comparing drug delivery of
testosterone across the skin of the axilla and the inner forearm, which results were later
adjusted by inventor Dr. Adam Watkinson to account for the surface areas of the
respective application sites. Based on his calculations, Dr. Watkinson asserted that the
drug delivery across the axilla was seven-fold greater per unit surface area than that
across the forearm. Id.
Clinical Study DDS16 is entitled: “A pharmacokinetic phase I study to assess the
effect of different application sites on the pharmacokinetics of testosterone from a
Testosterone Metered Dose (MD) LotionTM.” PTX-96 at 1. In this study, a transdermal
testosterone composition was applied to the skin of the axilla and the inner forearm. Id.
83
at 7; Potts Tr. 1406:6-21. The study investigators did not measure the surface area of the
application site on the axilla or the forearm or otherwise control for the size of the surface
area of the application site. Id. The study found that “mean baseline-corrected total
testosterone AUC0-72 for the axilla was 5617 ng.hr/mL, a result almost double that
achieved for the inner arm (2979 ng.hr/mL).” PTX-96 at 45; Potts Tr. 1406:22-1407:5.
The study investigators found that “the different extents of absorption observed for the
two application sites in this study are consistent with a previous investigation of
variations in skin penetration where the extent of hydrocortisone absorption from the
axilla was 3.6 times greater than from the ventral forearm,” as reported in Feldmann
(1967). PTX-96 at 45, 77 (emphasis added); Potts Tr. 1406:22-1407:7. Dr. Hadgraft
does not dispute that the two-fold enhanced permeation of the axilla relative to the
forearm as measured in Clinical Study DDS16 would have been expected. Hadgraft Tr.
459:10-25; see also Watkinson Dep. Tr. 114:22-116:14. His opinion on unexpected
results based on enhanced permeation is limited to the seven-fold size adjustment made
by Dr. Watkinson. Id.
In his 2010 declaration, Dr. Watkinson relied on a measurement of the median size
of the female axilla obtained from the measurements of 60 women who had their axillae
measured for a deodorant/antiperspirant study reported in Cowan-Ellsberry (2008) (PTX299) and a measurement of the median size of the inner forearm of 15 women from
Acrucx’s offices who had their forearms measured by Dr. Watkinson in order to calculate
the “flux” per unit surface area of testosterone across the skin in the axilla and inner
84
forearm of the subjects in DDS16. PTX-14 at 5-6, ¶¶ 13-15. Flux is a term used to
describe the rate of transfer of a drug across the skin. Hadgraft 303:23-304:3. When Dr.
Watkinson performed this calculation correcting for the surface area of the two
administration sites in DDS16, he determined that there was a seven-fold increase in flux
for the axilla as compared to the inner arm. PTX-14 at 8, ¶ 21; Hadgraft 299:18-304:6.
In making this comparison, Dr. Watkinson relied upon the assumption that the areas of
the axillae and forearms measured represented the areas of application in the original
Clinical Study DDS16. Potts 1411:12-20, 1411:24-1412:7. In his 2010 declaration to the
PTO regarding unexpected results, Dr. Watkinson explained that the seven-fold greater
absorption of testosterone in the axilla was unpredictable in view of the variability in the
prior art, depending on the compound and site of application. PTX-14 at 9, ¶ 22.
Clinical Study DDS16 did not include any discussion of the axilla providing a
seven-fold greater permeation than the forearm. Potts 1407:8-11. None of the
publications of the Clinical Study DDS16 results, other than Dr. Watkinson’s declaration
to the PTO, included any discussion of the axilla providing a seven-fold greater
permeation than the forearm. Id. at 1407:12-1410:3. Specifically, the results of Clinical
Study DDS16 are reported in Example 1 of the axilla patent, but the inventors did not
make any claim in the specification that the axilla resulted in a seven-fold greater
permeation than the forearm. Id. at 1407:19-1408:4; PTX-4 at Example 1. The study
investigators later published the results of Clinical Study DDS16 in a 2014 peer-reviewed
article by lead author Dr. Susan Davis. Potts 1408:5-1409:5; PTX-303. The authors
85
report that administration of testosterone to the axilla resulted in two-fold greater
absorption than across the forearm. Potts 1409:9-17; PTX-303 at 1, 6. The authors did
not make any claim that absorption across the axilla was seven-fold greater than across
the forearm. Id.
VI.
The Applicator Patent
The ‘861 applicator patent, entitled “Spreading Implement,” claims an implement
for topical delivery of a therapeutic liquid or lotion – here, the claimed transdermal
testosterone lotion – to the “axilla area of the user.” PTX-5 at Abstract.
Definition of a Person of Ordinary Skill in the Art for the ‘861 Patent
A person of ordinary skill in the art (“POSA”) for the ‘861 applicator patent would
have been someone with a bachelor of science degree in mechanical engineering or the
packaging fields and one to three years of experience, or equivalent education and/or
experience, in the design of medical products and/or design and manufacture of products
and packaging for pharmaceutical applications. Slocum 565:11-567:17; DDX-418
(Singh definition of POSA for ‘861 patent).
The Invention and the ‘861 Patent
For safety and efficacy, Acrux needed to show that its patented testosterone
solution could be applied accurately and consistently. PTX-75 at 30-32 (listing requests
from FDA regarding the applicator). Since there were no similar products on the market
at the time (i.e., a low-viscosity transdermal testosterone formulation applied to the
86
axilla), Acrux did not believe an applicator was then in existence that was suitable for its
purpose. PTX-1093 at 7 (providing market research on known applicators for other
products to the axilla).
To assist in developing a no-touch applicator implement to apply its testosterone
formulation to the axilla, Acrux engaged the Bayly Group. PTX-1066 at 3; PTX-1093;
PTX-1153; Slocum 541:12-24. The inventors considered numerous possible designs for
the applicator. PTX-1093 at 6-7, 10; PTX-1148 at 4; Slocum 545:3-16, 548:11-549:25.
Their first design attempts embodied applicators with convex heads, similar to roll-on
and ball-shaped applicators for the axilla known at the time. PTX-1148 at 4, 6; Slocum
548:4-549:25. Because the axilla is primarily a concave surface, the general wisdom at
the time was to use an applicator with a complementary shape: a convex applicator to fit
the concave surface. PTX-1093 at 7; Slocum 546:15-22.
The first design pursued by the inventors was a dome-shaped applicator referred to
as the “mushroom” applicator. E.g., PTX-1093 at 6-7; Slocum 545:3-546:2, 549:19-25.
As previously noted, the mushroom applicator had a convex head and was designed to
apply the solution in a manner similar to the known roll-on deodorant applicators. PTX1066 at 6, 8. The mushroom applicator concept was eventually abandoned, however, for
several reasons. PTX-1066 at 7. Importantly, the metered-dose testosterone lotion was
not effectively retained on the surface of the head; the solution would run down the bottle
and did not reliably deliver the required dose. PTX-1066 at 6, 7; PTX-1144 at 2; Slocum
552:3-15, 559:18-23.
87
The inventors began to pursue a design of a “simple axilla applicator.” (PTX1066 at 6, 7, 10. The “simple axilla applicator” was so named because it was made with
fewer parts than the mushroom applicator. PTX-1066 at 7, 10. Ultimately, the inventors
struck upon the idea of an applicator with a concave receptacle. PTX-1066 at 17; PTX1157 at 3-5; PTX-1158 at 2, 4-6; Slocum 554:4-555:3. The simple axilla applicator: (1)
retains the solution dispensed from the pump and allows for the applicator to be tilted to
angles up to 45 degrees without spilling the dose; (2) includes a soft, collapsible head to
aid in the smooth and effective dosing to the axilla; (3) delivers a full dose; and (4) is
easy to clean. PTX-1066 at 6, 10, 17. Those applicator concepts were the foundation of
the patent application that issued as the ’861 patent. Slocum 554:4-555:3.
An overview of the preferred applicator embodiment is shown in Figure 1 (PTX-5
at col. 3, ll. 6-17 and Fig. 1.); a cross-sectional view of the applicator with additional
detail is shown in Figure 2 (Id. at col. 3, ll. 18-33 and Fig. 2). The applicator is used as
follows: therapeutic liquid is dispensed into the applicator reservoir (4) (Figure 1), after
which the user places the applicator in contact with the skin surface to deposit and spread
the liquid onto the skin. See id. at col. 3, ll. 6-17. The ’861 patent claims describe the
applicator and its components, various therapeutic compositions, and the application
method. PTX-5.
88
Figure 1.
The preferred embodiment of the ’861 patent is an applicator
(1) having a receptacle (2), support means (3), and reservoir
space (4).
Figure 2.
The cross-section of the applicator (1) shows that the
receptacle (2) contains a base (5) and wall (6). The wall (6)
has an inner portion (7) and an upper portion (8). The outer
side of the wall contains a skirt portion (9) and a lower edge
(10). The lower edge (10) is attached to the support means (3)
(see Fig. 1 and Fig. 3).
PTX-5 at col. 3, ll. 6-17 and Fig. 1; id. at col. 3, ll. 18-33 and Fig. 2.
Claims 9 and 10 of the ‘861 Patent
89
As discussed above, in this litigation, Plaintiffs have asserted against
Defendants dependent claims 9 and 10 of the ’861 patent. These claims (and those
from which they depend) recite as follows:
1.
A system for transdermal administration of a physiologically
active agent from a liquid composition, the system including a
container containing the liquid composition including the
physiologically active agent, a dispensing device for delivering liquid
composition from the container; and an applicator for applying the
liquid to an area of skin for transdermal administration said applicator
including a support detachably contactable to the dispensing device or
container being adapted to detach to permit said dispensing device to
deliver said liquid composition, a receptacle mounted on the support
defining a reservoir space which receives a volume of the liquid
composition from the container, the receptacle having a base and a
resiliently deformable wall, the wall being substantially transverse to
the base and having a working surface that is used to spread the liquid
composition over the area of the skin surface, the base having a
surface such that the liquid composition cannot pass through the base.
9. A method of transdermal administration of a physiologically active
agent to a subject including providing a system according to claim 1;
applying the liquid composition including the physiologically active
agent to the reservoir space; and deforming the wall of the receptacle
containing the liquid composition against the skin of the subject and
spreading the liquid composition over the area of the skin surface in
at least one axilla.
10.
A system according to claim 1 wherein the receptacle defining
the reservoir space has an open top being configured to receive the
liquid composition from the dispensing device through the open top.
PTX-5 at claims 1, 9, 10.
Claim Construction of the ‘861 Patent
90
The parties have agreed that the claimed “wall” is defined as “[p]art of the
receptacle having an inner portion and an outer skirt portion which form a double-wall
structure.” Dkt. 105 at 2. The “double-wall structure” is “[a] structure having two walls,
i.e., not the two surfaces of a single wall.” Id. In the context of the ’861 applicator
patent, the claimed wall must comprise an inner portion (“[o]ne of the two walls of the
double-wall structure that is closest to the reservoir space”) and an outer skirt portion
(“[o]ne of the two walls of the double-wall structure that is furthest from the reservoir
space”) that together form a double-wall structure. Id. at 1-2; PTX-5 at claim 1. The
parties agree that the asserted claims of the ‘861 patent require a wall that is
“substantially transverse to the base.”
The parties have also agreed that the terms “has a continuous surface such that
liquid cannot pass through the base” and “having a surface such that the liquid
composition cannot pass through the base,” mean “[the] surface does not contain
openings or pores that would permit liquid to pass through the base.”
A.
The Actavis and Perrigo Applicators 13
The Actavis Applicator
13
Plaintiffs’ expert Dr. Slocum testified that his infringement opinions and analyses regarding
the claimed “wall” were substantively the same with respect to the Actavis applicator and the
Perrigo applicator, and that there are no differences between the Actavis applicator and the
Perrigo applicator that are material to his opinions regarding the “wall” limitation. See, e.g.,
Slocum 817:4-11, 818:1-14, 819:13-820:1, 829:8-11, 979:8-981:4. Plaintiffs have stipulated that
Dr. Singh’s testimony, including, among other things, his testimony regarding the Actavis
applicator, applies equally to Perrigo and the Perrigo applicator, and that Perrigo may rely on
that testimony (and the exhibits Dr. Singh relied on during his testimony) for any purpose related
to this case. Dkt. 410 ¶ 1.
91
Actavis’s ANDA applicator is depicted in the schematics below:
Schematics of Actavis’s Applicator
PTX-218 at 1658-59; see PTX-1174; DTX-1277. Detail B depicts the single wall of
Actavis’s applicator that Plaintiffs allege folds over to form a double-wall structure when
used in accordance with Actavis’s labeling instructions.
The Perrigo Applicator
92
Perrigo Israel submitted ANDA No. 204255 to FDA on April 3, 2012. Dkt. 134
¶ 58; DTX-13 at 1-4. As originally submitted, Perrigo Israel’s ANDA included
information regarding an original proposed applicator device, including:
DTX-13 at 756; see also DTX-13 at 753-55.
In 2014, Perrigo Israel’s ANDA was amended to include information regarding
the current proposed applicator device, which is the applicator that Perrigo intends to
include as part of the its ANDA Product. See PTX-206 at 992-95.
The Perrigo ANDA applicator is depicted in the schematics below:
Schematics of the Perrigo Applicator
93
DTX-32 at 1-3; PTX-206 at 992, 994-95; DTX-30 at 1-3; see PTX-1175.
The “Wall” Limitation 14
As discussed above, the “wall” limitation in the asserted claims has been
construed to require a double-walled structure. Plaintiffs concede that both the Actavis
and Perrigo applicators have only a single wall at rest, and therefore neither applicator
meets the limitations of claims 9 and 10 of the ‘861 patent at rest. See, e.g., Slocum
14
Because, for the reasons detailed infra in Section IV.A.1, we hold that Plaintiffs have failed to
establish by a preponderance of the evidence that the Actavis and Perrigo applicators meet the
wall limitation, and therefore cannot show that the accused devices meet every limitation of the
asserted claims as required to prove infringement, we need not and do not address the disclaimer
and disclosure issues or any other disputed claim limitations raised by Actavis and Perrigo.
94
774:14-17, 978:18-20; Slocum 817:16-20, 856:8-22. Plaintiffs contend, however, that
the wall of both the Actavis and Perrigo applicators folds over when used in accordance
with the devices’ respective labeling instructions to form the infringing double-walled
structure.
The Basis of Dr. Slocum’s Testimony Regarding the Wall Limitation
Plaintiffs rely in support of this contention solely on Dr. Slocum’s testimony that the
Actavis and Perrigo applicators form a claimed double-wall structure in use. Dr. Slocum
based his opinion that the Actavis and Perrigo applicators form a claimed double-wall
structure in use on:
• portions of the Actavis and Perrigo labeling (Slocum 778:20-779:15; PDX
4088; Slocum 819:13-820:1; PDX 4067; PDX 4068);
• his theoretical understanding of the materials used in the wall (Slocum 781:1423);
• his manipulation of the applicators in the offices of the Finnegan lawyers
(“Finnegan testing”) (Slocum 783:5-25); and
• his March 2016 at-home testing in his shower (“wet testing”) (id.)
See id. at 817:9-11, 818:1-14. In reaching his conclusions, Dr. Slocum never saw a
patient or any other person actually use the Actavis or Perrigo applicator. Id. at 895:2-4;
979:8-981:4.
The Structure and Materials Used in the Walls of the Actavis and Perrigo Applicators
95
The wall of Actavis’s applicator is made of a thermoplastic elastomer; Perrigo’s
applicator has a wall made of silicone. Both thermoplastic elastomer and silicone are
flexible plastics. Dr. Slocum testified, and Dr. Singh did not dispute, that the walls of
both the Actavis and Perrigo applicators can be deformed when force is applied to them
and will then return to their original shape when the force is removed. Slocum 793:23794:6, 827:6-16; Singh 1015:24-1016:4, 1116:18-1118:14.
Dr. Slocum further testified that, when Actavis’s and Perrigo’s applicators are
used as directed in the labeling instructions, the flexible walls are pressed against the
axilla. He also opined that the instructions included with the Actavis and Perrigo
applicators teach the patient to use the applicators in a manner that would avoid leakage
of the testosterone formulation. According to Dr. Slocum, the force created when the
devices are pressed against the surface of the axilla with enough pressure to prevent
leakage causes the walls of the respective applicators to double over on themselves,
forming a double-walled structure as disclosed in claims 9 and 10 of the ‘861 patent. To
support this testimony, Dr. Slocum relies on Actavis’s and Perrigo’s labeling instructions
as well as his personal observations during his hands-on testing of the accused
applicators.
Dr. Slocum’s Finnegan Testing
Prior to submitting his January 2016 infringement reports, in which he opined that
the Actavis and Perrigo applicators would form a claimed double wall in use, Dr. Slocum
met at the law offices of Plaintiffs’ counsel which provided him an opportunity to handle
96
the accused applicators; this visit was referenced at trial as the “Finnegan testing.”
Slocum 783:5-25, 862:14-863:8, 870:5-11, 872:25-873:3; 979:8-981:4. Dr. Slocum’s
Finnegan testing consisted of him manipulating by hand in a fashion he described as
“playing with” the Actavis and Perrigo applicators there in Plaintiffs’ counsel’s office.
Id. at 783:5-17, 862:14-863:8, 863:18-864:10, 864:19-865:11, 865:19-866:21, 979:8981:4. Dr. Slocum was uncertain as to whether he used liquid in the applicators during
the testing, but he testified that, if he had, it would have been “just a little bit of water.”
Id. at 863:18-23, 864:1-10, 1172:8-16. Dr. Slocum’s Finnegan testing process did not
include placement of the Actavis or Perrigo applicators against the axilla, nor did it
include utilizing the applicators according the Actavis or Perrigo labeling. Id. at 864:110, 864:19-865:11, 865:19-24. Dr. Slocum admitted that his Finnegan testing was not
performed in a way that a typical user would use the applicators, and that a typical user
would not have Dr. Slocum’s level of knowledge regarding sealing structures. Id. at
865:25-866:14.
Dr. Slocum took no photographs, video, or contemporaneous notes to document or
otherwise record his Finnegan testing on the Actavis and Perrigo applicators. Slocum
866:15-21, 867:7-25. Generally, in his testing conducted outside a litigation context, Dr.
Slocum keeps notes, photographs, video, computer records, or other documentation of his
testing procedures, data, and results. Id. 856:23-857:5, 860:21-861:11.
Dr. Slocum’s Wet Testing
97
After reading defendants’ expert reports rebutting his January 2016 infringement
report opinions, Dr. Slocum performed his “wet testing” experiment in March 2016 for
purposes of preparing his reply report. Slocum 783:5-25, 862:14-863:17, 870:5-11,
872:25-873:8, 979:8-981:4. Dr. Slocum’s wet testing consisted of his using the Actavis
and Perrigo applicators to apply a homemade contrived liquid formulated by him from
ingredients he found at his personal residence (consisting of a combination of cranberry
juice and household rubbing alcohol in unknown amounts) to his own axilla, while
standing in his bathroom shower. See, e.g., id. at 783:5-784:9, 863:14-17, 874:17-19,
875:24-876:6, 877:13-21, 878:13-18; 979:8-981:4. He testified that he “pretend[ed]” to
be “a typical user” during his wet testing and that he did not intend for the wet testing to
be a scientifically reliable experiment, rather he simply wanted to do a “quick play” with
the accused applicators. Id. at 783:5-25, 786:17-21, 863:14-17, 891:9-892:2.
At trial, Dr. Slocum could not recall various details about his wet testing. For
example, he was unable to remember the date on which he performed his wet testing.
Slocum 873:4-12. He also testified that he could not remember the length of time it took
him to perform the wet testing on each applicator because “he did not record the time,”
but he believed that it took “less than an hour and more than a minute.” Id. at 875:14-23.
He could not recall precisely how many times he tested the Actavis or Perrigo applicators
during the wet testing, (see, e.g., Slocum 884:4-16), stating that it was “a bunch of
times,” and “probably around ten” times, but was “more than one time and less than 20”
times. Id. Additionally, although Dr. Slocum reportedly tested all four applicators on the
98
same day, one after the other, he did not recall the order in which he tested defendants’
accused applicators. See Slocum 874:17-875:9. Dr. Slocum testified that he was “pretty
sure [he] did Lupin last, but [he doesn’t] recall,” nor does he recall whether he tested
Actavis’s, Perrigo’s, or Amneal’s applicator first. 15 Id.
When conducting his wet testing, Dr. Slocum did not use either Actavis’s or
Perrigo’s ANDA formulation that will be sold with the applicators, or even an accurate
substitute for those formulations. See, e.g., Slocum 783:5-784:9, 875:24-876:15, 877:1321, 878:13-18, 878:21-879:2; see also id. at 979:8-981:4. Dr. Slocum conceded that he
could have asked for and used an Axiron placebo formulation, but he did not. Id. at
876:3-17. He also admitted that he had access to Perrigo’s ANDA and the formulation
described therein, but he did not use that information to make a placebo formulation
because he is “not a chemist” and “wouldn’t know what to do with [that information]
anyway.” Id. at 876:18-877:3; see also id. at 877:8-12. Instead, Dr. Slocum used a
homemade mixture of his own devising – cranberry juice and “household rubbing alcohol
that [he] found at [his] house” – as a substitute for Actavis’s and Perrigo’s ANDA
formulations. See, e.g., id. at 875:24-876:15, 877:13-21. Dr. Slocum did not know how
the rubbing alcohol he used in his cranberry juice/alcohol mixture compared to the
isopropyl alcohol in the ANDA formulations. See id. at 877:4-7.
15
During his testimony at trial, Dr. Slocum also exhibited confusion regarding the various
accused applicators. See, e.g., Slocum 871:4-11, 895:2-10, 978:18-24.
99
Despite knowing that Actavis’s and Perrigo’s ANDA formulations contain a
thickening agent, Dr. Slocum did not include any thickener in his cranberry juice/rubbing
alcohol mixture. Slocum 877:18-878:7; see also id. at 979:8-981:4. He admitted that a
formulation containing a thickener would have a higher viscosity than his cranberry
juice/alcohol mixture, and that his cranberry juice/alcohol mixture is “more sensitive to
detecting leakage from the applicator.” Id. at 878:8-18. Dr. Slocum did not measure the
viscosity of the cranberry juice/alcohol mixture used in his wet testing of the Actavis and
Perrigo applicators, but he estimated that it would be “about one centipoise” and “very
close to water.” Id. at 879:4-9. Plaintiffs’ expert, Dr. Hadgraft, testified that, based on
the ingredients in the Axiron formulation, the viscosity of the Axiron formulation is
“between 14 and 35 centipoise,” which is “roughly the viscosity of something like
vegetable oil.” Hadgraft 171:3-18. Actavis’s ANDA formulation and Perrigo’s ANDA
formulation have the same ingredients in roughly the same amounts as the Axiron
formulation. Cf. PTX-218 at 239 (Actavis ANDA formulation) and DTX-14 at 20
(Perrigo ANDA formulation) with PTX-75 at 211 (Axiron formulation); see Hadgraft
168:14-169:22.
Thus, according to the testimony of plaintiffs’ experts, the viscosity of Dr.
Slocum’s cranberry juice/alcohol mixture differed significantly from the viscosity of the
Actavis and Perrigo ANDA formulations, and Dr. Slocum’s wet testing exaggerated the
leakage that one would expect from use of Actavis’s and Perrigo’s applicators by patients
100
according to the Actavis or Perrigo labeling to apply the Actavis or Perrigo ANDA
formulations. See Hadgraft 171:3-18; Slocum 877:18-878:18, 879:4-9, 979:8-981:4.
Dr. Slocum also failed to use the amount of liquid directed in Actavis’s and
Perrigo’s labeling instructions when he performed his wet testing. Both Actavis’s and
Perrigo’s labeling specifies that only 1.5 ml of liquid (one pump) at a time is to be
transferred into the Actavis and Perrigo applicators for application to the axilla. See, e.g.,
PTX-218 at 2614-15, 2623; PTX-216 at 16-17. Dr. Slocum admitted that the Actavis and
Perrigo labeling tells the patient “exactly” how much liquid to use. Slocum 881:17-19.
Dr. Slocum, however, did not precisely measure the amount of liquid he used in
Actavis’s and Perrigo’s applicators during his wet testing. He testified that he did not use
any type of medical syringe or accurate measuring device to measure the amount of
liquid he transferred to the Actavis and Perrigo applicators during his wet testing.
Slocum 881:6-8. Rather, he used a common kitchen teaspoon that “[they] eat with,”
which holds approximately “4 to 5 mL total.” 16 Id. at 880:9-881:5, 785:7-21, 882:16883:5.
At his deposition, Dr. Slocum first testified that he used 3 ccs per application for
his wet testing, which is 3 ml and double the amount of liquid called for in Actavis’s and
Perrigo’s labeling. Slocum 881:20-22, 979:8-981:4. Later in his deposition, he testified
16
At trial, Dr. Slocum admitted that, at his deposition, he “couldn’t remember” whether he had
used a teaspoon or a tablespoon (which is about 15 ml) to measure the liquid for his wet testing,
and that he “had some confusion in [his] mind” that apparently cleared up between his May 2016
deposition testimony and his July 2016 trial testimony. Slocum at 785:7-21, 879:10-880:19.
101
that he used 1.5 ccs per application for his wet testing. Id. at 881:23-882:3. At trial, Dr.
Slocum could not recall the exact amount of liquid he used in Actavis’s and Perrigo’s
applicators during the wet testing. He testified variously that he used “what looked like a
reasonable amount” of liquid for his wet testing, (id. at 785:7-21, 882:13-15); “a fraction
of a teaspoon,” (id. at 785:7-14), “about a third of a teaspoon,” (id. at 879:10-880:6), “a
reasonable guesstimate,” (id. at 882:13-21), “a few milliliters lower than the rim” of the
teaspoon, (id.), “less than [4 to 5 mL], on the order of the one and a half, (id. at 882:16883:2), and “a third to a half, probably.” Id. at 883:3-5.
As with his Finnegan testing, Dr. Slocum took no photographs, video, or
contemporaneous notes to document his wet testing on the Actavis and Perrigo
applicators. Slocum 873:13-16, 875:10-23, 880:24-881:5, 888:1-6, 894:20-21, 895:1119. Because he elected to perform his wet testing in the bathroom of his home, without
anyone witnessing his use or otherwise documenting the testing with photographs or
video, Dr. Slocum was able to determine whether a double-wall formed only by looking
at himself directly while using the applicators, and, for parts he could not observe in that
way, by looking at himself in his bathroom mirror while standing in his shower about five
or six feet away from the mirror. See, e.g., Slocum 885:15-886:16.
Based on his wet testing, Dr. Slocum testified that users will “learn” to form a
double wall when using the Actavis and Perrigo applicators because they are instructed to
prevent all leakage during application. See, e.g., Slocum 783:5-785:6, 883:12-884:3,
890:5-891:4. He testified that the applicators would not be “working right” if there were
102
any amount of leakage more than “a drip now and then.” Id. at 892:19-893:21. Thus, Dr.
Slocum testified that patients will press the Actavis and Perrigo applicators with
sufficient force to form a double wall simply because he did so to avoid excessive
leakage, which he defines as anything more than “a drip now and then.” Dr. Slocum did
not test the Axiron® applicator as a control, in order to compare the leakage experienced
with the Actavis and Perrigo applicators with leakage associated with the Axiron®
applicator. With regard to his belief as to the acceptable amount of leakage, Dr. Slocum
testified that “if it was drippy, runny, ineffective … I don’t think the FDA would have
approved it as a product.” Slocum Tr. 869:5-870:4, 902:3-903:2.
Dr. Slocum testified that he cannot say precisely the amount of force he applied in
order for the single wall of Perrigo’s applicator to fold over in use. Slocum 884:17885:14, 890:11-891:8, 979:8-981:4. Although Dr. Slocum testified that the amount of
force with which the applicator is pressed against the axilla can affect whether a double
wall is formed, he utilized no special instrument to control (or measure) the amount of
force that he used when wet testing Actavis’s and Perrigo’s applicators. Id. at 884:17885:14, 890:11-891:8. Dr. Slocum testified that he himself pressed Actavis’s and
Perrigo’s applicators to his axilla with enough force to create a so-called “rolling
diaphragm” seal in order to avoid what he deemed to be excessive leakage, but he
conceded that typical users do not have his level of knowledge regarding sealing
structures. See id. at 777:18-778:8, 783:5-785:6, 866:12-14.
103
Dr. Slocum also testified that he followed the instructions on Actavis’s and
Perrigo’s labeling “as closely as possible.” Dkt. 318 at 11. He concedes that neither
Actavis’s nor Perrigo’s labeling contains express instructions to apply sufficient force to
avoid all leakage or to create a seal. See Dkt. 318 at 10. The instructions direct patients
only to “keep[] the applicator upright” and to “place [the applicator] up into the axilla and
wipe steadily down and up into the axilla.” E.g., DTX-258. Actavis’s and Perrigo’s
labeling both warn patients about the risk of secondary exposure to testosterone and
instruct the user to apply the testosterone lotion only to the axilla and not to touch the
solution with their hands. With regard to possible leakage, the instructions direct that
“[i]f the solution drips or runs, it can be wiped back up with the applicator cup.” Id.
Dr. Slocum’s Animation of the Accused Applicators
During cross examination, Dr. Slocum admitted that an animation he used in
connection with his infringement testimony (PDX 4084), which demonstrated the wall of
Actavis’ applicator folding over to form a double wall in use, depicted the axilla as a
“simple,” “upside-down bowl” that lacked any “other stuff that’s in the axilla,” such as
hair. Slocum 1214:25-1215:23, 1216:7-15; see also id. at 817:6-11, 818:1-819:7; PDX
4063. However, Dr. Slocum had previously testified that the axilla is a “very complex”
surface, is “not just a smooth bowl,” and has “all kinds of stuff going on in there.”
Slocum 1214:12-24; see id. at 794:22-795:6. Dr. Slocum admitted that his animation
does not show the applicator being wiped up and down according to the labeling or
moving laterally across the skin surface. Id. at 1217:1-4, 11-13. Dr. Slocum provided no
104
pictures or video of the Actavis or Perrigo applicators actually being used in a human
axilla, nor did he demonstrate use of the applicators on a human axilla. Slocum 1216:1625.
Dr. Singh’s Testimony Regarding the Wall Limitation
At trial, Dr. Singh opined that the Actavis and Perrigo applicators, when used in
accordance with the Actavis and Perrigo labeling, do not form a double wall and
therefore do not infringe claims 9 and 10 of the ‘861 patent. His opinions were based on,
among other things, his review of the ’861 applicator patent and its prosecution history,
the Actavis (and Perrigo) ANDA labeling, Lilly’s demonstrative videos of the Axiron
applicator, information regarding the Actavis (and Perrigo) applicator including
schematics, and a sample of the Actavis (and Perrigo) applicator. Singh 1013:2-17,
1015:6-8; see Dkt. 410 at ¶ 1.
Dr. Singh testified that the Actavis and Perrigo labeling does not include any
requirements or directions that, in using the Actavis or Perrigo applicators, the patient
should or must use them in such a way to form a double wall, apply a certain amount of
force against the axilla, or form a seal against the axilla. Singh 1018:4-1019:2; PTX-218;
see also Dkt. 410 ¶ 1; PTX-206; PTX-216. He further testified that, contrary to Dr.
Slocum’s opinion, the labeling does not instruct the patient to push the applicators with
enough pressure against the axilla to cause the single wall to fold over onto itself. Singh
Tr. 1019:13-19. According to Dr. Singh, a patient using the Actavis or Perrigo
105
applicators consistent with the labeling will not form a seal or double wall against the
axilla. Singh 1019:3-12, 1023:14-16, 1024:4-16.
In support of this opinion, Dr. Singh testified that, contrary to Dr. Slocum’s
description, the surface of the armpit is relatively flat (rather than concave) when the
applicators first make contact with the skin. Singh 1019:20-1020:5. Dr. Singh pointed to
Figure 3 of the Actavis labeling as showing the relatively flat surface to which the
applicator is initially applied:
PTX-218 at 2633; see Singh 1019:20-1020:5. Figure 3 of the Perrigo labeling also shows
the relatively flat surface to which the Perrigo applicator is initially applied:
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PTX-216 at 19; see Singh 1019:20-1020:5; Dkt. 410 at ¶ 1.
Dr. Singh also referenced Lilly’s Axiron® video (DTX-1283), entitled
“Application Video,” which purports to provide patients with “step by step instructions
on how to properly apply Axiron,” according to the Axiron® labeling. DTX-1283 at
00:00 to 00:06, available at http://axiron.com/how-to-apply-axiron-for-testosteronetreatment.aspx. As Dr. Slocum admitted, the Axiron labeling and the Actavis and Perrigo
labeling are substantively the same. Slocum Tr. 904:22-905:6; see also id. at 979:8-25.
Thus, Lilly’s Axiron video also illustrates the proper application of the Actavis and
Perrigo applicators according to the Actavis and Perrigo labeling. Indeed, Dr. Singh
testified that Lilly’s Axiron video is representative of applications using Actavis’ and
Perrigo’s applicators according to the Actavis and Perrigo labeling. See id. at 1022:201023:16, 1025:23-1026:5; see also Dkt. 410 ¶ 1.
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During Lilly’s Axiron video, patients are instructed to “start swiping a little above
and ending a little below your underarms to help avoid spilling and to speed drying.”
DTX-1283 at 01:19 to 01:25. Excerpted photographs from video show the following:
DDX 405; see DTX-1283.
DDX 408; see DTX-1283.
Using Lilly’s Axiron video (DTX-1283), specifically at the 1:24 mark to the 1:39
mark, Dr. Singh explained that the applicator is first placed up against a relatively flat
surface of the axilla (as opposed to a relatively concave or convex surface), then is
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swiped down and steadily up. Singh 1020:24-1022:7; DTX-1283. He also testified that,
as the applicator is swiped down and up, the leading portion of the wall is folded inwards
into the receptacle while the trailing wall portion is not deformed at all. Id. at 1021:141022:19; DDX 405, 408; DTX-1283.
Dr. Singh opined that the Actavis and Perrigo applicators would behave similarly
during application according to the Actavis and Perrigo labeling. Singh 1022:201023:16; DDX 407; see also Dkt. 410 ¶ 1. Specifically, Dr. Singh testified that, during
application, the leading edge of the Actavis and Perrigo applicators would fold inward
(therefore not forming a double wall even according to Dr. Slocum’s theory) and the
trailing edge would not deform against the axilla (therefore not forming a double wall
even according to Dr. Slocum’s theory). Singh 1022:25-1023:16; DDX 407; see also
Dkt. 410 ¶ 1. Dr. Singh specifically stated that the Actavis and Perrigo applicators do not
form a double wall during application. Singh 1023:14-16; see also Dkt. 410 ¶ 1. He also
testified that the video shows that the applicators do not form a seal during application
(including a “rolling diaphragm seal”), primarily because the applicators are held
relatively upright and a portion of the wall is not touching the axilla skin in any way.
Singh 1023:17-1024:20, 1025:23-1026:5; DDX 408.
Dr. Singh’s interpretations of Lilly’s Axiron video, including the position of the
leading and trailing edges of the applicators during application, was not rebutted by Dr.
Slocum or any other witness.
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Dr. Singh pointed out that Dr. Slocum had not demonstrated that the Actavis or
Perrigo applicators form a “rolling diaphragm effect” or a “rolling diaphragm seal.”
Singh Tr. 1025:12-22; see also Dkt. 410 ¶ 1. In his view, “[a] diaphragm seal is usually
used to retain fluids or liquid under high pressure,” and that he is not aware of any
instances of a diaphragm seal being used to apply a liquid to the skin, such as in the
cosmetics or pharmaceutical fields. Singh 1025:16-1026:11. He testified that the Actavis
and Perrigo applicators do not, in fact, form a rolling diaphragm seal during application.
Singh 1025:23-1026:5.
B.
The Amneal Applicator
Plaintiffs have brought claims for direct and indirect infringement against Amneal,
alleging that Amneal’s proposed applicator literally infringes claims 9 and 10 of the ‘861
patent. Amneal maintains that its applicator does not infringe the asserted claims because
it does not meet the “wall” limitation of the ‘861 patent.
Components of the Amneal Applicator
Amneal’s non-infringement expert, Hermann Plank, testified that Amneal’s
proposed applicator includes a handle (2), a cap (3), a moveable skirt (4), diaphragm (5),
a diaphragm insert (6), and a set-screw (7), as shown in the figure below and described in
detail in Amneal’s ANDA. 17 DTX-2082 at 16-17; PTX-1091 at 128; see also PTX-186
17
By stipulation, in lieu of live testimony from Mr. Plank at trial, the parties admitted the Expert
Report of Hermann Plank MSc., dated February 19, 2016 (“Plank Report”), including Exhibits 1
and 2 of the Plank Report as his direct testimony. See Dkt. 411. Mr. Plank’s report was admitted
as DTX-2082.
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at 1646. The handle (blue), the cap (white), the skirt (blue), and the diaphragm insert
(white) are all made of the same material, polypropylene, with differences only in colors.
DTX-2082 at 16-17; PTX-1091 at 128; see also PTX-186 at 1646.
Mr. Plank testified that the diaphragm (5) is a single piece of membrane made of
clear silicone. DTX-2082 at 16-17; PTX-1091 at 128; see also PTX-186 at 1646. The
first end of the diaphragm (5) is mounted onto the rigid handle (2) through the diaphragm
insert (6) through the set-screw (7). DTX-2082 at 16-17; PTX-1091 at 128; see also
PTX-186 at 1646. The other end (i.e. the second end) of the diaphragm (5) is folded over
and coupled with the moveable skirt (4). DTX-2082 at 16-17; PTX-1091 at 128; see also
PTX-186 at 1646. The second end of the diaphragm (5) and the moveable skirt (4) are
not affixed to the handle (2) or the diaphragm insert (6), and can move freely relative to
the handle (2) in a longitudinally axial direction. DTX-2082 at 16-17; DDX 148; see also
DTX-2082 at 9, 17.
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The diaphragm (5) of the Amneal applicator is the “wall” of the receptacle and the
element of the device that Plaintiffs contend meets the double-wall structure limitation of
the ‘861 patent. Id. at 2072-73; PDX-4014 and 4017; Slocum 843:3-13. Dr. Slocum
testified that the silicone rubber diaphragm of Amneal’s applicator comprises an inner
portion and an outer skirt portion that forms a double-wall structure. PTX-186 at 207273; PDX-4014 and 4017; Slocum 843:3-13. Mr. Plank agreed that there is a portion of
the silicone wall of the Amneal applicator that is closed to the reservoir space and one
that is furthest from the reservoir space. DTX-2083, Plank Dep. Tr. 39:19-40:1.
Relevant Claim Construction
As explained above, the agreed construction of “wall” in terms of the device
claimed in the ‘861 patent is a “part of the receptacle having an inner portion and an outer
skirt portion which form a double-wall structure” Dkt. No. 105; DTX-2021. A “doublewall structure” has been construed to mean “a structure having two walls, i.e., not the two
surfaces of a single wall.” Id. The two walls are the inner portion (“one of the two walls
of the double-wall structure that is closest to the reservoir space”) and the outer skirt
portion (“one of the two walls of the double-wall structure that is furthest from the
reservoir space”). Id. The parties’ agreed constructions for the “double-wall structure”
and the “outer skirt portion”/“skirt portion” do not require the outer skirt to be attached to
the support to be a double-wall structure. See Dkt. 105 at 2.
The “Double-Wall Structure” Claim Amendment
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During prosecution of the related application for U.S. Patent No. 8,177,449 (“the
’449 patent”), the feature of “wherein the inner portion and skirt portion form a doublewall structure” was added in an attempt to distinguish prior art such as U.S. Patent No.
3,462,230 (“Beard”). See PTX-10 at 335, 343-45; DTX-2082 at 13-15.
Applicants argued in the Amendment that Beard does not teach or disclose an
implement with a double-wall structure because Beard only discloses a single-walled
device made of a flexible molded plastic material. See PTX-10 at 344; DTX-2082 at 1315. Further, the applicants represented that Beard is distinguishable from the claimed
invention, because “Beard does not teach or suggest an implement having a wall that
includes an inner portion which extends from the base to an upper end and an outer skirt
portion, wherein the inner portion and skirt portion form a double wall structure, as
recited in the instant claims.” See PTX-10 at 344; DTX-2082 at 13-15. The applicants
made no specific statements during the claim amendment process regarding attachment
of the wall to the support.
The term “double-wall structure” is not expressly defined in either the ’861 or
’449 patents. DTX-2082 at 13-15. In amending the pending claims, the patent applicants
represented that “support for the added clause regarding the wall is found at page 5,
paragraph 26, and in figures, and in original claims 10 and 36, which are canceled
without prejudice or disclaimer.” See PTX-10 at 341; DTX-2082 at 14-15. Dr. Slocum
admitted on cross examination that all three sources of support for the claim amendment
illustrate that the outer skirt portion of the double-wall structure is attached to the
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support. Slocum 1226:24-1227:2, 1231:5-9, 1234:13-1235:14. For example, Paragraph
26 of the specification reads as follows:
Referring now to Figure 2 which shows the implement 1 in
cross section 10 and it can be noted that the receptacle 2
includes a base 5 and a wall 6. The wall includes an inner
portion 7 which extends continuously from the base 5 towards
an upper end 8 of the wall 6. A skirt portion 9 of the wall
extends continuously from the upper end 8 of the wall to a
lower edge 10 which is attached to the support means 3. Figure
3 shows more clearly the lower edge of 15 the skirt being
formed with a thickened rib 10 which locates in a recess 12
formed on the support means 3. Other means for connecting
the receptacle to the support means are clearly possible
however this arrangement allows the receptacle 2 to be
detached from the support means 3 for purposes such as
cleaning of the receptacle 2.
PTX-10 at 10 (emphasis added).
Paragraph 26 of the specification references Figures 2 and 3 and describes how the
inner portion and the skirt portion together create a double-wall structure. Id. at 10 and
38. As shown in FIGS. 2-3 (copied below), the receptacle 2 of the implement 1 includes
a base 5 and a wall 6. Wall 6 includes an inner portion 7 and an outer skirt potion 9
which is attached to the support means 3. Specifically, the lower edge of the skirt is
formed with a thickened rib 10 which locates in a recess 12 formed on the support means
3. PTX-5 at col. 3, ll. 18-34. Although paragraph 26 suggests that other means for
connecting the receptacle to the support means (besides the disclosed “thickened rib”)
may be “possible,” no such other means are disclosed in the specification. Dr. Slocum
agreed on cross examination that each of the embodiments featured in the Figures shows
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a double-wall structure with the outer skirt attached to the support. PTX-10 at 10, 38-40;
PTX-5 at 4-6; DDX 120-126; Slocum 1227:3-5, 1227:20-25, 1228:24-1229:11, 1229:211230:1, 1230:10-19, 1231:5-9, 1236:10-13.
Dr. Slocum also confirmed on cross examination that both original claims 10 and
36 depend from original claim 8, which requires “the wall includes a skirt portion a lower
edge of which is attached to the support means.” PTX-10 at 2, 5; see also Slocum
1234:13-25. Because a dependent claim incorporates every limitation of the claim from
which it depends, these original claims incorporate the limitation that the outer skirt be
attached to the support.
As a result of the claim amendment process, claim 1 of the ’449 patent was
amended during prosecution to add the clause “wherein the wall includes an inner portion
which extends from the base to an upper end and an outer skirt portion, wherein the inner
portion and skirt portion form a double-wall structure.” PTX-10 at 335. Paragraph 26
contains almost verbatim support for the clause added to claim 1. In particular, paragraph
26 states: “[t]he wall includes an inner portion 7 which extends continuously from the
base 5 towards an upper end 8 of the wall 6. A skirt portion 9 of the wall extends
continuously from the upper end 8 of the wall to a lower edge 10 which is attached to the
support means 3.” Compare PTX-10 at 10, with PTX-10 at 335 (emphasis added to show
the overlap between paragraph 26 and the clause added to claim 1). Even though
paragraph 26 contains language that would have allowed the applicants to amend claim 1
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to recite that the skirt portion is attached to the support, the patentees did not amend
claim 1 to recite this requirement. PTX-10 at 335; Slocum 850:1-5.
The Claims of the ‘861 Patent Regarding Attachment of the Wall to the Support
Independent claim 1 of the ‘861 patent is the broadest claim, and it does not
expressly require the outer skirt portion to be attached to the support. PTX-5, ’861
patent, at claim 1; see also PDX-4138 (depicting an embodiment consistent with claims
1, 9, and 10 with the outer skirt portion unattached); Slocum 849:25-850:9. Dependent
claim 12, however, does include this requirement, explicitly stating that the “lower edge
of the skirt portion is attached to the support.” PTX-5, ’861 patent, at claim 12; see also
PDX-4137 (depicting an embodiment consistent with claim 12 with the skirt portion
attached to the support); Slocum 849:5-24.
This understanding of the claims is consistent with the ’861 patent specification,
which indicates that the outer skirt portion is optionally attached to the support. Slocum
848:10-25. That is, although the skirt of the wall may have “a lower edge of which is
attached to the support means,” this is only an example of a “preferred embodiment,” and
does not require that the skirt be attached to the support means. PTX-5 at col. 2, ll. 15-17;
Slocum 848:10-25.
Differences in Structure and Function Between the Amneal and Claimed Applicators
116
Mr. Plank testified that Amneal’s proposed applicator has a different structure and
functions differently from the applicator in the asserted claims of the ’861 applicator
patent. DTX-2082 at 17-19. For example, in the applicator of claim 1 of the ’861
applicator patent, the double-wall structure acts as “a blade-like member when spreading
the liquid across the treatment surface.” PTX-5 at col. 3, ll. 34-57. The structure and the
moving direction of the wall are shown in annotated FIG. 3, which illustrate that the
“blade-like” action occurs when the applicator is moved back and forth parallel to the
base. PTX-5 at 3:34-57; see also DTX-2082 at 15-16; DDX 145, 146.
Mr. Plank testified that, unlike the claimed device, when the user applies the
membrane in Amneal’s proposed applicator to a treatment surface, and pressure is
applied to the upper folded end, the second end moves distally down, resulting in little to
no lateral deformation of the upper folded end against the surface. DTX-2082 at 17-19.
Rather, the upper folded end deforms relatively uniformly around its perimeter along an
axis traverse to the diaphragm insert, resulting in a rolling action. Id. As a result,
Amneal’s proposed applicator uniformly deforms in the axial direction to create a
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controlled, free sliding movement of the single wall against the user’s skin using a rolling
action without lateral deformation. Id.
However, the asserted claims do not require the wall to move or deform in any
particular way. Claim 1 merely recites that the wall is “resiliently deformable,” and
claim 9 recites “deforming the wall of the receptacle containing the liquid composition
against the skin of the subject and spreading the liquid composition over the area of the
skin surface in at least one axilla.” There is no directionality in these elements, and
nothing in the asserted claims or specification suggest to a POSA that the wall must move
in a certain direction (i.e., axially but not laterally).
Despite the differences testified to by Mr. Plank, Amneal has informed the FDA
that “it is confirmed that the Amneal applicators are [the] same as that of the RLD
[Reference Listed Drug (Axiron®)] in their performance and functionality.” PTX-186 at
885. Amneal has represented to the FDA that “the Amneal applicator was designed,
fabricated and manufactured to function in the similar fashion as the RLD applicator,”
and that “[i]t is evident from the pictures that the physical shape and applicability of
Amneal drug product packaging components are very similar to that of the RLD.” Id. at
476. Furthermore, Amneal told the FDA that “Amneal has chosen these packaging
components, based on their design, reproducibility and performance characteristics for
the drug product and their sameness with respect to the principal operation to the
applicator of the Reference Listed drug (RLD).” Id. at 489.
Amneal’s Labeling Instructions
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Amneal intends for its applicator to be used to apply its testosterone solution,
supplying its applicator with its generic testosterone solution and providing instructions
on how to apply the solution using its applicator. PTX-186 at 27 (“For topical use only
with enclosed applicator”), 54-56 (“When it is time to throw away the bottle, safely throw
away all parts of the testosterone topical solution dispenser including bottle applicator
cup and cap.”).
Amneal instructs users to “[r]emove the cap and the applicator cup from the pump.
Then, position the nozzle over the applicator cup and depress the pump gently,” thus
applying the liquid composition including the physiologically active agent to the
reservoir space. Id. at 54-55. Similar instructions are found throughout Amneal’s
labeling. Id. at 37-38.
Amneal further directs users “[t]o apply the testosterone topical solution, keep the
applicator upright, place it up into the armpit application site and wipe steadily down and
up.” Id. at 55. Amneal also instructs users that “[i]f testosterone topical solution drips or
runs, wipe it back up with the applicator cup. Do not rub in the solution with your fingers
or hand once it has been applied.” Id. When Amneal’s applicator is used according to
Amneal’s instructions, the wall of the receptacle containing the liquid composition is
deformed against the skin of the subject and the liquid composition is spread over the
skin of the user’s axilla. Id. at 54-55; Slocum 844:15-845:1.
Amneal’s U.S. Patent No. 9,227,044
119
The U.S. Patent and Trademark Office issued Amneal U.S. Patent No. 9,227,044
on January 5, 2016 for its applicator with knowledge of the ’449 patent. See DTX-2028
at 5:15-39.
Prior Art to the ‘861 Patent
The relevant scope and content of the prior art is determined as of January 11,
2007, the priority date of U.S. Provisional Application No. 60/884,482, to which the ’861
patent is entitled priority under 35 U.S.C. § 119. PTX-5; Slocum 568:3-9.
Amneal contends that U.S. Patent No. 6,773,187 (PTX-373, “the Gueret ‘187
patent) anticipates the claims of the ‘861 patent, and further, that if not anticipatory, the
Gueret ‘187 patent, when combined with the teachings of U.S. Patent Application No.
2007/0206986 (PTX-374, “the Gueret ‘986 publication”), renders the claims of the ‘861
patent obvious. Both the Gueret ’986 Publication and the Gueret ’187 Patent were
considered by the USPTO prior to allowance of the ’861 patent. PTX-5 at 3. The Gueret
’187 Patent was examined by the same examiner, David Walczak, who reviewed and
granted the ’861 patent. PTX-5 at 2; PTX-373 at 1; Slocum 576:16-23, 583:3-7.
1.
Gueret ‘187 Patent
The Gueret ’187 patent discloses “a device for packaging and applying a
substance, for example, a cosmetic or a care product.” PTX-373 at 13, col. 1, ll. 4-6. The
assignee of the Gueret ’187 patent is L’Oréal SA. PTX-373 at 1; Slocum 576:11-15. The
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applicators of the Gueret ’187 Patent are generally directed to cosmetics applicators.
Slocum 576:24-577:2.
Amneal cites Figures 11 and 12, reproduced below, as disclosing the claimed
applicator. Slocum 577:3-8.
PTX-373 at 7.
Figures 11 and 12 are different perspectives of the same applicator device.
Slocum 577:10-14. Figures 11 and 12 depict a device made of an open cell foam.
Slocum 579:1-13. As shown in Figures 11 and 12, the applicator element (200) of the
Gueret ’187 patent may also include a “central depression 205 and the groove 203” that
“may be suitable for becoming filled with substance P for application purposes.” PTX373 at col. 11, ll. 1-4. The annular rib (204) illustrated in Figures 11 and 12 may be
excluded. Id. at col. 10, l. 61- col. 11, l. 4.
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Neither the peripheral portion (202) nor the annular rib (204) provides a doublewall structure. Slocum 275:17-25. The ridges that form the peripheral portion (202) and
annular rib (204) are textural ridges that do not have the geometry capable of forming a
double-wall structure. Slocum 578:17-25. A POSA would understand that to form a
double-wall structure, the wall should be at least five times taller than it is thick (i.e., the
thickness of the wall should be at most 1/5 of its height) to achieve a flexible wall that
will fold over on itself. Slocum 571:13-572:3. Nothing in the Gueret ’187 Patent teaches
or suggests such a wall. That is, each ridge may show some flexibility, but not enough to
fold over on itself to form a double-wall structure given its geometry. Slocum 578:17-25.
Dr. Singh admitted that “there’s no disclosure of a double wall in the original
language [of the Gueret ’187 patent],” but asserts that “in anticipation there is a double
wall.” Singh 1070:11-15. According to Dr. Singh, a POSA would modify the device of
Figures 11 and 12 by (1) replacing the open cell foam with an elastomeric material, (2)
removing annular rib (204), and (3) molding the elastomeric material to “form the outer
shape of [the] applicator,” but to be hollow on the inside. DDX-454; Singh 1070:11-15.
Dr. Singh testified that the first two modifications (replacing the open cell foam
with an elastomeric material and removing annular rib (204)) are disclosed in the Gueret
’187 patent. DDX-454; Singh 1071:14-1073:17. Dr. Singh did not testify that there is
any disclosure of this third modification, to wit, to use a thin sheet of elastomeric
material, molding it so that the applicator would be hollow inside. DDX-454 (failing to
cite any support in the Gueret ’187 Patent for the third modification); Singh 1072:21122
1073:17, 1136:4-6 (agreeing that his modified figure 11 is “nowhere directly shown in
the patent”), 1136:14-19.
Dr. Singh testified on cross examination that if the applicator in Figures 11 and 12
of the Gueret ’187 patent were modified as he suggests, it would no longer work for its
intended purpose. PTX-373; Singh 1137:22-1138:3. The proposed modification to
replace the open cell foam of the applicator in Figures 11 and 12 of the Gueret ’187
patent with an impermeable sheet of elastomeric material would mean that it would no
longer be able to absorb cosmetics as it was intended to do. PTX-373; Singh 1137:221138:6.
2.
Gueret ‘986 Publication
The Gueret ’986 Publication discloses systems for “the cosmetic or dermatological
treatment of the skin.” PTX-374 at 13, ¶ [0002]. The assignee is L’Oréal, a company
that is in the business of manufacturing and selling cosmetics. Slocum 568:22-25.
Cosmetics are typically applied to convex surfaces such as the cheek and nose. Slocum
569:1-4.
The Gueret ’986 Publication is directed to devices for use in applying substances
that are heated. PTX-374 at 1; Singh 1124:20-1126:15. The abstract of the Gueret ’986
publication states that “[t]he applicator further includes at least one material with thermal
properties such that, when the at least one material is heated to a temperature above 30°
C . . . application surface maintains . . . a temperature above or equal to 30° C.” PTX374 at Abstract. As described in the Gueret ’986 Publication, its heated applicators can
123
beneficially dilate the pores, stimulate circulation, and “impart a relaxing effect” on the
user. Id. at 13, ¶ [0012]. Further explanation of how to make, and the benefits of, the
heated applicators is disclosed throughout the Gueret ’986 publication. Id. at ¶¶ [0007],
[0012], [0014], [0015], [0021]-[0026], [0031]-[0039], [0063], [0065], [0097], [0098], etc.
Figure 42 of the Gueret ‘986 patent (reproduced below) is the primary focus of
Amneal’s invalidity challenge.
PTX-374 at 10.
Compound L of Figure 42 is intended to store heat, for example, a wax, an oil, or
water. Id. at 17, ¶ [0097]; Singh 1124:15-1127:7. The device depicted in Fig. 42 “can
include a flexible lip, for example arranged in the manner of a suction cup.” PTX-374 at
15, ¶ [0053]. The reference teaches that the applicator (3) “can be at least partially
resiliently deformable.” PTX-374 at [0151]; see also Singh Tr. 1054:3-12. The Gueret
‘986 publication discloses that the applicator wall may take different shapes.
Specifically, it discloses that the “applicator can be made with a shape adapted to the area
of the body to be treated,” and made with a wide variety of external shapes, for example,
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an elongated shaped with a widened head.” PTX-374 at [0104], [0132].) The reference
goes on to explain that the wall “can include [] flexible” material. Id. at [0023].
Figure 42 does not disclose the claimed wall. There is no disclosure anywhere in
the Gueret ’986 publication of the wall of the device depicted in Figure 42 folding over to
form a double-wall structure, and Defendants offered no evidence that the wall of the
Gueret ’986 publication would form a double-wall structure. Singh 1127:21-1128:4. Dr.
Singh testified only that a POSA would know that single walls could fold over to form
double-wall structures. Singh 1090:16-1091:7.
Secondary Considerations of Nonobviousness
The devices disclosed in both the Gueret ’986 publication and the Gueret ‘187
patent are generally directed to cosmetics applicators. Dr. Slocum testified that, even if a
POSA were to review these references in searching for a solution to the issues faced by
the inventors of the ’861 patent, he or she would recognize that the cosmetics applicators
in the Gueret ’986 publication and Gueret ‘187 patent do not have the degree of sealing
and spreading ability required to apply a volume of liquid onto a largely concave surface,
like the axilla. Slocum 573:2-11; 582:5-10.
Some of the modifications proposed by Amneal would render the disclosed
devices unsuitable for their intended purposes. For example, as discussed above, the
proposed modification to replace the open cell foam of the applicator in Figures 11 and
12 of the Gueret ’187 patent with an impermeable sheet of elastomeric material would
125
render it inoperable since it would no longer be able to absorb cosmetics as it was
intended to do. PTX-373; Singh 1137:22-1138:6.
In internal documents, the inventors of the ‘861 patent reported that the applicator
claimed therein was unexpectedly capable of accurately applying a liquid composition
when the applicator is tilted. PTX-1066, Applicator Development Presentation, at 6, 10.
The inventors reviewed the state of the art at the time and could find no applicator that
was known to be suitable to the application of a liquid composition to the surface of the
axilla. PTX-1093 at 7; Slocum 546:15-22. The inventors tried the conventional wisdom
of the day, starting with a “mushroom applicator” design. PTX-1148 at 4, 6; Slocum
548:4-549:25. It was only after failed attempts to develop the traditional roll-on style
applicators that the inventors struck upon an entirely different type of applicator, the
claimed applicator having a resiliently deformable double-wall structure with a working
surface to spread the composition. PTX-1093, Acrux Design Report, at 6-7; PTX-1066,
Presentation ‐ Simple Axilla Phase 1, at 3-5; PTX-1158, Oct. Design Concepts
Applicator Development Presentation, at 17; PTX-1157, Sept. Design Concepts
Presentation ‐ Simple Axilla Phase 2, at 2, 4-6; Slocum 545:3-546:2, 549:19-25, 554:4-
555:3. It was reported internally that the applicator claimed in the ‘861 patent was
unexpectedly able to apply and spread a liquid composition without scraping up the
composition upon application. PTX-1066, Applicator Development Presentation, at 6,
10. And it had the added benefit of having no moving parts so that it was easy for a user
to operate. PTX-1066, Applicator Development Presentation, at 6, 10.
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C.
The Lupin Applicator
Plaintiffs offered no evidence to show that Lupin’s applicator literally infringes
asserted claims 9 and 10 of the ’861 applicator patent. Slocum 1258:24-1259:5;
MacLean 1675:12-19; DDX 528. Instead, Plaintiffs’ infringement claim against Lupin
rests entirely on a doctrine of equivalents theory. Slocum 1258:24-1259:5, 1259:21-23;
MacLean 1675:12-19; DDX 528.
Components of the Lupin Applicator
Lupin’s applicator as described in ANDA No. 208061 (depicted below) consists of
a plunger holder, wall, ring, and cap. MacLean 1678:8-16; DTX-3067; DDX 533. The
plunger holder is a two-shot injection molded component. MacLean at 1678:17-24; DDX
534. The first shot is made of polypropylene and consists of a support, a base and prong
features as shown in Lupin Figure (a), below. MacLean 1679:4-7, 1680:23-1681:25;
DTX-3067; DDX 534. The second shot (outlined in grey in Lupin Figure (a)), which is
selectively over-molded on top of the base feature of the first shot, is made of Santoprene
thermoplastic vulcanizate (TPE) and forms the base of the applicator receptacle.
MacLean 1679:4-10, 1679:14-1680:1, 1680:23-1682:8; DTX-3067; DDX 534. The
plunger holder has prongs that fit between the inner and outer portions of the wall (Lupin
Figure (b)). MacLean 1680:4-14; DDX 35. The wall, as shown in Lupin Figure (c), is
made of polypropylene. MacLean 1680:4-14; DDX 535. The base and upper portion of
the wall form a reservoir for the therapeutic liquid. MacLean 1683:11-13.
Lupin’s ANDA applicator is depicted in the figures below:
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(a)
(b)
(c)
Lupin Figures.
The plunger holder of Lupin’s applicator has a support
with prongs and the receptacle base (a). When
assembled with the plunger holder, the wall (c) fits
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around the base and rests on the prongs (b).
DDX 533-535.
Operation of the Lupin Applicator
The user applies the treatment solution using the Lupin applicator by repeatedly
pressing it up against the axilla in a stamping motion. MacLean 1684:5-14, 1684:251686:1; DTX-3010_004 (“place [the applicator] up into the axilla and squeeze it steadily
down and up into the axilla”); DDX 536. During use, the Lupin applicator and its wall
move in an up and down, uni-axial motion, to accomplish depositing of the liquid into the
axilla, rather than side-to-side spreading. MacLean 1691:16-1692:1; DDX 537.
According to the instructions in Lupin’s product label, “[i]f the solution drips or runs, it
can be wiped up with the applicator.” DTX-3010_004; DDX 543. This wiping
instruction is a conditional event needed only if some amount of the therapeutic liquid
has escaped the treatment surface or dripped. MacLean 1692:2-14. The wiping motion is
used merely to collect excess liquid that escapes the treatment area back into the reservoir
and then to subsequently stamp back into the axilla, not to spread the liquid within the
axilla. MacLean 1691:21-1692:18.
During use, the wall of Lupin’s applicator experiences downward displacement.
MacLean 1686:10-23, 1687:6-25, 1688:18-20, 1688:23-1689:7; DDX 537-539. The
prongs are bent inwards as the user pushes the applicator up against the treatment surface.
MacLean 1687:14-18; DDX 537-539. The wall moves down relative to the base,
allowing the therapeutic liquid to contact and be deposited onto the treatment surface.
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MacLean 1687:19-25. The prongs act as springs to push the wall up to its resting
position when the downward force is removed. MacLean 1686:10-1687:25, 1689:1-7;
DDX 537-539. Only the prongs, which are part of the plunger holder, deform to any
meaningful degree during use. MacLean 1686:10-23. The wall, on the other hand,
simply translates up and down relative to the base during use. Id. at 1687:6-13; DDX
537-539.
Lupin’s Prescribing Information
Lupin’s prescribing information instructs users as follows:
Keeping the applicator upright, patients should place it up into the axilla
and squeeze it steadily down and up into the axilla. If the solution drips or
runs, it can be wiped back up with the applicator. The solution should not
be rubbed into the skin with fingers or hand.
DTX-3010_004. Lupin’s prescribing information does not instruct or encourage
users to spread the liquid within the axilla. See, e.g., DTX-3010, PTX-188.
Operation of the Applicator Claimed in the ‘861 Patent
The ’861 patent discloses the applicator shown in Figure 1 and Figure 2 for
topical delivery of a therapeutic liquid or lotion (e.g., testosterone gel). See PTX-5
at col. 3, ll. 6-33 and Figs. 1 and 2. The user dispenses therapeutic liquid into the
applicator reservoir (4) (Figure 1) and then places the applicator in contact with
the skin surface to deposit and spread the liquid onto the skin. See id. at col. 3, ll.
6-16. The claims of the ’861 patent describe the applicator and its components,
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various therapeutic compositions, and the application method. See id. at col. 14, l.
56 – col. 16, l. 39. During use, the “resiliently deformable” wall “maintains
contact with the treatment surface when spreading the liquid.” Id. at col. 2, ll. 1-3.
Figure 1.
The preferred embodiment of the ’861 patent is an applicator
(1) having a receptacle (2), support means (3), and reservoir
space (4).
Figure 2.
The cross-section of the applicator (1) shows that the
receptacle (2) contains a base (5) and wall (6). The wall (6)
has an inner portion (7) and an upper portion (8). The outer
side of the wall contains a skirt portion (9) and a lower edge
(10). The lower edge (10) is attached to the support means (3)
(see Fig. 1 and Fig. 3).
PTX-5 at col. 3, ll. 6-17 and Fig. 1; id. at col. 3, ll. 18-33 and Fig. 2; DDX 530.
131
According to the ’861 patent, during use, the “working surface” of the wall “is
used to spread the liquid over the treatment surface.” Id. at col. 1, l. 64 – col. 2, l. 3. The
wall resiliently deforms during use so that the “working surface maintains contact with
the treatment surface when spreading the liquid.” Id. The “working surface” intended to
maintain contact with the skin during use preferably “extends along the wall between the
inner portion and the skirt” and may also include the “inner portion of the wall” as well
as “over the skirt of the wall.” Id. at col. 2, ll. 33-37. The working surface described in
the specification is shown in Annotated Figure 2, below. DDX 541. A POSA would
understand that the working surface of the wall, not the base or any other component,
applies the therapeutic liquid during use. MacLean 1677:9-19, 1690:6-1691:13; PTX-5
at col. 3, ll. 37-39, col. 3, ll. 43-48, col. 14, ll. 4-6; DDX 531, DDX 541, DDX 546.
The receptacle and wall are further described as follows:
... the receptacle 2 is formed from a relatively flexible membrane which
allows at least the wall 6 to flex acting as a blade-like member when
spreading the liquid across the treatment surface. The relative flexibility of
the membrane allows the wall 6 to roll across the treatment surface spreading
the liquid rather than wiping the liquid off the treatment surface.
PTX-5 at col. 3, ll. 42-48. The receptacle wall of the ’861 patent applicator is designed to
spread the liquid with a blade-like motion. Given that the working surface is disclosed to
consist of both inner and outer portions of the wall (Annotated Figure 2), a POSA would
understand that the blade-like motion is achieved by a side-to-side bending motion of the
wall. MacLean Tr. 1677:9-19. During use, the applicator of the ’861 applicator and its
walls move in a multi-axial manner to accomplish spreading of the liquid across the
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axilla. MacLean Tr. at 1677:9-1678:2; DDX 531. The ’861 patent teaches that the
applicator wall spreads the liquid onto the treatment surface and expressly teaches away
from an applicator wall that wipes the liquid off the treatment surface. MacLean Tr. at
1693:4-19; PTX-5 at col. 3, ll. 45-48; DDX 543.
Annotated Figure 2. Annotated version of Fig. 2 of the ’861 patent with
“working surface” that extends from inner portion (7) to
skirt portion (9) as indicated by the grey outline.
(DDX 541.)
Conclusions of Law
I.
Controlling Principles of Law
As noted above, Plaintiffs have asserted infringement claims against each
defendant as to each patent in suit – the ‘075 formula patent only against Actavis, the
‘944 axilla patent against all defendants and the ‘861 patent against all defendants.
Actavis has conceded infringement of the ‘075 patent, but challenges its validity on
grounds of lack of written description and enablement. All Defendants concede
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infringement of the ‘944 patent, but challenge its validity on grounds of anticipation and
obviousness. With regard to the ‘861 patent, all Defendants contend that their respective
applicators do not infringe, and that, even if their products do infringe, the ‘861 patent is
invalid on the grounds that it is anticipated, obvious, and contains indefinite terms.
To prove infringement of the ‘861 patent, Plaintiffs must demonstrate by a
preponderance of the evidence that Defendants’ applicators infringe the asserted claims
of that patent. Tech. Licensing Corp. v. Videotek, Inc., 545 F.3d 1316, 1327 (Fed. Cir.
2008). In order to satisfy this burden, Plaintiffs “must supply sufficient evidence to prove
that the accused product … meets every element or limitation of a claim.” Rohm and
Haas Co. v. Brotech Corp., 127 F.3d 1089, 1092 (Fed. Cir. 1997).
Because issued patents are statutorily presumed valid under 35 U.S.C. § 282, with
regard to their invalidity defenses and counterclaims, Defendants have “the ultimate
burden of persuasion to prove invalidity by clear and convincing evidence, as well as the
initial burden of going forward with evidence to support [their] invalidity allegation[s].”
Titan Tire Corp. v. Case New Holland, Inc., 566 F.3d 1372, 1377 (Fed. Cir. 2009)
(citation omitted). Clear and convincing evidence “has been described as evidence which
produces in the mind of the trier of fact ‘an abiding conviction that the truth of [the]
factual contentions are ‘highly probable.’” Buildex Inc. v. Kason Indus. Inc., 849 F.2d
1461, 1463 (Fed. Cir. 1988) (quoting Colorado v. New Mexico, 467 U.S. 310, 316
(1984)).
II.
The ‘075 Patent
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A.
Scope of Claim 13
Actavis contends that claim 13 of the ‘075 patent is invalid for lack of written
description and enablement. Claim 13 recites a method of treating a hypogonadal man by
applying a therapeutically effective amount of testosterone. PTX-1 at claim 13. As a
dependent claim, claim 13 must “incorporate … all the limitations of the claim[s] to
which it refers.” See 35 U.S.C. § 112(d). Accordingly, claim 13 comprises a formulation
with: (a) a therapeutically effective amount of testosterone to treat a testosterone deficient
hypogonadal man; (b) the penetration enhancer octyl salicylate in an amount from 1010,000% by weight of testosterone; and (c) ethanol and/or isopropanol in an amount
sufficient to act as a vehicle. PTX-1 at claims 1, 5, 9-11, 13.
Actavis contends that claim 13 is invalid because the specification of the ‘075
patent does not provide adequate written description to suggest to a POSA that the
inventors possessed a testosterone formulation with 10,000% octyl salicylate by weight
of testosterone and also would not have enabled a POSA to use such a formulation for
transdermal drug delivery without undue experimentation. Although Plaintiffs asserted
throughout the preliminary stages of this litigation, including up to and through opening
statements at trial, that the 10-10,000% range from claim 1 was incorporated into asserted
claim 13, (see PDX-2019; Tr. 11:4-9), they now argue that there is no explicit
requirement that the method of claim 13 make use of testosterone formulations that
contain amounts of penetration enhancer throughout the entire range recited in claim 1 as
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long as the amount of penetration enhancer used in the formulation falls somewhere
within the 10-10,000% by weight of testosterone range.
In support of this contention, Plaintiffs argue that, unlike claim 1, which is
directed to “therapeutically effective” treatments for any number of conditions, including
treatment for testosterone deficient women, claim 5, from which claim 13 depends,
narrows claim 1 to include only those treatments that would be effective for treating
hypogonadal men. Claim 11, from which claim 13 also depends, further narrows claim 1,
Plaintiffs assert, by naming octyl salicylate as the penetration enhancer to be used. The
‘075 patent specification states that the performance of the penetration enhancer to
deliver testosterone varies with differences in the nature of the penetration enhancer and
further teaches in examples 6, 10, 12, 13, and 15 that the particular combination of
testosterone and octyl salicylate does not require operating at the high end of the
penetration enhancer range. On this basis, Plaintiffs argue, a POSA would understand
claim 13 to be narrowed to an amount of octyl salicylate less than the 10-10,000% by
weight of testosterone found in independent claim 1.
By failing to raise this theory until trial was well underway, Plaintiffs waived this
interpretation. Even if not waived, however, we do not find it to have merit. As noted
above, dependent claims, like claim 13, incorporate all of the limitations of the claims
from which they depend, unless further limitation is specified in the dependent claim.
See 35 U.S.C. § 112(d). Here, while it is true that claim 13 depends from claims 5 and 11
and is therefore limited to formulations that use octyl salicylate as the penetration
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enhancer and are therapeutically effective for the treatment of hypogonadal men, neither
claim 13 nor any of the claims on which it depends contains a further limitation on the
range of penetration enhancer recited in claim 1. We cannot read such a limitation into
the claim when it is not otherwise there. This conclusion is in line with the testimony of
Defendants’ expert, Dr. Potts, who explained that claim 13 allows for use of up to 100
times more octyl salicylate than testosterone. Potts 1308:2-8. Plaintiffs’ expert, Dr.
Hadgraft, never contradicted Dr. Potts’s testimony on this point, nor did he offer the
opinion that a POSA would interpret claim 13 to cite a narrower range of the amount of
octyl salicylate than that recited in claim 1 or what a POSA would understand the bounds
of such a narrower range to be. Accordingly, we hold that claim 13 encompasses a
formulation having up to 10,000% by weight of testosterone, or 100 times more octyl
salicylate than testosterone.
B.
Validity of Claim 13
Having determined the scope of the claimed method of treatment recited in claim
13 of the ‘075 patent, we now turn to address whether the specification provides adequate
written description and enablement of the full scope of the invention. A valid patent must
have adequate written description and enablement support in the patent specification. 35
U.S.C. § 112. The statutory basis for these requirements is laid out in 35 U.S.C. § 112,
which provides that the specification must contain: “a written description of the invention
and of the manner and process of making and using it, in such full, clear, concise and
exact terms as to enable any person skilled in the art to which it pertains, or with which it
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is most nearly connected, to make and use the same.” Id. § 112(a). We address each of
these requirements in turn below.
1.
Written Description
“The test for the sufficiency of the written description ‘is whether the disclosure of
the application relied upon reasonably conveys to those skilled in the art that the inventor
had possession of the claimed subject matter as of the filing date.’” Vasudevan Software,
Inc. v. MicroStrategy, Inc., 782 F.3d 671, 682 (Fed. Cir. 2015) (quoting Ariad Pharms.,
Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010)). In other words, the written
description requirement is met when a POSA would find it “reasonably clear what the
invention is and that the patent specification conveys that meaning.” All Dental Prodx,
LLC v. Advantage Dental Prods., Inc., 309 F.3d 774, 779 (Fed. Cir. 2002). The
specification “must describe an invention understandable to [a POSA] and show that the
inventor actually invented the invention claimed.” Ariad Pharms., 598 F.3d at 1351.
“Whether a patent claim is supported by an adequate written description is a question of
fact.” AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285,
1297 (Fed. Cir. 2014) (citation omitted).
Here, it is undisputed that the ‘075 patent contains no examples of a transdermal
drug formulation containing a therapeutically effective amount of testosterone with the
penetration enhancer octyl salicylate present in an amount of 100 times (or 10,000%) the
amount of testosterone for the treatment of hypogonadal men. Hadgraft 324:16-325:4;
Potts 1321:11-1322:6. Rather, the only examples of testosterone samples set forth in the
138
specification include 12% w/v testosterone and 8% v/v of penetration enhancer, which
computes to approximately 0.67 times (or 67%) of the penetration enhancer by weight of
testosterone, which is clearly far below the upper most end of the claimed range of
penetration enhancer. PTX-1 at Examples 6, 10, 12, 13, and 15; Potts 1320:8-17,
1321:11-1322:6; Hadgraft 348:5-8.
It is true that “a claim will not be invalidated on section 112 grounds simply
because the embodiments of the specification do not contain examples explicitly covering
the full scope of the claimed language.” LizardTech, Inc. v. Earth Res. Mapping, Inc.,
424 F.3d 1336, 1346 (Fed. Cir. 2005). However, the purpose of the written description
requirement is “to ensure that the scope of the right to exclude, as set forth in the claims,
does not overreach the scope of the inventor’s contribution to the field of art as described
in the patent specification.” Ariad Pharms., 598 F.3d at 1353 (quotation marks and
citation omitted). Accordingly, the specification must in some way “reasonably convey
to a person skilled in the art that [the inventor] had possession of the claimed subject
matter at the time of filing. LizardTech, 424 F.3d at 1346. We are not persuaded that the
‘075 patent specification reasonably conveys to a POSA that the inventors had possession
of the full scope of the claimed invention, namely, using a formulation consisting of 100
times more octyl salicylate than testosterone.
Although the specification states that the amount of penetration enhancer “may be
in the range of 10-10,000 weight percent” (PTX-1 at col. 12, ll. 35-45) and that for some
active ingredients, it “may well be that the upper range of 10,000% [of penetration
139
enhancer] will be required,” (id.) the specification does not identify testosterone as an
active ingredient for which the inventors believed that 100 times more penetration
enhancer might be required nor does the specification support such a conclusion. Potts
1319:13-22; Hadgraft 339:20-340:6, 341:23-342:20. Rather, as described above, the
examples set forth in the specification teach a POSA that testosterone is effectively
delivered using less penetration enhancer than testosterone. See PTX-1 at Examples 6,
10, 12, 13, 15. The specification also discusses the fact that dermal penetration enhancers
are irritating and emphasizes the importance of minimizing skin irritation by using as
little penetration enhancer as possible. PTX-1 at col. 2, ll. 51-53, col. 4, ll. 13-15, col. 12,
ll. 41-42. Another objective of the invention listed in the specification is to minimize
drying time following application of the testosterone product. PTX-1 at col. 4, ll. 1-6,
col. 10, ll. 50-56. Defendants’ expert, Dr. Potts, testified that the wide range of
penetration enhancer incorporated in claim 13 of the ‘075 patent, particularly at the upper
end of the range, “would be at odds” with the goals of reducing skin irritation and
minimizing drying time discussed in the specification. 18 Potts 1324:15-18.
For these reasons, we conclude that, while there is adequate written description
support for some narrower part of the range of penetration enhancer claimed, given the
absence of information regarding formulations using testosterone and penetration
enhancer in an amount anywhere near the upper end of the disclosed range, coupled with
18
Dr. Potts’s testimony on the written description requirement was not contested by Plaintiffs’
experts. Dr. Hadgraft’s opinions were limited to the issue of enablement, a distinct requirement,
and he did not opine as to whether a POSA would understand that the inventors possessed the
invention.
140
the explicit direction in the specification to limit as much as possible the amount of
penetration enhancer used, there is insufficient written description support for the entire
range disclosed. In reading the specification, a POSA would not have understood the
inventors to have possessed a formulation with 100 times more octyl salicylate than
testosterone. To satisfy the written description requirement, the specification must do
more than merely invite other researchers to discover the upper amount of penetration
enhancer that could conceivably work. See Boston Sci. Corp. v. Johnson & Johnson, 647
F.3d 1353, 1367 (Fed. Cir. 2011) (“The patent laws do not reward an inventor’s invitation
to other researchers to discover which of the thousands of macrocyclic lactone analogs of
rapamycin could conceivably work in a drug-eluting stent.”). Accordingly, we find that
Actavis has presented clear and convincing evidence that the ‘075 patent specification
does not reasonably convey to a POSA that the inventors had possession of the full scope
of their claimed invention. Claim 13 of the ‘075 patent is therefore invalid for lack of
written description.
2.
Enablement
“To meet the enablement requirement, ‘the specification of a patent must teach
those skilled in the art how to make and use the full scope of the claimed invention
without undue experimentation.’” Martek Biosciences Corp. v. Nutrinova, Inc., 579 F.3d
1363, 1378 (Fed. Cir. 2009). “A claim is sufficiently enabled even if ‘a considerable
amount of experimentation’ is necessary, so long as the experimentation ‘is merely
routine, or if the specification in question provides a reasonable amount of guidance with
141
respect to the direction in which the experimentation should proceed.’” Vasudevan
Software, 782 F.3d at 684 (quoting In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988)). In
determining whether a disclosure requires undue experimentation, courts consider the
following factors: “(1) the quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence of working examples, (4) the
nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the
art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1336 (Fed. Cir. 2013) (quoting
Wands, 858 F.2d at 737).
Enablement does not require the specification to “necessarily describe how to
make and use every possible variant of the claimed invention, for the artisan’s knowledge
of the prior art and routine experimentation can often fill gaps, interpolate between
embodiments, and perhaps even extrapolate beyond the disclosed embodiments,
depending upon the predictability of the art.” AK Steel Corp. v. Sollac and Ugine, 344
F.3d 1234, 1244 (Fed. Cir. 2003). However, it does require that, “when a range is
claimed, there must be reasonable enablement of the scope of the range.” Id.
At trial, Defendants’ expert, Dr. Potts, conceded that, with routine
experimentation, a POSA would be able to make a transdermal formulation with up to
100 times more octyl salicylate than testosterone because “[m]aking is simply a recipe.”
Potts 1327:6-7. The parties’ dispute regarding enablement, therefore, is limited to
whether the patent contains sufficient enabling support for a POSA to use a transdermal
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formulation containing 100 times more octyl salicylate than testosterone to effectively
deliver testosterone for the treatment of hypogonadism without undue experimentation.
We find that Actavis has established by clear and convincing evidence that the ‘075
patent would not enable a POSA to use such a formula without undue experimentation,
and thus the full scope of claim 13 is not enabled.
As discussed above, the specification does not disclose any transdermal drug
formulation containing a therapeutically effective amount of testosterone with a
penetration enhancer present in an amount of 100 times the amount of testosterone for the
treatment of hypogonadal men. Both Dr. Potts and Dr. Hadgraft testified that they are
unaware of any person who has ever made or tested a transdermal formulation containing
100 times more penetration enhancer than testosterone. Hadgraft 325:9-12; Potts
1334:10-13. Although the specification notes that “for some actives, it may well be that
the upper range of 10,000% by weight will be required,” (PTX-1 at col. 12, ll. 35-45),
there is no indication that testosterone is one of those active ingredients and the examples
contained in the specification teach otherwise, as each testosterone formulation includes
approximately 0.67 times of the penetration enhancer by weight of testosterone, much
less than the upper limit of 100 times the weight of testosterone that is claimed. PTX-1 at
Examples 6, 10, 12, 13, and 15; Potts 1320:8-17, 1321:11-1322:6; Hadgraft 348:5-8.
Nowhere in the specification are the particular actives that could require the upper range
of penetration enhancer listed, nor does it conclusively state that such a high ratio of
enhancer would necessarily be required, only that such an amount “may well be
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required.” The specification’s disclosure that certain active ingredients might require
using 100 times more enhancer than active ingredient is insufficient to enable using 100
times more of octyl salicylate to deliver testosterone. See Genentech, Inc. v. Novo
Nordisk, 108 F.3d 1361, 1366 (Fed. Cir. 1997) (“Patent protection is granted in return for
an enabling disclosure of an invention, not for vague intimations of general ideas that
may or may not be workable.”).
The ‘075 patent specification in fact teaches away from using the large amounts of
penetration enhancer at the upper end of the claimed range. For example, Dr. Potts
testified that in order to make a formulation with 100 times more octyl salicylate than
testosterone according to the asserted claim, a POSA would need to use 12.5 milligrams
of testosterone, 1,250 milligrams of octyl salicylate, and 5,050 milligrams of volatile
liquid, for a total of approximately 6,300 milligrams of material. According to Dr. Potts,
this amount of material would need to be spread over several thousand square centimeters
of skin. Potts 1330:14-1331:3. It is not clear how such a substantial formulation could
be put to practical use for transdermal drug delivery, particularly considering that it
would defeat the objective listed in the ‘075 patent of ensuring a convenient application
and drying time by applying the formulation to a small area of the skin. Potts 1324:1-5.
Additionally, using such a large amount of octyl salicylate at a higher concentration than
is generally recognized as safe contradicts the specification’s teaching to use the least
amount of penetration enhancer as necessary to avoid skin irritation. The Federal Circuit
has held that in cases in which “the specification teaches against a purported aspect of an
144
invention, such a teaching ‘is itself evidence that at least a significant amount of
experimentation would have been necessary to practice the claimed invention.” LiebelFlarsheim Co. v. Medrad, Inc., 481 F.3d 1371 (Fed. Cir. 2007) (quoting AK Steel, 344
F.3d at 1244).
Moreover, even if a POSA prepared a formulation with 100 times more octyl
salicylate than testosterone, undue experimentation would be needed to test whether a
formulation with such an extreme ratio of low active ingredient to high penetration
enhancer could be used to treat hypogonadism. Plaintiffs’ own expert, Dr. Hadgraft,
testified regarding the significant experimentation on the formulation that would be
required, including skin penetration studies to ensure that it delivered a therapeutically
effective amount of testosterone into the bloodstream, stability studies to determine it
remained physically stable, and skin irritancy studies to make sure that it would not be
excessively irritating when applied to the skin, particularly considering that such a
formulation would require using a higher concentration of octyl salicylate than is
generally recognized as safe. 19 Hadgraft 320:4-23. Dr. Hadgraft further testified on
cross-examination that transitioning from these in vitro experiments to in vivo
experiments can itself be an unpredictable process. Hadgraft 323:14-21. According to
Dr. Hadgraft, even if a POSA knew how much testosterone he wanted to deliver into a
19
Octyl salicylate is generally recognized as safe in concentrations up to 5%, but in Dr. Pott’s
hypothetical formulation, the octyl salicylate is present in an amount of about 19.8%. Potts.
1330:2-1331:5, 1439:2-15.
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patient’s bloodstream, such a person would still not be able to formulate a transdermal
product with any degree of certainty without further testing. 20 Hadgraft 324:11-15.
Given that the patent provides no working examples or other guidance for a POSA
to use a formulation with such an extreme ratio between penetration enhancer and active
ingredient to treat hypogonadism, the level of experimentation that would be required to
enable a POSA to do so is far from routine and clearly undue. There is no indication that
a POSA’s knowledge of the prior art combined with routine experimentation could “fill
in the gaps” left by the specification to enable him to use the invention on the upper end
of the range of penetration enhancer disclosed, particularly given that there is no
indication that anyone had ever tried to make such a formula and the specification points
away from such an embodiment. AK Steel, 344 F.3d at 1244. For these reasons, we find
that claim 13 of the ‘075 patent is invalid for lack of enablement.
III.
The ‘944 Patent
A.
Anticipation
Defendants contend that claim 20 of the ‘944 patent is invalid as anticipated in
light of the Morgan ‘725 publication/‘983 patent. “Invalidity on the ground of
‘anticipation’ requires lack of novelty of the invention as claimed. The invention must
20
In his direct examination, Dr. Hadgraft opined that the ‘075 patent specification enabled a
POSA to make and use the commercial Axiron® product, which contains 2.5 times more octyl
salicylate than testosterone. This opinion, however, does not address the relevant question
before us, to wit, whether the specification enables the full scope of the claimed invention, which
recites a formulation having up to 100 times more octyl salicylate than testosterone.
146
have been known to the art in the detail of the claim; that is, all of the elements and
limitations of the claim must be shown in a single prior reference, arranged as in the
claim.” Karsten Mfg. Corp. v. Cleveland Golf Co., 242 F.3d 1376, 1383 (Fed. Cir. 2001).
Even if a reference does not explicitly disclose a feature of the claimed invention, a prior
art reference may still be deemed to anticipate “if that missing characteristic is
necessarily present, or inherent, in the single anticipating reference.” SmithKline
Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343 (Fed. Cir. 2005) (citing
Continental Can Co. v. Monsanto Co., 948 F.2d 1264, 1268 (Fed.Cir.1991)).
Claim 20 recites a method of treating a testosterone-deficient man by applying a
therapeutically effective amount of testosterone. PTX-1 at claim 13. As a dependent
claim, claim 20 must “incorporate … all the limitations of the claim[s] to which it refers.”
See 35 U.S.C. § 112(d). Accordingly, incorporating all of the limitations of the claims to
which it refers, claim 20 comprises a method of increasing the testosterone blood level of
an adult male subject in need thereof by applying to at least one axilla of the subject,
without occlusion by a patch device, a non-occlusive transdermal drug delivery
composition consisting of: (a) a pharmaceutically effective amount of testosterone; (b)
one or more lower alkyl alcohols selected from a group consisting of ethanol,
isopropanol, and mixtures thereof, wherein the combined volume of the lower alkyl
alcohol(s) is more than 80% (v/v) of the composition; 21 (c) the penetration enhancer
21
Claims 13 and 17, from which claim 20 depends, require the combined volume of the alkyl
alcohol(s) to be greater that 60% and 70%, respectively. However, because claim 18 requires the
combined volume to be greater than 80%, we have incorporated only that limitation into claim
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octisalate in an amount of from 0.01% to 15% (w/v); (d) the viscosity modulating agent
polyvinyl pyrrolidone present in an amount from 1% to 3% (w/v) of the composition, in
an amount effective to increase the viscosity of the composition to within the range of
from greater than the viscosity of water to less than 300 centipoise; and (e) optionally,
water, wherein the composition is applied in an amount effective to achieve a testosterone
blood level in the subject of at least 200 ng/dL. PTX-4 at claims 13, 14, 15, 16, 17, 18,
19, 20.
In his testimony at trial, Dr. Chambliss broke these limitations into three groups –
(1) the “blood level” limitations, which include the method of increasing the testosterone
blood level of an adult male subject in need to at least 200 ng/dL; (2) the “formula”
limitations, which include the non-occlusive testosterone composition limitation as well
as limitations (a) through (e) listed above; and (3) the “axilla” limitation, which requires
the composition be applied to at least one axilla of the subject. For the reasons detailed
below, while we find that Defendants have established by clear and convincing evidence
that the formula and blood level limitations are disclosed by the ‘725 publication, they
have failed to show that the axilla limitation is disclosed therein and therefore have failed
to establish that claim 20 of the ‘944 patent is anticipated by the ‘725 publication.
1.
Blood Level Limitations
20 because, if satisfied, the lower thresholds required in claims 13 and 17 are also necessarily
met.
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We find that Defendants have shown by clear and convincing evidence that the
‘725 publication discloses the “blood level limitations” of claim 20, which require, “a
method of increasing the testosterone blood level of an adult male subject in need
thereof” and “wherein the composition is applied in an amount effective to achieve a
testosterone blood level in the subject of at least 200 ng/dL.” The abstract of the ‘725
publication states in relevant part that the invention “provides a method for administering
at least one acting hormone to an animal which comprises applying an effective amount
of the hormone in the form of the drug delivery system of the present invention.” PTX483 at 1. Paragraph 57 of the ‘725 publication teaches that the formulations disclosed in
the publication, including the formulation in 13A, are methods of the invention which
include “male hormone therapy in testosterone deficient hypogonadal men.” PTX-483 at
[0057].
Dr. Chambliss testified that although the ‘725 publication does not explicitly
disclose the testosterone blood level of at least 200 ng/dL, that limitation is inherently
disclosed because the ‘725 publication discusses providing a therapeutically effective
amount of the hormone to treat a testosterone deficient hypogonadal man and it was
known in the art at that time that effectively treating a testosterone deficient hypogonadal
man would raise his testosterone blood level to at least 200 ng/dL. Chambliss 1560:1-13.
In other words, following the method disclosed in the ‘725 publication would necessarily
result in a testosterone blood level in the subject of at least 200 ng/dL. Chambliss 1560:
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14-17. Plaintiffs presented no evidence that contradicted Dr. Chambliss’s testimony
regarding the blood level limitations.
2.
The Formula Limitations
Example 13A of the ‘725 publication explicitly discloses a number of the formula
limitations set forth in claim 20 of the ‘944 patent. Specifically, Example 13A discloses
a topical lotion composition with testosterone in an amount of 1% w/v; octyl salicylate in
an amount of 2.5% w/v; hydroxyl propyl cellulose in an amount of 1.5% w/v; and
aqueous ethanol (90% v/v) in an amount to 100 mL. PTX-483 at Example 13A.
Dr. Chambliss testified that the composition disclosed in Example 13A is a
nonocclusive lotion formulation that is not a patch, so it meets the limitation of claim 20
that requires a nonocclusive, non-patch transdermal drug delivery composition.
Chambliss 1548:19-23. Example 13A also discloses testosterone 1%, which Dr.
Chambliss testified was known to be a pharmaceutically effective amount of testosterone,
thereby meeting limitation (a) of claim 20. Chambliss 1546:12-14. The last ingredient
listed in Example 13A is aqueous ethanol 90%, which Dr. Chambliss testified equates to
85% ethanol, thereby meeting limitation (b) of claim 20 which discloses one or more
lower alkyl alcohols selected from a group consisting of ethanol, isopropanol, and
mixtures thereof, wherein the combined volume of the lower alkyl alcohol(s) is more than
80% (v/v) of the composition. Chambliss 1552:6-18. Because aqueous ethanol is a
mixture of ethanol and water, this ingredient also meets limitation (e) of claim 20, which
is optionally water. Chambliss 1547:11-13. The third ingredient listed in Example 13A
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is octyl salicylate, 2.5%, which is simply another name for octisalate (the penetration
enhancer disclosed in limitation (c) of claim 20) and falls within the 0.01% to 15% (w/v)
range disclosed in claim 20 for the penetration enhancer. Chambliss 1546:15-18.
Plaintiffs’ expert, Dr. Hadgraft, offered no testimony that rebuts Dr. Chambliss’s
testimony on these limitations.
Dr. Chambliss also opined that the ‘725 publication discloses limitation (d) of
claim 20, to wit, the viscosity modulating agent polyvinyl pyrrolidone – often referred to
as povidone – present in an amount from 1% to 3% (w/v) of the composition, in an
amount effective to increase the viscosity of the composition to within the range of from
greater than the viscosity of water to less than 300 centipoise. Chambliss 1557:7-12.
Paragraph 24 of the ‘725 publication discloses the optional use of a thickening agent in
the formulations and specifically lists povidone as a potential option. PTX-483 at [0024].
Paragraph 27 of the ‘725 publication then teaches that a preferred formulation would
include 1-3% of the hormone, a penetration enhancer, ethanol or isopropanol, water, and,
optionally, 0.5 to 5% of a thickening agent. PTX-483 at [0027]. Dr. Chambliss testified
that these paragraphs teach a POSA to use the thickening agents listed in paragraph 24
(which include povidone) in a range of 0.5 to 5% in formulations that contain the other
elements listed in paragraph 27. Both Examples 13A and 13B disclose variations of such
a preferred formula, and each contains different thickening agents from the list in
paragraph 24 (hydroxyl propyl cellulose in Example 13A and ethyl cellulose in Example
13B) at 1.5%. According to Dr. Chambliss, the teachings in paragraphs 24 and 27,
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combined with the disclosure in Examples 13A and 13B showing that the thickening
agents listed in paragraph 24 are interchangeable, would teach and disclose to a POSA
that he could replace the thickening agents contained in Examples 13A and 13B with
povidone in the same amount (which is within the range specified in claim 20) and that
the formulation would have the same type of composition. 22 Chambliss 1555:10-25;
1556:1-15. In Dr. Chambliss’s expert opinion, using such thickening agents in this
manner would necessarily result in a viscosity between that of water and 300 centipoise
as required in claim 20. Plaintiffs’ expert, Dr. Hadgraft, again offered no testimony that
rebuts Dr. Chambliss’s testimony on the thickening agent limitation.
We do not find persuasive Plaintiffs’ argument that one or more of the non-axilla
limitations are not disclosed in the ‘725 publication because they are not all disclosed in a
single example or because impermissible “picking and choosing” from the disclosures in
the ‘725 publication is required in order to arrive upon the formulation disclosed in claim
20. See Application of Arkley, 59 CCPA 804, 455 F.2d 586, 587 (1972) (stating that
anticipating reference “must clearly and unequivocally disclose the claimed compound to
direct those skilled in the art to the compound without any need for picking, choosing,
and combining various disclosures not directly related to each other by the teachings of
22
Plaintiffs argue that arriving at the thickening agent limitation set forth in claim 20 (i.e., using
povidone in a range of 1-3%) would require impermissible picking and choosing among the
disclosures of the ‘725 patent. Because the disclosures in paragraphs 24 and 27 providing the list
of thickening agents and the preferred range of those agents are directly related to the disclosure
in Example 13A, however, it does not require an impermissible combining of distinct disclosures
to arrive at the thickening agent limitation in claim 20. See Purdue v. Pharma L.P. v. Epic
Pharma, LLC, 811 F.3d 1345, 1359 (Fed. Cir. 2016) (“The disclosures pointed to by the district
court are all ‘directly related’ and thus there is no impermissible picking and choosing.”).
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the cited reference”). As Dr. Chambliss’s testimony established, the majority of the
formulation limitations are expressly disclosed in Example 13A. Those disclosures that
are not found explicitly in Example 13A are directly related to the disclosures in Example
13A and to the same embodiment, namely, a transdermal testosterone formulation to treat
male hypogonadism. Therefore, arriving at the formulation disclosed in claim 20 does
not require impermissibly combining of unrelated and distinct disclosures in the ‘725
publication. See Purdue Pharma L.P. v. Epic Pharma, LLC, 811 F.3d 1345 (Fed. Cir.
2016) (rejecting argument that court erred by “using distinct sections of [the anticipatory
reference] and reassembling them into an embodiment to find that all of the limitations
were present). For these reasons, we hold that Defendants have shown by clear and
convincing evidence that each of the formulation limitations in claim 20 is disclosed in
the ‘725 publication as arranged in the claim.
3.
Axilla Limitation
Finally, claim 20 requires that the claimed testosterone formulation be applied to
at least one axilla of the subject. It is undisputed that there is no express reference of
transdermal testosterone application to the axilla in the Morgan ‘725 publication. Rather,
Defendants assert that the ‘725 publication discloses this limitation because it teaches
applying the formulations to human skin (which would include the axilla) and also
discloses a preferred surface area over which to apply the formulations (within which the
surface area of the axilla would fall). The relevant disclosure in the ‘725 publication
provides as follows: “Preferably, the drug delivery system is applied to the skin of the
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animal covering a delivery surface area between about 10 and 800 cm2, more preferably
between about 10 and 400 cm2, and most preferably between about 10 and 200 cm2.”
PTX-483 at [0058].
Defendants have failed to establish by clear and convincing evidence that a POSA
would have understood the ‘725 publication to disclose application of the testosterone
formulation to the axilla based on this generic disclosure, which describes only how
much surface area is preferred to deliver a therapeutic dose, but not where to apply the
formulation. The amount of surface area to be covered for purposes of delivering an
effective dose of a hormone is simply not the same as a description of a site of
application. The ‘725 publication therefore does not suggest that the transdermal
formulation disclosed be applied to any location in particular, much less express any
preference for a specific location of administration.
The surface area of the skin of a normal adult is about 20,000 cm2. PTX-611 at 6;
Hadgraft 185:2-6. Accordingly, there are many skin surfaces that a POSA would have
understood to fall within the preferred surface area ranges disclosed in the ‘725
publication, particularly considering that each anatomical region on the body could be
further divided into smaller application sites that would meet the preferred ranges
disclosed, resulting in countless options. Hadgraft 291:11-15, 292:11-293:10; Chambliss
1603:10-14, 1607:19-25. Defendants argue that based on the disclosure of the preferred
surface area, a POSA would think in terms of a limited genus of application sites then
known in the art to be suitable for transdermal drug delivery, including the axilla. It is
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true that in situations in which the genus is so limited that a POSA can “at once envisage
each member of this limited class,” a reference “describing the genus anticipates every
species within the genus.” In re Gleave, 560 F.3d 1331, 1337-38 (Fed. Cir. 2009). But
the ‘725 publication does not disclose the genus of known transdermal application sites.
Rather, the disclosure in the ‘725 publication is limited to preferred surface areas for
application of the transdermal drug formulations disclosed. It was well known in the art
at the time that the efficacy of transdermal drug delivery could be affected by at least
three variables, including the surface area of application, the permeability of the skin at
the application site, and the type of compound being delivered. Defendants have failed to
establish by clear and convincing evidence that a POSA would understand the ‘725
publication’s disclosure which is focused solely on the first of these variables, to wit,
surface area, to necessarily disclose the limited genus of known transdermal application
sites that would include the axilla. This is particularly true given that the ‘725
publication is silent regarding the distinct issue of location of application.
Because we are not persuaded that a POSA would understand the generic
disclosure of application to the skin of preferred surface area ranges in the ‘725
publication to be a specific disclosure of application to the axilla, Defendants have failed
to establish by clear and convincing evidence that the Morgan ‘725 publication
anticipates every limitation of claim 20 of the ‘944 patent.
B.
Obviousness
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Although Defendants have failed to establish that the Morgan ‘725 publication
anticipates claim 20 of the ‘944 patent, they have shown by clear and convincing
evidence that a POSA would have been motivated to combine the teachings of the ‘725
publication with the teachings of other prior art to develop the claimed invention and
would have had a reasonable expectation of success in doing so. Accordingly, for the
reasons detailed below, we rule that claim 20 of the ‘944 patent is invalid as obvious. 23
A patent claim is invalid on the grounds of obviousness “if the differences
between the subject matter sought to be patented and the prior art are such that the subject
matter as a whole would have been obvious at the time the invention was made to a
person having ordinary skill in the art to which said subject matter pertains.” 35 U.S.C. §
103(a) (2006). 24 When assessing obviousness, courts consider “whether a [POSA] would
have been motivated to combine the prior art to achieve the claimed invention and
whether there would have been a reasonable expectation of success in doing so.” DyStar
Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360
(Fed. Cir. 2006) (citation omitted).
“Obviousness under 35 U.S.C. § 103(a) is ultimately a legal question, based on
underlying factual determinations.” Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353,
23
The prior art references we have relied on in rendering our obviousness determination were
considered by the PTO before allowance of the ‘944 patent. Therefore, while the standard of
proof remains clear and convincing evidence, in proving obviousness, Defendants “shoulder an
enhanced burden.” Tokai Corp. v. Easton Enterprises, Inc., 632 F.3d 1358, 1367 (Fed. Cir.
2011). Defendants have met that burden here.
24
Because the application for the ‘944 patent was filed before March 16, 2013, the pre-AIA
amended version of 35 U.S.C. § 103(a) is applicable here. See § 3(n)(1) of the AIA.
156
1356 (Fed. Cir. 2008). The factual determinations underlying the obviousness analysis
include consideration of the scope and content of the prior art; the differences between
the prior art and the claimed subject matter as a whole; the level of skill in the art; and
any relevant secondary factors, also known as objective evidence of non-obviousness.
Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286, 1290-91 (Fed. Cir. 2013). Secondary
considerations include surprising or unexpected results, prior art teaching away from the
claimed invention, and unpredictability in the art. See, e.g., id.; Gator Tail, LLC v. Mud
Buddy LLC, 618 F. App’x 992, 998-99 (Fed. Cir. 2015).
As discussed above, the Morgan ‘725 publication teaches a POSA to use a nonocclusive transdermal testosterone formulation to increase testosterone blood levels of
testosterone deficient hypogonadal men as disclosed in claim 20 of the ‘944 patent.
Example 13A of the ‘725 publication also expressly discloses the composition of the
claimed non-occlusive transdermal testosterone formulation, save for its use of hydroxyl
propyl cellulose as the thickening agent, rather than the polyvinyl pyrrolidone (also
known as povidone) disclosed in claim 20. However, the ‘725 publication teaches that
the thickening agent used in Example 13A is interchangeable with a number of other
thickening agents listed in paragraph 24 of the ‘725 publication, including povidone, and,
in paragraph 27, the publication also teaches using a range of 0.5 to 5% of the chosen
thickening agent. Based on these disclosures, it would have been obvious to a POSA to
follow the teachings of the ‘725 publication to replace the thickening agent used in
Example 13A with povidone in the claimed range of 1 to 3%. Given the ‘725
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publication’s disclosure, coupled with the FDA’s prior approval of two transdermal
testosterone gels, a POSA would have understood that testosterone could be effectively
delivered transdermally to raise the testosterone blood level of a testosterone deficient
hypogonadal man to within a normal range.
The dispositive issue, before us, therefore, is whether it would have been obvious
to a POSA to apply the testosterone formula to the axilla. Based on the evidence adduced
at trial, we find, as explained in detail below, that Defendants have established by clear
and convincing evidence that application of the formulation to the axilla would have been
obvious in light of the teachings of the prior art.
1.
Prima Facie Evidence of Obviousness
First, the axilla was expressly disclosed as a potential site for transdermal
testosterone application in the relevant literature. The Aschkenasy ‘268 publication, for
example, discloses pharmaceutical compositions for transdermal drug delivery, including
testosterone, and also discloses a list of seven potential application sites including “the
abdomen, an armpit, an inside arm, the back, a thigh, a shoulder, or the scrotum.” PTX243 at [0065], [0066]. It is undisputed that a POSA would understand the armpit to be a
reference to the axilla. As Dr. Hadgraft conceded, each of these application sites other
than the axilla were areas of the skin where prior FDA-approved transdermal testosterone
products had been applied. Hadgraft 447:5-452:16. Accordingly, a POSA would have
understood these seven application sites to be a curated and finite list of sites appropriate
for transdermal drug delivery, and, among those application sites, the industry would
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have viewed application of testosterone to the armpit as an opportunity for differentiation
from prior commercial products. Potts 1365:2-1366:6, 1473:5-14; Chambliss 1611:101612:10.
The fact that the Aschkenasy ‘268 publication also discloses an extensive list of
deodorants and antiperspirants that could be added to the topical testosterone
formulations disclosed therein buttresses the conclusion that a POSA would have viewed
Aschkenasy as contemplating application of testosterone to the axilla, given that these are
common products applied to the axilla. See PTX-243 at [0141], [0142]. While it is true
that the Aschkenasy ‘268 publication does not include any exemplary data from a clinical
study, that fact does not lessen the teaching of the publication, particularly when
considered in combination with other prior art at the time.
For example, by June 2005, it was known that the skin of the axilla was more
permeable to transdermal drug delivery than other skin sites, including the forearm,
trunk, back, and abdomen. PTX-340 at 2; PTX-449 at 4; PTX-607 at 1; Potts 1357:211358:4, 1361:1-22. Based on the findings disclosed in prior art references like Feldmann
and Maibach, it would have been reasonable for a POSA to believe that administering a
topical testosterone formulation to the axilla could yield higher testosterone blood levels
than administering to other identified skin sites, given the axilla’s greater than average
skin permeability.
Cutter 2000 and Cutter 2001 provide further motivation for a POSA to apply a
transdermal testosterone formulation to the axilla to increase testosterone blood levels.
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Cutter (2000) recommends transdermal application of testosterone to “the trunk or
axillary area” and reports that such administration in adult men results in a balance of
testosterone, DHT, and estradiol blood levels that is “very much in the normal
physiologic range. PTX-301 at 3 (emphasis added). Cutter (2001) discusses data from a
clinical study of ten patients instructed to apply testosterone gel to “either the upper inner
arm or chest near the axilla or the inner thigh and scrotum.” PTX-302 at 3. The study
results demonstrated that selecting the “axilla” as the site of application for transdermal
delivery of testosterone effectively increases testosterone blood levels while maintaining
normal physiologic levels of DHT. Id. at 4. Dr. Cutter further reported that in his
clinical practice he found that the “most useful starting dose [of testosterone] for most
men is 6% gel, 2.5 mL, applied to the nonhairy area of the axilla.” Id. at 9.
A POSA would have understood Cutter (2000) and Cutter (2001) as teaching the
application of testosterone to a part of the axilla. The Cutter references specifically
report application to the axilla’s “nonhairy area,” and, as Dr. Hadgraft testified, the axilla
is comprised of both hairy and nonhairy parts. Hadgraft 362:14-17. Despite this clear
reference to a portion of the axilla, as well as Dr. Cutter’s references to the application of
testosterone to “the axilla,” “the axillary area,” and “the upper inner arm or the chest near
the axilla,” Dr. Hadgraft nevertheless unconvincingly reads the Cutter references as “not
applying the testosterone to the axilla.” Hadgraft 255:8-18. Dr. Hadgraft opined that Dr.
Cutter was either using a “shorthand” when he referenced the axilla or may have been
“misleading” in describing his work. Hadgraft 416:19-417:12, 420:18-421:12. Given
160
that the Cutter references stress that “[t]he choice of application site is quite important,”
we do not find it credible to infer that when Dr. Cutter subsequently recommended
application of testosterone to the “axillary area” in order to maintain normal testosterone
and DHT levels, and identified the “nonhairy area of the axilla” as an effective
application site used in his clinical practice, that he must have been using those terms as
some sort of shorthand to refer instead to an area that excludes the axilla. 25 This
interpretation simply makes no sense. Accordingly, upon reading the Cutter references, a
POSA would have reasonably expected that administering a testosterone composition to
the axilla would succeed in effectively increasing the testosterone blood levels of a
hypogonadal man as the clinical study reported in Cutter (2000) and Cutter (2001)
demonstrated that administration to the axilla would in fact work.
Cutter (2000) and Cutter (2001) also disclose additional motivation for a POSA to
have applied the transdermal testosterone composition to the axilla in order to reduce the
risk of inadvertent transfer of testosterone to others. It was widely known by June 2005
that transference of testosterone to women and children was linked with serious adverse
side effects. See, e.g., PTX-1059 at 12; PTX-641 at 10. Recognizing this risk, Cutter
(2001) recommends that “by using the gel in the axillary area, at bedtime, transmission
[of testosterone] can be avoided.” PTX-302 at 10. A POSA would understand from this
disclosure that one significant benefit of choosing the axilla as an application site would
25
A POSA would have understood other prior art references at the time, including the Chein
‘790 patent, Ben-Galim (1980), and Papa (1967), to have also identified the axilla as a potential
site for administration of testosterone.
161
be to avoid inadvertent transference of testosterone as the armpit is an area that does not
frequently come into contact with others.
For at least these reasons, a POSA would have been motivated to combine the
teachings of the prior art to apply, with a reasonable expectation of success, the
testosterone composition taught in the Morgan ‘725 publication to the skin of the axilla to
develop the claimed method of treatment recited in claim 20 of the ‘944 patent. As
explained above, the Morgan ‘725 publication explicitly disclosed the elements of the
claimed testosterone formulation. When combined with the Aschkenasy ‘268
publication’s disclosure of a finite list of application sites appropriate for transdermal
drug delivery that included the axilla, it would have been sheer common sense to select
the axilla as an application site. See C.W. Zumbiel Co. v. Kappos, 702 F.3d 1371, 1387
(Fed. Cir. 2012) (finding obviousness where the invention involved “no more than the
exercise of common sense in selecting one out of a finite – indeed very small – number of
options”). A POSA would have been particularly motivated to select the axilla as an
application site, considering that application to the axilla not only addressed the known
issue of inadvertent transference of testosterone but also represented a way to
differentiate from other transdermal testosterone products on the market. Moreover, a
POSA would have had a reasonable expectation of success in doing so, given the axilla’s
known above-average permeability and the teaching of the Cutter references that
application of testosterone to the axillary area effectively increases testosterone blood
levels while maintaining normal DHT levels.
162
2.
Secondary Considerations
It is well-established that “[s]econdary considerations of non-obviousness must be
considered when present.” Geo M. Martin Co. v. Alliance Machine Sys. Int’l, LLC, 618
F.3d 1294, 1304 (Fed. Cir. 2010). Here, Plaintiffs argue that the secondary
considerations of teaching away and unexpected results preclude a conclusion that claim
20 of the ‘944 patent is obvious.
Plaintiffs’ first argument is the prior art teaches away from the application of
testosterone to the axilla. A reference teaches away “when a person of ordinary skill,
upon reading the reference, would be discouraged from following the path set out in the
reference, or would be led in a direction divergent from the path that was taken by the
applicant.” Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013)
(quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed.
Cir. 2009)). According to Plaintiffs, the prior art teaches away from the axilla as a
suitable site for transdermal testosterone application due to concerns of elevated DHT
levels as well as the presence of hair, creases and folds in the skin, sweat, bacteria, and
cosmetics in the axilla. Upon careful review of the prior art, however, we are not
persuaded that a POSA would understand the applicable references to teach away from
administering testosterone to the axilla for any of these reasons.
Plaintiffs maintain that the prior art teaches away from applying testosterone to the
axilla due to concerns of elevated levels of DHT. Specifically, Plaintiffs contend that a
POSA would have been discouraged from applying testosterone to the axilla because of
163
concerns that high 5-alpha reductase activity in the axillary skin, similar to the level of
activity found in scrotal skin, would result in elevated DHT levels associated with
negative side effects, including BPH and prostate cancer. However, in reaching his
conclusion on this issue, Plaintiffs’ expert, Dr. Goldstein, did not rely on any prior art
references which compare the 5-alpha reductase activity in axillary skin to that observed
in scrotal skin nor did he cite to any prior art reference teaching that administration of
testosterone to the axilla results in elevated DHT levels. To the contrary, the only prior
art reference that reported DHT levels following application of testosterone to any part of
the axilla is Cutter (2001), which reported normal DHT levels following application to
the axillary area.
In support of his opinion that a POSA would, in fact, be concerned about elevated
DHT levels associated with application of testosterone to the axilla, Dr. Goldstein relies
solely upon a single study reported in Takayasu (1980), which measured the 5-alpha
reductase activity of various skin tissues, including the “sweat (probably apocrine)
glands” obtained from microscopic samples of axillary skin of two patients. PTX-583 at
188. Takayasu (1980) reported that the sweat glands of the axillary skin demonstrated
high 5-alpha reductase activity, while the activity of the sebaceous glands and dermis in
the axilla fell in the middle of the reported results. PTX-583 at 4. However, the study
measured the 5-alpha reductase activity only in isolated components of the skin, such as
the sweat glands, rather than such activity of the entire, intact axillary skin and did not
report the amount of sweat gland in the skin sample relative to other components.
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Accordingly, a POSA would not have understood Takayasu (1980)’s measure of the 5alpha reductase in axillary sweat glands to be representative of the entire axillary skin,
nor would a POSA have relied upon Takayasu (1980) to compare the 5-alphas reductase
activity in differing whole skin samples. Additionally, the study was not designed to
consider the amount of testosterone that would actually be delivered to the components
tested. In other words, the study was not designed to assess the diffusion of testosterone
from the surface of the skin into the sweat pores and through the sweat ducts to reach the
sweat glands. 26
Importantly, neither Takayasu (1980) nor any other prior art reference disclosed a
direct comparison between the 5-alpha reductase activity found in scrotal skin with that
found in the axillary skin; thus, it was not clear in the art how the activity compared.
Assuming, however, that a POSA would have understood the skin of the axilla and the
scrotum to have comparable 5-alpha reductase activity and would have expected that both
would increase DHT levels in the same manner, the clinical significance of elevated DHT
levels was uncertain in June 2005 and thus would not have dissuaded a POSA from
pursuing the axilla as a site of administration for transdermal testosterone therapy.
To explain further: although it was well-known in the art that transdermal
administration of testosterone to the scrotum increased DHT levels, the FDA nevertheless
approved the Testoderm® scrotal patch in 1993, and, by 2000, studies on long-term use
26
Dr. Potts testified that a POSA would understand that drug delivery through the sweat ducts
into the sweat glands comprises a minor fraction – roughly 0.03-0.05% -- and is not a major
route for drug delivery through the skin. Potts 1393:21-1394:17.
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of the Testoderm® patch had been performed, revealing that “the incidence of prostate
problems in those who wore scrotal patches was no greater than in subjects given
placebo.” PTX-301 at 7. In the 1990s, the prior art acknowledged that the clinical
significance of elevated DHT levels was “unknown,” (PTX-290 at 3), and that, after
much research, it was recognized that “less credence is given to the simple concept that
elevated DHT levels may be a factor in BPH.” PTX-468 at 4. Moreover, despite it being
known that scrotal administration of testosterone resulted in elevated DHT levels, the
prior art continued to recommend the scrotum as a site of application for transdermal
testosterone leading up to June 2005. See, e.g., PTX-302 at 4; PTX-431 at col. 4, ll. 3650. On this basis, we conclude that, if the known connection between transdermal
application of testosterone to the scrotum and elevated DHT levels did not discourage
those in the art from considering the scrotum as an appropriate application site, a POSA
likewise would not have been dissuaded from pursuing the axilla as an application site
based on a potentially comparable level of 5-alpha reductase activity. For these reasons,
we hold that a POSA would not have found that concerns of elevated DHT levels taught
away from using the axilla as an application site.
Plaintiffs also contend that a POSA would have been discouraged from
administering testosterone to the axilla because of the presence of hair in the area as well
as creases and folds in the skin. Although Dr. Hadgraft testified that a number of prior
references taught away from transdermal administration of testosterone in areas of the
skin with hair and/or significant creases and folds, on cross-examination he conceded that
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such concerns were primarily associated with transdermal patch devices which rely on
secure adhesion to be effective. Hadgraft 189:8-190:10, 457:18-458:15. The prior art, in
fact, recognizes that the presence of hair and creases and folds of the skin do not present a
significant problem for non-occlusive transdermal formulations such as the testosterone
lotions at issue in this litigation. PTX-592 at col. 2, ll. 25-32, col. 2, l. 63 – col. 3, l. 5;
Potts 1401:23-1402:11. Moreover, both AndroGel® and Testim®, the two prior art nonocclusive testosterone gels, are applied to areas in which men often grow hair, including
the shoulders, upper arms, and abdomen. Potts 1400:1-15. Accordingly, a POSA would
not understand the prior art to point away from transdermal testosterone application to the
axilla on the basis of hair or creases and folds of the skin and would not expect these
characteristics of the axilla to impede transdermal drug delivery.
Nor does the prior art point away from the axilla as an application site because of
the presence of sweat, bacteria, antiperspirants or deodorants on the surface of the
axillary skin. There is no prior art reference that discusses any adverse effects on
transdermal drug delivery due to the presence of any of these characteristics. Indeed, the
Aschkenasy ‘268 publication anticipates that deodorants and antiperspirants may be
added to its transdermal testosterone formulations. PTX-243 at 12. Even assuming a
POSA would be concerned regarding the possible impact that sweat, bacteria,
antiperspirants, or deodorants might have on transdermal drug delivery, the prior art
testosterone gels, AndroGel® and Testim®, address the issue by instructing users to
apply the gels to “intact, clean, dry skin.” PTX-1059 at 1; PTX-641 at 1. The instruction
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to wash and dry the skin prior to application of the testosterone formulation would avoid
concerns related to sweat, bacteria, or cosmetics in the axillary area. Potts 1404:11-22.
For these reasons, teach away from transdermally applying testosterone to the axilla on
this basis.
Plaintiffs also point to what they contend were unexpected results of the invention
of the ‘944 patent as evidence of nonobviousness. “To be particularly probative,
evidence of unexpected results must establish that there is a difference between the
results obtained and those of the closest prior art, and that the difference would not have
been expected by one of ordinary skill in the art at the time of the invention.” BristolMyers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014). Here,
Plaintiffs cite four examples of unexpected results: (1) seven-fold greater absorption of
testosterone per unit area in the axilla than the forearm; (2) no excessive sweating or odor
following transdermal application of testosterone to the axilla; (3) normal DHT levels
following application of testosterone to the axilla; and (4) effectiveness of transdermal
delivery of testosterone to axilla despite presence of hair, bacteria, creases and folds in
the skin, and deodorants and antiperspirants. We address these contentions in turn below.
In support of their argument that application of the testosterone formulation of the
‘944 patent to the axilla resulted in unexpectedly better absorption compared to the
forearm, Plaintiffs rely on Acrux Clinical Study DDS16 (“DDS16”) and inventor Dr.
Watkinson’s adjustment of that data to account for the surface area of the respective
application sites. DDS16 reported that the axilla provided two-fold greater delivery of
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testosterone than the forearm, which Dr. Hadgraft conceded was not unexpected. Such a
result was not surprising (or unexpected) as a POSA would have reasonably anticipated,
based on the known permeabilities of the axilla and the forearm, that administering a
dosage of testosterone to the axilla would result in higher blood serum concentration
levels than administering the same dosage to the forearm. DDS16 likewise reported that
the approximately two-fold greater absorption in the axilla was “consistent with” the
prior art’s disclosure of variations in skin permeation.
Plaintiffs’ unexpected results argument is based, therefore, not on the data from
the DDS16 study alone, but rather on Dr. Watkinson’s attempt to use that data to
retroactively calculate the amount of testosterone delivered per unit area of the respective
skin surfaces. Dr. Watkinson’s finding that, after an adjustment of the clinical data for
the supposed size of the respective application sites, the axilla provided seven-fold
greater absorption per unit area than the forearm, was calculated using measurements
from three unrelated sources – the testosterone absorption data from the ten women who
were administered testosterone in the DDS16 study; the axilla measurements of the sixty
women who had their axillae measured for an antiperspirant/deodorant study reported in
Cowan-Ellsberry (2008); and the forearm measurements from fifteen women from
Acrux’s offices who had their forearms measured by Dr. Watkinson. Potts 1412:111413:6. In reaching his conclusion, Dr. Watkinson necessarily relied upon the
assumption that the areas of the axillae and forearms measured in women who were not
participants in the DDS16 study accurately represented the areas of application in the
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original clinical study. Because Dr. Watkinson used data from three distinct groups of
women and also relied upon the unsubstantiated assumption that the application sites in
the DDS16 study corresponded with the measurements of completely different women,
we are not persuaded that Dr. Watkinson’s retroactive size adjustment represents a
reliable measurement of the difference in absorption per unit area between the axilla and
the forearm. 27
Moreover, even if the axilla did demonstrate a seven-fold increase in testosterone
permeation per unit area as compared to the forearm, a POSA would not find that result
altogether unexpected. The prior art, for example, reported that the physiological agent,
parathion, permeated the skin of the axilla in an amount 7.4-fold greater than that of the
forearm. PTX-340. Given that the axilla was known in the art to be more permeable
than the forearm for various compounds, any enhanced permeation of testosterone would
be, at most, only a “difference in degree” of a known and expected property, rather than a
difference in “kind.” Bristol-Myers, 752 F.3d at 977. It is well-established under Federal
Circuit precedent that differences in degree “are not as persuasive in rebutting
obviousness as differences in ‘kind’ – i.e., a new property dissimilar to the known
property.” Id.; see Galderma, 737 F.3d at 739 (“Unexpected results that are probative of
nonobviousness are those that are different in kind and not merely in degree from the
results of the prior art.”) (citation and quotation marks omitted).
27
We note that Dr. Watkinson’s size adjustment calculation is not included in the clinical study
report, the ‘944 patent specification, or the peer-reviewed publication of the results from clinical
study DDS16.
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Plaintiffs next invoke their clinical study results showing that application of a
testosterone formulation to the axilla did not cause excessive sweating or odor as
unexpected, given that testosterone increases the activity of the apocrine glands and
would be expected to result in increased sweat and odor in the axilla. Goldstein 675:11676:13. However, Plaintiffs presented no prior art reference(s) suggesting that a POSA
would have expected that administering testosterone to the axilla of a hypogonadal man
would result in excessive sweating. Failure to present “any evidence of what the skilled
artisan would have expected” defeats a claim of unexpected results. See Pfizer, Inc. v.
Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007) (emphasis removed). To the contrary,
because a hypogonadal man has below normal levels of testosterone and sweats less than
the average adult male, a POSA would not expect that applying testosterone to the axilla
of a hypogonadal man would lead to excessive sweating and odor. Rather, one skilled in
the art would expect that, if testosterone therapy returns a hypogonadal man to normal
physiologic ranges, that the amount of sweating and odor would increase to normal levels
as well, and would not be excessive.
Finally, Plaintiffs contend that the invention of the ‘944 patent of applying
testosterone to the axilla was surprisingly effective at increasing testosterone blood levels
without increasing DHT levels and despite the presence of hair, sweat, and/or
antiperspirants or deodorants. However, as discussed above, a POSA would not have
expected anything other than normal DHT levels when applying testosterone to the axilla,
given the disclosure in the Cutter references that application of testosterone to the axillary
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area resulted in normal DHT levels, coupled with the absence in the prior art of any
disclosure showing elevated DHT levels following testosterone application to the axilla.
The fact that Acrux and Lilly’s clinical studies showed normal DHT levels when a
testosterone formulation was applied to the axilla therefore cannot be evidence of
unexpected or surprising results. Similarly, Plaintiffs have failed to establish that its
studies showing that application of Axiron® to the axilla was effective despite the
presence of hair, bacteria, creases and folds in the skin, and deodorants and
antiperspirants were, in fact, surprising. The prior art did not teach away from applying
testosterone to the axilla based on any of these factors, nor has it been shown that a
POSA would have expected that these factors would materially affect transdermal drug
delivery.
For these reasons, we hold that Plaintiffs’ asserted secondary considerations of
non-obviousness do not overcome the strong prima facie evidence of obviousness
rendering claim 20 of the ‘944 patent invalid as obvious.
IV.
The ‘861 Patent
A.
Infringement
Plaintiffs allege that each of Defendants’ respective applicators infringes the ‘861
patent, either directly or indirectly. Plaintiffs bear the burden of “proving infringement
by a preponderance of the evidence,” and the “failure to meet a single limitation is
sufficient to negate infringement of [a] claim.” Laitram Corp. v. Rexnord, Inc., 939 F.2d
1533, 1535 (Fed. Cir. 1991). A determination of direct patent infringement requires a
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two-step analysis. The court first must construe the claims to determine their scope and
meaning and then compare the properly construed claims to the allegedly infringing
device. Dynacore Holdings, Corp. v. U.S. Phillips Corp., 363 F.3d 1263, 1273 (Fed. Cir.
2004). “To prove infringement, the patentee must show that the accused device meets
each claim limitation, either literally or under the doctrine of equivalents.” Id.
Liability for indirect infringement, whether inducement to infringe or contributory
infringement “is dependent upon the existence of direct infringement.” Joy Techs., Inc. v.
Flakt, Inc., 6 F.3d 770, 774 (Fed. Cir. 1993). It is well-established that “[t]here can be no
inducement or contributory infringement without an underlying act of direct
infringement.” Linear Tech. Corp. v. Impala Linear Corp., 379 F.3d 1311, 1326 (Fed.
Cir. 2004). For a party to be liable for contributory infringement under 35 U.S.C. §
271(c), the plaintiff must establish: (1) “there is direct infringement,” (2) “the accused
infringer had knowledge of the patent,” (3) “the component has no substantial
noninfringing uses,” and (4) “the component is a material part of the invention.” Fujitsu
Ltd. v. Netgear, Inc., 620 F.3d 1321, 1326 (Fed. Cir. 2010). “To prove inducement of
infringement, the patent must show that the accused inducer took an affirmative act to
encourage infringement with the knowledge that the induced acts constitute patent
infringement.” Info-Hold, Inc. v. Muzak LLC, 783 F.3d 1365, 1372 (Fed. Cir. 2015)
(internal quotation marks and citation omitted).
We address Plaintiffs’ infringement claims against each Defendant in turn below.
1.
The Actavis and Perrigo Applicators
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Plaintiffs have stipulated that Actavis and Perrigo do not directly infringe claims 9
and 10 of the ‘861 patent because their respective applicators are both single wall devices
and therefore do not meet the “wall” limitation of the asserted claims, which has been
construed to require “an inner portion and an outer skirt portion which form a doublewall structure.” Dkt. 105 at 2 (emphasis added). Instead, Plaintiffs claim that Actavis
and Perrigo are liable for indirect infringement of claims 9 and 10.
As noted above, there can be no indirect infringement without proof of direct
infringement, “though the direct infringer is typically someone other than the defendant
accused of direct infringement.” Dynacore, 363 F.3d at 1272. Such is the case here,
where Plaintiffs’ indirect infringement claims against Actavis and Perrigo are premised
on the assertion that users of the respective applicators, when using the accused products
in the manner set forth in Actavis’s and Perrigo’s labeling instructions, will directly
infringe the ‘861 patent. Specifically, Plaintiffs claim that, although both Actavis’s and
Perrigo’s accused products are single-wall applicators at rest, when used in accordance
with the included directions for use, the single wall folds over to form a double wall that
meets the limitations set forth in claims 9 and 10.
Upon careful consideration of the evidence adduced at trial, we find that Plaintiffs
have failed to establish by a preponderance of the evidence that Actavis’s and Perrigo’s
applicators directly infringe claims 9 and 10. Plaintiffs rely exclusively on the testimony
of their expert, Dr. Slocum, to support their claim that the single wall in the Actavis and
Perrigo applicators folds over in use to form an infringing double wall. Dr. Slocum, in
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turn, based his opinion that Actavis’s and Perrigo’s applicators form a double wall in use
on his professional knowledge and experience, Defendants’ proposed drug labeling, and
his own testing of the accused applicators.
Before trial, Defendants sought to have Dr. Slocum’s testimony regarding the
testing he performed on the Actavis and Perrigo applicators as well as his opinions based
on that testing excluded under Federal Rule of Evidence 702 and the principles set forth
in Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579 (1993). At the final
pretrial conference, the Court withheld a ruling on the Daubert issue, recognizing that
because Dr. Slocum’s testimony would be offered at a bench trial, not before a jury, it
was unnecessary to address the admissibility issues in advance of trial. At trial,
Defendants’ Daubert objection was renewed and the Court, recognizing the continuing
objection, permitted Dr. Slocum to testify, explaining that the Daubert issues would be
considered “in the context of the testimony and taking into account the cross-examination
and so forth.” Tr. 523:9-11.
“Where a trial judge conducts a bench trial, the judge need not conduct a Daubert
(or Rule 702) analysis before presentation of the evidence, even though [s]he must
determine admissibility at some point.” Kansas City So. Railway Co. v. Sny Island Levee
Drainage District, ___ F.3d ___, 2016 WL 4123857, at *6 (7th Cir. Aug. 3, 2016).
Having now heard the testimony and cross-examination of Dr. Slocum, we begin by
addressing Defendants’ Daubert challenge.
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The admissibility of expert testimony is governed by Rule 702 and the Daubert
principles. To be admissible, expert testimony must be both relevant and reliable.
United States v. Allen, 390 F.3d 944, 949 (7th Cir. 2004). The case law recognizes that
this test “is a flexible one, and no single factor is either required in the analysis or
dispositive as to its outcome.” Smith v. Ford Motor Co., 215 F.3d 713, 719 (7th Cir.
2000). Moreover, the Federal Circuit has observed that, while expert testimony must still
meet the Daubert standards of relevance and reliability where the case is tried to the
court, Daubert concerns are “of lesser import in a bench trial.” Seaboard Lumber Co. v.
United States, 308 F.3d 1283, 1302 (Fed. Cir. 2002). Accordingly, as explained by Judge
Posner, “a judge in a bench trial should have discretion to admit questionable technical
evidence, though of course [s]he must not give it more weight than it deserves.”
SmithKline Beecham Corp. v. Apotex Corp., 247 Fed. Supp. 2d 1011, 1042 (N.D. Ill.
2003) (Posner, J., sitting by designation), aff’d on other grounds, 403 F.3d 1331 (Fed.
Cir. 2005).
Here, it is undisputed that Dr. Slocum is an expert by “knowledge, skill,
experience, training, [and] education” qualified to render an opinion concerning
infringement. See Fed. R. Evid. 702. The thrust of Defendants’ Daubert challenge is that
Dr. Slocum’s opinions based on the at-home testing methods he performed on the Perrigo
and Actavis applicators are inadmissible because that testimony is not the product of
reliable principles and methods. However, the case law recognizes that expert testimony
based on personal observation is not inherently unreliable and that “hands on testing” as
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Dr. Slocum performed here “may suffice as a reasonable methodology upon which to
base an opinion.” Clark v. Takata Corp., 192 F.3d 750, 758 (7th Cir. 1999). Dr.
Slocum’s testimony that, based on his informal tests in which he acted as a regular “user”
of the Actavis and Perrigo devices, the accused applicators meet the limitations of the
asserted claims, is relevant to the ultimate infringement issue. While Defendants
question whether the testing performed by Dr. Slocum supports his infringement
opinions, the “[s]oundness of the factual underpinnings of the expert’s analysis and the
correctness of the expert’s conclusions based on that analysis are factual matters to be
determined by the trier of fact.” Smith, 215 F.3d at 718. Given that Daubert concerns
are not implicated to the same degree when the case is tried to the court and because we
find that Defendants’ objections to Dr. Slocum’s testimony and opinions go more to their
weight, rather than their admissibility, we deny the Daubert objections and decline to
exclude Dr. Slocum’s testimony on those grounds.
At trial, Dr. Slocum opined that both the Actavis and Perrigo applicators form a
double-wall structure when the devices are used as instructed by Actavis’s and Perrigo’s
respective labeling and package inserts. Specifically, Dr. Slocum testified that the
materials used in the Actavis and Perrigo wall structures – and silicone, respectively – are
flexible, and thus, when the devices are pressed against the surface of the axilla with
sufficient force, the pressure combined with the motion cause the wall of each accused
device to double over on itself, when in use, such that the wall meets the limitations of
the asserted claims. To support his opinions regarding the “wall” limitation, Dr. Slocum
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relies heavily on the results of the hands-on testing he performed on the Actavis and
Perrigo applicators. Our review of Dr. Slocum’s testimony including Defendants’ crossexamination explicating the testing he performed, for the reasons detailed below, we find
that, while admissible, Dr. Slocum’s opinions fail to establish the threshold requirement
of direct infringement.
Dr. Slocum testified that he first tested the accused applicators in the Finnegan law
firm office (“Finnegan testing”), wehre he manipulated the applicators with his hands by
“play[ing] with” them and placing them in “different body regions,” while observing the
manner in which they behaved and responded. Slocum 862:18-25. However, Dr.
Slocum did not document any of these manipulations he performed on the applicators,
either by taking notes or with photographs or video, and in fact he testified that he did not
“exactly recall the exact things I did.” Slocum 862:23-24. Dr. Slocum testified that
during the Finnegan law office testing, he may have put water in the applicators and used
the applicators on his forearm and in the crook of his arm, but he did not attempt to use
the applicators in his axilla or to use any liquid in the applicators other than water.
Slocum 863:22-25, 864:5-10, 864:22-25, 865:1-2.
Following the Finnegan law office procedures, Dr. Slocum prepared his January
2016 expert report, setting forth his opinion that both the Actavis and Perrigo applicators
form double-walled structures while in use. This testing is wholly insufficient to show
the manner in which the respective walls of Actavis’s and Perrigo’s applicators behave in
use. As Dr. Slocum himself conceded, his testing did not simulate the manner in which
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patients would actually use the applicators, since he did not follow the labeling
instructions for either applicator when manipulating the devices, nor did he use either
applicator to apply liquid to the axilla. Slocum 863:18-23, 864:1-10, 864:19-865:11,
865:19-866:14, 1172:8-16. For these reasons, Dr. Slocum’s opinion based on his
incomplete and undocumented manipulations of the applicators during the Finnegan law
firm office testing that, when used as directed, the Actavis and Perrigo applicators form a
claimed double-wall structure has only limited, if any, relevance, including for the reason
that his opinion was not based on any use or testing of the applicators according to
Actavis’s or Perrigo’s labeling.
Shortly after reviewing Defendants’ experts’ rebuttal reports, Dr. Slocum
performed a second set of tests on the accused applicators for purposes of preparing his
reply report. These follow-up tests were referred to at trial as the “wet testing.” Dr.
Slocum’s wet testing involved using the Actavis and Perrigo applicators to apply to his
own axilla a homemade liquid of his own devising that he created by combining
cranberry juice and rubbing alcohol. Dr. Slocum testified that he performed the wet
testing at home, alone, in his bathroom shower, and, as with the Finnegan testing, Dr.
Slocum took no contemporaneous notes or otherwise documented the wet testing
protocol or his findings with photographs or video. As a result, at trial, Dr. Slocum could
not remember the specific date on which he performed the wet testing, (Slocum 873:412), the order in which he tested the accused applicators, (id. 874:17-875:9), the precise
number of times he tested each applicator, (id. 884:4-16), or, with any specificity, the
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length of time it required to complete the testing. Id. 875:14-23 (recalling only that his
wet testing took “less than an hour and more than a minute”). Based on his personal
observations of the accused applicators during the wet testing, Dr. Slocum opined that in
order to avoid excessive leakage of the testosterone formulation, patients would “learn”
to push the Actavis and Perrigo applicators against the axilla with sufficient force to
create a seal, which in turn would cause the wall of the device to fold over and thereby
create the infringing double wall. Dr. Slocum’s wet testing protocol and procedures are
riddled with inadequacies. It thus cannot be received as support for his opinion that the
Actavis and Perrigo applicators meet the “wall” limitation of the ‘944 patent.
Dr. Slocum explained that the purpose of his wet testing was to allow him to
“pretend[]” to be a “typical user” in order to observe how the applicators would perform
under such conditions. Slocum 783:5-25, 863:14-17. However, rather than use a placebo
formulation of Actavis’s or Perrigo’s testosterone product to simulate the experience of
an actual user, the liquid Dr. Slocum applied to his axilla during the wet testing was a
homemade mixture of unknown amounts of cranberry juice and rubbing alcohol that he
created from ingredients he found at his home. Slocum 875:24-876:15, 877:13-21. Dr.
Slocum conceded at trial that this mixture had a lower viscosity than a placebo
formulation and was therefore “more sensitive to detecting leakage from the applicator.”
Slocum 878:8-18. This distinction is particularly important here as Dr. Slocum’s opinion
that the Actavis and Perrigo applicators will form the double wall structure in use is
based on his belief that, in order to avoid “excessive leakage,” which he defined as “more
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than a drip now and then,” users will be required to use an amount of force that will
necessarily cause the single wall of the accused applicators to fold over and create the
infringing double wall. Slocum 892:19-893:21. Dr. Slocum’s failure to use placebo
formulations of the ANDA formulations that will be sold with the Actavis and Perrigo
applicators, or, at the very least, a formulation that included a thickening agent to
approximate the same viscosity as those testosterone formulations, renders his opinion
that the force a user of the Actavis and Perrigo applicators would be required to apply to
avoid excessive leakage would necessarily cause the single wall of the respective
applicators to fold over to create a double wall, pure conjecture.
In addition to using a liquid mixture of a completely different type and
composition than that of Actavis’s and Perrigo’s ANDA formulations, Dr. Slocum also
failed to precisely measure the amount of liquid he used in Actavis’s and Perrigo’s
applicators during his wet testing. The labeling accompanying both the Actavis and the
Perrigo applicators instructs patients to use exactly 1.5 mL of liquid (one pump) for
application to the axilla. See, e.g., PTX-218 at 2614-15, 2623; PTX-216 at 16-17;
Slocum 881:17-19. Rather than use a syringe or other precise measuring tool, Dr.
Slocum instead used a common kitchen teaspoon he had stored in his bathroom (which he
testified holds a total of 4 to 5 mL) to measure the liquid he transferred to the accused
applicators during his wet testing. At trial, Dr. Slocum could not testify definitively as to
the amount of liquid he used in the Actavis and Perrigo applicators, alternatively
testifying that he used “a fraction of a teaspoon,” (Slocum 785:7-14), “what looked like a
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reasonable amount,” (id. 785:15-21, 882:13-15), “about a third of a teaspoon,” (id.
879:10-880:6), “a reasonable guesstimate,” (id. 882:13-21), “a few milliliters lower than
the rim” of the teaspoon, (id.), “less than [4 to 5 mL], on the order of the one and a half,”
(id. 882:16-883:2), and “[a] third to a half, probably.” 28 Id. 883:3-5.
Dr. Slocum’s inability to testify definitively regarding the amount of liquid he
used for each application during the wet testing no doubt stemmed in part from his failure
to utilize an accurate measuring device to ensure that he was, in fact, delivering the
correct amount of liquid into the applicator each time. As with the viscosity variable, the
amount of liquid used in the applicator can clearly affect the amount of leakage that is to
be expected. Without knowing the exact amount of liquid used by Dr. Slocum, in his wet
test, it is impossible to know the effect of such imprecision on his observations and
findings. Accordingly, Dr. Slocum’s failure to ensure that he was applying the amount of
liquid indicated in Actavis’s and Perrigo’s labeling completely undermines the reliability
of his opinion that the Actavis and Perrigo applicators infringe the ‘944 patent’s “wall”
limitation when used in accordance with those labeling instructions. Having clearly
failed to follow those instructions himself when performing the wet testing that is the
basis for his opinion, his opinion is not credible.
Dr. Slocum also performed the wet testing in the bathroom (at his home) without
any witnesses, photographs, or video. His conclusion that both the Actavis and Perrigo
28
At his deposition, Dr. Slocum first testified that he used 3 ccs (or 3 mL) per application for his
wet testing. He later testified at his deposition that he used 1.5 ccs (or 1.5 mL) per application.
Slocum 881:20-22; 881:23-882:3; 979:8-981:4.
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applicators formed the double wall during the wet testing is thus based only on his
personal, undocumented observations of himself made while he was in the process of
using the devices. For the parts of the test when he could not observe himself, by looking
at himself in his bathroom mirror as he stood in his shower, approximately five or six feet
away, his testimony is further impeached. Thus, the results of the wet testing by Dr.
Slocum consist solely of his undocumented and unrecorded observations, some of which
were made as he observed his reflection in a mirror some five feet away. Dr. Slocum’s
memory of the order in which he tested Defendants’ accused applicators was also
lacking. Plaintiffs have failed to establish that Dr. Slocum’s observations were accurate
and reliable and complete with regard to the way in which the wall of the respective
applicators behaved during use. Further, his reported results for a particular defendant’s
applicator were unconvincing, given that they were based on his unorthodox testing
procedures and resultant observations of each defendant’s applicator.
In sum, Dr. Slocum’s wet testing does not support his infringement opinion that a
patient using either the Actavis or Perrigo applicator in accordance with the labeling
instructions will press the applicator against his axilla with sufficient force to cause the
single wall to fold over in use because, absent such force, the patient would experience
excessive leakage of the testosterone formula. This opinion emanates from Dr. Slocum’s
use of the accused applicators in accordance with the products’ labeling. However, Dr.
Slocum clearly did not do so, having used a liquid composition without a thickening
agent that he conceded was less viscous than Actavis’s and Perrigo’s ANDA
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formulations and having failed to ensure that only 1.5 mL of liquid was used for each
application as described in the labeling instructions. Both of these steps as part of the wet
testing would make the applicators more susceptible to leakage, thereby impacting the
amount of force that would have been required to prevent leakage under Dr. Slocum’s
theory. Given that Dr. Slocum testified that the amount of force with which the
applicator is pressed against the axilla can affect whether a double wall is formed (which
is confirmed by the fact that Dr. Slocum conceded that in some of his trials the accused
products did not form the claimed double-walled structure), his failure to control for these
variables errodes the credibility of his opinion that the respective walls of the Actavis and
Perrigo applicators would fold over when used in accordance with the labeling
instructions and it is therefore entitled to very little weight. 29
The fact that Dr. Slocum testified that he did not intend his wet testing to be a
scientifically reliable test, but rather intended only to do a “quick play” with the Actavis
29
While these factors alone render his wet testing results unreliable, Dr. Slocum’s infringement
opinion is also based on the premise that the labeling instructions in some way direct patients to
use sufficient force with the applicators to create a seal with the device in order to avoid leakage.
But, Dr. Slocum acknowledged that neither Actavis’s nor Perrigo’s labeling instructions direct
patients in this manner. Rather, the labeling instructions direct patients only to “keep[] the
applicator upright” and to “place [the applicator] up into the axilla and wipe steadily down and
up into the axilla.” E.g., DTX-258. Further, the instructions specifically contemplate at least
some leakage, directing that “[i]f the solution drips or runs, it can be wiped back up with the
applicator cup.” Id. Because Dr. Slocum failed to document his wet testing protocol, there is no
way to determine whether the leakage he contends would occur if insufficient force was used on
the applicators to create the double wall would nonetheless have been within the bounds
contemplated in the labeling instructions. Nor did Dr. Slocum conduct a control with Plaintiffs’
applicator to determine how much leakage a user experiences with Axiron®. Accordingly, even
if Dr. Slocum had documented the amount of leakage experienced with the Actavis and Perrigo
applicators, we would have no way of knowing whether such leakage was excessive in
comparison.
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and Perrigo applicators (Slocum 783:5-25, 786:17-21, 891:9-892:2), does not excuse or
explain away the many procedural inadequacies described above. Dr. Slocum’s failure to
accurately recall many seemingly basic as well as critical details about his testing and
alleged results puts the credibility of his opinions in serious doubt. For these reasons, Dr.
Slocum’s testimony, which comprised the only evidence on which Plaintiffs rely for their
assertion that the Actavis and Perrigo applicators meet the “wall” limitation of the ‘944
patent, is insufficient as proof of that assertion, to wit, that, when in use, the Actavis and
Perrigo applicators have the claimed double wall required by claims 9 and 10.
Contrary to Dr. Slocum’s opinion, Dr. Singh testified that Actavis’s and Perrigo’s
applicators will not form a double wall when used according to their labeling. Dr. Singh
based his non-infringement opinion first on the Actavis and Perrigo labeling, which does
not include any requirement or direction that, in using the respective applicators, a patient
should apply a certain amount of force against the axilla or form a seal against the axilla.
Singh 1018:4-1019:2, 1019:13-19; PTX-218. In support of his conclusion that a patient
using the Actavis or Perrigo applicators in accordance with their labeling will not form a
seal or double wall against the axilla, Dr. Singh relied on video evidence of actual
application of a testosterone solution to a human axilla. Specifically, Dr. Singh analyzed
Lilly’s Axiron® application video (it is undisputed that the instructions for using the
Axiron® applicator are substantively the same as those for the Actavis and Perrigo
applicators), opining that the patient is shown applying the applicator up against a
relatively flat surface of the axilla to start and then wipes up and down, but does not form
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a seal or double wall. In fact, as Dr. Singh testified, the Axiron® video shows that, as the
applicator is swiped down and up, the leading portion of the wall folds inward toward the
receptacle while the trailing wall is not deformed at all. Singh 1020:24-1022:7; DTX1283 at 1:24 to 1:39. Dr. Singh opined that the Actavis and Perrigo applicators would
perform in substantially the same way, to wit, the leading edge of the single wall of the
accused applicators would likewise deform inward and the trailing edge would remain
undeformed, therefore not forming the double wall structure even according to Dr.
Slocum’s theory. Singh 1022:25-1023:16; DDX-407. We found Dr. Singh’s testimony
in this regard, based on the labeling instructions as well as the actual application of a
testosterone formulation to the axilla, to be both credible and supported by a
preponderance of the evidence adduced at trial.
For these reasons, we hold that Plaintiffs have failed to establish that Activas and
Perrigo’s applicators will meet the “wall” limitation of the ‘861 patent. Because
Plaintiffs have failed to establish by a preponderance of the evidence that the Actavis and
Perrigo applicators meet every limitation of claims 9 and 10 of the ‘944 patent, their
effort to prove direct infringement falls short. 30 See Dynacore, 363 F.3d at 1273 (“To
30
At trial, Actavis and Perrigo raised several other arguments in response to Plaintiffs’
infringement claim, including their contention that Plaintiffs previously disclaimed single-wall
devices as a matter of law and that claims 9 and 10 of the ‘861 patent do not encompass singlewall devices that fold over to fold a double wall. Actavis and Perrigo also argued that their
respective applicators failed to meet other limitations of claims 9 and 10, including, inter alia,
the “resiliently deformable” and “substantially transverse” limitations. We need not reach these
disclaimer and disclosure issues related to the wall limitation or Actavis and Perrigo’s arguments
regarding other claim limitations, however, because Plaintiffs have failed to satisfy their burden
to prove by a preponderance of the evidence that Actavis’s and Perrigo’s applicators will fold
over in use to form a double-wall structure when used according to the labeling.
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prove infringement, the patentee must show that the accused device meets each claim
limitation, either literally or under the doctrine of equivalents.”). Plaintiffs’ failure to
prove direct infringement necessarily dooms their indirect infringement claims as well
against Actavis and Perrigo because “[a]bsent direct infringement of the patent claims,
there can be neither contributory infringement nor inducement of infringement.” MetCoil Sys. Corp. v. Korners Unlimited, Inc., 803 F.2d 684, 687 (Fed. Cir. 1986) (internal
citations omitted).
2.
Amneal’s Applicator
Plaintiffs allege that Amneal’s applicator and its use will literally infringe the ‘861
patent. Amneal stipulates that, under the Court’s current claim construction, its
applicator and/or the use thereof meets all elements of claim 10 of the ‘861 patent except
for the “wall” limitation, and meets all elements of claim 9 of the ‘861 patent, except for
the “wall” limitation and the step of claim 9 reciting “deforming the wall.” For the
reasons detailed below, Plaintiffs have established by a preponderance of the evidence
that Amneal’s applicator has the required “double-wall structure” of the asserted claims
and also meets the “deforming the wall” limitation of claim 9 and therefore directly
infringes claims 9 and 10 of the ‘861 patent. See Southwall Techs., Inc. v. Cardinal IG
Co., 54 F.3d 1570, 1575 (Fed. Cir. 1995) (“To establish literal infringement, every
limitation set forth in a claim must be found in an accused product, exactly.”). Plaintiffs
have further shown by a preponderance of the evidence that Amneal’s applicator and its
use will indirectly infringe the asserted claims.
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The key dispute for purposes of Plaintiffs’ infringement claims is whether the
double-wall structure of the applicator claimed in the ‘861 patent requires that the outer
skirt be attached to the support. The wall of Amneal’s applicator consists of a membrane,
folded over, with the first end mounted onto the handle and the second end folded over
and coupled with the moveable skirt. PTX 1091 at 128; PTX 186 at 1646; DTX 2082 at
16-18. The second end and the moveable skirt are not affixed to the handle and can
uniformly deform to move freely relative to the handle in a longitudinally axial direction
without lateral deformation (basically, functioning like a plunger). DDX-148; DTX-2082
at 9, 17. Plaintiffs do not dispute that the second end of the membrane in Amneal’s
applicator is not affixed to the support. Accordingly, if claims 9 and 10 require
attachment, Amneal’s applicator does not meet such a limitation.
As discussed above, the parties have agreed to construe the term “wall” as “part of
the receptacle having an inner portion and outer skirt portion which form a double-wall
structure” and the phrase “double-wall structure” as “a structure having two walls, i.e.,
not the two surfaces of a single wall.” Dkt. 105 at 2. The parties’ agreed definition of
“outer skirt portion” is “one of the two walls of the double-wall structure that is furthest
from the reservoir space.” Id. None of these joint constructions include the requirement
that the outer skirt portion of the double-wall structure be connected to the support.
The parties’ agreed constructions are consistent with the specification of the ‘861
patent, which provides that, while the wall may have a “lower edge of which is attached
to the support means,” that is an example only of a “preferred embodiment.” PTX-5 at
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col. 2, ll. 15-17. The Federal Circuit has “repeatedly warned” that “although the
specification often describes very specific embodiments of the invention,” courts should
not “confin[e] the claims to those embodiments.” Phillips v. AWH Corp., 415 F.3d 1303,
1323 (Fed. Cir. 2005).
Amneal nonetheless argues that the prosecution history of the ‘449 patent, which
the grandparent of the ‘861 patent, establishes that the outer skirt of the wall must be
attached to the support to satisfy the double-wall structure limitation. “Double-wall
structure” is not expressly defined in either the ‘449 patent or the ‘861 patent.
Accordingly, Amneal contends that the limitation must be understood in the context of
the claim amendment. In pursuing the “double-wall structure” amendment, the patentees
argued that Beard discloses only a single-walled device made of a flexible molded
material and does not teach a double-wall structure. The applicants further argued that
Beard “does not teach or suggest an implement having a wall that includes an inner
portion which extends from the base to an upper end and an outer skirt portion, wherein
the inner portion and skirt portion form a double wall structure, as recited in the instant
claims.” PTX-10 at 344.
In support of its conclusion that the patentees’ representations during the claim
amendment process establish that there must be attachment of the outer skirt to the
support to be a double-wall structure, Amneal relies on the fact that each of the sources
cited by the patentees’ in support of the amendment, namely, paragraph 26, the figures,
and original claims 10 and 36, reference or show the outer skirt of the double-wall
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structure being attached to the support of the device. Paragraph 26, for example, states:
“The wall includes an inner portion 7 which extends continuously from the base 5
towards an upper end 8 of the wall 6. A skirt portion 9 of the wall extends continuously
from the upper end 8 of the wall to a lower edge 10 which is attached to the support
means.” PTX-10 at 10. Similarly, Figures 2 and 3, both of which are referenced in
Paragraph 26, as well as the other embodiments pictured in the application, show the
outer skirt attached to the support. PTX 10 at 10, 38-40. Finally, original claims 10 and
36 both depend from original claim 8 and therefore incorporate all the limitations set
forth in claim 8, which requires “the wall includes a skirt portion a lower edge of which is
attached to the support means.” PTX-10 at 2, 5; Slocum 1234:13-25.
However, the patentees never specifically argued during the claim amendment
process that, in order to distinguish Beard, the outer skirt portion of the double-wall
structure had to be attached to the support. Moreover, claim 1 of the ‘449 patent was not
amended to recite that the skirt portion was attached to the support, but rather only to add
the clause “wherein the wall includes an inner portion which extends from the base to an
upper end and an outer skirt portion, wherein the inner portion and skirt portion form a
double-wall structure.” PTX-10 at 335. Therefore, while it is true that the patentees cited
sources during the claim amendment process that would have allowed them to amend
claim 1 to recite that the skirt portion is attached to the support, they did not do so.
This understanding is consistent with the claims of the ‘861 patent. Independent
claim 1 is the broadest claim and does not require the outer skirt portion to be attached to
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the support. PTX-5 at claim 1. Dependent claim 12, however, does include this
requirement, explicitly requiring that the “lower edge of the skirt portion is attached to
the support.” PTX-5 at claim 12. Thus, a person of ordinary skill in the art would not
understand the requirement of claim 12—that the lower edge of the skirt portion be
attached to the support—to be present in broader claim 1 of the ’861 patent (or claims 9
and 10, which both depend from claim 1). See, e.g., Forest Labs., Inc. v. Abbott Labs.,
239 F.3d 1305, 1310 (Fed. Cir. 2001) (“Where claims use different terms, those
differences are presumed to reflect a difference in the scope of the claims.”); Karlin
Tech., Inc. v. Surgical Dynamics, Inc., 177 F.3d 968, 971-72 (Fed. Cir. 1999) (doctrine of
claim differentiation normally means that limitations stated in dependent claims are not to
be read into the independent claim from which they depend).
For these reasons, a POSA would understand in light of the prosecution history
and the specification of the ‘861 patent that there is no additional requirement that the
outer skirt portion of the double-wall structure be connected to the support. Having
determined that the “double-wall structure” disclosed in the ‘861 patent does not require
attachment, we find that Plaintiffs have established by a preponderance of the evidence
that Amneal’s applicator meets this limitation. While Amneal’s expert, Hermann Plank,
testified that Amneal’s applicator has a “single wall design” because it is made of a
“single piece of membrane,” (DTX-2082 at 9), he agreed that there is a portion of the
silicone wall of the Amneal applicator that is closest to the reservoir space and one that is
furthest from the reservoir space. DTX-2083 at 39:19-40:1. This understanding is
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consistent with Dr. Slocum’s testimony that the silicone rubber “diaphragm” of Amneal’s
applicator comprises an inner portion and an outer skirt portion, which satisfies the
parties’ agreed definition of a double-wall structure. PTX-186 at 2072-73; Slocum
843:3-13. Accordingly, we find that the diaphragm of Amneal’s applicator meets the
“wall” limitation of the asserted claims. Because Amneal stipulates that its applicator
meets all other elements of claim 10, Plaintiffs have established by a preponderance of
the evidence that Amneal’s applicator will directly infringe claim 10 of the ‘861 patent.
With regard to the method claim 9 of the ‘861 patent, Amneal stipulates that its
applicator meets all elements of claim 9, except the “wall” limitation, which we have
already addressed, and the step of claim 9 that requires “deforming the wall of the
receptacle containing the liquid composition against the skin of the subject and spreading
the liquid composition over the area of the skin surface of at least one axilla.” PTX-5 at
claim 9. Plaintiffs have established that use of Amneal’s applicator will meet this
limitation. Amneal’s ANDA instructs that the “[t]estosterone topical solution is applied
to the axilla,” and that patients should place the applicator “up into the armpit application
site and wipe steadily down and up.” PTX-186 at 37-38, 55. The evidence adduced at
trial also establishes that the wall of Amneal’s applicator will deform when pressed
against the axilla and then return to its original shape when the force is removed, given
that the wall is made of a flexible silicone rubber material. Slocum 844:15-22. Although
Amneal argues that its wall functions in a different manner than the claimed applicator
and therefore deforms in a different manner (i.e., deformation in the axial direction rather
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than the lateral deformation of the claimed applicator), the claim does not require
deformation of the wall to occur in any particular way and therefore any difference in the
manner of deformation is not dispositive. 31 Accordingly, Plaintiffs have established
direct infringement by a preponderance of the evidence.
Plaintiffs have further established that Amneal is liable for induced infringement
and contributory infringement of claims 9 and 10 of the ‘861 patent. “To prove
inducement of infringement, the patent must show that the accused inducer took an
affirmative act to encourage infringement with the knowledge that the induced acts
constitute patent infringement.” Info-Hold, 783 F.3d at 1372 (Fed. Cir. 2015) (internal
quotation marks and citation omitted). Here, Amneal’s applicator is known by Amneal to
be made or adapted for use in a manner that infringes the asserted claims of the ‘861
patent. The labeling information directly encourages and promotes infringement because
it instructs users to use Amneal’s applicator in a way that will infringe the asserted
claims. For example, Amneal intends for users to apply the prescribed dose of its generic
testosterone solution, which is a physiologically active agent, and for its applicator to be
31
We also note that Amneal represented to the FDA that “it is confirmed that the Amneal
applicators are [the] same as that of the RLD [Reference Listed Drug (Axiron®)] in their
performance and functionality.” PTX-186 at 885. Amneal has represented to the FDA that “the
Amneal applicator was designed, fabricated and manufactured to function in the similar fashion
as the RLD applicator,” and that “[i]t is evident from the pictures that the physical shape and
applicability of Amneal drug product packaging components are very similar to that of the
RLD.” Id. at 476. Amneal told the FDA that “Amneal has chosen these packaging components,
based on their design, reproducibility and performance characteristics for the drug product and
their sameness with respect to the principal operation to the applicator of the Reference Listed
drug (RLD).” Id. at 489.
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used to apply that formula, supplying its applicator with the testosterone solution and
providing instructions on how to apply it using its applicator. PTX-186 at 27, 54-56.
Amneal instructs users to “[r]emove the cap and the applicator cup from the pump.
Then position the nozzle over the applicator cup and depress the pump gently,” thereby
instructing users to apply the liquid composition, including the physiologically active
agent, to the reservoir space as required by the asserted claims. Id. at 54-55. Amneal’s
labeling instructions further direct users to “[t]o apply the testosterone topical solution,
keep the applicator upright, place it up into the armpit application site and wipe steadily
down and up.” Id. at 55. Amneal instructs users that “[i]f testosterone topical solution
drips or runs, wipe it back up with the applicator cup. Do not rub in the solution with
your fingers or hand once it has been applied.” Id. When Amneal’s applicator is used
according to Amneal’s instructions, the wall of the receptacle containing the liquid
composition is deformed against the skin of the subject and the liquid composition is
spread over the skin of the user’s axilla. Id. at 54-55; Slocum 844:15-845:1.
Accordingly, the distribution of Amneal’s label will encourage and cause patients
to use the system claimed in claim 10 of the ‘861 patent and cause the method claimed in
claim 9 of the ‘861 patent to be practiced by patients in the United States. For these
reasons, Amneal is liable for induced infringement of claims 9 and 10 of the ‘861 patent.
“A party is liable for contributory infringement if that party sells, or offers to sell,
a material or apparatus for use in practicing a patented process.” i4i Ltd. Partnership v.
Microsoft Corp., 598 F.3d 831 (Fed. Cir. 2010). The “material or apparatus” must be “a
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material part of the invention, have no substantial noninfringing uses, and be known (by
the party) ‘to be especially made or especially adapted for use in an infringement of such
patent.” Id. (quoting 35 U.S.C. § 271(c)). Here, Amneal intends to market its applicator,
with its associated container and pump dispenser, which, as shown above, infringes the
asserted system claim 10 and which Amneal intends to be used to infringe method claim
9 of the ‘861 patent.
The applicator is clearly a material part of the asserted claims as claim 1, from
which both asserted claims 9 and 10 depend, recites a system comprising three parts: a
container, a dispensing device, and an applicator. PTX-5 at claim 1.
We find that Amneal’s applicator has no substantial noninfringing uses, because:
(1) there is no evidence that Amneal’s applicator will be sold or used for any other
purpose than with Amneal’s generic testosterone product; and (2) there is no evidence
that Amneal’s applicator can be used in a noninfringing manner when applying Amneal’s
generic testosterone product. Id. at 25, 54-56.
Finally, Amneal’s labeling instructs its users that its transdermal testosterone
formula is “[f]or topical use only with enclosed applicator.” PTX-186 at 27. Amneal’s
applicator is especially made to apply its generic testosterone product according to the
instructions provided by Amneal, which for the reasons detailed above, will infringe
claims 9 and 10 of the ‘861 patent. Id. at 27, 54-56. Accordingly, Amneal’s applicator is
especially made or adapted for use in infringement of the ‘861 patent.
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For these reasons, Plaintiffs have successfully established that Amneal is liable for
contributory infringement of claims 9 and 10 of the ‘861 patent.
3.
Lupin’s Applicator
Plaintiffs also contend that Lupin’s applicator will infringe the asserted claims of
the ‘861 patent under the doctrine of equivalents. 32 Infringement under the doctrine of
equivalents requires proof that “a component in the accused subject matter performs
substantially the same function as the claimed limitation in substantially the same way to
achieve substantially the same result.” Ethicon Endo-Surgery, Inc. v. United States
Surgical Corp., 149 F.3d 1309, 1315-1316 (Fed. Cir. 1998) (citing Warner-Jenkinson Co.
v. Hilton Davis Chem. Co., 520 U.S. 17, 39 (1997)). For the reasons detailed below, we
hold that Lupin’s applicator will not infringe claims 9 and 10 of the ‘861 patent under the
doctrine of equivalents, given that Plaintiffs have failed to establish by a preponderance
of the evidence that Lupin’s applicator contains an element equivalent to the “resiliently
deformable wall” recited in claim 10 or that the use of Lupin’s device will include a step
equivalent to the “deforming the wall of the receptacle” step of the method recited in
claim 9 of the ‘861 patent.
Asserted claims 9 and 10 of the ‘861 patent both depend from claim 1, which
requires the applicator to have a “resiliently deformable wall.” PTX-5 at claim 1. Here,
Plaintiffs’ proof is insufficient in establishing by a preponderance of the evidence that a
32
Plaintiffs’ infringement case against Lupin rests solely on a doctrine of equivalents theory as
they presented no evidence of literal infringement at trial.
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component of Lupin’s applicator performs the function of the resiliently deformable wall,
to wit, allowing the wall to maintain a seal with the treatment surface in substantially the
same manner as the claimed device in the ‘861 patent.
It is undisputed that the wall of Lupin’s applicator is made of polypropylene,
which is a hard, rigid plastic. Slocum 833:14-17. Therefore, the wall of Lupin’s
applicator does not itself deform in any way when the applicator is used; rather, the wall
displaces or translates downward relative to the base of the applicator. MacLean 1687:613. This displacement allows the base to stand “proud” of the rigid wall and deposit the
liquid composition into the axilla. Id. at 1686:10-1687:25; DDX-537.
The downward displacement of the wall of Lupin’s applicator is effected by a
spring-driven mechanism where the prongs of the device act as springs, bending inward
as the patient pushes the applicator against the axillary skin. MacLean 1686:10-23,
1687:6-25, 1688:23-1689:23; DDX-537; DDX-539; DDX-540. When the downward
force is removed, the wall returns to its resting position. See MacLean 1686:10-1687:25,
1689:1-7. It is clear, therefore, that the wall of Lupin’s applicator experiences only up
and down displacement, not deformation during use. Dr. Slocum agreed that the wall of
Lupin’s applicator functions by displacing up and down. Slocum 831:21-832:3. Such
movement is not substantially similar to deformation. Dr. MacLean testified that
displacement is the act of a solid component undergoing movement from one spatial
location to another, while deformation is defined by the change in shape of a solid object
when subjected to forces. MacLean 1688:8-20. It is clear, therefore, that the displacing
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behavior of the wall of the Lupin applicator is not equivalent to the deforming behavior
of the wall in the asserted claims.
At trial, Dr. Slocum opined that the deformation of the prongs against the wall of
Lupin’s applicator is equivalent to the “resiliently deformable wall” of the ‘861 patent.
However, Dr. Slocum’s testimony on this issue, to wit, that the deformable prongs would
be equivalent to the resiliently deformable wall “in terms of the function of what
happens, the way it does it using deformations and the result that I can maintain a seal
and then I can wipe stuff up when it leaks, if it leaks,” is too general and conclusory to be
helpful for our analysis. Slocum 833:23-834:4. We find the opinion of Dr. MacLean to
be more credible and supported by the evidence adduced at trial, to wit, that the springdriven mechanism of the Lupin applicator, whereby the user applies force to the rigid
wall downward toward the base, causing the prongs to bend to facilitate the uni-axial
displacement of the wall does not function in substantially the same manner as the
flexible wall claimed in the ‘861 patent, which stretches and changes shape during use in
order to maintain a seal with the skin by moving multi-axially (i.e., both up-and-down
and side-to-side movement). See MacLean 1677:9-1678:2, 1686:10-1687:25, 1688:1020; DDX-531; DDX-537; DDX-538. Accordingly, we conclude that the prongs of the
Lupin applicator are not an equivalent to a “resiliently deformable’ wall, as claimed.
Plaintiffs have also failed to show that Lupin’s applicator meets the “deforming
the wall” limitation of claim 9 of the ‘861 patent. Claim 9 discloses the method of
applying a therapeutic liquid with the applicator of claim 1 and requires that the use of
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the applicator involve “deforming the wall of the receptacle containing the liquid
composition against the skin of the subject and spreading the liquid composition over the
area of the skin surface.” PTX-5 at col. 16, ll. 4-7. For the same reasons explicated
above, the displacing action of the wall of Lupin’s applicator is not equivalent to the
deforming behavior of the wall required in claim 9. Moreover, the substantial difference
in delivery method of the two applicators is evidenced by the fact that, while it is the skin
that deforms the wall of the device claimed in the ‘861 patent, the opposite is true of the
Lupin applicator, where it is the rigid wall of the device that deforms the skin in use.
MacLean 1686:24-1687:5, 1694:13-1695:21; DDX-537. Accordingly, Plaintiffs have
failed to show that Lupin’s applicator infringes the “deforming the wall” limitation of
claim 9 of the ‘861 patent under the doctrine of equivalents.
Given that “there can be no infringement under the doctrine of equivalents if even
one limitation of a claim or its equivalent is not present in the accused device,” (Lockheed
Martin Corp. v. Space Sys./Loral Inc., 324 F.3d 1308, 1321 (Fed. Cir. 2003), Plaintiffs’
have failed to prove that Lupin’s applicator infringes under the doctrine of equivalents.
Plaintiff’s indirect infringement claims against Lupin also necessarily fail because
“[a]bsent direct infringement of the patent claims, there can be neither contributory
infringement nor inducement of infringement.” MetCoil, 803 F.2d at 687.
B.
Invalidity
All Defendants have filed counterclaims seeking declaratory judgments that the
asserted claims of the ‘861 patent are invalid on various grounds, including anticipation,
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obviousness, and indefiniteness. It is well-established that “[a] district court judge faced
with an invalidity counterclaim challenging a patent that it concludes was not infringed
may either hear the claim or dismiss it without prejudice, subject to review only for abuse
of discretion.” Liquid Dynamics Corp. v. Vaughan Co., Inc., 355 F.3d 1361, 1370-71
(Fed. Cir. 2004). Because of the complexity of the invalidity arguments and the necessity
of issuing a timely ruling given exigencies associated with this case, we hold that it
would not be an efficient use of judicial resources to address the invalidity issues raised
by Actavis, Perrigo, and Lupin in light of our holding of non-infringement as to those
Defendants. Accordingly, Actavis’s, Perrigo’s, and Lupin’s counterclaims alleging that
the asserted claims of the ‘861 patent are invalid are hereby dismissed without prejudice.
We therefore address only those invalidity counterclaims raised by Amneal.
Amneal asserts that the ‘861 patent is invalid as anticipated and obvious. We resolve
these claims in turn below.
1.
Anticipation
Amneal contends that the asserted claims of the ‘861 patent are invalid as
anticipated by the Gueret ‘187 patent. As discussed above, “[a] prior art reference
anticipates a patent claim if the reference discloses, either expressly or inherently, all of
the limitations of the claim.” Marrin v. Griffin, 599 F.3d 1290, 1295 (Fed. Cir. 2010).
Because, for the reasons detailed below, Amneal has failed to establish by clear and
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convincing evidence that the Gueret ‘187 patent 33 discloses the claimed wall of the ‘861
patent, we hold that the reference does not anticipate the asserted claims.
The Gueret ‘187 patent discloses “a device for packaging and applying a
substance, for example, a cosmetic or a care product.” PTX-373 at col. 1, ll. 4-6.
Amneal focuses on Figures 11 and 12 of the Gueret ‘187 patent as disclosing the claimed
applicator. Figures 11 and 12 are different perspectives of the same applicator device and
both depict a device made of an open cell foam. The applicator element (200) of the
Gueret ‘187 patent may also include a “central depression 205 and the groove 203” that
“may be suitable for becoming filled with substance P for application purposes.” PTX373 at col. 11, ll. 1-4. The annular rib (204) illustrated in Figures 11 and 12 may be
excluded and the open cell foam may be replaced with an elastomeric material. Id. at col.
10, l. 61-col. 11, l. 4.
33
The PTO considered the Gueret ‘187 patent prior to allowance of the ‘861 patent. The Gueret
‘187 patent and the ‘861 patent both had the same examiner.
201
PTX-373 at 7.
The parties’ have agreed that the term “wall,” as used in the asserted claims of the
‘861 patent, means “part of the receptacle having an inner portion and an outer skirt
portion which form a double-wall structure.” Dkt. 105 at 2. The parties further agree
that “double-wall structure” means “a structure having two walls, i.e., no the two surfaces
of a single wall.” Id. On direct examination, Dr. Singh conceded that “there’s no
disclosure of a double wall in the original language [of the Gueret ‘187 patent].” Singh
1070:11-15. Dr. Singh testified that the Gueret ‘187 patent nevertheless anticipates the
wall limitation of the ‘861 patent because a POSA would know to modify the device
depicted in Figures 11 and 12 in order to create the double-wall structure by, first,
replacing the open cell foam with an elastomeric material; second, removing the annular
rib (204); and finally, molding the elastomeric material to retain the same outside shape
of the applicator, but to be hollow on the inside. Singh 1070:19-1073:20; DDX-454.
Even assuming that the Gueret ‘187 patent specification discloses that the
applicator can be made with an elastomeric material instead of open cell foam and that
the annular rib is optional and therefore removable as Dr. Singh testified, there is no
disclosure of Dr. Singh’s third suggested modification, to wit, the use of a thin sheet of
elastomeric material to form only the outer shape of the applicator and molded to be
hollow. On cross-examination, Dr. Singh conceded that his modified versions of Figure
11 are “nowhere directly shown in the patent,” (Singh 1136:4-9), and Dr. Singh failed to
202
cite any other part of the Gueret ‘187 patent specification that would evidence support for
his third modification, much less an express or inherent disclosure of such.
Moreover, Dr. Singh further admitted on cross-examination that, if the applicator
in Figures 11 and 12 of the Gueret ‘187 patent were modified in the manner he suggests,
then the resulting device would no longer work for its intended purpose. Specifically, Dr.
Singh agreed that his proposed modification of replacing open cell foam with an
impermeable sheet of elastomeric material would mean that the device could no longer
absorb cosmetics as designed. Singh 1137:22-1138:6; PTX-373. The fact that Dr.
Singh’s proposed modification would render the device inoperable for its intended
purpose is further evidence that the proposed modification is not disclosed in the Gueret
‘187 patent.
For these reasons, a POSA would not understand the Gueret ‘187 patent to
disclose a double-wall structure as required under the parties’ agreed definition of the
claimed wall in the asserted claims. Accordingly, Amneal has failed to establish by clear
and convincing evidence that the reference discloses, either expressly or inherently, all
limitations of the asserted claims of the ‘861 patent, and therefore the Gueret ‘187 patent
is not anticipatory.
2.
Obviousness
Amneal also claims that the asserted claims of the ‘861 patent are invalid for
obviousness. According to Amneal, a POSA would be motivated to combine the
teachings of the Gueret ‘986 publication and the Gueret ‘187 patent to create the claimed
203
double-wall structure. Upon careful review of the relevant prior art references, we find
that Amneal has failed to prove by clear and convincing evidence that it would have been
obvious to a POSA to combine the teachings of the prior art to create the claimed doublewall structure of the ‘861 patent, particularly considering that Amneal relies solely on
prior art that was before the patent examiner during prosecution of the ‘861 patent and
thus bears an “especially difficult” burden. Al-Site Corp. v. VSI Int’l, Inc., 174 F.3d
1308, 1323 (Fed. Cir. 1999).
Dr. Singh testified that a POSA would have been motivated to create the doublewall structure claimed in the ‘861 patent because the ‘861 patent “requires a
pharmaceutical type composition to be applied to the axilla,” which is a “sensitive area of
the skin, and therefore … a double-wall structure provides a more soothing application as
opposed to a single-wall sharped-edge kind of applicator.” Singh 1082:1-1083:1. Dr.
Singh further opined that “creating the double-wall design would be obvious because of
the requirement of an increased comfort. This applicator is to be used in the axilla, which
is a sensitive area.” Id. 1093:4-9. However, Dr. Singh failed to identify any teaching or
suggestion within the cited references (which disclose only applying “liquids on the
skin”) that disclosed concerns about comfort or sensitivity such that it would have served
to motivate a POSA to create the double-walled structure.
Moreover, while Dr. Singh testified that the combination of the Gueret ‘986
publication and the Gueret ‘187 patent render the asserted claims obvious, he did not
opine as to how the combination of the Gueret ‘986 publication and the Gueret ‘187
204
patent would lead to the creation of the claimed double-wall structure. Rather, Dr. Singh
testified as to each reference separately, providing testimony regarding how a POSA
could modify the figures in each reference to form a double-wall structure without
reference to each other.
With respect to the Gueret ‘986 publication, Dr. Singh testified only that a POSA
would understand that a flexible single wall could fold over to form double-wall
structures, so it would be obvious to modify a single-wall structure to include a double
wall structure. However, he provided no testimony or explanation as to the manner in
which a POSA would modify Figure 42 in order to do so, or why one would make such a
modification to the device disclosed in Figure 42, considering that it functions as an
applicator for its intended purpose, to wit, to store heat to raise the temperature of a wax,
an oil, or water. The only modification of Figure 42 that Dr. Singh discussed was making
the lip of Figure 42 more transverse to the base: “if you would need a surface that
requires a larger amount of liquid, you would make the walls more transverse.” Singh
1084:2-10 (emphasis added). Most importantly, the only motivation Dr. Singh identified
was based on the language of the ‘861 patent, not on any teaching or suggestion within
the Gueret references.
Dr. Singh also opined that a POSA would modify the applicator shown in Figures
11 and 12 of the Gueret ‘187 patent by removing the annular rib (2014), replacing the
open cell foam with an elastomeric material, and molding a sheet of elastomeric material
to retain the same outer shape of the applicator, but leave the applicator hollow on the
205
inside. Singh 1091:9-1092:19. But Dr. Singh identified no credible reason why a POSA
would have been motivated to do so. Moreover, as discussed above, making such
modifications would render the device inoperable for the purpose disclosed in the Gueret
‘187 patent, and thus, there would have been no suggestion to modify the device in such a
manner. See In re Gordon, 733 F.2d 900, 902 (Fed. Cir. 1984) (finding no suggestion to
modify a prior art device where the modification would render the device inoperable for
its intended purpose).
In short, it is simply a bridge too far to conclude that a POSA would have been
motivated to combine the teachings in the Gueret ‘986 publication and Gueret ‘187 patent
to create the claimed double-wall structure, particularly considering that some of those
modifications would render the disclosed devices inoperable for their intended purposes.
Moreover, the source of motivation cited by Dr. Singh, to wit, to create a more
comfortable applicator for a sensitive area like the axilla was not based on anything
disclosed in either of the Gueret references. Dr. Singh’s testimony failed to establish any
reason a POSA would have been motivated to combine the teachings of the two
references to arrive at the claimed double-wall structure. 34 Neither the Gueret ‘986
reference nor the Gueret ‘187 patent suggests, much less teaches, the claimed wall
As Dr. Slocum testified, the applicators disclosed in the Gueret references are generally
directed to cosmetics applicators. Therefore, even if a POSA were to review these references in
searching for a solution to the issues faced by the inventors of the applicator claims, he or she
would recognize that the cosmetics applicators in these prior art references do not have the
degree of sealing and spreading ability required to apply a volume of liquid onto the axilla,
which is a largely concave surface. Instead, a POSA would focus on modifying the known
mechanisms for applying substances to the axilla, such as those found in, for example, the
deodorant arts. Slocum 582:14-583:1.
34
206
disclosed in the asserted claims of the ‘861 patent. The nonobviousness of the inventions
of the ‘861 patent is further reinforced by the fact that the disclosures of both the Gueret
’986 publication and the Gueret ’187 patent were considered by the PTO during
examination of the ’861 patent. See Sciele Pharma, Inc. v. Lupin Ltd., 684 F.3d 1253,
1260 (Fed. Cir. 2012) (recognizing that there is “a high burden of proof created by the
necessary deference to the PTO”). For these reasons, we hold that Amneal has failed to
establish that the asserted claims of the ‘861 patent are invalid as obvious.
V.
Conclusion
For all of the reasons explicated above, the Court hereby declares that:
(1) Actavis has proved by clear and convincing evidence that claim 13 of the ‘075
patent is invalid for lack of written description and enablement under 35 U.S.C. §
112 and is therefore invalid.
(2) Defendants have proved by clear and convincing evidence that claim 20 of the
‘944 patent is invalid for obviousness under 35 U.S.C. § 103 and is therefore
invalid.
(3) Plaintiffs have failed to prove by a preponderance of the evidence that Actavis’s,
Perrigo’s or Lupin’s applicators will directly or indirectly infringe claims 9 and 10
of the ‘861 patent, either literally (Actavis’s and Perrigo’s applicators) or under
the doctrine of equivalents (Lupin’s applicator).
207
(4) Amneal has failed to prove by clear and convincing evidence that claims 9 and 10
of the ‘861 patent are invalid for anticipation or obviousness. The asserted claims
of the ‘861 patent are therefore valid and enforceable as to it.
(5) Plaintiffs have proved by a preponderance of the evidence that Amneal’s
applicator and/or its use will directly and indirectly infringe claims 9 and 10 of the
‘861 patent.
Accordingly, it is hereby ordered that:
(1) Actavis is found not to have infringed any valid and enforceable patent-in-suit,
and therefore is entitled to proceed to assert its rights based on its ANDA No.
205328 (including its statutory exclusivity rights) and is not otherwise enjoined.
(2) Perrigo is found not to have infringed any valid and enforceable patent-in-suit, and
therefore is entitled to proceed to assert its rights based on its ANDA No. 204255
as soon as statutorily permitted and is not otherwise enjoined.
(3) Lupin is found not to have infringed any valid and enforceable patent-in-suit, and
therefore is entitled to proceed to assert its rights based on its ANDA No. 208061
as soon as statutorily permitted and is not otherwise enjoined.
As to Amneal:
(1) U.S. Patent No. 8,435,944 is invalid and therefore unenforceable against Amneal;
(2) Pursuant to 35 U.S.C. § 271(e)(4)(A), the effective date of any approval of the
testosterone applicator product that is the subject of ANDA No. 206998 SHALL
208
NOT BE a date earlier than the latest date of expiration of Plaintiffs’ U.S. Patent
No. 8,807,861; and
(3) Pursuant to 35 U.S.C. § 238 and 35 U.S.C. § 271(e)(4)(B), Defendant Amneal
Pharmaceuticals, LLC, and its officers, agents, servants, employees, privies, and
others acting for, on behalf of, or in concert with it are PERMANENTLY
ENJOINED from the commercial manufacture, use, offer to sell, or sale within the
United States, or importation into the United States, of the testosterone applicator
product that is the subject of ANDA No. 206998 or any testosterone applicator
product not colorably different therefrom prior to the latest date of expiration of
Plaintiffs’ United States Patent No. 8,807,861. This permanent injunction order is
effective immediately upon the entry of this ruling on this Court’s docket.
By stipulation, the parties proceeded to trial only on certain claims of the patentsin-suit, agreeing that disposition of the representative claims controls the disposition of
the remaining asserted claims. However, with regard to other non-asserted claims of the
patents-in-suit that were not pursued at trial, Plaintiffs have failed to adduce any evidence
in support of patent infringement. Because Plaintiffs presented no evidence at trial on the
following claims, final judgment of noninfringement shall enter in favor of Defendants
on the following claims
(1) Perrigo: claims 11 and 12 of the ‘944 patent; claims 2-8, 12-18 and 20 of the
‘861 patent; claim 5 of the ‘307 patent; claims 2-9, 11-16, 21-22, 24, and 26-35
of the ‘449 patent.
209
(2) Actavis and Amneal: claims 11 and 12 of the ‘944 patent; and claims 2-8 and
12-20 of the ‘861 patent.
(3) Lupin: claims 11 and 12 of the ‘944 patent; and claims 2-8 and 11-20 of the
‘861 patent.
By stipulation, final judgment of noninfringement in favor of Actavis, Amneal,
and Lupin shall issue as to claims 1-23 of the ‘307 patent and claims 1-35 of the ‘449
patent. Dkt. 219; Dkt. 272; Dkt. 284.
IT IS SO ORDERED.
Date: _____________________
8/22/2016
210
Distribution:
Jan M. Carroll
BARNES & THORNBURG LLP
jan.carroll@btlaw.com
Terri L. Bruksch
BARNES & THORNBURG LLP
tbruksch@btlaw.com
Jan M. Carroll
BARNES & THORNBURG LLP (Indianapolis)
jan.carroll@btlaw.com
Oni N. Harton
BARNES & THORNBURG LLP (Indianapolis)
oharton@btlaw.com
Briana Lynn Clark
BINGHAM GREENEBAUM DOLL LLP
bclark@bgdlegal.com
James M. Hinshaw
BINGHAM GREENEBAUM DOLL LLP
jhinshaw@bgdlegal.com
Emily N. Winfield
DUANE MORRIS LLP
ewinfield@duanemorris.com
Vincent L. Capuano
DUANE MORRIS LLP
vcapuano@duanemorris.com
Anthony J. Fitzpatrick
DUANE MORRIS, LLP
ajfitzpatrick@duanemorris.com
Carolyn A. Alenci
DUANE MORRIS, LLP
caalenci@duanemorris.com
211
Christopher S. Kroon
DUANE MORRIS, LLP
cskroon@duanemorris.com
Manisha Arvind Desai
ELI LILLY & COMPANY
madesai@lilly.com
Charles Edmund Lipsey
FINNEGAN HENDERSON FARABOW GARRETT & DUNNER LLP
charles.lipsey@finnegan.com
Jennifer M. Vein
FINNEGAN HENDERSON FARABOW GARRETT & DUNNER LLP
jennifer.vein@finnegan.com
Mareesa A. Frederick
FINNEGAN HENDERSON FARABOW GARRETT & DUNNER LLP
mareesa.frederick@finnegan.com
Alissa Keely Lipton
FINNEGAN HENDERSON FARABOW GARRETT & DUNNER LLP - Boston
alissa.lipton@finnegan.com
L. Scott Burwell
FINNEGAN HENDERSON FARABOW GARRETT & DUNNER, LLP
scott.burwell@finnegan.com
Laura P. Masurovsky
FINNEGAN HENDERSON FARABOW GARRETT & DUNNER, LLP
laura.masurovsky@finnegan.com
Danielle A. Duszczyszyn
FINNEGAN HENDERSON FARABOW GARRETT DUNNER LLP
danielle.duszczyszyn@finnegan.com
Jessica L.A. Marks
FINNEGAN, HENDERSON FARABOW, GARRETT & DUNNER, LLP
jessica.marks@finnegan.com
Sally F. Zweig
KATZ & KORIN P.C.
szweig@katzkorin.com
212
Carolyn A. Blessing
LOCKE LORD LLP
cblessing@lockelord.com
David B. Abramowitz
LOCKE LORD LLP
dabramowitz@lockelord.com
Keith D. Parr
LOCKE LORD LLP
kparr@lockelord.com
Michael J. Gaertner
LOCKE LORD LLP
mgaertner@lockelord.com
Scott B. Feder
LOCKE LORD LLP.
sfeder@lockelord.com
Jonathan D. Mattingly
MATTINGLY BURKE COHEN & BIEDERMAN LLP
Jon.mattingly@mbcblaw.com
Sean P. Burke
MATTINGLY BURKE COHEN & BIEDERMAN LLP
sean.burke@mbcblaw.com
Erin M. Forbes
RAKOCZY MOLINO MAZZOCHI & SIWIK LLP
eforbes@rmmslegal.com
Christine J. Siwik
RAKOCZY MOLINO MAZZOCHI LLP
csiwik@rmmslegal.com
Alice L. Riechers
RAKOCZY MOLINO MAZZOCHI SIWIK LLP
ariechers@rmmslegal.com
Conly Wythers
RAKOCZY MOLINO MAZZOCHI SIWIK LLP
cwythers@rmmslegal.com
213
Gregory Andrew Duff
RAKOCZY MOLINO MAZZOCHI SIWIK LLP
gduff@rmmslegal.com
Lauren M. Lesko
RAKOCZY MOLINO MAZZOCHI SIWIK LLP
llesko@rmmslegal.com
Anuj K. Wadhwa
RAKOCZY MOLINO MAZZOCHI SIWIK, LLP
awadhwa@rmmslegal.com
William A. Rakoczy
RAKOCZY MOLINO MAZZOCHI SIWIK, LLP
wrakoczy@rmmslegal.com
Robert J. Schuckit
SCHUCKIT & ASSOCIATES - Zionsville
rschuckit@schuckitlaw.com
Robert J. Schuckit
SCHUCKIT & ASSOCIATES - Zionsville
rschuckit@schuckitlaw.com
Dan H. Hoang
WINSTON & STRAWN LLP
dhoang@winston.com
Kurt A. Mathas
WINSTON & STRAWN LLP
kmathas@winston.com
Michael Keenan Nutter
WINSTON & STRAWN LLP
mnutter@winston.com
Samantha Maxfield Lerner
WINSTON & STRAWN, LLP
smaxfield@winston.com
214
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