in the united states district court for the eastern … · 2019-12-18 · backing and a membrane,...

IN THE UNITED STATES DISTRICT COURT

FOR THE EASTERN DISTRICT OF TEXAS

MARSHALL DIVISION

PROSTRAKAN, INC., STRAKAN

INTERNATIONAL S.A R.L.,

Plaintiffs,

v.

ACTAVIS LABORATORIES UT, INC.,

Defendant.

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CIVIL ACTION NO. 2:16-CV-00044-RWS

FINDINGS OF FACT AND CONCLUSIONS OF LAW

In this patent infringement action, Plaintiffs ProStrakan, Inc. and Strakan International S.a

r.l. (“ProStrakan”) allege Defendant Actavis Laboratories UT, Inc. (“Actavis”) infringes U.S.

Patent No. 7,608,282 (“the ’282 patent”). The ’282 patent relates to an adhesive patch for the

transdermal administration of granisetron, which is used to prevent nausea and vomiting in patients

receiving chemotherapy.

The Court held a five-day bench trial in this matter in February of 2018. Docket Nos. 127–

137. The parties submitted proposed findings of fact and conclusions of law on March 23, 2018.

Docket Nos. 138 and 139. Pursuant to Federal Rule of Civil Procedure 52(a) and after having

considered the record and applicable law, the Court concludes that (1) ProStrakan has

demonstrated by a preponderance of the evidence that Actavis’s ANDA product infringes the ’282

patent and that (2) Actavis has not proved by clear and convincing evidence that the patent is

invalid or unenforceable. The Court’s findings of fact and conclusions of law are detailed below.

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I. FINDINGS OF FACT

This Section contains the Court’s findings of fact on the issues raised by the parties during

trial.

Plaintiff ProStrakan, Inc. (“ProStrakan”) received U.S. Food & Drug

Administration (“FDA”) approval for its Sancuso® product in September 2008. JTX-059.

Sancuso ® is indicated for use in the prevention of nausea and vomiting in patients receiving

moderately and/or highly emetogenic chemotherapy for up to 5 consecutive days. JTX-059 at 2.

The composition of Sancuso® and its FDA-approved use are covered by

the claims of the ’282 Patent, which is titled “Transdermal Granisetron.” JTX-001 at 1.

Actavis submitted Abbreviated New Drug Application (“ANDA”) No.

208726 requesting FDA-approval for the commercial marketing of its own generic version of

Sancuso® (“ANDA product”). JTX-069.

A. The Parties

ProStrakan is a Delaware corporation with its principal place of business at

135 Route 202/206, Suite 6, Bedminster, New Jersey 07921. After the filing of the Complaint,

ProStrakan amended its Certificate of Incorporation with the State of Delaware Secretary of State

to change the name of the corporation to Kyowa Kirin, Inc. Docket No. 110 at 14.

Strakan International S.á r.l. (“Strakan”) is a company organized under the

Laws of Luxembourg with an office at 6, rue Eugène Ruppert, L-2453 Luxembourg, Luxembourg.

After the filing of the Complaint, Strakan converted from a société à responsabilité limitée into a

société anonyme and subsequently registered a change of name with The Registrar of Companies

for England and Wales to Strakan International S.A. Docket No. 110 at 14.

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ProStrakan is a specialty pharmaceuticals company founded in Scotland in

1995. Trial Tr. Day 1 (2/1/2018 AM) at 80:21-24, Docket No. 128.

The company was acquired by Tokyo-based Kyowa Hakko Kirin in 2011.

Id. 80:25-81:2. ProStrakan, Inc., a New Jersey corporation, is now the United States affiliate of

Kyowa Kirin. See id.; Docket No. 138 ¶ 5.

Strakan International S.á.r.l, a Luxembourg company, is the European

affiliate. Docket No. 138 ¶ 6.

Actavis Laboratories UT, Inc. is a Delaware corporation, having a place of

business at 577 Chipeta Way, Salt Lake City, Utah 81408. Docket No. 110 at 14.

B. Procedural History

In December of 2015, Actavis sent ProStrakan a letter, pursuant to 35

U.S.C. § 355(j)(2)(A)(vii)(IV), alerting ProStrakan to Actavis’s ANDA and explaining Actavis’s

position that the ’282 patent would not be infringed by the generic product. See Compl. ¶¶ 38-40,

Docket No. 1; Ans. ¶ 38, Docket No. 86. This prompted ProStrakan’s lawsuit about a month later,

on January 13, 2016. ProStrakan’s complaint alleges that Actavis’s ANDA submission was an act

of infringement under 35 U.S.C. § 271(e)(2)(A) and that marketing, selling, or importing the

generic product would infringe the ’282 patent under 35 U.S.C. §§ 271(a) and (b). Compl. ¶¶ 43-

60, Docket No. 1.

ProStrakan’s lawsuit prevents the FDA from approving the ANDA until 30

months from when Actavis provided the paragraph IV certification notice, or until a court decides

“that the patent is invalid or not infringed.” 35 U.S.C. § 355(j)(5)(B)(iii)(1).

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C. Background

Scientists began developing transdermal drug delivery systems in the 1980s.

See JTX-020 at 1. The first transdermal product to reach the United States market was Transderm-

Scop™, a transdermal system for delivering scopolamine, a motion sickness drug. Id. More than

25 different transdermal delivery products had been developed by early 1999. Id. at 1-2. These

products deliver drug through the skin and into the bloodstream, avoiding metabolism by the liver

and digestive system. Id. at 1. The products have other advantages, including reduced dose

frequency and the ability to halt drug delivery in the event of an adverse side effect. Id.

Transdermal drug delivery is a science of its own. Transdermal patches

typically include either a reservoir system, in which drug is kept in a pocket between an adhesive

backing and a membrane, or a matrix system, which includes drug in the adhesive matrix itself.

Trial Tr. Day 4 (2/6/2018 AM) at 108:25-109:4, Docket No. 134. In either case, drug must pass

from the transdermal patch through the skin and into the bloodstream.

Human skin has multiple layers, the outermost of which is the stratum

corneum. Trial. Tr. Day 1 (2/1/2018 PM) at 12:1-8, Docket No. 129. The stratum corneum is like

a brick wall—any substance that passes through this layer must go around the relatively

impermeable skin cells and through the mortar, or intracellular lipids. Id. 12:20-13:6. The

outermost layer is designed to keep beneficial substances, such as water, in the body, while keeping

foreign substances out. Id. 12:11-19. Developing a transdermal patch capable of releasing a drug

through the skin and into the blood at a desirable rate and concentration is, therefore, a difficult

task. Id. 12:13-16.

This lawsuit involves a transdermal product for treating chemotherapy-

induced nausea and vomiting (CINV). Chemotherapy causes endothelial cells lining the

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gastrointestinal (GI) tract to release the neurotransmitter serotonin (5-hydroxytryptamine or “5-

HT”) into the stomach and colon. JTX-068 at 6. Once released, serotonin binds to 5-HT receptors,

which prompt nerves to transmit signals from the bowel to the brain. Id. This biochemical

mechanism is responsible for CINV. Id. at 5-6.

CINV is a common side effect of cancer therapy. Id. at 5. Studies have

shown that from 30% to 90% of patients experience CINV following moderately emetogenic

chemotherapy (MEC), and greater than 90% of patients experience CINV following highly

emetogenic chemotherapy (HEC). Id. If left untreated, CINV may cause electrolyte imbalances,

dehydration, tearing of the esophageal mucosa, and other complications, resulting in increased

medical costs and diminishment of a patient’s quality of life. Id. Severe cases of CINV may result

in patients delaying or refusing further chemotherapy. Id.

5-HT3 receptor antagonists are known to be useful for treating and

preventing CINV. See ’282 Patent 1:23-26. As the name implies, 5-HT3 receptor antagonists

interfere with serotonin binding at 5-HT3 receptors, thus decreasing nerve stimulation that would

otherwise trigger the vomiting reflex. See id. at 1:20-27. A number of serotonin antagonists were

developed for treating CINV beginning in the 1980s, first with ondansetron (sold as Zofran™), a

serotonin antagonist approved by the Food and Drug Administration (FDA) for intravenous

administration in 1991 and oral administration in 1997. See Trial Tr. Day 3 (2/5/2018 AM) 95:12-

21, Docket No. 132. Granisetron (first sold as Kytril™) was approved by the FDA for intravenous

administration in 1993 and oral administration in 1995. Id. 95:16-20. Dolasetron (sold as

Anzemet™) was approved for both intravenous and oral administration in 1997. Id. 95:22. These

are just a few examples; by the late 1990s, several serotonin antagonists had been approved for

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intravenous, subcutaneous, and oral administration, including solutions and sublingual tablets. Id.

95:23-96:4.

Traditional routes of administering a serotonin antagonist to treat CINV

have disadvantages. Generally, a patient prescribed an oral tablet may have difficulty complying

with a regular dosage regimen. Trial Tr. Day 2 (2/2/2018 PM) at 12:1-5, Docket No. 131.

Subcutaneous injections are uncomfortable, and in the case of serotonin antagonists, can result in

noticeable deposits of medication directly below the skin. Id. 12:6-18. Chemotherapy can make

matters worse. A patient with a tumor in the head or neck, for example, may be “mechanically

compromised” if cancer tissue interferes with swallowing, or if chemotherapy targeting the head

or neck results in oral mucositis. Trial Tr. Day 1 (2/1/2018 AM) at 91:5-17. Oral mucositis is

particularly debilitating—it can cause large ulcers to form and erupt throughout the mouth and is

extremely painful. Id. 91:12-15.

Given the difficulty with treating CINV through conventional routes of drug

administration, it is not surprising that reports of transdermal products for treating CINV began

appearing in the literature at least by the late 1990s. The Minnesota Mining and Manufacturing

Company (3M) and inventor Jochen Effing, for example, filed a patent application under the Patent

Cooperation Treaty (PCT) in May of 1997 that describes a matrix-type transdermal patch capable

of delivering a therapeutically effective amount of tropisetron or granisetron. See Transdermal

Drug Delivery Device for the Delivery of Tropisetron or Granisetron, Int’l PCT Pub. No. WO

98/53815 (hereinafter, “Effing”) at Abstract (Dec. 3, 1998), Def.’s Ex. 61. Effing discloses a

transdermal patch with from 1 to 25 percent of tropisetron or granisetron in an adhesive matrix

formed from an acrylate copolymer. See id. at Abstract, 5:3-9.

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More generally, it was known by the late 1990s and early 2000s that certain

drugs work better with transdermal patches than others. Wan Suk Lee and co-inventors, for

example, filed a European patent application in June of 2000 that explains why hydrophobic or

basic drugs (i.e., drugs having low affinity to water) perform better in transdermal patches than

hydrophilic or salt drugs (i.e., drugs having high affinity to water). See Transdermal Preparation

Containing Hydrophilic or Salt-Form Drug, EP 1,163,902 (hereinafter, “Lee”) ¶¶ 4-6 (June 16,

2000), JTX-019. It is difficult for hydrophilic drugs to pass through lipid (or hydrophobic) layers

of the skin. See id. ¶ 4. To overcome this problem, more drug may be loaded into the patch, but in

the case of hydrophobic acrylates, the hydrophilic drug may not easily dissolve in the matrix. See

id. ¶ 6.

Granisetron is a serontonin-3 (5-HT3) receptor antagonist that can be used

to prevent nausea and vomiting in patients receiving moderately and/or highly emetogenic

chemotherapy regimens. See JTX-059; JTX-005 at 3; see also, e.g., JTX-001 at 5, 1:11-27; id. at

7, 5:26-47. Actavis’s Accused Product includes 34.3 mg of granisetron that is contained in the

adhesive matrix and is adapted to deliver 3.1 mg of granisetron every 24 hours. See JTX-006 at 3;

JTX-026.

D. The ’282 Patent

1. Development

In the early 2000s, ProStrakan began investigating a transdermal patch for

treating CINV or post-operative nausea and vomiting (PONV). Def’s Ex. 33 at 2-3; Def’s. Ex. 34

at 1-7. ProStrakan initially focused on incorporating two drug candidates, ondansetron and

granisetron, into a proprietary adhesive patch later sold commercially as MatriDerm®. Def’s Ex.

33 at 2; Def’s Ex. 34 at 8. Given the proprietary nature of MatriDerm and projections regarding

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intellectual property protection of ondansetron and granisetron, ProStrakan believed its efforts

could culminate in a patent-protected product that would be commercially successful. See Def’s

Ex. 33 at 10-15; Trial Tr. Day 3 (2/5/2018 PM) at 133:6-17, Docket No. 133.

ProStrakan’s focus narrowed shortly after development began. Early studies

showed that ondansetron and MatriDerm were not compatible. Def’s Ex. 34 at 23. Granisetron, by

contrast, appeared compatible with MatriDerm, though granisetron was not as commercially

successful as ondansetron, and not approved for treating PONV in the United States. Id. at 24.

ProStrakan later abandoned MatriDerm and instead focused on a commercially available adhesive

sold as DuroTak® 387-2287, though the reason for this change is unclear. Trial Tr. Day 4

(2/6/2018 AM) at 43:12-15. ProStrakan’s target therefore became a transdermal DuroTak® patch

loaded with granisetron for treating CINV.

ProStrakan collaborated with Novosis AG to develop and manufacture a

product suitable for clinical trials. Trial Tr. Day 4 (2/6/2018 AM) at 45:13-46:14. Although a

number of scientists from both companies were involved, the project leader for ProStrakan was

Dr. Adam Watkinson. Id. 49:22-50:1. A ProStrakan executive testified that Dr. Watkinson is “an

expert in transdermal drug delivery.” Id. 51:22-25. Dr. Watkinson emphasized that his contribution

to the project was the selection of granisetron as a transdermal drug delivery candidate, based on

granisetron’s known physiochemical and pharmacokinetic properties. Trial Tr. Day 3 (2/5/2018

PM) at 72:10-22. The Novosis team, and Novosis scientist Dr. Peter Altenschöpfer in particular,

was responsible for selecting and testing potential adhesives. Id. 74:21-75:6; Trial Tr. Day 4

(2/6/2018 AM) at 52:11-23.

2. Prosecution History

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Consistent with what was known in the prior art at the time, the application

that preceded the ʼ282 patent (Application No. 10/544259 or “the ’259 application”) describes the

benefits of a non-oral drug delivery system capable of maintaining sufficient levels of antiemetic

drug over time. See JTX-002 at 6. The ’259 application acknowledges that attempts to make

successful transdermal products had been made, but that the majority of published accounts were

unsatisfactory. See id. at 6-7. While publications had disclosed the possibility of administering an

antiemetic drug transdermally, the publications did not include specific examples or data

demonstrating the therapeutic viability of the product. See id. at 7. One publication described a

transdermal granisetron patch, but the patch had to be 100 cm2 to deliver enough drug through the

skin of a hairless mouse, which is ten times easier to permeate than human skin. Id. at 7. The ’259

application therefore describes a need for a reasonably sized granisetron patch capable of

maintaining a therapeutic flux of the drug through the skin over time. See id. at 7-9.

The discovery from ProStrakan’s granisetron project, according to the ’259

application, had to do with the acrylic adhesive used in the patch. Id. at 9. Generally, an adhesive

used for a transdermal patch includes a polymer made from one or more monomers; drug stability,

drug release, and adhesive ability all depend on the chemical and physical composition of the

monomer(s) and resulting polymer. See Trial Tr. Day 2 (2/2/2018 PM) at 74:21-75:2. The ’259

application explains that adhesives made from monomers having electronegative groups, such as

carboxylic acid groups, “cannot be used in the manufacture of effective transdermal patches.” JTX-

002 at 9. Although counterintuitive, adhesives made from monomers with non-acidic hydroxyl

groups, even though these groups are electronegative, do not cause the same problem as monomers

with carboxylic acid groups, and in fact, “substantially enhance flux of granisetron.” See id.

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Experiments using different DuroTak® adhesives, according to the ’259

application, demonstrate the discovery. Example 1 describes tests comparing four different

DuroTak® adhesives, DuroTak® 4098, DuroTak® 2052, DuroTak® 2353, and DuroTak® 2287.

Id. at 41-42. DuroTak® 4098 is an acrylate-vinyl acetate copolymer without carboxylic acid or

hydroxyl functional groups. Id. at 41; J. Trial. Ex. 3 at 1. DuroTak® 2052 and 2353 are acrylate-

vinyl acetate and acrylate polymers, respectively, both with carboxylic acid groups. JTX-002 at

41; JTX-003 at 1. DuroTak® 2287 is an acrylate-vinyl acetate copolymer with non-acidic hydroxyl

groups. JTX-002 at 41; JTX-003 at 1. The ’259 application reports significantly better results with

DuroTak® 2287 (DT 2287), the adhesive with non-acidic hydroxyl groups, as shown in Figure 1

below. JTX-002 at 20, Fig. 1.

The initial claims of the ’259 application were broad, reciting in the first

independent claim, “[a]n adhesive patch suitable for the transdermal administration of granisetron,

wherein the adhesive is an acrylic adhesive containing non-acidic hydroxyl moieties.” Id. at 50.

This claim was later amended to recite “[a]n adhesive patch suitable for the transdermal

administration of granisetron, wherein the adhesive is an acrylic adhesive containing non-acidic

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hydroxyl moieties, a physiologically effective amount of granisetron being loaded in the

adhesive.” Id. at 507.

ProStrakan’s claims were rejected by the examiner as being anticipated by

or obvious in view of Effing. Effing describes a transdermal adhesive containing a therapeutically

effective amount of tropisetron or granisetron prepared from a copolymer of an alkyl acrylate

monomer and another hydrophilic monomer. Effing at Abstract, Def’s Ex. 61. The hydrophilic

monomer can be 2-hydroxyethylacrylate, which has a non-acidic hydroxyl moiety. See id. at 3.

The examiner therefore concluded that Effing anticipated the claims. See JTX-002 at 501.

ProStrakan argued that Effing taught away from using monomers with

hydroxyl groups. See id. at 511. As the ’259 application explains, Effing teaches away from

“adhesives containing nucleophilic, such as hydroxyl moieties” because “it is demonstrated that

tropisetron is unstable in their presence.” JTX-002 at 9. According to the ’259 application, the

authors of Effing “speculate that this instability may be caused by increased cross-linking within

the adhesive that may also involve binding of the drug to the polymer.” Id. ProStrakan pointed out

that Example 7 of Effing, which used the 2-hydroxyethylacrylate monomer, showed a 10% drop

in drug content within four weeks of storage. JTX-002 at 511. This result was inferior to results

obtained with polymers that did not have hydroxyl groups. See id. at 511-12.

The examiner was not persuaded. According to the examiner, it did not

matter that Example 7 of Effing showed inferior results because “a reference may be relied upon

for all that it would have reasonably suggested to one having ordinary skill in the art, including

nonpreferred embodiments.” Id. at 531 (citing Merck & Co. v. Biocraft Labs., 874 F.2d 804 (Fed.

Cir. 1989)). Effing did not teach away from using monomers with hydroxyl moieties, the examiner

reasoned, because Effing includes 2-hydroxyethylacrylate in the list of possible hydrophilic co-

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monomers. Id. at 530. In other words, Effing disclosed all the elements of ProStrakan’s claims.

See id. at 531.

ProStrakan eventually amended claim 1 as follows:

1. An adhesive patch suitable for the transdermal administration of granisetron

to a subject in need thereof, wherein the adhesive is said patch comprising:

an acrylic adhesive comprising:

50 to 98% w/w of a primary acrylate monomer, and

0.5 to 20% w/w of a monomer containing non-acidic hydroxyl moieties, and

a physiologically effective amount of granisetron [[being]] loaded in the adhesive,

wherein the granisetron content of said patch remains substantially unchanged

when stored at 25°C for at least six weeks.

Id. at 588. It appears that ProStrakan made this amendment to align the scope of the claims with

the results achieved with DuroTak® 2287. See id. at 584.

Along with the claim amendment, ProStrakan submitted evidence of the

composition of DuroTak® 2287: 68.2% 2-ethylhexylacrylate, 26.5% vinyl acetate, 5.2% 2-

hydroxyethylacrylate, and 0.15% glycidylmethacrylate. Id. at 572. DuroTak® 2287 therefore has

68.2% of a “primary acrylate monomer,” or 2-ethylhexylacrylate, and 5.2% of a “monomer

containing non-acidic hydroxyl moieties,” or 2-hydroxyethylacrylate. See id. at 588. The newly

claimed adhesive, according to ProStrakan, was not taught or suggested by Effing. See id. at 584.

The examiner agreed that “Effing does not expressly teach the claimed

transdermal patch with specific amounts of monomers.” Id. at 602. The examiner nevertheless

responded with a new obviousness rejection based on Effing and two other references, U.S. Patent

No. 5,656,286 (“Miranda”) and U.S. Patent No. 3,269,994 (“Horn”). Id. at 602.

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According to the examiner, Miranda and Horn collectively taught the

specific amounts of the primary acrylate monomer and the monomer with non-acidic hydroxyl

groups. Id. at 603. These references, combined with Effing, would have therefore suggested the

claimed adhesive. Id.

The examiner maintained these rejections until issuing a notice of allowance

in June of 2009. Id. at 648. The notice of allowance followed an examiner interview in which the

examiner suggested that the claims be amended to recite an adhesive “consisting essentially of”

specific claimed ingredients, rather than an adhesive “comprising” the ingredients. See id. at 652.

This amendment, according to the examiner, precluded “all other monomers and/or polymers in

the acrylic adhesive layer taught in the cited prior art.” Id. at 654. The examiner’s reason for

allowance referred to the phrase “consisting of,” however. Id. This prompted ProStrakan to submit

a comment clarifying that “[t]he use of the transitional phrase ‘consisting essentially of’ precludes

all other monomers and/or polymers in the acrylic adhesive layer taught in the cited prior art, to

the extent any such monomer or polymer would materially effect [sic] the basic and novel

characteristics of the claimed adhesive layer.” Id. at 686-87.

The ’282 patent issued on October 27, 2009. See ’282 Patent at Title Page.

The patent includes 28 claims, all of which depend from or refer to claim 1.

The ’282 patent received 352 days of patent term extension, due to the more

than three-year delay in issuing the patent. See JTX-002 at 710. The ’282 patent is therefore

scheduled to expire on January 22, 2025.

3. The Asserted Claims

The ’282 Patent, entitled “Transdermal Granisetron,” was filed in the

United States as a 35 U.S.C. § 371 national stage entry of International Application No.

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PCT/GB2004/000403, filed on February 5, 2004. JTX-001 at 1; see Docket No. 110 at 7-8, 14-15.

This PCT Application (PCT/GB2004/000403) claimed priority to Great Britain Application No.

GB 0302662.2, filed on February 5, 2003. JTX-001 at 1; see Docket No. 110 at 7-8, 14-15. The

’282 Patent was granted on October 27, 2009. JTX-001 at 1; see Docket No. 110 at 8, 14.

Plaintiffs have asserted claims 1, 2, 4, 5, 7, 10, 11, 21-23, 26, and 28 of the

’282 Patent against Actavis. Claims 2, 4, 5, 7, 10, 11, 21-23, 26, and 28 depend directly or

indirectly from claim 1.

Claim 1 of the ’282 Patent reads as follows:

1. An adhesive patch suitable for the transdermal administration of granisetron

to a subject in need thereof, said patch comprising:

an acrylic adhesive consisting essentially of:

50 to 98% w/w of a primary acrylate monomer wherein said primary

acrylate monomer is either 2-ethylhexyl acrylate or butyl acrylate, and

0.5 to 20% w/w of a monomer containing non-acidic hydroxyl moieties, and

a physiologically effective amount of granisetron loaded in the acrylic adhesive,

wherein the granisetron content of said patch remains substantially unchanged

when stored at 25° C. for six weeks.

JTX-001 at 10, 12:52-65.


2. A patch according to claim 1, wherein the monomer containing non-acidic

hydroxyl moieties is selected from the group consisting of hydroxymethyl

acrylates, hydroxyethyl acrylates and hydroxypropyl acrylates.

Id. at 10-11, 12: 66–13:2.


4. A patch according to claim 1, which is pressure sensitive.

Id. at 11, 13:7.

Claim 5 the ’282 Patent reads as follows:

5. A patch according to claim 1, containing 50 to 90% w/w of said primary

acrylate monomer.

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Id. at 11, 13:8-9.


7. A patch according to claim 1, having up to about 10% by weight of

granisetron.

Id. at 11, 13:13-14.


10. A patch according to claim 7, having a level of between 6% and 7.7% w/w

of granisetron.

Id. at 11, 13:19-20.


11. A patch according to claim 1, wherein no crystallisation is

observed after one month storage at room temperature and pressure.

Id. at 11, 13:21-23.


21. A patch according to claim 19, wherein the acrylic adhesive

is loaded with between 5 and 8% w/w granisetron.

Id. at 11, 14:11-12.


22. A patch according to claim 1, incorporating no plasticizers

or permeation enhancers.

Id. at 11, 14:13-14.


23. A patch according to claim 1, wherein, at an acrylic adhesive

loading of 6% w/w of active granisetron, the acrylic adhesive has a

surface area of between 10 and 100 cm2.

Id. at 11, 14:15-17.

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26. A method for the treatment and/or prophylaxis of chemotherapy induced

nausea and vomiting in a patient in need thereof, said method comprising

applying an adhesive patch is according to claim 1 to the skin of the patient.

Id. at 11, 14:25-28.


28. A patch according to claim 1, wherein the granisetron

content of said patch remains substantially unchanged when stored

at 40° C. for six weeks.

Id. at 11, 14:31-33.

4. Claim Construction

During the Markman proceedings in this case, the Court was asked to

construe certain claim terms in the ’282 Patent. The Court construed the below disputed claim

terms in the Claim Construction Memorandum Opinion and Order dated July 15, 2017 (Docket

No. 62):

Claim Term Court’s Construction

“consisting essentially of” (claim 1) “including the listed ingredient and open to

unlisted ingredients that do not materially

affect the basic and novel properties of the

invention, the basic and novel properties of

the invention being 1) increased

transdermal delivery of granisetron, 2)

granisetron stability in the patch, and 3) the

complete release of granisetron from the

patch.” (Docket No. 62 at 7)

“physiologically effective amount of

granisetron” (claim 1)

“an amount effective to prevent and/or treat

nausea and vomiting in a subject.” (Id. at

20)

“incorporating no plasticizers or

permeation enhancers” (claim 22)

“[a patch] that does not contain plasticizers

or permeation enhancers.” (Id. at 24)

E. SANCUSO®

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On June 29, 2007, while the application for the ’282 patent was pending,

ProStrakan filed a new drug application (NDA) for FDA approval to market and sell Sancuso®.

Pl.’s Ex. 94 at 3; see also Docket No. 139 ¶ 287.

The Sancuso® label describes the product as a 52-cm2 patch containing 34.3

mg of granisetron, 3.1 mg of which releases every 24 hours for up to seven days. JTX-059 at 2.

The adhesive matrix is DuroTak® 2287. JTX-055 at 3-4. In September of 2008, the FDA approved

Sancuso® for treating nausea and vomiting in patients receiving moderately or highly emetogenic

chemotherapy for up to five consecutive days. JTX-059 at 2; see also Docket No. 139 ¶ 1.

ProStrakan listed the ’282 patent in the Orange Book as covering Sancuso®.

See, e.g., Trial Tr. Day 5 (2/7/2018 AM) at 81:15-18, Docket No. 136.

Sancuso®

is the first and only adhesive patch marketed and sold in the United

States pursuant to the FDA’s approval in September 2008 of NDA No. 022198 for use in the

prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic

chemotherapy for up to five consecutive days. See JTX-059 at 1-2; Trial Tr. Day 1 (2/1/2018 AM)

at 86:5–87:20 (Paolillo); Trial Tr. Day 1 (2/1/2018 PM) at 25:11–26:2, 29:18–30:8 (Enscore); Trial

Tr. Day 2 (2/2/2018 PM) at 10:4–11:17, 13:2-8, 24:6-23, 38:16-17 (Walther); Trial Tr. Day 5

(2/7/2018 AM) at 70:14-17 (Enscore); Trial Tr. Day 5 (2/7/2018 AM) at 145:15-18 (Michniak-

Kohn).

Once Sancuso® received regulatory approval, ProStrakan began marketing

the product, initially without much success. Sancuso® was first marketed broadly for any patient

receiving moderately or highly emetogenic chemotherapy. Trial Tr. Day 1 (2/1/2018 AM) at 88:1-

9. In 2013, ProStrakan commissioned market research demonstrating that the “value proposition

of the product is in the patch.” Id. 88:8-9. ProStrakan then altered its approach to focus on the

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patch and patients who needed the patch most, such as patients who had difficulty in swallowing.

Id. 88:18-23. The new marketing strategy led to Sancuso®’s first profitable year in 2014. Id. 89:17-

22. The product has been profitable every year since. Id. 89:21-22. In recent years, Sancuso® has

yielded about $20-$25 million in net sales, which is about 60% of gross sales. Id. 120:4-6; JTX-

011 at 11.

The Sancuso®

patch consists of a rectangular 52 cm2

pressure sensitive

acrylic adhesive matrix (537.7 mg of Duro-Tak®

387-2287) that contains 6% (w/w) granisetron

base (34.3 mg/patch or 660 μg/cm2

) that is coated on to a printed polyethylene terephthalate (PET)

backing (Hostaphan MN 15 DMF, 52 cm2

). JTX-059 at 2; JTX-055 at 3-4; PTX-094 at 3, 16-21,

29-32, 34-40; see Trial Tr. Day 1 (2/1/2018 PM) at 26:3-19, 27:5–27:14 (Enscore); Trial Tr. Day

2 (2/2/2018 PM) at 26:11-13 (Walther). Sancuso®

is manufactured using the solvents N,N-

dimethylacetamide and ethyl acetate, both of which are removed during manufacturing and not

present in any substantial amounts in the finished product. See PTX-094 at 3, 16-21, 29-32, 34-40.

A release liner (a sheet of FL2000 PET 100 um 1S) is applied to the face of

the active pressure sensitive adhesive matrix during manufacturing and removed prior to use. PTX-

094 at 3, 20-21, 31-32; see Trial Tr. Day 1 (2/1/2018 PM) at 26:3-15 (Enscore).

Clinical testing of Sancuso®

has shown that it delivers granisetron through

the skin at a rate of 3.1 mg per 24 hours for up to seven days. See JTX-059 at 2; Trial Tr. Day 1

(2/1/2018 PM) at 27:5–14, 29:18–30:12 (Enscore).

The parties dispute whether the patent claims cover Sancuso.

F. Prostrakan’s ANDA No. 2087260 and ANDA Product

In early 2014, Actavis began investigating a generic product that could

compete with Sancuso®. See Trial Tr. Day 2 (2/2/2018 PM) at 56:11-15, Docket No. 130; JTX-

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05 at 123. After deformulating Sancuso®, Actavis tested several formulations, including

formulations with different DuroTak® adhesives, but ultimately arrived at a product that is

essentially identical to Sancuso®. Id. 65:12-97:1; JTX-05 at 1, 5-7. The proposed Actavis product

includes a DuroTak® 2287 adhesive in a 52-cm2 patch containing 34.4 mg of granisetron, 3.1 mg

of which is released every 24 hours for up to seven days. Trial Tr. Day 2 (2/2/2018 PM) at 92:3-

25, 94:8-18; JTX-025 at 3. Actavis applied for FDA-approval of this generic product by submitting

an ANDA in late 2015. See JTX-069 at 1; Trial Tr. Day 2 (2/2/2018 PM) at 56:13-15.

Granisetron is the active ingredient of Actavis’s Accused Product. See, e.g.,

JTX-006 at 4. Actavis’s Accused Product contains the free base of granisetron, which is

hydrophobic and therefore insoluble in water. See JTX-059 at 7; Trial Tr. Day 5 (2/7/2018 AM) at

13:20-23; see also Trial Tr. Day 4 (2/6/2018 PM) at 64:18–65:3 (Michniak-Kohn).

G. Facts relating to infringement of the patent:

1. A Person of Skill in the Art

As an initial matter, the Court must identify the level of skill in the art.

As Dr. Michniak-Kohn testified, a Person of Ordinary Skill in the Art

(POSA) would be a person with education and/or experience in the field of pharmaceutics and/or

experience or knowledge of formulations of patches. Trial Tr. Day 4 (2/6/18 PM) at 8:17–19. The

education and experience levels of a POSA may vary, with some persons holding basic degrees

and many years of experience formulating products and some persons holding more advanced

degrees, e.g. Pharm. D., Ph.D. or M.D., but having fewer years of experience. Trial Tr. Day 4

(2/6/2018 PM) at 8:17–23. The POSA may be one or more persons and may include a combination

of persons with experience in varying fields, for example the combined experience of formulation

development and the treatment of disease states/symptoms. Id. at 8:24–9:6.

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This definition is not substantively different from that which was offered by

Plaintiffs’ expert, Dr. Enscore, and Dr. Tan and Dr. Michniak-Kohn each agreed that regardless of

the definition of a POSA adopted by the Court, their respective opinions would not change. Trial

Tr. Day 5 (2/7/2018 AM) at 6:4–10; Trial Tr. Day 2 (2/2/2018 PM) at 65:23–66:3; Trial Tr. Day

4 (2/6/2018 PM) at 9:14–17.

2. Infringement

a) The ANDA Product

Actavis’s Accused Product (like Sancuso®) is an adhesive patch designed

for the transdermal administration of granisetron to prevent nausea and vomiting in patients

receiving moderately and/or highly emetogenic chemotherapy regimens. See PTX-017 at 2, 4;

JTX-059 at 2; JTX-026 at 2; Trial Tr. Day 2 (2/2/2018 AM) at 104:15-110:15 (Petrie); Trial Tr.

Day 2 (2/2/2018 PM) at 13:2-8, 28:6-15, 29:11-15 (Walther); see also Trial Tr. Day 1 (2/1/2018

PM) at 29:18-30:8 (Enscore). As such, Actavis’s Accused Product is “an adhesive patch suitable

for the transdermal administration of granisetron to a subject in need thereof,” as required by claim

1 of the ’282 Patent. See JTX-006 at 3; JTX-026; PTX-014; PTX-017; Trial Tr. Day 1 (2/1/2018

PM) at 52:18-53:7, 62:2-10 (Enscore); see also Trial Tr. Day 1 (2/1/2018 PM) at 30:9-12

(Enscore).

Actavis’s Accused Product includes the same components as Sancuso®—

namely, 34.3 mg of granisetron contained in the Duro-Tak® 387-2287 acrylic adhesive. JTX-006

at 4-7; JTX-025; PTX-102; PTX-106; see Trial Tr. Day 1 (2/1/2018 PM) at 52:22-53:7, 60:2-4,

63:21-64:8 (Enscore); see also PTX-020 at 4; Trial Tr. Day 2 (2/2/2018 AM) at 63:25-64:18

(Rifaat). As discussed above, the Duro-Tak® 387-2287, used in Actavis’s Accused Product, is a

random copolymer of 2-ethylhexyl acrylate (68.2%), vinyl acetate (26.5%), 2-

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hydroxyethylacrylate (5.2%) and glycidyl methacrylate (0.15%), (JTX-002 at 572; see JTX-055 at

3-4; DTX0181 at 2, and contains no added crosslinking agent. See JTX-002 at 571; JTX-004 at 2;

DTX0181 at 1; Trial Tr. Day 1 (2/1/2018 PM) at 50:14-25 (Enscore).

The 2-ethylhexyl acrylate (68.2%) present in the Duro-Tak® 387-2287 of

Actavis’s Accused Product satisfies the feature of claim 1 that requires “50 to 98% w/w of a

primary acrylate monomer wherein said primary acrylate monomer is either 2-ethylhexyl acrylate

or butyl acrylate.” See JTX-002 at 572; JTX-006; Trial Tr. Day 1 (2/1/2018 PM) at 63:21-64:8

(Enscore); see also Trial Tr. Day 1 (2/1/2018 PM) at 31:24–32:8 (Enscore).

The 2-hydroxyethyl acrylate present in Duro-Tak® 387-2287 is an acrylic

monomer containing non-acidic hydroxyl moieties. See Trial Tr. Day 1 (2/1/2018 PM) at 32:9-14,

64:9-15 (Enscore). The 2-hydroxyethyl acrylate (5.2%) present in Duro-Tak® 387-2287 that is

used to prepare Actavis’s Accused Product satisfies the feature of claim 1 that requires “0.5 to

20% w/w of a monomer containing non-acidic hydroxyl moieties.” See JTX-006 at 4; JTX-002 at

572; DTX0181 at 2; Trial Tr. Day 1 (2/1/2018 PM) at 64:9-17 (Enscore); see also JTX-055 at 3-

4; Trial Tr. Day 1 (2/1/2018 PM) at 32:9-15 (Enscore).

The Duro-Tak® 387-2287 acrylic adhesive used in Actavis’s Accused

Product also includes vinyl acetate (26.5%) and glycidyl methacrylate (0.15%). JTX-002 at 572;

JTX-055 at 3–4; DTX0181 at 2. Actavis’s Accused Product is also prepared from a mixture of

ethyl acetate and ethanol, but these solvents are largely, if not completely, removed from the final

patch Accused Product. See JTX-006 at 11, 49–50; Trial Tr. Day 1 (2/1/2018 PM) at 70:2–16

(Enscore). Finally, a release liner and backing film are also present in the final Accused Product.

See JTX-006 at 3–4; Trial Tr. Day 1 (2/1/2018 PM) at 53:11–25, 70:2–20 (Enscore). None of these

additional ingredients (monomers or solvents) present in the acrylic adhesive (or additional

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excipients used in Actavis’s Accused Product as a whole) materially affects its basic and novel

properties—i.e., increased transdermal delivery of granisetron, granisetron stability in the patch,

and the complete release of granisetron from the patch. See infra § (I)(G)(2)(d). Therefore, the

Duro–Tak® 387-2287 present in Actavis’s Accused Product satisfies the feature of claim 1 that

requires “an acrylic adhesive consisting essentially of: 50 to 98% w/w of a primary acrylate

monomer wherein said primary acrylate monomer is either 2-ethylhexyl acrylate or butyl acrylate;

and 0.5 to 20% w/w of a monomer containing non-acidic hydroxyl moieties.”

As to the feature “a physiologically effective amount of granisetron loaded

in the acrylic adhesive” recited in claim 1, the term “physiologically effective amount of

granisetron” has been construed by the Court to have its plain and ordinary meaning, which is “an

amount effective to prevent and/or treat nausea and vomiting in a subject.” See Docket No. 62 at

20. Actavis’s Accused Product contains 34.3 mg of granisetron in the acrylic adhesive, which is

delivered at a rate of 3.1 mg of granisetron per 24 hours. See JTX-006 at 3; JTX-025 at 3–5, 15–

17; PTX-014; PTX-017; JTX-061 at 3–4, 20–21; JTX-005 at 22; JTX-026; Trial Tr. Day 1

(2/1/2018 PM) at 52:18–53:7, 62:2–10 (Enscore); Trial Tr. Day 2 (2/2/2018 PM) at 27:18– 28:5

(Walther); JTX-059 at 2; JTX-055 at 3; Trial Tr. Day 1 (2/1/2018 PM) at 30:14–31:11 (Enscore).

Plaintiffs’ expert, Ms. Walther, testified that in her thirteen-year clinical experience treating

thousands of patients dealing with CINV, this amount of granisetron administered through the skin

is sufficient to prevent and/or treat nausea and vomiting in a subject for up to five days. See Trial

Tr. Day 2 (2/2/2018 PM) at 15:22–16:1, 21:8– 22:21, 25:15– 30:1, 34:3– 35:6 (Walther); see also

JTX-026 at 10; JTX-059 at 12; PTX-180 at 12. Ms. Walther also spoke to the phase III clinical

study in Actavis’s proposed Prescribing Information, which demonstrated that Sancuso® delivered

long-acting CINV-control for a full five days. See JTX-026 at 10; JTX-059 at 12; PTX-180 at 12;

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Trial Tr. Day 2 (2/2/2018 PM) at 21:8– 22:21 (Walther). Thus, Actavis’s ANDA Product includes

a physiologically effective amount of granisetron loaded in the acrylic adhesive. See Trial Tr. Day

1 (2/1/2018 PM) at 62:11–22 (Enscore); see also Trial Tr. Day 1 (2/1/2018 PM) at 30:14 –31:11

(Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 104:15–110:15 (Petrie); Trial Tr. Day 2 (2/2/2018

PM) at 25:15–28:22, 34:3–35:6 (Walther).

According to Actavis’s ANDA, “[t]he only true excipient [present in

Actavis’s Accused Product] is the adhesive, and the compatibility between the adhesive and the

drug substance is therefore demonstrated unambiguously through the routine stability

evaluations.” JTX-025 at 9. Thus, the granisetron present in Actavis’s Accused Product is

incorporated into the Duro-Tak® 387-2287 by mixing the adhesive and active to form a “casting

solution,” which is then coated onto the polyester/EVA backing layer to prepare a cast laminate

film from which solvents are removed by heating. See id. at 5–31. The result is a drug/adhesive

matrix of granisetron and acrylic adhesive solution consisting of 6% granisetron and 94% Duro-

Tak® 387-2287, where the granisetron is contained in the adhesive. See id. at 3; JTX-005 at 22;

Trial Tr. Day 1 (2/1/2018 PM) at 62:23–63:6 (Enscore). For these reasons, Actavis’s Accused

Product satisfies the feature “a physiologically effective amount of granisetron loaded in the

acrylic adhesive” recited in claim 1. See Trial Tr. Day 1 (2/1/2018 PM) at 62:11–63:6 (Enscore);

see also Trial Tr. Day 1 (2/1/2018 PM) at 30:14–31:11 (Enscore); Trial Tr. Day 2 (2/2/2018 PM)

at 25:15–28:22, 32:17–33:4 (Walther).

The proposed Prescribing Information for Actavis’s Accused Product

recommends storage of Actavis’s Accused Product at 20 °C to 25 °C. JTX-026 at 10; see JTX-025

at 3–5, 15–17; JTX-005 at 17; PTX-014; PTX-017; JTX-061 at 3–4, 20–21; see also PTX-094 at

63. Stability tests also show that the granisetron in Actavis’s Accused Product is stable after 26

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weeks at room temperature (25 ºC). See JTX-005 at 17; JTX-006 at 8–9, 70; Trial Tr. Day 1

(2/1/2018 PM) at 63:7–19 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 91:19–93:5, 93:16–97:1

(Rifaat); Trial Tr. Day 2 (2/2/2018 AM) at 98:21–103:6 (Anderson). Through six months of

storage at 25 °C/60% RH, the granisetron content of Actavis’s Accused Product remains stable

and “substantially unchanged,” which meets the claimed minimum time of six weeks. JTX-025 at

8–9. Thus, Actavis’s Accused Product satisfies the claim element “wherein the granisetron content

of said patch remains substantially unchanged when stored at 25° C. for six weeks” recited in claim

1. See JTX-005 at 17; JTX-006 at 8–9, 70; Trial Tr. Day 1 (2/1/2018 PM) at 63:7–19 (Enscore);

Trial Tr. Day 2 (2/2/2018 AM) at 91:19–93:5, 93:16–97:1 (Rifaat); Trial Tr. Day 2 (2/2/2018 AM)

at 98:21–103:6 (Anderson); see also PTX-094 at 63; Trial Tr. Day 1 (2/1/2018 PM) at 31:12–23

(Enscore).

Actavis’s Accused Product is a matrix-type transdermal system consisting

of three consecutive layers: (1) a translucent backing layer composed of polyester/EVA laminate;

(2) a drug/adhesive matrix of granisetron and acrylic adhesive; and (3) a release liner which

protects the drug reservoir layer during storage and is removed immediately prior to application.

JTX-006 at 3; see Trial Tr. Day 1 (2/1/2018 PM) at 53:11–25, 70:2–16, 77:21–78:7 (Enscore).

Actavis’s Accused Product has a rectangular shape with rounded corners

and has a surface area of 52 cm2. JTX-006 at 3; see Trial Tr. Day 1 (2/1/2018 PM) at 52:18–53:7,

62:2–10 (Enscore). Actavis’s Accused Product includes 34.3 mg of granisetron per patch (or 660

μg/cm2) and provides a nominal dose of 3.1 mg/24 hours. JTX-006 at 3; JTX-026 at 2; PTX-014

at 2, 4; see Trial Tr. Day 1 (2/1/2018 PM) at 52:18–53:7, 62:2–10 (Enscore); Trial Tr. Day 2

(2/2/2018 PM) at 27:18–28:5 (Walther); Trial Tr. Day 2 (2/2/2018 PM) at 94:8–23 (Tan). These

characteristics of Actavis’s Accused Product are summarized in the following table:

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JTX-006 at 3.

The composition of the drug adhesive matrix and Actavis’s Accused

Product as a whole are summarized in the following table:

JTX-006 at 4; see Trial Tr. Day 2 (2/2/2018 AM) at 91:2–18 (Rifaat). Granisetron base is

considered the active ingredient in Actavis’s Accused Product, and Duro-Tak® 387-2287 is the

inactive ingredient of Actavis’s Accused Product. See DTX0156 at 1.

Actavis’s Accused Product meets each and every limitation recited in claim

1 of the ’282 Patent. See Trial Tr. Day 1 (2/1/2018 PM) at 62:2–64:17 (Enscore). Therefore,

Actavis’s Accused Product, and the use thereof, as specified and described in its ANDA No.

208726, literally infringes claim 1 of the ’282 Patent. See Trial Tr. Day 1 (2/1/2018 PM) at 78:18–

24 (Enscore).

Duro-Tak

387-2287 is a commercially available transdermal pressure

sensitive adhesive made by Henkel Corporation (“Henkel”), and previously available from

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National Starch. See JTX–006 at 4-6; JTX-004; JTX-003; PTX-102; PTX-106; DTX0181; JTX-

002 at 572; Trial Tr. Day 1 (2/1/2018 PM) at 93:14–19 (Enscore). According to product

information submitted during prosecution of the ’282 Patent, Duro-Tak®

387-2287 / 87-2287 is an

acrylate/vinyl acetate, non-curing pressure sensitive adhesive supplied in an organic solvent

solution. JTX-002 at 571; see DTX0181; JTX-004; JTX-003.

As reflected in Actavis’s ANDA and the product literature, the prefix “87”

(viz. “87-2287”) indicates a product that is manufactured in the United States, whereas the

proprietary name Duro-Tak®

387-2287 is used to describe the same product manufactured outside

of the United States. See JTX-006 at 6; JTX-004; JTX-002 at 571; Trial Tr. Day 1 (2/1/2018 PM)

at 94:4–95:11 (Enscore). There is no substantial difference between Duro-Tak®

87-2287 and Duro-

Tak®

387-2287 other than the point of origin, and the two tradenames may, at times, be used

interchangeably. See Trial Tr. Day 1 (2/1/2018 PM) at 94:4–95:11 (Enscore).

Duro-Tak®

387-2287 / 87-2287 is a random copolymer of 2-ethylhexyl

acrylate (68.2%), vinyl acetate (26.5%), 2-hydroxyethylacrylate (5.2%) and glycidyl methacrylate

(0.15%), (JTX-002 at 571–74; see JTX-004; JTX-003; JTX-055 at 3–4; DTX0181; Trial Tr. Day

1 (2/1/2018 PM) at 31:24– 32:15, 96:8–15 (Enscore)), and contains no added crosslinking agent.

See JTX-002 at 571–574; JTX-004 at 2; DTX0181; Trial Tr. Day 1 (2/1/2018 PM) at 50:14–25

(Enscore). As described in the product specification, Duro-Tak®

87-2287 / 387-2287 has the

following polymeric structure:

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The Duro-Tak®

87-2287 / 387-2287 polymer is provided from the

manufacturer as a solution that is typically cast as a thin film and oven dried to remove the solvents.

See id. at 572. When used in transdermal drug delivery applications (e.g., transdermal patches),

the resulting pressure sensitive adhesive is an inactive ingredient whose primary function is to

adhere to the skin for the prescribed length of therapy, and the adhesive may also serve as a matrix

to hold a drug. See id.

b) Literal Infringement of Claim 1

The 2-ethylhexyl acrylate (68.2%) present in the Duro-Tak®

387-2287 of

Actavis’s Accused Product satisfies the feature of claim 1 that requires “50 to 98% w/w of a

primary acrylate monomer wherein said primary acrylate monomer is either 2-ethylhexyl acrylate

or butyl acrylate.” See JTX-002 at 572; JTX-006; Trial Tr. Day 1 (2/1/2018 PM) at 63:21–64:8

(Enscore); see also Trial Tr. Day 1 (2/1/2018 PM) at 31:24–32:8 (Enscore).

The 2-hydroxyethyl acrylate present in Duro-Tak®

387-2287 is an acrylic

monomer containing non-acidic hydroxyl moieties. See Trial Tr. Day 1 (2/1/2018 PM) at 32:9-14,

64:9-15 (Enscore). The 2-hydroxyethyl acrylate (5.2%) present in Duro-Tak®

387-2287 that is used

to prepare Actavis’s Accused Product satisfies the feature of claim 1 that requires “0.5 to 20% w/w

of a monomer containing non-acidic hydroxyl moieties.” See JTX-006 at 4; JTX-002 at 572;

DTX0181 at 2; Trial Tr. Day 1 (2/1/2018 PM) at 64:9–17 (Enscore); see also JTX-055 at 3–4;

Trial Tr. Day 1 (2/1/2018 PM) at 32:9–15 (Enscore).

The Duro-Tak®

387-2287 acrylic adhesive used in Actavis’s Accused

Product also includes vinyl acetate (26.5%) and glycidyl methacrylate (0.15%). JTX-002 at 572;

see JTX-055 at 3–4; DTX0181 at 2. Actavis’s Accused Product is also prepared from a mixture of

ethyl acetate and ethanol, but these solvents are largely, if not completely removed from the final

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patch Accused Product. See JTX-006 at 11, 49–50; Trial Tr. Day 1 (2/1/2018 PM) at 70:2–16

(Enscore). Finally, a release liner and backing film are also present in the final Accused Product.

See JTX-006 at 3–4; Trial Tr. Day 1 (2/1/2018 PM) at 53:11–25, 70:2–20 (Enscore). None of these

additional ingredients (monomers or solvents) present in the acrylic adhesive (or additional

excipients used in Actavis’s Accused Product as a whole) materially affect its basic and novel

properties—i.e., increased transdermal delivery of granisetron, granisetron stability in the patch,

and the complete release of granisetron from the patch. See infra § (I)(G)(2)(d). Therefore, the

Duro-Tak®

387-2287 present in Actavis’s Accused Product satisfies the feature of claim 1 that

requires “an acrylic adhesive consisting essentially of: 50 to 98% w/w of a primary acrylate

monomer wherein said primary acrylate monomer is either 2-ethylhexyl acrylate or butyl acrylate;

and 0.5 to 20% w/w of a monomer containing non-acidic hydroxyl moieties.”

As to the feature “a physiologically effective amount of granisetron loaded

in the acrylic adhesive” recited in claim 1, the term “physiologically effective amount of

granisetron” has been construed by the Court to have its plain and ordinary meaning, which is “an

amount effective to prevent and/or treat nausea and vomiting in a subject.” See Docket No. 62 at

20. Actavis’s Accused Product contains 34.3 mg of granisetron in the acrylic adhesive, which is

delivered at a rate of 3.1 mg of granisetron per 24 hours. See JTX-006 at 3; JTX-025 at 3–5, 15–

17; PTX-014; PTX-017; JTX-061 at 3–4, 20–21; JTX-005 at 22; JTX-026; Trial Tr. Day 1

(2/1/2018 PM) at 52:18–53:7, 62:2–10 (Enscore); Trial Tr. Day 2 (2/2/2018 PM) at 27:18–28:5

(Walther); see also JTX-059 at 2; JTX-055 at 3; Trial Tr. Day 1 (2/1/2018 PM) at 30:14–31:11

(Enscore). Plaintiffs’ expert, Ms. Walther, testified that in her thirteen year clinical experience

treating thousands of patients dealing with chemotherapy-induced nausea and vomiting (“CINV”),

this amount of granisetron administered through the skin is sufficient to prevent and/or treat nausea

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and vomiting in a subject for up to five days. See Trial Tr. Day 2 (2/2/2018 PM) at 15:22–16:1,

21:8–22:21, 25:15–30:1, 34:3–35:6 (Walther); see also JTX-026 at 10; JTX-059 at 12; PTX-180

at 12. Ms. Walther also spoke to the phase III clinical study in Actavis’s proposed Prescribing

Information, which demonstrated that Sancuso®

delivered long-acting CINV-control for a full five

days. See JTX-026 at 10; JTX-059 at 12; PTX-180 at 12; Trial Tr. Day 2 (2/2/2018 PM) at 21:8–

22:21 (Walther). Thus, Actavis’s ANDA Product includes a physiologically effective amount of

granisetron loaded in the acrylic adhesive. See Trial Tr. Day 1 (2/1/2018 PM) at 62:11–22

(Enscore); see also Trial Tr. Day 1 (2/1/2018 PM) at 30:14–31:11 (Enscore); Trial Tr. Day 2

(2/2/2018 AM) at 104:15–110:15 (Petrie); Trial Tr. Day 2 (2/2/2018 PM) at 25:15–28:22, 34:3–

35:6 (Walther).

According to Actavis’s ANDA, “[t]he only true excipient [present in

Actavis’s Accused Product] is the adhesive, and the compatibility between the adhesive and the

drug substance is therefore demonstrated unambiguously through the routine stability

evaluations.” JTX-025 at 9. Thus, the granisetron present in Actavis’s Accused Product is

incorporated into the Duro-Tak®

387-2287 by mixing the adhesive and active to form a “casting

solution,” which is then coated onto the polyester/EVA backing layer to prepare a cast laminate

film from which solvents are removed by heating. See id. at 5–31. The result is a drug/adhesive

matrix of granisetron and acrylic adhesive solution consisting of 6% granisetron and 94% Duro-

Tak®

387-2287, where the granisetron is contained in the adhesive. See id. at 3; JTX-005 at 22;

Trial Tr. Day 1 (2/1/2018 PM) at 62:23–63:6 (Enscore). For these reasons, Actavis’s Accused

Product satisfies the feature “a physiologically effective amount of granisetron loaded in the

acrylic adhesive” recited in claim 1. See Trial Tr. Day 1 (2/1/2018 PM) at 62:11–63:6 (Enscore);

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see also Trial Tr. Day 1 (2/1/2018 PM) at 30:14–31:11 (Enscore); Trial Tr. Day 2 (2/2/2018 PM)

at 25:15–28:22, 32:17–33:4 (Walther).

The proposed Prescribing Information for Actavis’s Accused Product

recommends storage of Actavis’s Accused Product at 20 °C to 25 °C. JTX-026 at 10; see JTX-025

at 3–5, 15–17; JTX-005 at 17; PTX-014; PTX-017; JTX-061 at 3–4, 20–21; see also PTX-094 at

63. Stability tests also show that the granisetron in Actavis’s Accused Product is stable after 26

weeks at room temperature (25 ºC). See JTX-005 at 17; JTX-006 at 8–9, 70; Trial Tr. Day 1

(2/1/2018 PM) at 63:7–19 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 91:19–93:5, 93:16–97:1

(Rifaat); Trial Tr. Day 2 (2/2/2018 AM) at 98:21–103:6 (Anderson). Through six months of

storage at 25 °C/60% RH, the granisetron content of Actavis’s Accused Product remains stable

and “substantially unchanged,” which meets the claimed minimum time of six weeks. JTX-025 at

8–9. Thus, Actavis’s Accused Product satisfies the claim element “wherein the granisetron content

of said patch remains substantially unchanged when stored at 25° C. for six weeks” recited in claim

1. See JTX-005 at 17; JTX-006 at 8–9, 70; Trial Tr. Day 1 (2/1/2018 PM) at 63:7–19 (Enscore);


at 98:21–103:6 (Anderson); see also PTX-094 at 63; Trial Tr. Day 1 (2/1/2018 PM) at 31:12–23

(Enscore).

Actavis’s Accused Product meets each and every limitation recited in claim

1 of the ’282 Patent. See Trial Tr. Day 1 (2/1/2018 PM) at 62:2–64:17 (Enscore). Therefore,

Actavis’s Accused Product and the use thereof, as specified and described in its ANDA No.

208726, literally infringes claim 1 of the ’282 Patent. See Trial Tr. Day 1 (2/1/2018 PM) at 78:18–

24 (Enscore).

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c) Basic and Novel Properties

Actavis argues that its Accused Product does not infringe claim 1 of the

’282 Patent because Actavis’s Accused Product: (1) administers granisetron at a greater or lesser

rate than disclosed in the ’282 Patent; (2) has a greater or lesser granisetron stability than that

disclosed in the ’282 Patent; and/or (3) provides less than the complete release of granisetron. (See

Trial Tr. Day 1 (2/1/2018 PM) at 32:16–33:3 (Enscore). However, Actavis’s Accused Product does

not show a substantial difference in any of the rate of transdermal delivery of granisetron, the

stability of granisetron, and/or the complete release of granisetron as compared to either the data

set forth in the ’282 Patent and/or Sancuso®. (See JTX-001 at 9, 9:1–10; JTX-005; Trial Tr. Day

1 (2/1/2018 PM) at 33:4–42:7, 65:4–69:17 (Enscore).

The Court agrees with Dr. Enscore that although some properties associated

with a patch are tested in vivo (i.e., adhesion, pharmacokinetics, irritation), in this case, each basic

and novel property of the ’282 Patent is found independently using in vitro testing. JTX-001 at 8–

9, 8:35–11:l. 50 (Examples 1–3); see also JTX-069 at 1 (“pharmacokinetic and adhesion study”);

Trial Tr. Day 2 (2/2/2018 AM) at 15:11–21, 16:8–15 (Enscore); Trial Tr. Day 5 (2/7/2018 AM) at

22:25–23:5 (Enscore). Indeed, Actavis concedes that the basic and novel properties of increased

permeation of granisetron and stability are measured in vitro. Dr. Tan admitted that increased

permeation of granisetron is measured in an in vitro study. See Trial Tr. Day 3 (2/5/2018 AM) at

59:7–11 (Tan). In fact, Actavis’s own documents stated that “[t]arget formulation will be chosen

based on in-vitro skin permeation, physical attributes and research stability results[.]” PTX-012 at

12; see Trial Tr. Day 2 (2/2/2018 AM) at 59:5–16 (Rifaat); Trial Tr. Day 3 (2/5/2018 AM) at 53:6–

54:5 (Tan). Lastly, stability is never tested in vivo. See Trial Tr. Day 2 (2/2/2018 AM) at 14:11–

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13 (Enscore); Trial Tr. Day 3 (2/5/2018 AM) at 59:2–6 (Tan); see also JTX-001 at 9, 9:l. 60–10:l.

10).

Actavis alleges that “complete release” is measured in vivo. At trial, Dr.

Tan testified that Actavis’s Accused Product does not exhibit the property of complete release of

granisetron from the patch because this property must be measured in vivo. See Trial Tr. Day 2

(2/2/2018 PM) at 63:13–21 (Tan). Dr. Tan points to the Sancuso® label to support his opinion that

the complete release of granisetron was not achieved in vivo. Trial Tr. Day 3 (2/5/2018 AM) at

48:14–49:7 (Tan). However, Dr. Tan admitted that this data was produced after the filing date of

the ’282 Patent, and thus could not have been included in the ’282 Patent. Trial Tr. Day 3 (2/5/2018

AM) at 48:14–49:7 (Tan). Further, Dr. Tan testified that a POSA would understand that it is not

possible for a transdermal drug patch to have “complete release” in vivo, and that he is not aware

of any commercially available passive transdermal patch that achieves complete release of the

drug load in vivo. See Trial Tr. Day 3 (2/5/2018 AM) at 49:8–17 (Tan). Conversely, Example 1 of

the ’282 Patent shows the increased transdermal delivery and 100% complete release of

granisetron was observed through in vitro drug permeation tests using a Franz cell that employed

murine (mouse) skin. See JTX-001 at 8–9, 8:l. 35–9:l. 57 (Example 1); Trial Tr. Day 1 (2/1/2018

PM) at 33:4–35:20, 36:21–37:10, 40:13–41:19 (Enscore); Trial Tr. Day 3 (2/5/2018 AM) at 39:5–

16, 41:24–42:2, 42:14–44:9 (Tan).

For these reasons and the reasons discussed further below, the Court finds

that a POSA would have understood that the complete release of granisetron from the patch should

be measured in vitro.

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(1) Transdermal Delivery

Actavis’s Accused Product demonstrates increased transdermal delivery of

granisetron. See JTX-005 at 4–7; Trial Tr. Day 1 (2/1/2018 PM) at 65:21–66:21 (Enscore). During

development of Actavis’s Accused Product, Actavis tested several formulations against Sancuso®

for transdermal granisetron flux across human skin in vitro using a Franz cell. JTX-005 at 4–6; see

Trial Tr. Day 1 (2/1/2018 PM) at 47:6–16 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 57:18–

59:18, 59:20, 65:6–80:7 (Rifaat); Trial Tr. Day 3 (2/5/2018 AM) at 49:25–50:20 (Tan). As in

Example 1 of the ’282 Patent, Actavis tested the Sancuso®

product and a formulation that ultimately

became its final formulation, both of which contained an adhesive with non-acidic hydroxyl (-OH)

functional groups, and a formulation with carboxylic acid (-COOH) functional groups. JTX-005

at 6; see JTX-001 at 8–9, 8:l. 35–9: l. 57.

As demonstrated in Actavis’s Formulation Transfer Report, the in vitro

transdermal drug permeation of Table 2 (Study 1784-080714-A-HN) was measured over a one

week period (168 hours). JTX-005 at 6–7; see Trial Tr. Day 2 (2/2/2018 AM) at 75:12–80:7

(Rifaat). Specifically, Table 2 (Study 1784-080714-A-HN) from Actavis’s Formulation Transfer

Report provides the following data:

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JTX-005 at 6.

The granisetron permeation measured by Actavis (relative to Sancuso®,

“R”) represents the ratio of total drug permeated across human skin in vitro in comparison to that

for Sancuso®. See JTX-005 at 6; Trial Tr. Day 1 (2/1/2018 PM) at 35:21–36:20, 47:6–16

(Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 77:11–78:5 (Rifaat); Trial Tr. Day 3 (2/5/2018 AM)

at 53:6–54:5 (Tan). System 1784-HN2829-191-1L was prepared using the same Duro-Tak®

polymer—387-2287—that is used in both Sancuso® and Actavis’s Accused Product. (JTX-005 at

6.) This formulation also was identical to that of Sancuso®. See id.; Trial Tr. Day 2 (2/2/2018 AM)

at 78:6–17, 85:23–86:5 (Rifaat). System 1784-HN2829-191-2L was prepared using the Duro-

Tak® polymer 87-2196, which contained carboxylic acid (-COOH) groups. JTX-005 at 6; see

PTX-022.

Both Systems 1784-HN2829-191-1L and 1784-HN2829-191-2L include

pressure sensitive adhesives that contain vinyl acetate and 6% granisetron, the only difference

being that the former system includes a functional monomer containing non-acidic hydroxyl (-

OH) groups whereas the latter system includes a functional monomer containing carboxylic acid

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(-COOH) groups. See JTX-005 at 6; PTX-022; Trial Tr. Day 2 (2/2/2018 AM) at 78:25–81:22,

82:4–7, 82:16–86:5 (Rifaat). Notably, system 1784-HN2829-191-1L (the one with -OH groups)

has more than five times the cumulative transdermal granisetron permeation of that of 1784-

HN2829-191-2L (the one with -COOH groups). JTX-005 at 6; see Trial Tr. Day 1 (2/1/2018 PM)

at 35:21–36:20, 47:6–16, 65:21–66:21 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 84:18–86:5

(Rifaat).

Actavis’s Formulation Transfer Report also discloses that Actavis’s

Accused Product shows an equivalent rate of granisetron permeation compared to Sancuso® for

each and every day from day 1 to day 7. See JTX-005 at 8–10 (Table 4 (Studies 1784-091014-HN,

1784-100214-HN, and 1784-101414-HN), Table 5 (Study 1784-021815-HN), and Table 6 (Study

1784-031115-HN)). Further, the average permeation ratio compared to Sancuso® for these studies

is 1.04, showing the two products have virtually the same transdermal drug permeation rate. See

JTX-005 at 8–10.

The Court found no evidence in the record of data showing the transdermal

delivery of granisetron with an adhesive containing functional monomers of both carboxylic acid

(-COOH) groups and non-acidic hydroxyl (-OH) groups. See Trial Tr. Day 1 (2/1/2018 PM) at

86:8–87:3 (Enscore). However, the ’282 Patent specification states that “it is preferred that the OH

group not be part of any COOH . . . group[] . . . [and] it is preferred that adhesives of the present

invention have substantially no detectable levels of such groups.” JTX-001 at 6, 3:l. 65–4:l. 4. Dr.

Enscore testified that a POSA would interpret that to not use carboxylic acid (-COOH) groups in

an acrylic adhesive containing granisetron. Trial Tr. Day 2 (2/2/2018 AM) at 34:6–22 (Enscore).

The Court therefore credits Dr. Enscore’s testimony in finding that Actavis’s Accused Product

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exhibits the basic and novel property of increased transdermal delivery of granisetron. See Trial

Tr. Day 1 (2/1/2018 PM) at 65:21–66:21 (Enscore).

(2) Stability

Actavis’s Accused Product shows granisetron stability comparable with that

of Sancuso®

. See JTX-005 at 17; Trial Tr. Day 1 (2/1/2018 PM) at 68:25–69:9 (Enscore); see also

PTX-094 at 63; JTX-006 at 7–9, 70; Trial Tr. Day 1 (2/1/2018 PM) at 27:5–14, 31:12–22, 41:21–

42:3 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 91:19–93:5, 93:16–97:1 (Rifaat); Trial Tr. Day

2 (2/2/2018 AM) at 98:21–103:6 (Anderson). Dr. Enscore provided unrebutted testimony. See

Trial Tr. Day 1 (2/1/2018 PM) at 68:25–69:9 (Enscore). For example, Actavis’s Formulation

Transfer Report (and other ANDA documents) discloses that Actavis’s Accused Product shows

equivalent granisetron stability compared to Sancuso®

from week 0 to week 26 at 100.2% of the

target content, demonstrating that the granisetron drug had not degraded. See JTX-005 at 17 (Table

10, Granisetron Assay, lot 1748-HN2984-15-1); Trial Tr. Day 1 (2/1/2018 PM) at 68:25–69:10

(Enscore); see also PTX-094 at 60–80 (the corresponding results of stability testing of Sancuso®

);

JTX-025 at 8–9; JTX-006 at 70; Trial Tr. Day 2 (2/2/2018 AM) at 98:21–103:6 (Anderson).

Therefore, Actavis’s Accused Product demonstrates granisetron stability in the patch. See Trial Tr.

Day 1 (2/1/2018 PM) at 68:25–69:15 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 91:19–93:5,

93:16–97:1 (Rifaat); Trial Tr. Day 2 (2/2/2018 AM) at 98:21–103:6 (Anderson).

(3) Complete Release

Actavis purports to rely on the Actavis’s proposed Prescribing Information

for its Accused Product (which is identical to the Sancuso®

label (“3.1 mg of granisetron per 24

hours for up to seven days”)) and an Analysis of Residual Granisetron from Actavis’s ANDA

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(JTX-064), as demonstrating that Actavis’s Accused Product has less than complete granisetron

release in vivo, and also that the phrase “suitable for the transdermal administration of granisetron

to a subject in need thereof” in claim 1, and the Court’s Claim Construction of “physiologically

effective amount of granisetron,” requires “complete release” to be proven through in vivo testing.

See JTX-064 at 4–9; JTX-069; JTX-026 at 2, 7; Trial Tr. Day 2 (2/2/2018 AM) at 43:14–23

(Enscore); Trial Tr. Day 2 (2/2/2018 PM) at 103:12–107:25, 110:10–21, 111:11–112:18 (Tan);

Trial Tr. Day 3 (2/5/2018 AM) at 48:14–19, 75:18–21 (Tan); Docket No. 62 at 20. However, the

Court credits the testimony of Plaintiffs’ expert Dr. Enscore that in vitro testing is the proper

measure of complete release of granisetron from the patch, and disagrees with Actavis’s expert Dr.

Tan on this issue. See JTX-001 at 9, 9:44–57; Trial Tr. Day 1 (2/1/2018 PM) at 36:21–37:10,

38:25–39:14, 40:9–11 (Enscore) (“[Transdermal patches] are not designed to release completely

in vivo.”); see also Trial Tr. Day 3 (2/5/2018 AM) at 42:14–43:3 (Tan).

Both Dr. Enscore and Dr. Tan rely on Example 1 (Table 2) of the ’282

Patent for the definition of “complete release,” i.e. “complete depletion,” and both agree that the

complete release of granisetron was observed through in vitro drug permeation tests that employed

murine (mouse) skin. (JTX-001 at 9, 9:44–57; Trial Tr. Day 1 (2/1/2018 PM) at 36:21–37:10,

37:19–38:9, 40:13–41:19 (Enscore); Trial Tr. Day 3 (2/5/2018 AM) at 39:5–16, 42:14–44:9,

46:10–12, 47:12–15 (Tan); Trial Tr. Day 5 (2/7/2018 AM) at 74:19–75:11, 76:9–11, 80:19–24

(Enscore).) A POSA would understand “complete release” to mean that there is no lasting

interaction between the drug and adhesive. See Trial Tr. Day 1 (2/1/2018 PM) at 41:13–19, 87:21–

88:2, 88:15–25, 124:5–20 (Enscore); Trial Tr. Day 3 (2/5/2018 AM) at 42:14–44:9 (Tan); Trial

Tr. Day 5 (2/7/2018 AM) at 74:19–75:7 (Enscore).

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Both Dr. Enscore and Dr. Tan testified to the variability of in vitro

laboratory testing with a Franz cell due to the skin sample (±10%) or the amount of drug load in

the patch (±5%), and that a POSA would understand this variability with in vitro transdermal flux

testing. See Trial Tr. Day 1 (2/1/2018 PM) at 38:10–24 (Enscore); Trial Tr. Day 3 (2/5/2018 AM)

at 39:17–40:9 (Tan); Trial Tr. Day 5 (2/7/2018 AM) at 77:8–21 (Enscore). Dr. Enscore testified

that a release greater than 100% would not cause a POSA to label the result as unreliable, and Dr.

Tan agreed that drug loading in patches is often not exact. See Trial Tr. Day 2 (2/2/2018 AM) at

37:1–9 (Enscore); Trial Tr. Day 3 (2/5/2018 AM) at 48:7–13 (Tan); Trial Tr. Day 5 (2/7/2018 AM)

at 77:8–78:6 (Enscore). Moreover, Dr. Tan admits that in vitro testing is commonly used to

evaluate whether a patch should proceed to in vivo tests (i.e., administration to a subject), and

indeed, that is exactly what Actavis did. See JTX-005 at 5–7; Trial Tr. Day 3 (2/5/2018 AM) at

53:6–56:8, 58:14–59:1 (Tan); see also Trial Tr. Day 4 (2/6/2018 PM) at 81:23–25, 95:16–19

(Michniak-Kohn) (stating she did not think it was necessary for Lee to do in vivo testing).

In fact, Dr. Tan admits that: (1) he only relied on Example 1 of the ’282

Patent to support his definition of “complete release” from the patch; (2) the only time the ’282

Patent discusses “complete release” is in relation to in vitro data; (3) the ’282 Patent does not

contain any in vivo data on complete release of granisetron; (4) Example 1 shows the complete

release of granisetron within 24 hours from the patch; and (5) the ’282 Patent does not require a

specific skin type in the in vitro experiment for “complete release.” See Trial Tr. Day 3 (2/5/2018

AM) at 43:4–44:21, 45:10–13, 47:4–15 (Tan). Still, despite Dr. Tan’s reliance on Example 1 of

the ’282 Patent, Dr. Tan’s opinion is that Actavis’s Accused Product does not infringe the asserted

claims of the ’282 Patent because it does not achieve the “complete release” in vivo after being

worn for seven days. See Trial Tr. Day 3 (2/5/2018 AM) at 57:25–58:13 (Tan).

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The Court disagrees with Dr. Tan’s opinion that the “complete release”

should be measured in vivo. The Court agrees with Dr. Enscore that (1) the proper measure for

“complete release” is in vitro, (2) claim 1 is silent on in vitro versus in vivo testing, (3) there is no

in vivo data in the ’282 Patent on complete release of granisetron from the patch, and (4) the

language “to a subject in need thereof” is merely a stand-alone limitation that the patch is suitable

for use on a subject. See Trial Tr. Day 1 (2/1/2018 PM) at 36:21–37:10, 38:7–9, 38:25–39:14,

40:9–11 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 13:12–22, 14:6–13, 34:23–37:9, 45:8–21

(Enscore) (“[Claim 1] inherently [speaks to in vitro testing] when it talks about stability because

that’s never done in vivo.”); Trial Tr. Day 3 (2/5/2018 AM) at 44:18–21, 47:4–15 (Tan); see also

Trial Tr. Day 2 (2/2/2018 PM) at 110:5–9 (Tan). The Court’s Claim Construction did not require

a time period associated with the “complete release” or that “complete release” of granisetron be

from a patch applied to human skin, let alone in a clinical trial involving human subjects. See Trial

Tr. Day 1 (2/1/2018 PM) at 36:21–37:10, 38:7–9, 38:25–39:14, 40:9–11 (Enscore); see also Trial

Tr. Day 2 (2/2/2018 AM) at 45:8–46:7 (Enscore); Trial Tr. Day 3 (2/5/2018 AM) at 37:3–7, 42:14–

45:13 (Tan); Trial Tr. Day 5 (2/7/2018 AM) at 75:8–16 (Enscore); Docket No. 62. Indeed, Dr. Tan

admits that the in vivo granisetron release data that is reported in the Sancuso®

label came after the

filing date of the ’282 Patent, and thus could not be part of the data relied upon in the ’282 Patent

when discussing “complete release.” Trial Tr. Day 3 (2/5/2018 AM) at 48:14–49:7 (Tan).

Accordingly, Actavis’s ANDA includes the results of in vitro tests using a

Franz cell showing that Actavis’s Accused Product provides for the complete release (100% or

more) of granisetron. See, e.g., JTX-005 at 4, 9–10 (showing complete granisetron release on day

7); Trial Tr. Day 1 (2/1/2018 PM) at 66:25–67:17 (Enscore); Trial Tr. Day 3 (2/5/2018 AM) at

49:18–50:6, 54:9—56:8 (Tan). For example, in Actavis’s Formulation Transfer Report, Tables 5

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and 6 provide the results from Study 1784-021815-HN and Study 1784-031115-HN, which show

the complete release of granisetron from Actavis’s Accused Product in the exhibit batches

submitted to FDA (Code# 4161-1 Control# 15Z008; Code# 4161-1 Control # 15Z044; Control

4161-1 Control# 15Z0121). JTX-005 at 9–10; see Trial Tr. Day 1 (2/1/2018 PM) at 66:25–68:21

(Enscore). On day 7, the granisetron cumulative permeation was calculated as 640.37 ± 213.68

(μg/cm2

), 686.60 ± 145.45 (μg/cm2

), and 672.41±168.31. See JTX-005 at 9–10; Trial Tr. Day 1

(2/1/2018 PM) at 66:25–67:17 (Enscore).

Lastly, the Court also finds Actavis’s argument not credible that the phrase

“suitable for the transdermal administration of granisetron” in claim 1 would require in vivo testing

because it is defined as in vitro in the specification. Dr. Tan admits that in vitro studies are one of

the steps to determine whether a patch is suitable for administration to a subject. See Trial Tr. Day

3 (2/5/2018 AM) at 58:14–59:1 (Tan). Indeed, Dr. Tan admits that the only way to prove the

increased permeation and stability of granisetron in the patch is through in vitro studies. See Trial

Tr. Day 3 (2/5/2018 AM) at 59:2–11 (Tan).

For these reasons, Actavis’s Accused Product exhibits an increased rate of

transdermal delivery of granisetron, granisetron stability, and complete release of granisetron that

is comparable to the inventive patch of the ’282 Patent as well as to Sancuso®. See Trial Tr. Day

1 (2/1/2018 PM) at 65:4–69:17 (Enscore); see also JTX-001 at 9, 9:1–10, 44–57; JTX-005 at 6;

Trial Tr. Day 1 (2/1/2018 PM) at 33:4–42:7 (Enscore).

d) Additional components do not make the Actavis product

noninfringing

There is no evidence to support Actavis’s argument that its Accused Product

does not infringe claim 1 of the ’282 Patent because the acrylic adhesive used in its Accused

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Product (i.e., Duro-Tak® 387-2287) includes additional unclaimed monomers (or other materials)

that materially affect the basic and novel properties of its patch Accused Product. See Trial Tr.

Day 1 (2/1/2018 PM) at 69:18–25 (Enscore).

As construed by the Court, the term “consisting essentially of” merely

requires that no additional materials present in the acrylic adhesive have a material effect on the

basic and novel properties of the claimed invention. See Docket No. 62. The Court finds that the

definition of “material effect” was provided by Plaintiffs’ expert Dr. Enscore and went unrebutted.

See Trial Tr. Day 1 (2/1/2018 PM) at 87:21–89:4 (Enscore). For transdermal delivery, a material

effect “would be a large enough effect that it would project that [a POSA] could make a

[granisetron] transdermal patch based on that transdermal permeation from a reasonable size.” See

Trial Tr. Day 1 (2/1/2018 PM) at 87:21–88:13, 123:22–124:4 (Enscore). Dr. Enscore described

the other basic and novel properties, i.e., “complete release” and stability, as “binary properties.”

See Trial Tr. Day 1 (2/1/2018 PM) at 87:21–88:4, 88:15–89:4, 124:5–20 (Enscore). Therefore, a

“material effect” for “complete release” would mean that “the drug doesn’t chemically interact

with the adhesive such that it becomes immobilized . . . [or] prevented it from coming out” and for

stability would mean that “the component significantly causes the drug to degrade.” See Trial Tr.

Day 1 (2/1/2018 PM) at 87:21–88:5, 88:15–89:4 (Enscore). The Court therefore credits Dr.

Enscore’s testimony in finding that a material effect is a large enough effect that would project

that a POSA could make a reasonable size granisetron transdermal patch based on that transdermal

permeation. Further, the Court finds that in the context of “complete release,” a material effect is

something that would prevent the drug from leaving the patch. Finally, in the context of drug

stability, a material effect is one that causes significant drug degradation such that the patch would

not be suitable for pharmaceutical use.

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Based on the uncontroverted definition provided by Dr. Enscore for

“material effect,” there is no evidence to support a finding that additional components in the acrylic

adhesive used in Actavis’s Accused Product beyond those that are claimed—in particular vinyl

acetate and glycidyl methacrylate—materially affect the basic and novel properties of the claimed

patch as construed by the Court. See Trial Tr. Day 1 (2/1/2018 PM) at 69:18–25, 74:23–75:1,

77:14–18 (Enscore); Trial Tr. Day. 3 (2/5.2018 AM) at 70:21 –72:1 (Tan); infra §§ (I)(G)(2)(d)(1)-

(2).

Further, there is no evidence that Actavis’s Accused Product does not

embody or express one or more of the basic and novel properties of the claimed patch, as construed

by the Court. See Trial Tr. Day 1 (2/1/2018 PM) at 65:4–69:17 (Enscore); supra § (I)(G)(2)(C).

Actavis’s Accused Product is substantially similar to the formulations tested in the exemplary

embodiments of the ’282 Patent, and ample evidence suggests that Actavis’s Accused Product

functions in the same manner as disclosed and taught by the ’282 Patent. See supra §§ (I)(F),

(G)(2)(C).

Last, there is neither evidence to support a finding, nor did Actavis assert,

that any additional unlisted ingredients such as ethanol, ethyl acetate, the release liner, or backing

layer used in Actavis’s Accused Product materially affect the basic and novel properties of the

claimed patch, as construed by the Court. See Trial Tr. Day 1 (2/1/2018 PM) at 69:18–70:20,

77:21–78:7 (Enscore).

(1) Vinyl acetate

Vinyl acetate is present in Duro-Tak® 387-2287, but is not recited in claim

1 of the ’282 Patent. See, e.g., JTX-002 at 571–74; JTX-055 at 3–4; DTX0181; Trial Tr. Day 1

(2/1/2018 PM) at 42:8–20, 70:24–71:3 (Enscore). The Court credits the testimony of Dr. Enscore

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that there is no scientific basis to conclude that vinyl acetate materially affects the basic and novel

properties of the invention. Trial Tr. Day 1 (2/1/2018 PM) at 74:23–75:1 (Enscore); see also Trial

Tr. Day 1 (2/1/2018 PM) at 42:25–43:2, 52:1–5 (Enscore).

As disclosed in the ’282 Patent, and as Dr. Enscore testified, monomers

such as vinyl acetate are commonly used in polyacrylates as a copolymer to have a modifying

effect on bulk physical properties such as tack, adhesion, elasticity, and cohesive strength—not to

change transdermal delivery, “complete release,” or increase stability. See JTX-001 at 6, 4:12– 19;

Trial Tr. Day 1 (2/1/2018 PM) at 43:8–18, 71:4–6 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at

37:10–38:6 (Enscore). The prior art, such as Lee, Effing, Braun, and Li PCT, also all discuss

polymers that contain vinyl acetate, but they do not state that vinyl acetate affected the drug

delivery in any way, let alone having a material effect on permeation. See JTX-019; DTX0061;

DTX0139; JTX-017. Therefore, a control experiment comparing drug permeation from patches

with and without vinyl acetate is not necessary to demonstrate that vinyl acetate does not have a

material effect on permeation. Nevertheless, based on the examples in the record discussed below,

there is no reason to conclude that vinyl acetate would have any effect on the basic and novel

properties of the claimed invention, which are particular to the inventive patch’s interaction with

granisetron.

The Court does not find that vinyl acetate materially affects any of the basic

and novel properties. In reaching this conclusion, the Court credits the testimony of Dr. Enscore,

and does not agree with Dr. Tan. Contrary to Dr. Enscore, Dr. Tan cited to no documentary

evidence in reaching his conclusions or the percentage of monomers in other Duro-Tak®

adhesives, performed no laboratory experiments, and provided no data that vinyl acetate is

anything other than a bulking modifying monomer or materially affects any property. See Trial Tr.

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Day 3 (2/5/2018 AM) at 60:20–23, 61:16–20, 62:8–12, 70:21–72:1, 85:1–87:4 (Tan). Moreover,

an assumption underlying Dr. Tan’s analysis—that granisetron base is hydrophilic—was

contradicted by Actavis’s other expert, Dr. Michniak-Kohn, as well as Dr. Enscore. Compare Trial

Tr. Day 3 (2/5/2018 AM) at 62:13–63:15 (Tan), with JTX-059 at 7 (“Granisetron is . . . insoluble

in water”), and Trial Tr. Day 4 (2/6/2018 PM) at 64:18–65:3 (Michniak-Kohn); see also Trial Tr.

Day 2 (2/2/2018 PM) at 78:1–11, 79:23–24 (Tan); Trial Tr. Day 3 (2/5/2018 AM) at 12:6–7,

63:19–64:1, 64:23–66:2 (Tan); Trial Tr. Day 5 (2/7/2018 AM) at 13:20–23 (Enscore). What is

more, Dr. Tan cited no documentary evidence to support his opinions concerning the “relative”

hydrophilicity of granisetron base. See Trial Tr. Day 3 (2/5/2018 AM) at 66:5–18 (Tan). Further,

Dr. Tan’s testimony that vinyl acetate is hydrophobic is plainly contradicted by Actavis’s prior art

of record. Compare Trial Tr. Day 2 (2/2/2018 PM) at 79:14–17, 100:15–16 (Tan), with DTX0061

at 5 (listing vinyl acetate as a “Hydrophilic B monomer”. For these reasons, the Court finds Dr.

Tan’s testimony largely conclusory, and instead credits Dr. Enscore’s testimony in finding that

vinyl acetate does not have a material effect on the basic and novel properties.

As discussed below, Plaintiffs have met their burden that vinyl acetate has

no material effect on the basic and novel properties of the invention of the ’282 Patent. The

specification and claim 1 of the ’282 Patent also lead to the conclusion that the inventors did not

believe vinyl acetate to have a material effect on the basic and novel properties of the invention.

As the ’282 Patent states, “[t]ypical levels of . . . the modifying monomer [in adhesives], such as

vinyl acetate . . . is typically present in an amount of about 10 to 40% w/w.” See JTX-001 at 6,

4:20–23. Not once did the inventors put vinyl acetate into claim 1, even when amending the claim

from “comprising” to “consisting essentially of.” See generally JTX-002. However, the inventors

did put a monomer between 0.5 and 20% w/w into the claim because it affected the basic and novel

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properties. Accordingly, given that the vinyl acetate at 26.5% (w/w) is within the range given in

the specification, this further demonstrates that it has no material effect on the basic and novel

properties of the claimed invention. See JTX-002 at 571–74; JTX-055 at 3–4; DTX0181.

The comparative examples set forth in the ’282 Patent similarly lead to a

conclusion that the vinyl acetate present in Duro-Tak® 387-2287 does not materially affect the

transdermal delivery of granisetron. See JTX-001 at 2 (FIGs. 1–2), at 8–9, 8:l. 35– 9:l. 57; Trial

Tr. Day 1 (2/1/2018 PM) at 71:8–15 (Enscore). First, FIGs. 1–2 and Example 1 (Table 2) of the

’282 Patent provide the results of tests that examined the transdermal flux across mouse skin of

granisetron (3%) loaded into patches prepared using, inter alia, Duro-Tak® 2052 (DT 2052) and

Duro-Tak® 2287 (DT 2287). See JTX-001 at 2 (FIGs. 1–2); Trial Tr. Day 1 (2/1/2018 PM) at

45:8–19, 71:8–72:3 (Enscore). Specifically, Table 2 of the ’282 Patent provides the following data:

See JTX-001 at 9, 9:1–10.

Both DT 2052 and DT 2287 include vinyl acetate.1 See JTX-001 at 8, 8:45–

55 (Table 1); Trial Tr. Day 1 (2/1/2018 PM) at 43:23–44:7, 71:8–15 (Enscore); see also JTX-004.

The only difference between DT 2052 and DT 2287 is that DT 2287 includes a functional monomer

having a hydroxyl (-OH) group and DT 2052 includes a functional monomer having a carboxylic

1 The patent refers to vinyl acrylate in some instances, but this is in error. See Trial Tr. Day 1 (2/1/2018 PM) at

43:3:23–44:7, 71:8-15, 103:24–104:4 (Enscore). As set forth in the product specification sheet for Duro-Tak® 87-

2287 / 387-2287, vinyl acrylate is not present in this pressure sensitive adhesive. See JTX-004.

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acid (-COOH) group. See JTX-001 at 8, 8:45–52 (Table 1); see also JTX-004; Trial Tr. Day 1

(2/1/2018 PM) at 43:19–44:20 (Enscore). Dr. Enscore stated that the most valid comparisons

between DT 2052 and DT 2287 occur at hours 3 and 6 given that the DT 2287 formulation releases

the granisetron so quickly, and a majority of the drug content by hour 12. Trial Tr. Day 1 (2/1/2018

PM) 33:4–14, 120:23–121:9 (Enscore). Therefore, notably, the ’282 Patent in FIG. 1 and Table 2

shows that DT 2287 has a transdermal granisetron flux more than thirty times higher than DT 2052

at hours 3 and 6. See JTX-001 at 2 (FIG. 1), at 9, 9:1–10 (Table 2); Trial Tr. Day 1 (2/1/2018 PM)

at 44:8–45:2, 71:17–72:3 (Enscore). Moreover, in Table 3 (showing the same data as in Table 2

but to show average flux), the ’282 Patent displays that DT 2287 has a transdermal granisetron

flux more than sixteen times higher than DT 2052 at hour 24.2 See JTX-001 at 9, 9:14–25 (Table

3). Therefore, a comparison of granisetron patches prepared using the adhesives DT 2052 and DT

2287 shows that, for two adhesives that each contain vinyl acetate, the vinyl acetate was a

nonfactor in the transdermal flux of granisetron. See Trial Tr. Day 1 (2/1/2018 PM) at 43:19 –45:2,

71:8–72:3 (Enscore). Instead, as described in the ’282 Patent, the non-acidic hydroxyl functional

group appeared to play a substantial role in increasing the transdermal delivery of granisetron. See

JTX-001 at 9, 9:1–10, 18–25 (Tables 2–3).

A second comparison can be made between two acrylic adhesives that each

include a monomer having a carboxylic acid functional group (DT 2052 and DT 2353), with one

containing vinyl acetate (DT 2052) and the other lacking vinyl acetate (DT 2353). See JTX-001 at

8, 8:45–55 (Table 1); JTX-003; JTX-004; Trial Tr. Day 1 (2/1/2018 PM) at 46:10–17, 72:5–11,

109:12–14 (Enscore). Both adhesives are characterized by very low granisetron flux compared to

2 At hour 24, DT 2052 has a flux of 0.66 µg/cm2 /hr and DT 2287 has a flux of 10.7 µg/cm2 /hr. The flux of DT 2287

is 16.2 times higher than DT 2052 at hour 24. The decrease from hours 3 and 6 makes sense since most of the drug is

depleted at hour 24 when using DT 2287.(See JTX001 at 9, 9:1–10.

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that for the formulation prepared using Duro-Tak® 2287, particularly at hours 3 and 6. See JTX-

001 at 2 (FIG. 1); Trial Tr. Day 1 (2/1/2018 PM) at 46:18–47:5, 72:13–18 (Enscore); Trial Tr. Day

5 (2/7/2018 AM) at 17:16–24 (Enscore). Thus, vinyl acetate had no effect on increasing the

transdermal drug delivery in these exemplary acrylic adhesives loaded with 3% granisetron. See

JTX-001 at 2 (FIG. 1), at 9, 9:1–10 (Table 2); Trial Tr. Day 1 (2/1/2018 PM) at 46:18–47:5; 72:13–

18 (Enscore). Dr. Enscore stated his opinion would not change with 6% granisetron and that the

difference between the two adhesives demonstrates that the vinyl acetate has no material effect on

the transdermal permeation of granisetron. See Trial Tr. Day 1 (2/1/2018 PM) at 46:18–47:5,

111:13–23 (Enscore). Dr. Enscore further stated that it was his opinion a POSA could not build an

effective reasonable-size transdermal granisetron product using the fluxes of DT 2052 and DT

2353 as compared to DT 2287. See Trial Tr. Day 1 (2/1/2018 PM) at 112:1–7 (Enscore).

Accordingly, the exemplary embodiments disclosed in the ’282 Patent demonstrate that vinyl

acetate has no material effect on the transdermal delivery of granisetron. See Trial Tr. Day 1

(2/1/2018 PM) at 46:18–24, 71:8–15 (Enscore).

The same conclusion can be reached from a review of Actavis’s ANDA.

Actavis’s empirical data from its Formulation Transfer Report shows that vinyl acetate does not

affect the transdermal delivery of granisetron from the claimed inventive patch. See JTX-005 at 6.

During development of Actavis’s Accused Product, Actavis tested several formulations against

Sancuso® for transdermal granisetron flux across human skin in vitro. See, e.g., JTX005 at 6; Trial

Tr. Day 1 (2/1/2018 PM) at 47:6–16 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 57:18–59:18,

59:20, 65:6–80:7 (Rifaat). The in vitro transdermal drug permeation of Table 2 (Study 1784-

080714-A-HN) was measured over a one week period (168 hours). See JTX-005 at 6–7; Trial Tr.

Day 2 (2/2/2018 AM) at 76:13–80:7 (Rifaat). The permeation (relative to Sancuso® (“R”)

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represents the ratio of total drug permeated across human skin in vitro in comparison to that for

Sancuso®. See JTX-005 at 6; Trial Tr. Day 1 (2/1/2018 PM) at 35:21–36:20, 47:6–16, 72:19–73:9

(Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 77:11–78:5 (Rifaat).

System 1784-HN2829-191-1L was prepared using the same DuroTak®

polymer—87-2287—that is used in both Sancuso® and Actavis’s Accused Product. See JTX-005

at 6; Trial Tr. Day 1 (2/1/2018 PM) at 72:19–73:9 (Enscore). This formulation also was identical

to that of Sancuso®. See JTX-005 at 6; Trial Tr. Day 2 (2/2/2018 AM) at 78:6–17, 85:23–86:5

(Rifaat). Both Systems 1784-HN2829-191-1L and 1784-HN2829-191-2L include pressure

sensitive adhesives that contain vinyl acetate and 6% granisetron, the only difference being that

the former system includes a functional monomer containing non-acidic hydroxyl (-OH) groups

whereas the latter system includes a functional monomer containing carboxylic acid (-COOH)

groups. See JTX-005 at 6; JTX-003; JTX-004; PTX-022; Trial Tr. Day 1 (2/1/2018 PM) at 72:19–

73:9 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 78:25–81:22, 82:4– 7, 82:16–86:5 (Rifaat).

Notably, as pointed out by Dr. Enscore, System 1784-HN2829-191- 1L, and also Sancuso®, has

more than five times the cumulative transdermal granisetron permeation of that of 1784-HN2829-

191-2L. See JTX-005 at 6; Trial Tr. Day 1 (2/1/2018 PM) at 35:21–36:20, 47:6–16, 72:19–73:9

(Enscore). Comparing the results from these formulations shows that the non-acidic hydroxyl

moiety is the factor that materially increased transdermal delivery of granisetron—not vinyl

acetate. See JTX-005 at 6; Trial Tr. Day 1 (2/1/2018 PM) at 35:21–36:20, 47:6–16, 72:19–73:9

(Enscore).

Based on the transdermal permeation data set forth in the ’282 Patent, as

well as a review of studies conducted by Actavis, vinyl acetate does not materially affect the

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transdermal delivery of granisetron from the claimed inventive patch. See Trial Tr. Day 1 (2/1/2018

PM) at 42:25–43:2, 43:8–14, 71:8–73:9 (Enscore).

The second basic and novel property of the claimed invention as construed

by the Court is “granisetron stability in the patch.” Docket No. 62 at 7. The ’282 Patent discloses

that the granisetron stability in the patches formulated in Duro-Tak® 387-2287 were tested at 5

ºC, 25 ºC, and 40 ºC for six weeks. See JTX-001 at 9, 9:l. 60–10: l. 21 (Example 2, Table 5). The

result shows that granisetron is stable in the patch formulated in Duro-Tak® 387-2287 for 6 weeks

at all three temperatures. See id.

Like the formulation studied in Example 2 (Table 5) of the ’282 Patent, as

well as Sancuso®, Actavis’s Accused Product is also formulated in Duro-Tak® 387-2287. See,

e.g., JTX-006 at 4. Actavis also tested the stability of its Accused Product, and the results show

that the granisetron in Actavis’s Accused Product is stable after 26 weeks at room temperature (25

ºC) and stable after 13 weeks at elevated temperature (40 ºC). JTX-005 at 17; JTX-006 at 70; Trial

Tr. Day 1 (2/1/2018 PM) at 68:25–69:10; 74:14–22 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at

98:21–103:6 (Anderson). The results show that the granisetron within Actavis’s Accused Product

is stable. JTX-005 at 17; JTX-006 at 8–9, 70; Trial Tr. Day 1 (2/1/2018 PM) at 68:25–69:10;

74:14–22 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 91:19–93:5, 93:16–97:1 (Rifaat); Trial Tr.

Day 2 (2/2/2018 AM) at 98:21–103:6 (Anderson). That is, the stability data reported in the ’282

Patent and for Actavis’s Accused Product (measured for adhesives containing vinyl acetate), meet

the stability limitation of claim 1 of the ’282 Patent. See JTX001 at 9, 9: l. 60–10:l. 21; JTX-005

at 17; Trial Tr. Day 1 (2/1/2018 PM) at 68:25–69:10; 74:14–22 (Enscore); see also PTX-094 at

63; Trial Tr. Day 1 (2/1/2018 PM) at 48:21–49:2 (Enscore). For these reasons, the Court finds that

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there is no basis to support an allegation that vinyl acetate materially affects the chemical stability

of granisetron in the claimed inventive patch.

The third basic and novel property of the claimed invention as construed by

the Court is “complete release of granisetron from the patch.” (Docket No. 62 at 7.) As discussed,

the ’282 Patent discloses that the granisetron loading of approximately 260 µg/cm2 is completely

released through murine skin in vitro after 24 hours. See JTX-001 at 2 (FIGs. 1–2), at 8, 8:56–61,

at 9, 9:1–10, 44–57; Trial Tr. Day 1 (2/1/2018 PM) at 47:21–48:20 (Enscore); Trial Tr. Day 3

(2/5/2018 AM) at 39:5–16, 42:14–44:9, 46:10–12, 47:12–15 (Tan). As a result of the Court finding

that the proper measure of “complete release” is in vitro, and demonstrated by the in vitro data of

Table 2 of the ’282 Patent for the fact that the Sancuso® (Duro-Tak® 387-2287) patch had

completely released 100% (or more given that its approximately 260 µg/cm2 ) of its granisetron

drug content between 24 and 48 hours, vinyl acetate had no material effect on the “complete

release,” i.e., depletion, of the granisetron from the patch. JTX-001 at 9, 9:1– 10, 44–57; Trial Tr.

Day 1 (2/1/2018 PM) at 36:21–38:9, 40:13–41:19, 47:21–48:20 (Enscore).

Actavis’s Formulation Transfer Report discloses that Actavis’s Accused

Product was tested using human skin in vitro and shows “complete release.” See, e.g., JTX-005 at

9–10 (showing complete granisetron release on day 7); PTX-219; Trial Tr. Day 1 (2/1/2018 PM)

at 66:25–68:21, 73:11–74:6 (Enscore); supra § (I)(G)(2)(c)(3). Therefore, vinyl acetate does not

materially affect the third basic and novel property of the invention as construed by the Court, i.e.,

complete release of granisetron from the claimed inventive patch. See Trial Tr. Day 1 (2/1/2018

PM) at 66:25–68:21, 73:11–74:6 (Enscore).

Dr. Enscore stated that it was not necessary to do experimental studies

because the data in the patent and in Actavis’s own formulation work provided the necessary

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information to conclude that vinyl acetate did not materially affect the basic and novel properties

of the invention of the ’282 Patent. See Trial Tr. Day 2 (2/2/2018 AM) at 38:7–39:14 (Enscore).

As Dr. Enscore testified, a POSA could not simply “remove” vinyl acetate from Duro-Tak® 387-

2287, as it would no longer be Duro-Tak® 387-2287 without the vinyl acetate at the specific

percentage. See Trial Tr. Day 1 (2/1/2018 PM) at 108:24–109:5 (Enscore).

In view of the above discussion, the Court finds that vinyl acetate does not

materially affect any of the basic and novel properties of the claimed inventive patch.

(2) Glycidyl Methacrylate

Glycidyl methacrylate is present in Duro-Tak® 387-2287, but is not recited

in claim 1 of the ’282 Patent. See, e.g., JTX-002 at 572; JTX-055 at 3–4; DTX0181; Trial Tr. Day

1 (2/1/2018 PM) at 49:11–16, 69:18–70:6 (Enscore). In addition to the arguments regarding vinyl

acetate, Actavis also alleges that Actavis’s Accused Product does not infringe claim 1 of the ’282

Patent due to the presence of 0.15% (w/w) glycidyl methacrylate in Duro-Tak® 387- 2287. See

Trial Tr. Day 1 (2/1/2018 PM) at 69:18–25 (Enscore). The Court credits Dr. Enscore’s testimony

in finding that glycidyl methacrylate does not materially affect the basic and novel properties of

the claimed patch. See Trial Tr. Day 1 (2/1/2018 PM) at 75:2–15, 77:14–18; see also Trial Tr.

Day 1 (2/1/2018 PM) at 43:3–5, 49:17–50:1 (Enscore).

Contrary to Dr. Enscore, Dr. Tan cited to no documentary evidence in

reaching his conclusions and provided no data that glycidyl methacrylate materially affects any

property. See Trial Tr. Day 3 (2/5/2018 AM) at 68:22–69:7, 70:21–72:1, 85:1–3 (Tan). Further,

Dr. Tan’s conclusory testimony that glycidyl methacrylate acts as a crosslinking agent in Duro-

Tak® 387-2287 is directly contradicted by National Starch’s literature for this product, as well as

Dr. Michniak-Kohn’s testimony. Duro-Tak® 387-2287 contains no crosslinking agent and,

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contrary to Dr. Tan’s testimony, is described as non-curing (in the product literature for 387-2287,

which Dr. Tan admitted means “not crosslinked”). JTX-004 at 2; JTX-002 at 571–74; DTX0181;

see Trial Tr. Day 1 (2/1/2018 PM) at 50:14–25, 75:16–20, 87:5–20 (Enscore); Trial Tr. Day 2

(2/2/2018 AM) at 39:15–40:15 (Enscore); Trial Tr. Day 3 (2/5/2018 AM) at 69:12–70:7, 70:18–

20 (Tan); Trial Tr. Day 4 (2/6/2018 PM) at 100:12–15 (Michniak-Kohn); Trial Tr. Day 5 (2/7/2018

AM) at 46:12–14 (Enscore).

The Court credits Dr. Enscore’s testimony in finding that glycidyl

methacrylate often functions as a crosslinking monomer at an appropriate concentration, and the

0.15% (w/w) is too low to produce any crosslinking in Actavis’s Accused Product. Trial Tr. Day

1 (2/1/2018 PM) at 22:1–10, 49:17–50:1, 75:2–15 (Enscore). Other prior art of record also describe

DuroTak® 387-2287 as “contain[ing] no crosslinking agent.” See JTX-018 at 3, 4:l.2; JTX-017 at

7; DTX0137 at 28; Trial Tr. Day 5 (2/7/2018 AM) at 46:17–20, 55:7–14 (Enscore). Moreover,

according to the product literature for 387-2287, “[t]he pressure sensitive adhesive may also

function as a polymer matrix to hold the drug and any excipients in the formulation.” DTX0181;

Trial Tr. Day 2 (2/2/2018 AM) at 41:14–42:7 (Enscore). As Dr. Enscore explained, the glycidyl

methacrylate in Actavis’s Accused Product is there to provide a site for crosslinking if an

additional crosslinking agent is added to the polymer for it to react with. See Trial Tr. Day 1

(2/1/2018 PM) at 49:17–50:13, 118:11–17 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 40:22–

42:7 (Enscore). Actavis’s Accused Product does not contain an additional crosslinker that would

react with glycidyl methacrylate to crosslink the Duro-Tak® 2287. See Trial Tr. Day 2 (2/2/2018

AM) at 41:3–13 (Enscore).

Further, in addition to Duro-Tak® 2287 (DT 2287), the ’282 Patent

discloses testing results of Duro-Tak® 2353 (DT 2353), which also contains glycidyl

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methacrylate. See JTX-001 at 8–9, 8: l. 35–9:l. 57 (Example 1); Trial Tr. Day 1 (2/1/2018 PM) at

51:4–15, 75:22–76:8 (Enscore). The difference between DT 2287 and DT 2353 is that DT 2287

includes a functional monomer of non-acidic hydroxyl (-OH) groups and DT 2353 includes a

functional monomer containing carboxylic acid (-COOH) groups. See Trial Tr. Day 1 (2/1/2018

PM) at 51:4–15, 75:22–76:10 (Enscore). Notably in Table 2, after 3 and 6 hours, the patch prepared

using DT 2287 exhibited cumulative granisetron permeation over a hundred times higher than that

achieved using the acrylic adhesive DT 2353. See JTX-001 at 9, 9:1–10 (Table 2) (displaying, for

example, that at hour 6, DT 2287 cumulative permeation was 92.0 µg/cm2 and DT 2353 was 0.8

µg/cm2 ). Therefore, a comparison of granisetron patches prepared using the adhesives DT 2253

and DT 2287 shows that for two adhesives that each contain glycidyl methacrylate, the glycidyl

methacrylate was a non-factor in the transdermal flux of granisetron. See Trial Tr. Day 1 (2/1/2018

PM) at 51:4–15, 75:22–76:10 (Enscore). Instead, the non-acidic hydroxyl functional group

appeared to play a substantial role in increasing the transdermal delivery of granisetron. See Trial

Tr. Day 1 (2/1/2018 PM) at 51:4–15, 75:22–76:10 (Enscore). Therefore, glycidyl methacrylate

does not materially affect the transdermal delivery of granisetron. See Trial Tr. Day 1 (2/1/2018

PM) at 75:22–76:10 (Enscore).

Glycidyl methacrylate also does not materially affect the “complete release”

or stability of granisetron in Actavis’s Accused Product. See Trial Tr. Day 1 (2/1/2018 PM) at

76:15–77:1 (Enscore). As explained above, Actavis’s ANDA includes the results of tests of exhibit

batches demonstrating that Actavis’s Accused Product provides for the complete release of

granisetron from the patch. See JTX-005 at 9–10 (showing complete granisetron release on day 7);

PTX-219; Trial Tr. Day 1 (2/1/2018 PM) at 66:25–68:21, 76:15–77:1 (Enscore); supra §§

(I)(G)(2)(c)(3), (c)(1). Moreover, Actavis Formulation Transfer Report (and other ANDA

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documents) proves the granisetron stability in the patch of Actavis’s Accused Product. See JTX-

005 at 17; JTX-006 at 70, Trial Tr. Day 1 (2/1/2018 PM) at 68:25–69:10, 77:8–13 (Enscore); Trial

Tr. Day 2 (2/2/2018 AM) at 91:19–93:5, 93:16–97:1 (Rifaat); Trial Tr. Day 2 (2/2/2018 AM) at

98:21–103:6 (Anderson); supra §§ (I)(G)(2)(c)(2); see also Trial Tr. Day 1 (2/1/2018 PM) at

51:19–24 (Enscore).

Finally, as discussed above, the concentration of glycidyl methacrylate in

the adhesive of Actavis’s Accused Product is 0.15% (w/w), which would be too low to have any

material effect on the granisetron stability, granisetron release, or granisetron permeation from the

inventive patch. See Trial Tr. Day 1 (2/1/2018 PM) at 43:3–5, 49:18–50:1, 51:19–24, 75:3– 15

(Enscore); see also PTX-094 at 63; Trial Tr. Day 1 (2/1/2018 PM) at 52:1–5 (Enscore). Moreover,

the specification of the ’282 Patent leads to the conclusion that the inventors also did not believe

glycidyl methacrylate to have a material effect on the basic and novel properties of the invention.

As the ’282 Patent states, the adhesive may contain glycidyl methacrylate at levels between 0.05

and 1% (w/w). See JTX-001 at 6, 4:28–30. Not once did the inventors put glycidyl methacrylate

into claim 1, even when amending the claim from “comprising” instead of “consisting essentially

of.” See generally JTX-002. Given that the glycidyl methacrylate at 0.15% (w/w) is within the

range given in the specification, this further demonstrates that it has no material effect on the basic

and novel properties of the claimed invention. See JTX-002 at 571–74; JTX-055 at 3–4; DTX0181.

Thus, a concentration of 0.15% (w/w) glycidyl methacrylate included in Duro-Tak® 387-2287 of

Actavis’s Accused Product does not materially affect, or even have any affect at all, on any of the

basic and novel properties of the invention.

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(3) Ethanol

Actavis’s ANDA discloses that “[d]ehydrated alcohol [i.e., ethanol], USP,

used as a processing aid, is evaporated during the process and testing is performed in the finished

product with a limit of NMT [i.e. no more than] 5000 ppm.” JTX-006 at 50; see JTX-005 at 3;

Trial Tr. Day 2 (2/2/2018 AM) at 87:13–88:19 (Rifaat). Further, Actavis informed the FDA that

ethanol is “ND,” i.e., not detectable in any of the patches it tested prior to bioequivalence study.

JTX-006 at 50. Actavis has not asserted that ethanol present in Actavis’s Accused Product

materially affects the basic and novel properties of the claimed invention of the ’282 Patent. See

Trial Tr. Day 1 (2/1/2018 PM) at 70:2–16 (Enscore). Nevertheless, to the extent Actavis’s Accused

Product contains any residual ethanol, which Actavis’s ANDA indicates it does not, such ethanol,

if present, would not materially affect the basic and novel properties construed by the Court—

neither increased transdermal delivery of granisetron, nor granisetron stability in the patch, nor the

complete release of granisetron from the patch. See JTX-006 at 4; Trial Tr. Day 1 (2/1/2018 PM)

at 70:2–16, 78:8–17 (Enscore); see also PTX-023; Trial Tr. Day 2 (2/2/2018 AM) at 88:25–89:14

(Rifaat).

(4) Ethyl acetate

Actavis has not asserted that ethyl acetate present in Actavis’s Accused

Product materially affects the basic and novel properties of the claimed invention of the ’282

Patent. See Trial Tr. Day 1 (2/1/2018 PM) at 70:2–16 (Enscore). Nevertheless, Actavis’s ANDA

discloses that ethyl acetate is present in the patch at an average concentration of 408 parts per

million (ppm)3—which is equivalent to 0.0408% (w/w). See JTX-006 at 50; JTX-005 at 3; Trial

3 Actavis’s ANDA discloses ethyl acetate as a residual solvent. (See JTX-006 at 11, 49-51.) Control # 4161-1/15Z008

has residual ethyl acetate 422 ppm; 4161-11/5Z044 has 539 ppm; and 4161-1/15Z121 has 263 ppm. (See id. at 50.)

The average residual concentration of ethyl acetate is calculated as 408 ppm = (422+539+263)/3. (See id.)

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Tr. Day 2 (2/2/2018 AM) at 87:13–88:19, 89:15–90:5 (Rifaat). Actavis’s corporate witness for

research and development confirmed that neither Actavis’s Accused Product nor Sancuso®

includes any permeation enhancer or plasticizer. See Trial Tr. Day 2 (2/2/2018 AM) at 89:15–90:5,

91:2–18, 93:6–15 (Rifaat). Thus, Actavis recognizes the residual ethyl acetate in Duro-Tak® 387-

2287 does not act as a permeation enhancer or plasticizer. See Trial Tr. Day 2 (2/2/2018 AM) at

89:15–90:5, 91:2–18, 93:6–15 (Rifaat). Nor would ethyl acetate be expected to have any effect on

granisetron release or stability, particularly given its very low residual concentration in Actavis’s

Accused Product. See JTX-006 at 4; Trial Tr. Day 1 (2/1/2018 PM) at 70:2–16, 78:8–17 (Enscore).

Therefore, any ethyl acetate present in Actavis’s Accused Product is present at too low a

concentration to materially affect the basic and novel properties. See JTX-006 at 4; Trial Tr. Day

1 (2/1/2018 PM) at 70:2–16, 78:8–17 (Enscore). Accordingly, any residual ethyl acetate in

Actavis’s Accused Product does not materially affect any of the basic and novel properties

construed by the Court, neither increased transdermal delivery of granisetron, nor granisetron

stability in the patch, nor the complete release of granisetron from the patch. See Trial Tr. Day 1

(2/1/2018 PM) at 70:2–16, 78:8–17 (Enscore).

(5) Backing film or release liner

Actavis has not asserted that the backing film nor the release liner present

in Actavis’s Accused Product materially affects the basic and novel properties of the claimed

invention of the ’282 Patent. See Trial Tr. Day 1 (2/1/2018 PM) at 70:2–16 (Enscore); Trial Tr.

Day 2 (2/2/2018 PM) at 93:2–15, 93:22–94:4 (Tan).

Actavis’s ANDA states that the pharmaceutical function of backing film is

occlusivity. JTX-006 at 39; see also Trial Tr. Day 1 (2/1/2018 PM) at 26:3–27:1, 53:11–17

(Enscore); Trial Tr. Day 2 (2/2/2018 PM) at 93:2–11 (Tan).)According to Actavis’s ANDA, the

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backing film “belongs to a class of polyester/EVA films that are commonly used in transdermal

drug delivery systems. It was selected due to its wear characteristics and its known compatibility

with the API [i.e., active pharmaceutical ingredient].” JTX-006 at 39; see JTX-005 at 3; Trial Tr.

Day 2 (2/2/2018 AM) at 87:13–88:19 (Rifaat). Actavis’s ANDA No. 208726 suggested nothing

regarding the backing film interacting with the active pharmaceutical ingredient, granisetron, in

any way. See JTX-006 at 39; see also Trial Tr. Day 1 (2/1/2018 PM) at 26:3–27:1, 53:18–25

(Enscore).

Actavis’s ANDA further discloses that the pharmaceutical function of the

release liner is to serve as a protective liner for the patch prior to use. JTX-006 at 39; see also Trial

Tr. Day 1 (2/1/2018 PM) at 26:3–27:1, 53:11–17 (Enscore); Trial Tr. Day 2 (2/2/2018 PM) at

93:22–94:1 (Tan).) According to Actavis’s ANDA, the release liner “belongs to a class of

siliconecoated polyester release liners that are commonly used as protective liners for transdermal

drug delivery systems.” JTX-006 at 39. Silicon-coated release liners are used generally because

both polyester and silicone have been established to be “safe and inert” polymers. (See id.) Given

the inertness of the release liner of Actavis’s Accused Product, no person skilled in the art would

expect the release liner would interact with granisetron in anyway. See Trial Tr. Day 1 (2/1/2018

PM) at 26:3–27:1, 53:18–25 (Enscore). Nevertheless, neither backing film nor release liner of

Actavis’s Accused Product materially affects any of the three basic and novel properties of the

invention as construed by the Court. See Trial Tr. Day 1 (2/1/2018 PM) at 26:3–27:1, 53:18–25,

77:21–78:7, 78:15–17 (Enscore).

e) Literal Infringement of Dependent Claims

Actavis’s Accused Product includes each limitation of claim 1. See Trial Tr.

Day 1 (2/1/2018 PM) at 78:18–24 (Enscore); supra § (I)(G)(2).

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Actavis’s Accused Product contains Duro-Tak® 387-2287, which includes

hydroxyethyl acrylate in a concentration of approximately 5.2% w/w. See, e.g., JTX-002 at 572;

JTX-055 at 3–4; DTX0181 at 2; JTX-006 at 4–7; JTX-061 at 4; JTX-025 at 9, 15–16; PTX102;

PTX-106; JTX-005; Trial Tr. Day 1 (2/1/2018 PM) at 52:23–53:7, 60:2–4, 64:9–17 (Enscore);

supra § (I)(G)(2). Actavis’s Accused Product satisfies the limitation of “the monomer containing

non-acidic hydroxyl moiet[y] is . . . hydroxyethyl acrylate[]. . . .” See Trial Tr. Day 1 (2/1/2018

PM) at 78:25–79:12 (Enscore).

Thus, Actavis’s Accused Product and the use thereof, as specified and

described in its ANDA No. 208726, literally infringes claim 2 of the ’282 Patent. See Trial Tr. Day

1 (2/1/2018 PM) at 78:25–79:12 (Enscore).

Actavis’s Accused Product (a patch), as well as the Duro-Tak® 387-2287

acrylic adhesive contained therein, are pressure sensitive. See, e.g., PTX-106; JTX-006 at 39; JTX-

061 at 39 (“[Duro-Tak®] belongs to a class of pressure sensitive adhesives that are commonly

used in transdermal drug delivery systems.”); JTX-025 at 5, 9, 15–17; Trial Tr. Day 1 (2/1/2018

PM) at 79:13–22 (Enscore).



1 (2/1/2018 PM) 79:13–22 (Enscore).

Actavis’s Accused Product contains Duro-Tak® 387-2287, which includes

2- ethylhexyl acrylate in a concentration of approximately 68% w/w, thereby satisfying the

limitation of “50 to 90% w/w of said primary acrylate monomer.” See, e.g., JTX-002 at 572; JTX-

055 at 3–4; DTX0181 at 2; JTX-006 at 4–7; JTX-061 at 4; JTX-025 at 9, 15–16; PTX-102; PTX-

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106; JTX-005; Trial Tr. Day 1 (2/1/2018 PM) at 52:23–53:7, 60:2–4, 63:21–64:8, 79:23–80:14

(Enscore); supra § (I)(G)(2).



1 (2/1/2018 PM) at 79:23–80:14 (Enscore).

Actavis’s Accused Product contains granisetron base in a concentration of

6.00% w/w, which is within the “up to about 10% by weight of granisetron” required by claim 7.

See, e.g., JTX-061 at 4, 15, 32; JTX-025 at 14–16; Trial Tr. Day 1 (2/1/2018 PM) at 80:15–81:5,

81:10–13 (Enscore); see also Trial Tr. Day 2 (2/2/2018 AM) at 86:10–87:12 (Rifaat).



1 (2/1/2018 PM) at 80:15–81:5, 81:10–13 (Enscore).

Actavis’s Accused Product contains granisetron base in a concentration of

6.00% w/w, which is within the “a level between 6% and 7.7% w/w of granisetron” required by

claim 10. See, e.g., JTX-061 at 4, 15, 32; JTX-025 at 14–16; Trial Tr. Day 1 (2/1/2018 PM) at

80:15–81:3, 81:6–7, 81:10–13 (Enscore); see also Trial Tr. Day 2 (2/2/2018 AM) at 86:10–87:12

(Rifaat).


described in its ANDA No. 208726, literally infringes claim 10 of the ’282 Patent. See Trial Tr.

Day 1 (2/1/2018 PM) at 80:15–81:3, 81:6–7, 81:10–13 (Enscore).

Actavis’s Accused Product shows “no crystallization [of granisetron] . . .

after one month storage at room temperature and pressure”, a result that was confirmed upon three

and six months of storage at room temperature (25 °C/60% RH) and at accelerated testing (40

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°C/75% RH), thereby satisfying the limitations of claim 11. See, e.g., JTX-061 at 52, 69–71

(“Crystal Determination: Stable. All comply.”); JTX-025 at 31; JTX-006 at 70–71; JTX-005; Trial

Tr. Day 1 (2/1/2018 PM) at 81:14–82:7 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 91:19–93:5,

93:16–97:1 (Rifaat); Trial Tr. Day 2 (2/2/2018 AM) at 98:21–103:6 (Anderson).



Day 1 (2/1/2018 PM) at 81:14–82:7 (Enscore).

Actavis’s Accused Product contains an acrylic adhesive that is loaded with

granisetron in a concentration of 6.00% w/w, which is within the claimed range of between 5 and

8% w/w. See, e.g., JTX-006 at 4; JTX-061 at 3–4, 15, 20, 32, 39; JTX-025 at 3, 5, 9, 14–18, 24,

34–35; PTX-017; JTX-026; Trial Tr. Day 1 (2/1/2018 PM) at 80:15–81:3, 81:8–12 (Enscore); see

also Trial Tr. Day 2 (2/2/2018 AM) at 86:10–87:12 (Rifaat).


described in its ANDA No. 208726, literally infringes claim 21 of the ’282 Patent.4 See Trial Tr.

Day 1 (2/1/2018 PM) at 80:15–81:3, 81:8–12 (Enscore).

In claim 22, the Court construed “incorporating no plasticizers or

permeation enhancers” as its plain and ordinary meaning, which is “[a patch] that does not contain

plasticizers or permeation enhancers.” Docket No. 62 at 24. Actavis’s Accused Product does not

contain a plasticizer or permeation enhancer. See, e.g., JTX-006 at 4; PTX-017; JTX-061 at 32;

JTX-025 at 9, 15–16 (“[T]he only true excipient is the adhesive . . . .”); Trial Tr. Day 1 (2/1/2018

PM) at 82:8–83:13 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 91:2–18, 93:6–15 (Rifaat).

4 Claim 21 depends from claim 19 and therefore incorporates each and every limitation of that dependent claim.

Because claim 19 merely specifies a broader range for the granisetron concentration, for the same reasons that

Actavis’s Accused Product meets the limitations of claim 21, the limitations of claim 19 are similarly satisfied

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Actavis’s Accused Product contains Duro-Tak® 387-2287, which does not include a permeation

enhancer or plasticizer. See, e.g., JTX-061 at 4; JTX-025 at 9, 15–16; JTX-055 at 3–4; JTX-002 at

571–574; DTX0181 at 2; JTX-006 at 4–7; PTX-102; PTX-106; JTX-005; Trial Tr. Day 2

(2/2/2018 AM) at 91:2–18, 93:6–15 (Rifaat).

There is no specification for a plasticizer or permeation enhancer in

Actavis’s Accused Product. See, e.g., JTX-025 at 12, 19–20; JTX-006 at 4; Trial Tr. Day 2

(2/2/2018 AM) at 91:2–18 (Rifaat). Testing of Actavis’s Accused Product revealed that no ethanol

was detected in Actavis’s Accused Product. See, e.g., JTX-025 at 22–23, 30; JTX-006 at 50;

PTX023; Trial Tr. Day 2 (2/2/2018 AM) at 88:25–89:14 (Rifaat); see also Trial Tr. Day 1

(2/1/2018 PM) at 70:2–16 (Enscore); supra § (I)(G)(2)(d)(3). While Actavis’s ANDA discloses

that residual ethyl acetate is present in the patch at an average concentration of 408 parts per

million (ppm)5—which is equivalent to 0.0408% (w/w), Actavis’s corporate witness for R&D

confirmed that neither Actavis’s Accused Product nor Sancuso® includes any permeation

enhancer or plasticizer. See JTX-006 at 4; Trial Tr. Day 2 (2/2/2018 AM) at 89:15–90:5, 91:2– 18,

93:6–15 (Rifaat); see also Trial Tr. Day 1 (2/1/2018 PM) at 70:2–16, 83:4–10 (Enscore).

Therefore, to the extent that solvents used to manufacture Actavis’s Accused Product may be

present, according to Actavis’s ANDA such solvents do not function as a plasticizer or permeation

enhancer. See, e.g., JTX-025 at 12, 19–20; Trial Tr. Day 1 (2/1/2018 PM) at 82:8–21 (Enscore);

Trial Tr. Day 2 (2/2/2018 AM) at 89:15–90:5, 91:2–18, 93:6–15 (Rifaat). Thus, Actavis recognizes

the residual ethyl acetate in Duro-Tak® 387-2287 does not act as permeation enhancer or

plasticizer. See, e.g., JTX-025 at 12, 19–20; Trial Tr. Day 2 (2/2/2018 AM) at 89:15–90:5, 91:2–

5 Actavis’s ANDA discloses ethyl acetate as a residual solvent. (See JTX-006 at 11, 49-51.) Control # 4161-1/15Z008

has residual ethyl acetate 422 ppm; 4161-11/5Z044 has 539 ppm; and 4161-1/15Z121 has 263 ppm. (See id. at 50.)

The average residual concentration of ethyl acetate is calculated as 408 ppm = (422+539+263)/3. (See id.)

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18, 93:6–15 (Rifaat); see also Trial Tr. Day 1 (2/1/2018 PM) at 70:2–16, 78:8–17 (Enscore); supra

§ (I)(G)(2)(d)(4)



Day 1 (2/1/2018 PM) at 82:8–83:13 (Enscore).

Actavis’s Accused Product contains an “acrylic adhesive loading of 6%

w/w of active granisetron . . . .” See, e.g., JTX-006 at 4; JTX-061 at 3–4, 15, 20, 32, 39; JTX-025

at 3, 5, 9, 14–18, 24, 34–35; PTX-017; JTX-026; PTX-014; Trial Tr. Day 1 (2/1/2018 PM) at

83:14–23 (Enscore). Actavis’s Accused Product is an acrylic adhesive with a 52 cm2 surface area,

which is within the claimed range of between 10 and 100 cm2. See, e.g., JTX-006 at 3; JTX-026;

PTX-014; PTX-017; JTX-061 at 3; JTX-025 at 3, 16, 24; Trial Tr. Day 1 (2/1/2018 PM) at 83:24–

84:2 (Enscore).



Day 1 (2/1/2018 PM) at 83:14–84:5 (Enscore).

Actavis’s Accused Product’s granisetron content “remains substantially

unchanged when stored at 40° C. for six weeks.” See, e.g., JTX-005 at 17; JTX-061 at 27, 44– 45;

JTX-025 at 8–9; JTX-005; JTX-006 at 70; Trial Tr. Day 1 (2/1/2018 PM) at 84:17–24 (Enscore);


at 98:21–103:6 (Anderson).



Day 1 (2/1/2018 PM) at 84:6–9, 84:17–24, 85:2–5 (Enscore).

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Actavis’s Accused Product meets each and every limitation recited in

claims 2, 4, 5, 7, 10, 11, 21–23, and 28 of the ’282 Patent. Therefore, Actavis’s Accused Product

and the use thereof, as specified and described in its ANDA No. 208726, literally infringes claims

2, 4, 5, 7, 10, 11, 21–23, and 28 of the ’282 Patent.

f) Literal Infringement of Claim 26

Actavis’s Accused Product includes each limitation of claim 1. See Trial Tr.

Day 1 (2/1/2018 PM) at 78:18–24, 85:2–5 (Enscore); supra § (I)(G)(2). The Court finds that

Actavis’s literal infringement of claim 26 of the ’282 Patent is established by Plaintiffs’ expert Ms.

Michele Walther, who has almost 20 years of nursing experience, including 13 years of experience

treating thousands of chemotherapy patients and CINV. See Trial Tr. Day 2 (2/2/2018 PM) at

5:21–6:2, 15:22–16:1 (Walther).) The Court does not accept the opinions relating to claim 26 from

Actavis’s expert Dr. Tan, who does not have a medical degree or training in prescribing

pharmaceutical drugs. (See Trial Tr. Day 3 (2/5/2018 AM) at 72:5–12 (Tan).

As set forth in Actavis’s proposed Prescribing Information, Actavis is

seeking FDA approval to sell or offer for sale its Accused Product for the “prevention of nausea

and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy for up to 5

consecutive days.” See PTX-014 at 2, 4; PTX-017 at 2, 4; JTX-026 at 1-2; Trial Tr. Day 2

(2/2/2018 AM) at 104:15–110:15 (Petrie); Trial Tr. Day 2 (2/2/2018 PM) at 28:6–9, 29:11–15

(Walther). Dr. Tan agreed that a medical professional would practice the method of claim 26, and

that Actavis’s proposed Prescribing Information provides instructions to a medical professional as

to how the product is to be used. See Trial Tr. Day 3 (2/5/2018 AM) at 72:16–19, 73:2–7 (Tan).

Therefore, the proposed indication in Actavis’s proposed Prescribing Information for which

Actavis is seeking FDA-approval satisfies the limitation of claim 26 of the ’282 Patent that requires

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“[a] method for the treatment and/or prophylaxis of chemotherapy induced nausea and vomiting

in a patient in need thereof.” See Trial Tr. Day 2 (2/2/2018 PM) at 28:23–30:22 (Walther).

Actavis’s proposed Prescribing Information further instructs healthcare

providers that its Accused Product “should be applied to clean, dry, intact healthy skin on the upper

outer arm.” See PTX-014 at 2, 4, 18–25; PTX-017 at 2, 4, 18–25; JTX-026 at 1–2, 12–16; Trial

Tr. Day 2 (2/2/2018 PM) at 29:19–30:1 (Walther). Dr. Tan agreed that Actavis’s proposed

Prescribing Information provides instructions to a medical professional as to how the product is to

be used. See Trial Tr. Day 3 (2/5/2018 AM) at 73:2–7 (Tan). Actavis’s Accused Product is “an

adhesive patch according to claim 1,” as required by claim 26 of the ’282 Patent. See JTX006 at

3; JTX-026; PTX-014; PTX-017; Trial Tr. Day 1 (2/1/2018 PM) at 62:2–64:17, 78:18– 24, 85:2–

5 (Enscore); supra § (I)(G)(2). For these reasons, Actavis intends for its Accused Product to be

used in a manner that satisfies the limitation of claim 26 of the ’282 Patent that requires “said

method comprising applying an adhesive patch according to claim 1 to the skin of the patient.”

See Trial Tr. Day 2 (2/2/2018 PM) at 28:23–30:22 (Walther). Thus, the use of Actavis’s Accused

Product, as specified and described in ANDA No. 208726, literally infringes claim 26 of the ’282

Patent. See Trial Tr. Day 2 (2/2/2018 PM) at 30:14–22 (Walther).

In view of the above, Actavis is seeking FDA-approval for an ANDA

product that, when used according to Actavis’s proposed Prescribing Information, will directly

infringe claim 26 of the ’282 Patent. See PTX-014; PTX-017; JTX-026; Trial Tr. Day 2 (2/2/2018

AM) at 104:15–110:15 (Petrie); Trial Tr. Day 2 (2/2/2018 PM) at 30:14–31:20 (Walther). Further,

the use of Actavis’s Accused Product, according to Actavis’s proposed Prescribing Information,

will result in direct infringement of claim 26 of the ’282 Patent if Actavis’s Accused Product is

sold in the United States. See Trial Tr. Day 2 (2/2/2018 PM) at 30:14–31:20 (Walther). Further,

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Actavis was and is aware of the ’282 Patent and intends for its Accused Product to be used in a

manner that would directly infringe claim 26 of the ’282 Patent when its Accused Product is

approved by the FDA. See Trial Tr. Day 2 (2/2/2018 AM) at 59:17–18, 59:20 (Rifaat); Trial Tr.

Day 2 (2/2/2018 PM) at 30:14–31:20 (Walther); Trial Tr. Day 5 (2/7/2018 AM) at 81:15–18

(Enscore). Finally, Actavis’s Accused Product is specifically adapted to deliver granisetron

through the skin such that healthcare professionals, patients, and others will use Actavis’s Accused

Product in a manner that directly infringes claim 26 of the ’282 Patent. See Trial Tr. Day 2

(2/2/2018 PM) at 31:4–20 (Walther).

H. Facts relating to invalidity

Actavis proffered the testimony of Dr. Hock Tan that the ’282 Patent is

invalid for lack of enablement and for indefiniteness under 35 U.S.C. § 112. Actavis also proffered

testimony from Dr. Bozena Michniak-Kohn and Ms. Marianna Holmes that the ’282 Patent is

invalid as anticipated under 35 U.S.C. § 102 and/or obvious under 35 U.S.C. § 103. In rebuttal,

Plaintiffs relied upon the testimony of Dr. David Enscore.

1. Enablement

Dr. Tan alleged that the specification of the ’282 Patent does not enable a

POSA to practice the claimed invention without undue experimentation because the ’282 Patent

does not enable the in vivo “complete release of granisetron from the patch.” (See Trial Tr. Day 2

(2/2/2018 PM) at 63:22–25 (Tan); Trial Tr. Day 3 (2/5/2018 AM) at 24:7–24; 41:19–42:13 (Tan).).

However, Dr. Tan admitted that:

- In vitro testing using a Franz cell apparatus was routinely performed in order to screen

and evaluate transdermal patch formulations for further study (Trial Tr. Day 3 (2/5/2018

AM) at 37:3–38:5 (Tan));

- The only data presented and discussed in the ’282 Patent concerning the complete release

of granisetron are the in vitro experiments described in Example 1, not in vivo experiments

(Trial Tr. Day 3 (2/5/2018 AM) at 38:25–39:16; 47:4–15 (Tan));

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- A POSA would understand that Example 1 of the ’282 Patent actually discloses a

transdermal patch that undergoes the complete release of granisetron within 24 hours (Trial

Tr. Day 3 (2/5/2018 AM) at 47:4–15 (Tan)); and

- A POSA would have known that no transdermal patch undergoes the complete release of

its drug load under normal in vivo conditions of use (Trial Tr. Day 3 (2/5/2018 AM) at

49:8–17 (Tan)).

Thus, the Court credits Dr. Enscore’s testimony that a POSA reading the

’282 Patent would not believe that the basic and novel property of “complete release” requires in

vivo testing. See Trial Tr. Day 5 (2/7/2018 AM) at 74:12–75:7; 76:19–77:5 (Enscore). Rather, as

set forth in the ’282 Patent a POSA would understand that the “complete release” was determined

using in vitro testing. See Trial Tr. Day 5 (2/7/2018 AM) at 75:17–76:18 (Enscore). And further,

that a POSA would reasonably rely on the in vitro experiments in Example 1 of the ’282 Patent as

enabling a POSA to practice the claimed invention without undue experimentation. See Trial Tr.

Day 5 (2/7/2018 AM) at 77:6–21 (Enscore).

The Court construed the term “consisting essentially of” as requiring the

listed monomers and open to unlisted monomers that do not materially affect the basic and novel

properties of the invention, the basic and novel properties of the invention being: (1) increased

transdermal delivery of granisetron; (2) granisetron stability in the patch; and (3) the complete

release of granisetron from the patch. See Docket No. 62 at 7. The Court has applied its claim

construction in analyzing whether claim 1 is enabled by the specification of the ’282 Patent such

that the invention can be practiced by a POSA without undue experimentation. a. The Specification

of the ’282 Patent Discloses the “Complete Release” of Granisetron from the Claimed Inventive

Patch.

A POSA would look to the ’282 Patent, which describes the “complete

release” of granisetron as being the “complete depletion” of granisetron from 72 complete release

of granisetron from the inventive patch. See Trial Tr. Day 3 (2/5/2018 AM) at 47:4–15 (Tan).

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The Court further credits Dr. Enscore’s testimony in finding that a POSA

would not view the data in Example 1 and Table 2 of the ’282 Patent as unreliable because a POSA

would have known that experimental variability and error are part and parcel of such experiments.

See Trial Tr. Day 5 (2/7/2018 AM) at 77:6–21; 80:19–24 (Enscore). Specifically, a POSA would

understand that variability up to plus or minus 10% in granisetron content is generally acceptable

in the commercial manufacture of patches, and that the variability could be even higher for

experimental patches. See Trial Tr. Day 5 (2/7/2018 AM) at 77:6–21 (Enscore, discussing JTX-

001, Example 1); 77:22–79:11 (Enscore, discussing JTX-005, Tables 5–6, and summary thereof

in PTX-219). Indeed, Dr. Tan agreed that in vitro tests using Franz cell apparatus necessarily

include variability based on the type of skin used for the testing (e.g., murine skin vs. human skin),

the surface area of the skin, as well as variability in the preparation of the patches. See Trial Tr.

Day 3 (2/5/2018 AM) at 39:17–40:9; 47:16–48:13 (Tan).

Such variability and experimental error is exemplified in Actavis’s own

specifications for its proposed product, which is permitted to have a granisetron content that varies

as much as ±10%. See JTX-005 at 20 (Table 13); Trial Tr. Day 5 (2/7/2018 AM) at 77:24–78:6

(Enscore). Further, in vitro testing of Actavis’s experimental patches showed cumulative

granisetron release of 102% (±34%), 109% (±23%), and 106 (±27%) (see JTX-005 at 9–10).

Thus, Actavis tested its own patches using the same in vitro testing set forth

in the ’282 Patent and observed an average drug release of 105.6%—confirming that variability in

such experiments is not unexpected. See JTX-005 at 9–10 (summarized at PTX-219); Trial Tr.

Day 5 (2/7/2018 AM) at 77:22–79:11 (Enscore); Trial Tr. Day 3 (2/5/2018) at 49:18–50:6; 54:6–

56:8 (Tan).

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Similar to Actavis’s in vitro testing of transdermal patches prepared using

DuroTak® 387-2287 having 6% by weight g 74 drug for another 24 hours. See JTX-001 at 9,

10:12–21; Trial Tr. Day 5 (2/7/2018 AM) at 80:25–81:3 (Enscore). Therefore, a POSA would have

understood, as Actavis’s own in vitro tests confirmed, that the patches tested in Example 2 of the

’282 Patent likewise would exhibit “complete release” of granisetron at longer time periods. See

JTX-005 at 9–10 (summarized at PTX-219); Trial Tr. Day 5 (2/7/2018 AM) at 77:22–79:11;

80:25–81:3 (Enscore); Trial Tr. Day 3 (2/5/2018) at 54:6–56:8 (Tan).

In sum, the Court finds that a POSA would have reasonably relied upon the

in vitro permeation data in Example 1 of the ’282 Patent as showing the complete release of

granisetron from the inventive patch. Trial Tr. Day 5 (2/7/2018 AM) at 77:8–21; 80:19–24

(Enscore); Trial Tr. Day 3 (2/5/2018 AM) at 39:17–40:9; 47:4–48:13 (Tan).

Despite the guidance and disclosure provided by the ’282 Patent, Dr. Tan

alleges that a POSA would understand that the “complete release of granisetron” requires in vivo

testing. See Trial Tr. Day 2 (2/2/2018 PM) at 24:7–24 (Tan); Trial Tr. Day 3 (2/5/2018 AM) at

42:9–13 (Tan). Further, Dr. Tan argues that the “complete release of granisetron” must occur

during the period of therapeutic use—in this case the seven-day period that Sancuso® is applied

to a patient’s skin. (See Trial Tr. Day 3 (2/5/2018 AM) at 24:19–24 (Tan).) For the following

reasons, the Court does not find Dr. Tan’s testimony credible, and instead credits the testimony of

Dr. Enscore in finding that a POSA would not have required in vivo testing showing the “complete

release” of granisetron in order to practice the claimed invention.

First, as discussed above, a POSA would have looked to the specification

of the ’282 Patent for a discussion of “complete release,” and, in doing so, would have seen that

the ’282 Patent itself lacks any disclosure of the “complete release” of granisetron using in vivo

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test methods. See Trial Tr. Day 5 (2/7/2018 AM) at 74:12–75:7; 76: (Enscore); Trial Tr. Day 3

(2/5/2018 AM) at 44:14–21; 47:4–15 (Tan). For this reason, a POSA would have relied upon the

in vitro testing that demonstrate this basic and novel property of the claimed inventive patches.

Trial Tr. Day 5 (2/7/2018 AM) at 75:17–76:18; 80:19–81:3 (Enscore).

Second, a POSA would have known that commercial transdermal products

“are not designed to completely deliver their entire drug load during the stated duration in vivo

because you don’t want patients running out of drug.” See Trial Tr. Day 5 (2/7/2018) at 76:19–

77:5 (Enscore). Therefore, in 2003-2004 a POSA would have known that no matrix-type patches

completely released an active agent during in vivo clinical use. See Trial Tr. Day 5 (2/7/2018 AM)

at 74:19–75:7; 76:19–77:5 (Enscore). Further, Dr. Tan admitted that the in vivo data that is

reported in the Sancuso® label came after the filing date of the ’282 Patent, and thus would not

have been something a POSA would have relied upon or even considered when reviewing the ’282

Patent. See Trial Tr. Day 3 (2/5/2018 AM) at 48:14–49:7 (Tan). Thus, a POSA would have had no

reason to look for in vivo testing to evaluate the “complete release” of granisetron from a patch,

let alone the complete release over a period of clinical use. See Trial Tr. Day 5 (2/7/2018) at

(Enscore).

Third, a POSA would not understand the Court’s claim construction to

require “the complete release of granisetron” within seven days of being applied to a patient to

prevent nausea and vomiting. See Trial Tr. Day 5 (2/7/2018) at 75:12–16 (Enscore). Indeed, Dr.

Tan admitted that the ’282 Patent does not include any limit on the time period over which the

“complete release of granisetron” can be measured. See Trial Tr. Day 3 (2/5/2018 AM) at 44:22–

45:9 (Tan). Moreover, Dr. Tan admitted that given sufficient time the inventive patches would

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eventually demonstrate complete in vivo release. See Trial Tr. Day 3 (2/5/2018 AM) at 46:13–

47:3 (Tan).

For these reasons, the Court finds that Actavis has improperly imposed

much too rigid of a test for evaluating whether the ’282 Patent enables the “complete release of

granisetron” that neither reflects the guidance provided in the specification of the ’282 Patent or

the background knowledge of a POSA.

Finally, Actavis’s allegations that the lack of guidance provided by the ’282

Patent would require a POSA to engage in undue experimentation in order to practice the claimed

invention are belied by Actavis’s own development of its ANDA Product. See PTX-012; Trial Tr.

Day 5 (2/7/2018 AM) at 81:4–83:10 (Enscore). Specifically, Actavis filed ANDA No. 208726 for

a generic granisetron transdermal system product, 3.1 mg/24 hours, on November 9, 2015, and the

’282 Patent was publicly available prior to Actavis’s development of its ANDA product. See, e.g.,

Trial Tr. Day 5 (2/7/2018 AM) at 81:12–18 (Enscore). On May 30, 2014, Actavis held an internal

meeting to kick off the development of its Accused Product. See PTX-012 at 1; Trial Tr. Day 2

(2/2/2018 AM) at 61:25–62:18 (Rifaat); Trial Tr. Day 5 (2/7/2018 AM) at 81:21–82:2 (Enscore).

Actavis’s development activities included: (i) reverse-engineering (deformulation) of Sancuso®;

(ii) in vitro granisetron transdermal flux experiments to verify analytical results and select the

specific adhesive; and (iii) demonstration of bioequivalence between Actavis’s Accused Product

and Sancuso®. See JTX-005; JTX-006; JTX-025; see also Trial Tr. Day 5 (2/7/2018 AM) at 82:3–

10 (Enscore) Trial Tr. Day 5 (2/7/2018 AM) at 153:2–10 (Michniak-Kohn). In total, over a period

of four to five months Actavis evaluated twelve different transdermal formulations compared to

Sancuso®, but eventually settled on a product that contains the same amount of granisetron in the

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same acrylic adhesive having the same surface area as Sancuso®. See JTX-005 at 6–7; JTX-006;

JTX-025; Trial Tr. Day 5 (2/7/2018 AM) at 82:22–83:10 (Enscore).

The Court credits Dr. Enscore’s testimony “[t]hat testing twelve

formulations over a four- and five-month period does not constitute undue experimentation.” Trial

Tr. Day 5 (2/7/2018 AM) at 83:3–10 (Enscore).

For the reasons discussed above, based on the disclosures and testing set

forth in the ’282 Patent, the Court finds that a POSA could make and use the inventive transdermal

patches of the Asserted Claims that provide the “complete release” of granisetron without undue

experimentation.

2. Indefiniteness

The Court will not consider whether the ’282 Patent is invalid for

indefiniteness, as Actavis did not provide any evidence to support such a defense, and Actavis’s

expert Dr. Tan did not even know what the term “indefinite” meant generally, let alone in the

context of patent law. See Trial Tr. Day 3 (2/5/2018) at 32:24–33:1 (Tan).

3. Anticipation

Lee (JTX-019, European Patent Application No. EP 1 163 902 A2)

discloses a novel acrylic adhesive capable of increasing the skin permeation and stability of

hydrophilic drugs or salt forms of various drugs. JTX-019 at 1, Abstract. Hydrophilic drugs and

salt forms of drugs are typically very difficult to administer through the skin, and there is not a

single commercial transdermal product that uses a salt form of a drug. Trial Tr. Day 5 (2/7/2018

AM) at 13:12–19 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 65:8–24 (Michniak-Kohn). In order

to administer such drugs transdermally, Lee’s inventive acrylic adhesives incorporate monomers

having poly(ethylene oxide) or poly(ethylene oxide) monomethyl ether side chains. JTX-019 at 3,

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¶¶ [0015]–[0016], [0018], [0022], [0024], claim 1;Trial Tr. Day 5 (2/7/2018 AM) at 12:15–13:19

(Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 65:8–14; 65:25–66:7; 76:13–21 (Michniak Kohn).

Poly(ethylene oxide) (and poly(ethylene oxide) monomethyl ether) groups are commonly referred

to as “PEG” (an abbreviation for “Poly(Ethylene Glycol)”), which has a similar chemical structure.

Trial Tr. Day 5 (2/7/2018 AM) at 13:24–14:6 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 66:2–

18 (Michniak-Kohn). The monomers having PEG side chains can be introduced into Lee’s

inventive acrylic adhesives by copolymerization or by chemical reaction after the acrylic adhesive

has polymerized. JTX-019 at 4, ¶ [0027]; Trial Tr. Day 5 (2/7/2018 AM) at 13:9–15; 18:9–20

(Enscore).

Lee distinguishes the inventive acrylic adhesives having PEG side chains

from “conventional” acrylic adhesives prepared using monomers that have, for example, hydroxyl

or carboxylic acid functional groups. See JTX-019 at 3–4, ¶ [0025]; Trial Tr. Day 5 (2/7/2018 AM)

at 14:16–15:24 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 87:24–88:15 (Michniak-Kohn). Thus,

Lee does not disclose or suggest that a “conventional” acrylic adhesive such as Duro-Tak® 87-

2287 / 387-2287 can provide superior granisetron permeation, granisetron release, and granisetron

stability. See Trial Tr. Day 5 (2/7/2018 AM) at 14:16–15:24 (Enscore).

What is more, Lee does not distinguish between acidic hydroxyl and non-

acidic hydroxyl functional groups, but instead characterizes both as being used commonly in

conventional acrylic adhesives. See Trial Tr. Day 5 (2/7/2018 AM) at 14:16–15:9 (Enscore); Trial

Tr. Day 4 (2/6/2018 PM) at 89:5–9 (Michniak-Kohn). Thus, Lee does not disclose that acrylic

adhesives having non-acidic hydroxyl functional groups can provide superior granisetron

permeation, the complete release of granisetron, and granisetron stability. Trial Tr. Day 5

(2/7/2018 AM) at 14:16–15:24 (Enscore).

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Finally, Lee is listed on the face of the ’282 Patent as having been

considered by the PTO during prosecution. See JTX-001 at 1; Trial Tr. Day 5 (2/7/2018 AM) at

12:4–12 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 61:18–62:5 (Michniak-Kohn). In view of the

fact that Lee was considered by the PTO before it issued the ’282 Patent, and because Lee plainly

does not teach or suggest the use of acrylic adhesives having non-acidic functional groups as

providing increased granisetron permeation, stability, and “complete release,” the Court finds that

Lee does not disclose the same invention as the ’282 Patent. See Trial Tr. Day 5 (2/7/2018 AM) at

15:12–24 (Enscore). Additionally, and as discussed in detail below, Lee does not disclose each

and every element of the Asserted Claims, either explicitly or inherently.

a) Claim 1

Claim 1 of the ’282 Patent requires an acrylic adhesive consisting

essentially of 50 to 98% by weight of 2-ethylhexyl acrylate or butyl acrylate and 0.5 to 20% by

weight of a monomer containing non-acidic hydroxyl moieties. See JTX-001 at 10, claim 1. Dr.

Michniak-Kohn alleges that Example 1(G) of Lee discloses acrylic adhesives prepared from

monomer compositions that meet this limitation. See Trial Tr. Day 4 (2/6/2018 PM) 47:21–49:19

(Michniak-Kohn, discussing JTX-019 at ¶¶ 45–47). However, Dr. Michniak-Kohn’s anticipation

analysis only considered whether Lee’s Example 1(G) included both of the monomers required by

claim 1 of the ’282 Patent. See Trial Tr. Day 4 (2/6/2018 PM) 71:3–14 (Michniak-Kohn).

In addition to 2-ethylhexyl acrylate and butyl acrylate, the acrylic adhesive

in Lee’s Example 1(G) also includes, inter alia, a monomer having a PEG side chain, acrylic acid

(a monomer having a carboxylic acid functional group), as well as vinyl acetate.20 See JTX-019

at 6, ¶¶ [0045–0047]; Trial Tr. Day 5 (2/7/2018 AM) at 18:9–16; 20:13–24; 24:7–26:8 (Enscore).

Lee discloses that the inventive acrylic adhesives having PEG side chains exhibit improved

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permeation and drug stability compared to “conventional” prior art acrylic adhesives that lack such

side chains. See JTX-019 at 11–12, Tables 1–2, ¶¶ [0090]–[0092]; see Trial Tr. Day 5 (2/7/2018

AM) at 18:3–19:21 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) 74:16–75:16, 76:13–22, 80:4–8

(Michniak-Kohn).

Further, the ’282 Patent teaches that monomers having carboxylic acid (-COOH) functional groups

materially affect the basic and novel property of drug permeation. See Trial Tr. Day 5 (2/7/2018

AM) at 17:8–24 (Enscore). Specifically, Table 2 of the ’282 Patent provides that the patches

prepared using the DT 2052 and DT 2353 adhesives, which both include carboxylic acid (-COOH)

functional groups, exhibited 30x lower granisetron permeation after 3 and 6 hours compared to

DT 2287, which includes only non-acidic hydroxyl (-OH) functional groups. See JTX-001 at 9,

9:1–10 (Table 2) (comparing permeation values of 31.7:0.8; 92:2.3; 170.8:16.1; and 256.6:15.9);

Trial Tr. Day 5 (2/7/2018 AM) at 17:10–18:6 (Enscore).

As construed by the Court, claim 1 of the ’282 Patent excludes any

monomers that materially affect the basic and novel properties of the invention. Docket No. 62 at

7. The Court credits the testimony of Dr. Enscore in finding that the monomers having PEG side

chains materially affect at least the basic and novel properties of drug permeation and stability,

and therefore are excluded from the acrylic adhesive of claim 1 of the ’282 Patent. See JTX-019

at 11–12, Tables 1–2, ¶¶ [0090]–[0092]; Trial Tr. Day 5 (2/7/2018 AM) at 18:7–20:10 (Enscore).

The Court further credits Dr. Enscore’s testimony in finding that monomers having acidic (-

COOH) functional groups materially affect at least the permeation of granisetron, and therefore

are excluded from the acrylic adhesive of claim 1 of the ’282 Patent. See JTX-001 at 9, 9:1–43;

Trial Tr. Day 5 (2/7/2018 AM) at 21:2–18 (Enscore).

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Further, the Court finds that Dr. Enscore’s testimony on these findings was

unrebutted by any Actavis witness. Specifically, Dr. Michniak-Kohn testified that she was aware

of the Court’s claim construction, but she did not analyze—and wasn’t asked to analyze— whether

any of the additional monomers in the adhesives of Lee (i.e., monomers having a PEG side chain,

a carboxylic acid functional group, or vinyl acetate) had a material effect on any of the basic and

novel properties (e.g., increased drug permeation and drug stability). See Trial Tr. Day 4 (2/6/2018

PM) 63:7–64:11; 73:6–74:15; 75:13–18; 76:23–77:2; 77:18–78:4 (Michniak-Kohn). The Court

therefore summarily rejects Dr. Michniak-Kohn’s anticipation analysis because she did not

properly apply the Court’s claim construction in her analysis of the prior art.

For these reasons, the Court finds that the inventive acrylic adhesives of Lee

(such as Examples 1(F), 1(G), and 1(H)) do not consist essentially of 50 to 98% by weight of 2-

ethylhexyl acrylate or butyl acrylate and 0.5 to 20% by weight of a monomer containing nonacidic

hydroxyl moieties because these adhesives include additional monomers having PEG side chains

that materially affect at least drug permeation and stability. See Trial Tr. Day 5 (2/7/2018 AM) at

20:3–10 (Enscore). Thus, the Court credits the testimony of Dr. Enscore in finding that Lee’s

exemplary adhesive 1(G) does not anticipate the “acrylic adhesive consisting essentially of”

element of claim 1 of the ’282 Patent. See Trial Tr. Day 5 (2/7/2018 AM) at 20:20–21:25 (Enscore).

Claim 1 of the ’282 Patent requires a patch that contains “a physiologically

effective amount of granisetron loaded in the acrylic adhesive, . . . .” JTX-001 at 10, claim 1. Dr.

Michniak-Kohn alleges that Lee’s Example 16 and Comparative Example 16, which are

transdermal patches that contain 10% and 5% by weight of granisetron hydrochloride,

respectively, disclose a physiologically effective amount of granisetron in a transdermal patch. See

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Trial Tr. Day 4 (2/6/2018 PM) at 26:12–27:18, 49:20–50:10, 80:14–81:9 (Michniak-Kohn, citing

JTX-019 at 4, 10, ¶¶ [0030], [0081]–[0082]).

Claim 1 of the ’282 Patent requires a patch that contains “a physiologically

effective amount of granisetron loaded in the acrylic adhesive, . . . .” JTX-001 at 10, claim 1. Dr.

Michniak-Kohn alleges that Lee’s Example 16 and Comparative Example 16, which are

transdermal patches that contain 10% and 5% by weight of granisetron hydrochloride,

respectively, disclose a physiologically effective amount of granisetron in a transdermal patch. See

Trial Tr. Day 4 (2/6/2018 PM) at 26:12–27:18, 49:20–50:10, 80:14–81:9 (Michniak-Kohn, citing

JTX-019 at 4, 10, ¶¶ [0030], [0081]–[0082]).

The Court construed the term “physiologically effective amount of

granisetron” as having its plain and ordinary meaning, which is “an amount effective to prevent

and/or treat nausea and vomiting in a subject.” Docket No. 62 at 20. On the one hand, Dr. Tan

testified that in order to determine if this claim limitation is present in Actavis’s Accused Product

for purposes of infringement, in vivo testing is required. See Trial Day 2 (2/2/2018 PM) at 111:17–

112:18 (Tan). On the other hand, Dr. Michniak-Kohn agreed that Lee does not disclose any in vivo

testing of any patch, but that such in vivo testing is not required for anticipation because

granisetron is “an old drug.” See Trial Tr. Day 4 (2/6/2018 PM) 81:23–82:5 (Michniak-Kohn). The

Court finds it troubling that two experts from the same party submitted conflicting interpretations

of what is required in order to satisfy this claim limitation, and therefore finds the testimony of

both Dr. Tan and Dr. Michniak-Kohn to be unreliable.

As the ’282 Patent discloses, in vitro experiments were first used to measure

the granisetron permeation achieved using various acrylic adhesives loaded with granisetron,

which was followed by in vivo testing of patches prepared using DT-2287 that contained 6% by

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weight granisetron in order to determine whether sufficient blood plasma levels could be achieved.

See JTX-001 at 8–10, 8:35–11:50; see also, e.g., Trial Tr. Day 5 (2/7/2018 AM) at 21:2–11

(Enscore). Based on the results of this in vivo testing, the inventors of the ’282 Patent concluded

that “a slightly larger patch, in the region of 40 cm2, would deliver appropriate levels of granisetron

for optimum efficacy. See JTX-001 at 10, 11:7–50. Thus, it was through in vivo testing that the

inventors determined a granisetron content of 6% by weight is a physiologically effective amount

when administered using the claimed acrylic adhesive. See Trial Tr. Day 5 (2/7/2018 AM) at

22:25–23:5 (Enscore).

Lee, on the other hand, only tested drug permeation using in vitro

experiments through guinea pig skin. See JTX-019 at 10–12, ¶¶ [0081]–[0085], Table 1; See Trial

Tr. Day 5 (2/7/2018 AM) at 22:14–24; 23:6–9 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 81:18–

22 (Michniak-Kohn). None of the patches disclosed in Lee, let alone patches that contain 5% or

10% by weight granisetron, were tested in vivo to assess whether sufficient blood plasma levels

could be achieved. See JTX-019 at 10, ¶¶ [0081]–[0092], Tables 1–2; see Trial Tr. Day 5 (2/7/2018

AM) at 24:7–25 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 81:23–25 (Michniak-Kohn). Because

Lee provides no disclosure of the blood plasma levels achieved using any patch, a POSA would

be required to conduct further experiments and testing in order to determine if 5% or 10% by

weight of granisetron in the patches of Lee was a physiologically effective amount. See Trial Tr.

Day 5 (2/7/2018 AM) at 22:3–24 (Enscore). For these reasons, the Court credits Dr. Enscore’s

testimony in finding that Lee does not explicitly or inherently disclose a transdermal patch that

contains a physiologically effective amount of granisetron as required by claim 1 of the ’282

Patent. See Trial Tr. Day 5 (2/7/2018 AM) at 22:3–11 (Enscore).

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Further, Dr. Michniak-Kohn admitted that the only exemplary patches in

Lee that include granisetron (Example 16 and Comparative Example 16) were prepared using

acrylic adhesives (Examples 1(A) and (I)) that do not anticipate the acrylic adhesive of claim 1 of

the ’282 Patent. See Trial Tr. Day 4 (2/6/2018 PM) at 69:24–71:2 (Michniak-Kohn); see also Trial

Tr. Day 5 (2/7/2018 AM) at 23:17–24:21 (Enscore). Rather, according to Dr. Michniak-Kohn, a

POSA would use granisetron with Lee’s acrylic adhesive 1(G), but as discussed above, this

adhesive similarly does not anticipate the acrylic adhesive of claim 1 of the ’282 Patent. See Trial

Tr. Day 5 (2/7/2018 AM) at 21:18–22:24 (Enscore). For this additional reason, the Court credits

Dr. Enscore’s testimony in finding that Lee does not disclose a transdermal patch containing a

physiologically effective amount of granisetron.

Claim 1 of the ’282 Patent further requires that “the granisetron content of

said patch remains substantially unchanged when stored at 25 ºC for six weeks.” JTX-001 at 10,

claim 1. Lee does not include results of stability testing of any transdermal patch that contains

granisetron. See JTX-019 at 10, ¶¶ [0081]–[0082], at 12, Table 2 (no stability tests are disclosed

for Example 16 or Comparative Example 16); Trial Tr. Day 5 (2/7/2018 AM) at 25:11–13

(Enscore); Trial Tr. Day 4 (2/6/2018 PM) 79:17–21 (Michniak-Kohn). Despite the fact that Lee

does not disclose the stability of granisetron in any patch, Dr. Michniak-Kohn alleges that this

element of claim 1 is anticipated by Lee because granisetron stability is an inherent property of the

patches disclosed in Lee. See Trial Tr. Day 4 (2/6/2018 PM) 50:11–52:5; 79:17–25 (Michniak-

Kohn) (citing JTX-019 at 10, ¶¶ [0016], [0045], [0081]–[0082]).

Lee discloses stability testing conducted on three exemplary embodiments

(Examples 4, 7, and 11) that are patches containing the active ingredients tolperisone

hydrochloride, ketotifen fumarate, and tulobuterol hydrochloride, respectively. See JTX-019 at 8,

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¶¶ [0058], [0064], at 9, ¶ [0072], at 12, ¶ [0086], Table 2; see Trial Tr. Day 5 (2/7/2018 AM) at

24:22–25:10 (Enscore). As discussed above, based on these examples Lee teaches that acrylic

adhesives that include monomers with PEG side chains provide increased drug stability. See JTX-

019 at 12, ¶¶ [0086], [0092], Table 2 (compare stability of Examples 4, 7, and 11 with that of

Comparative Examples 4–1, 4–2, 7, and 11); see Trial Tr. Day 5 (2/7/2018 AM) at 35:5–12

(Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 80:1–8 (Michniak-Kohn). Thus, Lee confirms that

many drugs, including at least tolperisone hydrochloride, ketotifen fumarate, and tulobuterol

hydrochloride, are not “inherently stable” in “conventional” acrylic adhesives that lack the

inventive PEG side chains taught by Lee. See Trial Tr. Day 5 (2/7/2018 AM) at 25:14–20

(Enscore). For this reason, the Court finds that Dr. Michniak-Kohn’s conclusion that drugs such

as granisetron are inherently stable in conventional acrylic adhesives is unsupported by any

evidence. Instead, the Court credits Dr. Enscore’s testimony in finding that because the inventive

acrylic adhesives of Lee provided increased drug stability, a POSA would understand that drugs

are not inherently stable in all acrylic adhesives. See Trial Tr. Day 5 (2/7/2018 AM) at 25:14–23

(Enscore).

Moreover, the stability of a particular drug in a particular adhesive is

unpredictable. See Trial Tr. Day 5 (2/7/2018 AM) at 29:17–31:10 (Enscore). Indeed, as Dr. Tan

testified, there is no way to tell if a particular functional group of an acrylic adhesive will interact

with a particular active agent except by experimental tests. See Trial Tr. Day 3 (2/5/2018 AM) at

51:11–14 (Tan). As discussed above, the stability data provided in Lee is for active agents other

than granisetron in acrylic adhesives that do not meet the limitations of claim 1 of the ’282 Patent.

See Trial Tr. Day 5 (2/7/2018 AM) at 25:14–23 (Enscore). Thus, the Court finds that Lee does not

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inherently disclose the stability of granisetron in the acrylic adhesive of claim 1 of the ’282 Patent,

and therefore Lee does not anticipate claim 1 of the ’282 Patent.

b) Dependent Claims

Claims 2, 4, 5, 7, 11, 21, 26, and 28 depend directly or indirectly from claim

1 and therefore incorporate each and every limitation of claim 1. See JTX-001 at 10–11, claims 2,

4, 5, 7, 11, 21, 26, 28. For the same reasons as discussed above for claim 1, the Court finds that

Lee does not explicitly or inherently disclose each and every element of claims 2, 4, 5, 7, 11, 21,

26, and 28 of the ’282 Patent, and therefore Lee does not anticipate these claims under 35 U.S.C.

§ 102 (pre-AIA). See Trial Tr. Day 5 (2/7/2018 AM) at 26:5–15 (Enscore); Trial Tr. Day 4

(2/6/2018 PM) at 82:6–16 (Michniak-Kohn).

Claim 7 of the ’282 Patent requires “[a] patch according to claim 1, having

up to about 10% by weight granisetron” and claim 21 requires that “the acrylic adhesive is loaded

with between 5 and 8% w/w of granisetron.” See JTX-001 at 11, claims 7, 21. Both of claims 7

and 21 ultimately depend from claim 1, which requires that the amount of granisetron in the

patch/adhesive be “physiologically effective,” which the Court has construed as “an amount

effective to prevent or treat nausea and vomiting in a subject.” Docket No. 62 at 20.

As discussed above, it was only through in vivo testing that the inventors

determined a granisetron content of 6% by weight is a physiologically effective amount when

administered using the claimed acrylic adhesive. See Trial Tr. Day 5 (2/7/2018 AM) at 22:25–23:5

(Enscore). Lee, on the other hand, only tested drug permeation using in vitro experiments through

guinea pig skin. See JTX-019 at 10–12, ¶¶ [0081]–[0085], Table 1; Trial Tr. Day 5 (2/7/2018 AM)

at 22:14–24; 23:6–9 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 81:18–22 (Michniak-Kohn).

None of the patches disclosed in Lee were tested in vivo to assess whether sufficient blood plasma

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levels could be achieved in a human subject. See JTX-019 at 10, ¶¶ [0081]–[0092], Tables 1–2;

Trial Tr. Day 5 (2/7/2018 AM) at 24:7–25 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 81:23–25

(Michniak-Kohn). Because Lee provides no disclosure of the blood plasma levels achieved using

any patch, a POSA would be required to conduct further experiments and testing in order to

determine if up to about 10% by weight, or between 5% to 8% by weight of granisetron would be

a physiologically effective amount. See Trial Tr. Day 5 (2/7/2018 AM) at 22:3–24 (Enscore).

For these reasons, the Court credits Dr. Enscore’s testimony in finding that

Lee does not explicitly or inherently disclose whether a patch having a granisetron concentration

of up to about 10% by weight, or an acrylic adhesive loaded with between 5 and 8% w/w of

granisetron, would constitute a physiologically effectively amount of granisetron. See Trial Tr.

Day 5 (2/7/2018 AM) at 22:3–11 (Enscore). For this additional reason, the Court finds that Lee

does not anticipate claims 7 or 21 of the ’282 Patent.

Claim 11 of the ’282 Patent requires “[a] patch according to claim 1,

wherein no crystallization is observed after one month storage at room temperature and pressure.”

JTX-001 at 11, claim 11. Dr. Michniak-Kohn again alleges this property is explicitly disclosed at

Table 2 of Lee, or alternatively that this “is the inherent property of the patch formulations

disclosed by Lee.” See Trial Tr. Day 4 (2/6/2018 PM) 52:6–24 (Michniak-Kohn, citing JTX019 at

¶¶ [0045]–[0047], [0081]–[0082]).

As discussed above, based on stability testing of three exemplary

embodiments (Examples 4, 7, and 11), Lee concludes that acrylic adhesives that include monomers

with PEG side chains provide increased drug stability. See JTX-019 at 12, ¶¶ [0086], [0092], Table

2; Trial Tr. Day 5 (2/7/2018 AM) at 24:22–25:10 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at

80:1–8 (Michniak-Kohn). What is more, Lee discloses nothing concerning whether crystals of any

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active agent formed over time within any transdermal patches, let alone whether granisetron

crystallized in any patches. See Trial Tr. Day 5 (2/7/2018 AM) at 27:5–17 (Enscore). Thus, Lee

does not explicitly disclose any of the limitations of claim 11. See Trial Tr. Day 5 (2/7/2018 AM)

at 27:5–17 (Enscore).

Further, the limitations of claim 11 of the ’282 Patent are not inherently

disclosed by Lee. (See Trial Tr. Day 5 (2/7/2018 AM) at 27:5–17 (Enscore).) The Court credits

Dr. Enscore’s testimony in finding that crystallization is not an inherent property of a particular

combination of a drug with an adhesive, but can also depend, for example, on the concentration of

active agent contained in the patch. See Trial Tr. Day 5 (2/7/2018 AM) at 58:24–59:3 (Enscore).

The Court credits Dr. Enscore’s testimony in finding that because Lee is silent as to what

concentrations crystallization of granisetron may lead to crystallization of granisetron, even to the

extent that crystallization is an inherent property, Lee does not anticipate claim 11. See Trial Tr.

Day 5 (2/7/2018 AM) at 27:5–17 (Enscore). For this additional reason, the Court finds that Lee

does not anticipate claim 11 of the ’282 Patent.

Claim 26 of the ’282 Patent requires “[a] method for the treatment and/or

prophylaxis of chemotherapy induced nausea and vomiting in a patient in need thereof, said

method comprising applying an adhesive patch according to claim 1 to the skin of the patient.”

JTX-001 at 11, 14:25–28. Dr. Michniak-Kohn alleges that Lee discloses the same method of

treatment set forth in claim 26 because paragraph 91 and 82 list granisetron hydrochloride at 0.5

grams and 1.0 grams and according to paragraph 24, the patch disclosed “was attached to the

stratum corneum for, obviously, transdermal administration.” Trial Tr. Day 4 (2/6/2018 PM)

52:22–53:15 (Michniak-Kohn) (citing JTX-019 at 10, ¶¶ [0081]–[0082]), [0084]).

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However, the section of Lee referenced by Dr. Michniak-Kohn merely

discloses the results of in vitro experiments using guinea pig skin. See JTX-019 at 10–12, ¶¶

[0083]–[0092], Tables 1–2, at 14, Figures 1–2; Trial Tr. Day 4 (2/6/2018 PM) at 81:18–22, Day 5

(2/7/2018 AM) at 143:9–21 (Michniak-Kohn). Therefore, unlike the ’282 Patent, Lee fails to

provide any disclosure that the patches containing the various active ingredients (let alone

granisetron) are suitable to provide a therapeutically effective dose across human skin under in

vivo conditions. See Trial Tr. Day 4 (2/6/2018 PM) at 81:23–82:5 (Michniak-Kohn); Trial Tr. Day

5 (2/7/2018 AM) at 143:9–21 (Michniak-Kohn). Thus, there is no disclosure within the four

corners of Lee that granisetron could be delivered in a sufficient dose from any patch in a manner

that would treat or prevent nausea or vomiting in a patient in need thereof. See Trial Tr. Day 5

(2/7/2018 AM) at 28:8–15 (Enscore). For these reasons, the Court credits Dr. Enscore’s testimony

in finding that Lee provides no data to suggest that the transdermal patches would be suitable for

the treatment of nausea and vomiting. See Trial Tr. Day 5 (2/7/2018 AM) at 28:8–15 (Enscore).

For this additional reason, the Court finds that Lee does not anticipate claim 26 of the ’282 Patent.

4. Obviousness

A POSA with respect to the technology relevant to the ’282 Patent would

have had a Master’s degree or doctorate in pharmaceutical science, chemical engineering, or

commensurate experience in a related field with some experience in the design and/or formulation

of transdermal drug delivery systems. See Trial Tr. Day 5 (2/7/2018 AM) at 5:3–10 (Enscore). The

POSA may have worked as a member of a team that included a person of ordinary skill in the art

in pharmacology and/or pharmacokinetics, who would have had a Master’s degree or doctorate or

commensurate experience in a related field. See Trial Tr. Day 5 (2/7/2018 AM) at 5:13–18

(Enscore). The POSA may have also worked as a member of a team that included a POSA in

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treating and/or preventing emesis in patients undergoing chemotherapy, who would have a nursing

degree or certification, or a medical degree with some experience prescribing 5-HT3 inhibitors for

the prevention and/or treatment of nausea and vomiting. See Trial Tr. Day 5 (2/7/2018 AM) at

5:21–6:3 (Enscore).

Dr. Michniak-Kohn testified that an analysis of anticipation or obviousness

requires consideration of the Court’s claim construction, and whether the prior art discloses all

three of the basic and novel properties of the Asserted Claims. See Trial Tr. Day 4 (2/6/2018 PM)

at 62:25–63:17 (Michniak-Kohn). Dr. Michniak-Kohn, however, admitted that she did not analyze,

nor was she asked to analyze, whether any monomers present in the acrylic adhesives of the prior

art materially affect the basic and novel properties of those prior art adhesives. See Trial Tr. Day

4 (2/6/2018 PM) at 73:6–74:15; 75:13–18; 76:13–78:4; 78:13–19 (Michniak-Kohn); see also Trial

Tr. Day 5 (2/7/2018 AM) at 149:11–25 (Michniak-Kohn). Rather, Dr. Michniak-Kohn’s invalidity

analysis merely focused on whether the monomers required by the acrylic adhesive of claim 1

were present in acrylic adhesives of the prior art. See, e.g., Trial Tr. Day 4 (2/6/2018 PM) at 47:21–

49:19; 71:3–14 (Michniak-Kohn).

The only specific prior art combinations that Dr. Michniak-Kohn testified

to were Lee in combination with Tan (JTX-020, Pharm. Sci. & Tech. Today 2(2):60–69 (1999)),

and Lee in combination with the background knowledge of a POSA (as evidenced by Xia (JTX-

018, U.S. Patent No. 5,693,335) or the Duro-Tak® Product Selection Guide (JTX-003)). See Trial

Tr. Day 4 (2/6/2018 PM) at 58:8–59:5 (Michniak-Kohn). However, Dr. Michniak-Kohn admitted

that in her mind a POSA at the time of the invention of the ’282 Patent would have identified Lee,

Effing, and Kamiyama as the three most relevant prior art references to developing a granisetron

formulation. See Trial Tr. Day 4 (2/6/2018 PM) at 83:3–25 (Michniak-Kohn).

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a) Relevant Prior Art

A POSA reviewing Lee, Effing, and Kamiyama as a whole would have been

led away from attempting to use conventional acrylic adhesives such as those available from

National Starch in favor of acrylic adhesives such as those taught in Lee, Effing, and Kamiyama.

Further, even if a POSA attempted to use commercially available acrylic adhesives (available

from, e.g., National Starch), Lee, Effing, and Kamiyama also taught away from the use of

granisetron in acrylic.

(1) Lee

According to Dr. Michniak-Kohn, Lee was “the first reference to actually

show granisetron formulations in acrylic adhesives,” thereby giving “the proof of the concept that

granisetron can actually be put in an acrylic adhesive.” Trial Tr. Day 4 (2/6/2018 PM) at 11:20–

21; 14:20–15:2 (Michniak-Kohn).

As discussed above, Lee’s invention is based on a finding that improved

skin permeation and drug stability is obtained using acrylic adhesives that incorporate monomers

having PEG side chains. See JTX-019 at 3, ¶¶ [0015], [0018], [0022], [0024], at 12, claim 1; see

Trial Tr. Day 5 (2/7/2018 AM) at 32:22–24 (Enscore). Indeed, Lee compared sixteen exemplary

patches with patches prepared using “conventional” acrylic adhesives and every single patch that

included monomers with PEG side chains exhibited better drug permeation and stability compared

to “conventional” acrylic adhesive patches. See Trial Tr. Day 5 (2/7/2018 AM) at 34:19–35:12

(Enscore). Despite Lee’s disclosure of novel adhesives having PEG side chains that uniformly

increased permeation and stability for every drug compared to “conventional” acrylic adhesives,

Dr. Michniak-Kohn alleged that a POSA viewing Lee nonetheless would have been led to use

“conventional” acrylic adhesives in order to develop a granisetron transdermal patch because this

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would have been “simple and efficient.” See Trial Tr. Day 4 (2/6/2018 PM) at 14:20–15:18

(Michniak-Kohn). However, Dr. Michniak-Kohn cites no evidence whatsoever to support this

testimony. See Trial Tr. Day 4 (2/6/2018 PM) at 15:19–16:25 (Michniak-Kohn). For this reason,

the Court credits Dr. Enscore’s testimony in finding that Lee would not have motivated a POSA

to attempt to formulate a granisetron patch using commercially available acrylic adhesives, let

alone with any expectation of success. See Trial Tr. Day 5 (2/7/2018 AM) at 35:22–36:15

(Enscore).

Further, a POSA attempting to formulate a granisetron transdermal patch

would have been aware of Example 16 and Comparative Example 16 of Lee, which is the only

disclosure anywhere in the prior art that actually formulated a granisetron transdermal patch. See

JTX-019 at 10; Trial Tr. Day 4 (2/6/2018 PM) at 70:6–13 (Michniak-Kohn). However, neither of

the acrylic adhesives in Lee’s Example 16 and Comparative Example 16 included a monomer

having a non-acidic hydroxyl (-OH) functional group. See JTX-019 at 5 (¶ [0040]), 6 (¶ [0048]),

10 (¶¶ [0081]–[0082]); Trial Tr. Day 4 (2/6/2018 PM) at 89:14–90:11 (Michniak-Kohn). Instead,

both of the granisetron patch examples in Lee were prepared using a monomer (acrylic acid) that

includes a carboxylic acid (-COOH) functional group. See JTX-019 at 5 (¶ [0040]), 6 (¶ [0048]),

10 (¶¶ [0081]–[0082]); Trial Tr. Day 5 (2/7/2018 AM) at 23:17–24 (Enscore); Trial Tr. Day 4

(2/6/2018 PM) at 89:14–90:11; Trial Tr. Day 5 (2/7/2018 AM) at 148:1–16 (Michniak-Kohn). And

Lee would not have directed a POSA to use monomers having non-acidic hydroxyl (-OH)

functional groups, but instead discusses them (along with carboxylic acid-containing monomers)

as generally used in “conventional” adhesives. See JTX-019 at 3–4, ¶ [0025]; Trial Tr. Day 5

(2/7/2018 AM) at 15:6–9 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 89:5–9 (Michniak-Kohn).

Therefore, because both of the granisetron patches in Lee include carboxylic acid (-COOH)

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functional groups, the Court finds that a POSA reviewing Lee would have been directed towards

formulating granisetron in a patch that includes carboxylic acid (- COOH) functional groups,

which clearly fall outside the scope of the Asserted Claims of the ’282 Patent. Trial Tr. Day 5

(2/7/2018 AM) at 23:17–24:4 (Enscore).

(2) Effing and Braun

According to Dr. Michniak-Kohn, Effing (DTX0061, PCT Pub. No. WO

98/53815) was the first prior art reference to disclose the “concept” of a transdermal patch

containing granisetron. See Trial Tr. Day 4 (2/6/2018) at 99:1–6 (Michniak-Kohn). However,

Effing discloses transdermal patches for the delivery of tropisetron or granisetron, but only

prepared exemplary patches that contained tropisetron. See DTX0061 at 10–15 (Examples 1–7);

Trial Tr. Day 4 (2/6/2018 PM) at 99:1–6; Trial Tr. Day 5 (2/7/2018 AM) at 147:4–12 (Michniak-

Kohn).

The Court credits Dr. Enscore’s testimony in finding that Effing teaches

away from the use of granisetron in acrylic adhesives prepared from monomers having a hydroxyl

(-OH) functional group, as required by claim 1 of the ’282 Patent. See Trial Tr. Day 5 (2/7/2018

AM) at 50:23–51:15 (Enscore). Specifically, Effing generally discloses acrylic adhesives that

contain “A” and “B” monomers, of which the “B” monomers have a hydrophilic functional group.

See DTX0061 at 4–6; see Trial Tr. Day 5 (2/7/2018 AM) at 49:16–18 (Enscore); Trial Tr. Day 4

(2/6/2018 PM) at 93:23–94:7 (Michniak-Kohn). However, Effing teaches that “[p]referably, the B

monomer is free of nucleophilic groups selected from the group consisting of hydroxyl, thiol,

primary amino groups, secondary amino groups and acid groups” because such monomers can

lead to unwanted crosslinking of the adhesive and drug instability. DTX0061 at 5–6; Trial Tr. Day

5 (2/7/2018 AM) at 48:20–49:12 (Enscore); Trial Tr. Day 4 (2/6/2018) at 95:2–15 (Michniak-

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Kohn). Thus, rather than using a monomer having a nonacidic hydroxyl functional group, Effing

teaches a POSA to instead preferably use N-vinyl-2- pyrrolidone as a hydrophilic monomer in

transdermal patches for tropisetron, and by implication, granisetron. See DTX0061 at 5

(“Particularly preferred is N-vinyl-2-pyrrolidone.”); see Trial Tr. Day 5 (2/7/2018 AM) at 50:23–

51:15 (Enscore); see also Trial Tr. Day 4 (2/6/2018 PM) at 94:13–95:1 (Michniak-Kohn).

Further, the only exemplary patch in Effing prepared using a monomer

having a hydroxyl (-OH) group (Example 7) is provided as a counter-example in that “[s]tability

testing of this formulation revealed a crosslinking of the drug-in-adhesive matrix and a decrease

in the drug content of more than 10% within 4 weeks of storage.” DTX0061 at 13–15, Example 7;

Trial Tr. Day 5 (2/7/2018 AM) at 51:18–52:1 (Enscore). This is the only exemplary embodiment

in Effing that shows a decrease in drug content during stability testing. See DTX0061 at 6, 13–15

(Examples 1–7); Trial Tr. Day 5 (2/7/2018 AM) at 52:2–4 (Enscore).

Braun (DTX0139, U.S. Patent No. 6,136,807), like Effing, is assigned to

3M, and discloses transdermal patch formulations that contain another 5-HT3 antagonist called

lerisetron. See DTX0139; Trial Tr. Day 4 (2/6/2018 PM) at 95:20–96:11 (Michniak-Kohn). Braun,

like Effing, describes novel acrylic adhesives that preferably include an N-vinyl-2-pyrrolidone

monomer, and which can optionally also include a macromer and permeation enhancer. See

DTX0139 at 2–3, 2:l. 3–4:l. 51; Trial Tr. Day 5 (2/7/2018 AM) at 61:23–63:17 (Enscore); Trial

Tr. Day 4 (2/6/2018 PM) at 96:17–20 (Michniak-Kohn).


Effing and Braun would have directed a POSA away from the use of granisetron in a transdermal

patch that included a non-acidic hydroxyl (-OH) functional group due to the risk of crosslinking

and drug instability. See Trial Tr. Day 5 (2/7/2018 AM) at 52:5–16 (Enscore).

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What is more, Effing was cited extensively by the PTO Examiner during

prosecution of the ’282 Patent, and claim 1 was amended to include the phrase “an acrylic adhesive

consisting essentially of . . .” in order to overcome prior art rejections over Effing. JTX-002 at

651–655; Trial Tr. Day 5 (2/7/2018 AM) at 48:20–49:12 (Enscore). Because claim 1 of the ’282

Patent was specifically amended to overcome a prior art rejection over Effing, the Asserted Claims

cannot be considered obvious over Effing alone, and, for reasons discussed herein, would not be

obvious over Effing in combination with any other prior art references cited by Actavis. See Trial


(3) Kamiyama

Kamiyama (DTX0137, PCT Pub. No. WO 00/44846) discloses novel

crosslinked acrylic adhesives designed for use with transdermal patches that contain plasticizers.

See DTX0137 at 1 (Abstract), 3–5; Trial Tr. Day 5 (2/7/2018 AM) at 52:21–25 (Enscore); Trial

Tr. Day 4 (2/6/2018 PM) at 99:1–25 (Michniak-Kohn). However, Kamiyama says nothing about

granisetron specifically, but instead discloses that a wide range of drugs may be used with the

crosslinked adhesives. See DTX0137 at 16–18; Trial Tr. Day 5 (2/7/2018 AM) at 53:21–54:4

(Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 100:21–101:3 (Michniak-Kohn). Rather, the only

things in common between Kamiyama and the ’282 Patent are that both are assigned to Strakan.

See Trial Tr. Day 5 (2/7/2018 AM) at 53:9–18 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 98:22–

99:6 (Michniak-Kohn).

Kamiyama (DTX0137, PCT Pub. No. WO 00/44846) discloses novel

crosslinked acrylic adhesives designed for use with transdermal patches that contain plasticizers.

See DTX0137 at 1 (Abstract), 3–5; Trial Tr. Day 5 (2/7/2018 AM) at 52:21–25 (Enscore); Trial

Tr. Day 4 (2/6/2018 PM) at 99:1–25 (Michniak-Kohn). However, Kamiyama says nothing about

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granisetron specifically, but instead discloses that a wide range of drugs may be used with the

crosslinked adhesives. See DTX0137 at 16–18; Trial Tr. Day 5 (2/7/2018 AM) at 53:21–54:4

(Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 100:21–101:3 (Michniak-Kohn). Rather, the only

things in common between Kamiyama and the ’282 Patent are that both are assigned to Strakan.

See Trial Tr. Day 5 (2/7/2018 AM) at 53:9–18 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 98:22–

99:6 (Michniak-Kohn).

To the extent that a POSA would have relied upon Kamiyama in

formulating a transdermal granisetron product, Kamiyama would have directed a POSA away from

commercially available acrylic adhesives, and specifically those such as Duro-Tak® 387-2287 that

contain a hydroxyl (-OH) functional group. Specifically, Kamiyama compares a novel crosslinked

adhesive to Duro-Tak® 387-2287 (a non-crosslinked adhesive available from National Starch),

and teaches that “[i]t is clearly shown that the vapour permeability of the crosslinked adhesive is

far greater than that of the commercial acrylic adhesive [i.e., Duro-Tak® 387- 2287].” DTX0137

at 26–28 Example 7; Trial Tr. Day 5 (2/7/2018 AM) at 54:19–55:10 (Enscore); Trial Tr. Day 4

(2/6/2018 PM) at 100:1–20 (Michniak-Kohn). Because “[h]igh water vapour permeability (wvp)

usually means high breathability for skin, important to reduce skin irritation,” a POSA seeking for

a long time period would have been motivated by Kamiyama to use a crosslinked acrylic adhesive

that would reduce skin irritation. DTX0137 at 26, Example 7; Trial Tr. Day 5 (2/7/2018 AM) at

54:19–55:14 (Enscore).

Further, Kamiyama teaches that monomers having “active hydrogen”

(generally in the form of hydroxyl (-OH) or carboxylic acid (-COOH) groups) should be limited

to avoid undesirable reactions/interactions, such as between a drug and the adhesive. See DTX0137

at 4, 8; Trial Tr. Day 5 (2/7/2018 AM) at 54:5–16 (Enscore). For this additional reason, the Court

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finds that a POSA viewing Kamiyama would have been led away from using an acrylic adhesive

that contains an “active hydrogen” group such as a hydroxyl (-OH) group that is present in Duro-

Tak® 387-2287. See Trial Tr. Day 5 (2/7/2018 AM) at 55:7–14 (Enscore).

For these reasons, when viewed as a whole, each of the references that Dr.

Michniak-Kohn asserted as being “the most relevant” prior art—Lee, Effing, and Kamiyama—

teaches away from the use of the claimed acrylic adhesive in combination with granisetron.

b) Asserted Claims Are Not Obvious Over Lee

Dr. Michniak-Kohn alleged that claims 1, 2, 4, 5, 7, 10, 11, 21, 22, and 28

would have been obvious to a POSA based on Lee in view of the background knowledge of a

POSA (as evidenced by Xia and/or the National Starch Product Selection Guide). See Trial Tr.

Day 4 (2/6/2018 PM) at 22:12–17; 38:21–39:6 (Michniak-Kohn). Dr. Michniak-Kohn also alleged

that claims 1, 2, 4, 5, 7, 10, 11, 21, 22, and 28 would have been obvious to a POSA based on Lee

in view of Tan. See Trial Tr. Day 4 (2/6/2018 PM) at 42:17–45:20 (Michniak-Kohn). Based on the

evidence of record, the Court finds that Lee alone or in combination with Tan or Xia would not

have directed a POSA to the claimed invention with any reasonable expectation that it would be

successful. See Trial Tr. Day 5 (2/7/2018 AM) at 33:21–34:9; 43:6–16 (Enscore).

According to Dr. Michniak-Kohn, a POSA viewing Lee would have been

directed to use “conventional” acrylic adhesives to develop a transdermal patch for granisetron.

See Trial Tr. Day 4 (2/6/2018 PM) at 12:13–17:13 (Michniak-Kohn). However, the National

Starch Product Selection Guide (JTX-003) discloses acrylic adhesives that were developed for

commercial use as early as the 1960s. See Trial Tr. Day 5 (2/7/2018 AM) at 84:16–18 (Enscore).

Anti-emetics such as granisetron first became available in intravenous and oral dosage forms in

the early 1990s. See Trial Tr. Day 4 (2/6/2018 PM) at 4:11–25 (Michniak-Kohn). However, the

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only prior art of record that actually speaks to the transdermal administration of granisetron (or

other 5-HT3 receptor antagonists) is Lee, Effing, Braun, and Kamiyama, which, as discussed

above, uniformly teaches the use of novel acrylic adhesives in order to administer drugs such as

granisetron transdermally and therefore would have led a POSA away from “conventional” acrylic

adhesives such as those available from National Starch. See supra § (I)(H)(4).

Tan is a review that surveyed the state-of-the-art in transdermal drug

delivery systems as of 1999. See JTX-020 at 1, Abstract; Trial Tr. Day 5 (2/7/2018 AM) at 41:1-3

(Enscore). Tan discloses nineteen different commercial transdermal patch products that were

available as of 1999, of which nine were formulated using an acrylate polymer, six using a

polyisobutylene polymer, three using a silicone polymer, and one using an ethylene-vinyl acetate

copolymer. See JTX-020 at 2; Trial Tr. Day 4 (2/6/2018 PM) at 84:22 – 85:20 (Michniak-Kohn).

However, none of the commercial drug products in Table 1 of Tan are structurally related to

granisetron, and Tan does not disclose any data related to transdermal drug permeation or drug

stability—for any active ingredient in any adhesive. See Trial Tr. Day 5 (2/7/2018 AM) at 41:7-

15 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 85:17-20 (Michniak-Kohn). Therefore a POSA

reviewing Tan would have no guidance as to which pressure sensitive adhesive or which patch

design would be best suited for granisetron. See Trial Tr. Day 5 (2/7/2018 AM) at 41:13- 15

(Enscore). Because Tan teaches nothing specific or relevant to the problem of developing a

transdermal patch for granisetron, a POSA would view Tan as largely irrelevant to the problem

that the inventors of the ’282 Patent were trying to solve. See Trial Tr. Day 5 (2/7/2018 AM) at

41:16-19 (Enscore).

While Dr. Michniak-Kohn referenced Tan’s discussion of “conventional”

acrylic adhesives in her obviousness analysis, she neglected to account for Tan’s discussion of

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“Recent Developments” in the transdermal drug delivery art as of 1999. See JTX-020 at 66-67;

Trial Tr. Day 4 (2/6/2018 PM) at 85:21 – 86:8 (Michniak-Kohn). Tan states that, as of 1999,

research in the transdermal drug delivery was focused on developing products with increased

transdermal drug delivery, as well as improved biocompatibility, skin adhesion, and wear

properties. See JTX-020 at 67; Trial Tr. Day 4 (2/6/2018 PM) at 86:5–13 (Michniak-Kohn). Tan

further teaches that in order to achieve these objectives, new polymers were being developed, and

existing polymers were being physically and/or chemically modified. See JTX-020 at 67; Trial

Tr. Day 4 (2/6/2018 PM) at 86:5-13 (Michniak–Kohn). What is more, Dr. Michniak-Kohn

admitted that Lee was an example of one of the novel approaches discussed in Tan—namely, using

chemistry to modify pressure sensitive adhesives that were currently in use. See Trial Tr. Day 4

(2/6/2018 PM) at 87:15–23 (Michniak-Kohn). Indeed, as discussed above, Lee teaches adhesives

with monomers having PEG side chains provide higher drug permeation and stability compared to

“conventional” acrylic adhesives. See JTX-019 at 3, ¶¶ [0015], [0018], [0022], [0024], at 12, claim

1; see Trial Tr. Day 5 (2/7/2018 AM) at 12:18–24; 18:17–19:11; 35:22–36:15 (Enscore).

Therefore, the Court finds that the specific combination of Lee and Tan would not have motivated

a POSA viewing Lee to use “conventional” acrylic adhesives to formulate a granisetron patch

because Lee exemplifies one of “new” approaches to transdermal drug delivery discussed in Tan.

See Trial Tr. Day 5 (2/7/2018 AM) at 43:2–16 (Enscore).

Even if a POSA had attempted to use “conventional” acrylic adhesives such

as those described in the National Starch Product Selection Guide to formulate a granisetron

transdermal patch, the prior art of record would not have directed a POSA to formulate a

granisetron patch using an acrylic adhesive having non-acidic functional groups. Indeed, the only

way prior art references such as the Xia, Tan, Li PCT, and National Starch Product Selection Guide

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are relevant to formulating a granisetron transdermal patch is through the use of impermissible

hindsight. See Trial Tr. Day 5 (2/7/2018 AM) at 31:16–32:1; 66:6-14 (Enscore).

Dr. Michniak-Kohn alleges a POSA simply would have used the

“conventional” acrylic adhesives disclosed in Tan to formulate a granisetron transdermal patch,

and would have therefore arrived at the combination of granisetron in the acrylic adhesive of claim

1 of the ’282 Patent. See Trial Tr. Day 4 (2/6/2018 AM) 116:1–10 (Michniak-Kohn). However,

Tan discloses a wide range of polymers can be used for transdermal drug delivery. JTX-020 at 6;

see Trial Tr. Day 5 (2/7/2018 AM) at 42:9–50:1 (Enscore). Moreover, Tan is wholly silent as to

which “conventional” acrylic adhesive would be appropriate to use with any specific active agent

and makes no differentiation between adhesives that include a non-acidic hydroxyl (-OH) groups

compared to those that contain acidic (-COOH) functional groups. See JTX-020 at 7; Trial Tr. Day

5 (2/7/2018 AM) at 41:4–6 (Enscore). Further, as Dr. Tan (who was a co-author of JTX-020)

himself testified, two approaches were being used in 1999 in order to enhance transdermal delivery

rates and develop adhesives with improved biocompatibility, skin adhesion, and wear properties.

See Trial Tr. Day 3 (2/5/2018 AM) at 56:9–57:2 (Tan). However, Dr. Tan explicitly stated that

Duro-Tak® 2287 was not developed under either of these approaches. See Trial Tr. Day 3

(2/5/2018 AM) at 57:10–24 (Tan).

Moreover, Dr. Michniak-Kohn’s obviousness analysis provided little

details concerning how allegedly routine experimentation with granisetron in “conventional”

adhesives would have been performed, how long it would have taken, or how a POSA would been

directed to the claimed invention. See Trial Tr. Day 4 (2/6/2018 PM) at 105:23–106:6 (Michniak-

Kohn). Nor did Dr. Michniak-Kohn consult with Actavis’s other expert, Dr. Tan, who had

extensive experience working at National Starch and Henkel formulating drug products using

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“conventional” adhesives. See Trial Tr. Day 4 (2/6/2018 PM) at 106:7–20 (Michniak-Kohn); see

also Trial Tr. Day 2 (2/2/2018 PM) at 57:7–59:5 (Tan). Indeed, the field of transdermal drug

delivery in the early 2000s was (and still in large part is) highly unpredictable, and the only way

to know if a particular functional group of an acrylic adhesive will interact with a particular active

agent is by experimental testing. See Trial Tr. Day 3 (2/5/2018 AM) at 51:1–52:4 (Tan).

Dr. Michniak-Kohn also cites Xia as disclosing the use of Duro-Tak® 87-

2287 / 387-2287 in transdermal patches. See Trial Tr. Day 4 (2/6/2018 AM) 90:16–23 (Michniak-

Kohn). Xia has nothing to do with granisetron transdermal patches, and instead teaches patches

for the transdermal delivery of sex steroids. See Trial Tr. Day 5 (2/7/2018 AM) at 33:10–18

(Enscore); Trial Tr. Day 4 (2/6/2018 PM) at 91:20–92:14 (Michniak-Kohn). Indeed, Dr. Michniak-

Kohn admitted that she only relied on Xia in her obviousness analysis for its disclosure of the

composition of Duro-Tak® 87-2287 / 387-2287 in Example 1 of Xia. See Trial Tr. Day 4 (2/6/2018

PM) at 91:4–23; Trial Tr. Day 5 (2/7/2018 AM) at 144:4–7 (Michniak-Kohn). However, Dr.

Michniak-Kohn acknowledged that Xia disclosed additional examples that used two other

“conventional” adhesives (namely Silicone 4202, which was available from Dow Corning and

Gelva® 737, which was available from Monsanto), but that these examples in Xia were not

considered in her obviousness analysis. See JTX-018 at 3, 4:30-55; Trial Tr. Day 4 (2/6/2018 PM)

at 91:24–92:14 (Michniak-Kohn). For these reasons, the Court credits Dr. Enscore’s testimony in

finding that Xia (and Li PCT) would not have been relevant to formulating a granisetron

transdermal patch, and that the only way these references could be used in an obviousness analysis

concerning the inventions claimed in the ’282 Patent is through the use of hindsight. See Trial Tr.

Day 5 (2/7/2018 AM) at 48:2–11 (Enscore).

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Nor would any other prior art have directed a POSA to the inventions

claimed in the ’282 Patent. For example, Dr. Michniak-Kohn cited Duan as teaching the use of

monomers having hydroxyl (-OH) functional groups to increase the drug solubility in acrylic

adhesives. See DTX0141; Trial Tr. Day 4 (2/6/2018 PM) at 58:1–7 (Michniak-Kohn). However,

Duan (DTX0141) fails to disclose any skin permeation data or stability data for any drug, let alone

granisetron, in any adhesive. See Trial Tr. Day 5 (2/7/2018 AM) at 64:1–23 (Enscore); Trial Tr.

Day 4 (2/6/2018 PM) at 98:8–14 (Michniak-Kohn). Thus, a POSA attempting to formulate a

granisetron transdermal patch would have no reason to look to the teachings of Duan. See Trial Tr.

Day 5 (2/7/2018 AM) at 64:21–23 (Enscore). For these reasons, the Court finds that Duan would

not have motivated a POSA to utilize a “conventional” acrylic adhesive having a hydroxyl (-OH)

functional group to formulate a granisetron transdermal patch. See Trial Tr. Day 5 (2/7/2018 AM)

at 65:12–17 (Enscore).

In addition to failing to direct a POSA to the combination of granisetron in

the claimed adhesive having a non-acidic hydroxyl (-OH) functional group, Lee in combination

with Tan, the background knowledge of a POSA, or any other prior art of record, does not teach

or suggest that a physiologically effective amount of granisetron could be included in the claimed

adhesive or delivered to a subject in an amount sufficient to treat or prevent CINV, that the claimed

transdermal patch would exhibit the required stability, or that the claimed transdermal patch would

be capable of transdermal granisetron delivery without the use of a permeation enhancer.

Claim 1 of the ’282 Patent requires “a physiologically effective amount of

granisetron,” and claims 7, 10, and 21 require “up to about 10% by weight granisetron,” “between

6% and 7.7% w/w of granisetron,” and “between 5 and 8% w/w of granisetron,” respectively. JTX-

001 at 10–11. Further, claim 23 requires that “at an acrylic adhesive loading of 6% w/w of active

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granisetron, the acrylic adhesive has a surface area of between 10 and 100 cm2 .” Id. at 11. And

claim 26 requires “[a] method for the treatment and/or prophylaxis of [CINV].” Id. Dr. Michniak-

Kohn testified that Lee’s disclosure of 2-30% by weight of an active agent, and more specifically,

exemplary granisetron patches that include 5% and 10% by weight of granisetron disclose “a

physiologically effective amount of granisetron loaded in the acrylic adhesive.” See Trial Tr. Day

4 (2/6/2018 PM) at 26:11–27:20 (Michniak-Kohn, citing JTX-019 at 4 (¶ [0030]), 10 (¶¶ [0081]-

[0082]). Dr. Michniak-Kohn also testified that “the use of the claimed concentrations of 5-8% by

weight granisetron would have been merely a matter of routine experimentation and optimization

in view of the teachings of Lee.” See Trial Tr. Day 4 (2/6/2018 PM) at 105:5–10 (Michniak-Kohn).

However, Dr. Michniak-Kohn can only assume that a granisetron concentration of about 1 to about

25%, or preferably about 4 to about 15% by weight would be a “physiologically effective amount”

suitable to treat or prevent CINV. See DTX0061 at 7; Trial Tr. Day 4 (2/6/2018 PM) 56:16–24

(Michniak-Kohn).

The Court credits Dr. Enscore’s testimony in finding that Lee, Effing, and

the other prior art of record would not have provided a POSA with any reasonable guidance as to

what amount of granisetron in a transdermal patch would be “physiologically effective.” See Trial

Tr. Day 5 (2/7/2018 AM) at 22:14–24; 55:24–56:6; 57:5–58:2 (Enscore). This is because Lee did

not administer a single patch to a human subject, let alone a patch that contains granisetron. See

Trial Tr. Day 5 (2/7/2018 AM) at 22:14–24 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) 81:23–25

(Michniak-Kohn). Effing (like Lee) similarly discloses only in vitro drug permeation data. See

DTX0061 at 13-15; see Trial Tr. Day 5 (2/7/2018 AM) at 57:16–58:2 (Enscore). Further, Effing

provides no teaching or suggestion to (i) use the acrylic adhesives of Examples 1-7 with

granisetron, (ii) whether such patches would provide sufficient transdermal permeation of

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granisetron to provide a physiologically effect, or (iii) how much granisetron would be required in

such patches to provide a physiologically effect. See DTX0061 at 13–15; Trial Tr. Day 5 (2/7/2018

AM) at 60:20–61:6 (Enscore). Other prior art such as Gebbia (Cancer 13(9) (Sept. 1996)) similarly

fails to provide a POSA any expectation that a physiologically effective amount of granisetron

could be delivered transdermally to treat or prevent CINV because Gebbia says nothing about

transdermal delivery. See Trial Tr. Day 4 (2/6/2018 PM) at 102:17–20 (Michniak-Kohn). Without

knowing what blood plasma levels result from the systemic administration of granisetron from a

particular patch, a POSA would be left to speculate as to what concentration, if any, would result

in permeation sufficient to provide physiologic effect. See Trial Tr. Day 5 (2/7/2018 AM) 57:22–

58:2 (Enscore).

As discussed above, it is only the ’282 Patent that teaches whether any

particular granisetron concentration is physiologically effective. See JTX-001 at 10, 11:7–50

(Table 6); see Trial Tr. Day 5 (2/7/2018 AM) at 22:14–23:9 (Enscore). Indeed, the concentration

of granisetron in any particular patch that is required for physiological effect can vary depending

on the rate at which granisetron permeation occurs from that patch. See Trial Tr. Day 5 (2/7/2018

AM) at 24:7–23 (Enscore). Thus, only through in vivo testing did the inventors determine that a

granisetron content of 6% by weight is a physiologically effective amount when administered

using the claimed acrylic adhesive. See Trial Tr. Day 5 (2/7/2018 AM) at 22:25–23:5 (Enscore).

Because none of the prior art references cited by Dr. Michniak-Kohn disclose any in vivo data, the

Court finds that, there is no teaching or suggestion anywhere in the prior art of a transdermal patch

capable of administering a physiologically effective amount of granisetron. See Trial Tr. Day 5

(2/7/2018 AM) at 10:19–11:5 (Enscore); Trial Tr. Day 5 (2/7/2018 AM) at 143:11–144:7

(Michniak-Kohn).

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For these reasons, the Court finds that regardless of whether a POSA knew

what amount of blood plasma levels of granisetron would be required for physiologic effect in a

human, a POSA viewing the prior art of record would have no idea whether any patch described

by Lee, Effing, or any other reference could actually provide those physiologically effective blood

plasma levels in a human subject, and particularly to treat or prevent CINV. See Trial Tr. Day 5

(2/7/2018 AM) at 22:14–24 (Enscore); Trial Tr. Day 4 (2/6/2018 PM) 82:1–5 (Michniak-Kohn).

For these reasons, claims 1 and 26 of the ’282 Patent are not obvious over the prior art.

The Court also finds that Lee, Effing, and the other prior art of record do

not teach or suggest that a granisetron concentration in the claimed acrylic adhesive of up to about

10% by weight, between 6% and 7.7% by weight, or between 5 and 8% by weight would be a

physiologically effectively amount. For these reason, claims 7, 10, 21, and 23 of the ’282 Patent

are not obvious over the prior art. See Trial Tr. Day 5 (2/7/2018 AM) at 38:13–24; 40:6–24

(Enscore).

For the same reasons discussed above, the Court finds that granisetron

stability is not an inherent property of the transdermal patches described in Lee. See supra, §

(I)(H)(3)(a). Indeed, if drugs such as granisetron were inherently stable in acrylic adhesives, as Dr.

Michniak-Kohn concludes, there would be no need for acrylic adhesives that include monomers

that provide increased drug stability. See Trial Tr. Day 5 (2/7/2018 AM) at 25:14–20 (Enscore).

Further, the improvement in drug stability set forth in Table 2 of Lee provided by acrylic adhesive

having the PEG chains confirms that drugs are not inherently stable in all acrylic adhesives. See

Trial Tr. Day 5 (2/7/2018 AM) at 25:14–20 (Enscore).

Further, as discussed above, Effing explicitly teaches that a structurally

similar active agent (tropisetron) is unstable in a patch having a monomer with a non-acidic

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hydroxyl functional group. See DTX0061 at 11–15; see Trial Tr. Day 5 (2/7/2018 AM) at 56:9–

21 (Enscore). Thus, Effing would have led a POSA to believe that granisetron would not be stable

in the acrylic adhesives of claim 1 of the ’282 Patent. See Trial Tr. Day 5 (2/7/2018 AM) at 56:9–

21 (Enscore).


wherein no crystallization is observed after one month storage at room temperature and pressure.”

(JTX-001 at 11, 13:11.) Actavis alleges that incorporating 5% w/w of granisetron into the claimed

adhesive would naturally result in a formulation wherein no granisetron crystallization is observed

after one month of storage. See Trial Tr. Day 4 (2/6/2018 PM) at 30:11–31:13 (Michniak-Kohn).

However, crystallization is not an inherent property of a particular drug in

a particular transdermal patch, but can also depend, for example, on the concentration of active

agent contained in the patch. See Trial Tr. Day 5 (2/7/2018 AM) at 27:15–17 (Enscore).

Specifically, as the ’282 Patent discloses, “in DuroTak 387-2287, an adhesive provided by

National Starch, 8% w/w is generally higher than preferred, as crystallization can occur. Thus, in

preferred adhesives of the invention, levels of granisetron are below 8% w/w.” JTX-001 at 7, 6:6–

9. Conversely, Lee and other prior art of record such as Effing and Kamiyama are wholly silent

concerning whether crystals of any active agent formed over time within any transdermal patches,

let alone what concentration of granisetron in a particular adhesive could lead to crystallization.

See Trial Tr. Day 5 (2/7/2018 AM) at 27:12–14; 58:5–59:3 (Enscore). Therefore, a POSA viewing

the prior art would have no idea what concentration of granisetron would potentially lead to

crystallization in any acrylic adhesive, let alone an acrylic adhesive having a non-acidic hydroxyl

(-OH) functional group. See Trial Tr. Day 5 (2/7/2018 AM) at 58:5–23 (Enscore).

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the prior art of record does not teach or suggest the claimed granisetron stability required by claims

1, 11, and 28 of the ’282 Patent because whether a specific drug may crystallize in any particular

acrylic adhesive is unpredictable and requires testing. See, e.g., JTX-005 at 1–7; See Trial Tr. Day

5 (2/7/2018 AM) at 27:19–21 (Enscore).


incorporating no plasticizers or permeation enhancers.” JTX-001 at 11. Dr. Michniak-Kohn

erroneously alleges that “by utilizing the base form [of granisetron], there was already an

expectation of increased permeation, further motivating the POSA not to consider adding extra

plasticizers or permeation enhancers.” See Trial Tr. Day 4 (2/6/2018 PM) at 31:20–32:24

(Michniak-Kohn). However, these conclusory statements are contradicted by the prior art of

record, which would have led a POSA to believe that a permeation enhancer would have been

necessary for the transdermal administration of granisetron.

For example, Lee teaches the use of permeation enhancers to improve skin

permeability. See JTX-019 at 4–5, ¶¶ [0034]-[0036]; see Trial Tr. Day 5 (2/7/2018 AM) at 13:12–

15 (Enscore). What is more, both of the granisetron formulations in Lee (i.e., Example 16 and

Comparative Example 16) include the permeation enhancer polyoxyethylene(2) oleyl ether. See

JTX-019 at 4–5, ¶ [0036], at 10, ¶¶ [0081]-[0082]; see Trial Tr. Day 5 (2/7/2018 AM) at 39:10–

20 (Enscore). Thus, far from teaching that granisetron base can be administered transdermally

without a permeation enhancer, the Court finds that Lee would have directed a POSA to use a

permeation enhancer in granisetron transdermal formulations. See JTX-019 at 4–5, ¶ [0036], at 10,

¶¶ [0081]–[0082]; see Trial Tr. Day 5 (2/7/2018 AM) at 39:10–20 (Enscore).

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Effing similarly teaches that the use of permeation enhancers to promote the

transdermal delivery of tropisetron and granisetron. See DTX0061 at 8; see Trial Tr. Day 5

(2/7/2018 AM) at 59:14–19 (Enscore). Indeed, each and every exemplary embodiment in Effing

incorporates an enhancer, namely isopropyl myristate (IPM). See DTX0061 at 13–15; see Trial Tr.

Day 5 (2/7/2018 AM) at 59:14–21 (Enscore). Further, Kamiyama includes the use of the

“plasticizer” isopropyl myristate (IPM) in numerous transdermal formulations. See DTX0137 at

19–20, 22–35, 44, 48–53; Trial Tr. Day 4 (2/6/2018 PM) at 99:7–10) (Michniak-Kohn). And Xia

and Braun similarly both teach the use of permeation enhancers in transdermal patch formulations.

See JTX-018 at 1–3, Abstract:1-10, 1:58–col. 2:16, 3:14– 30; Trial Tr. Day 4 (2/6/2018 PM) at

91:4–7; 96:21–97:6 (Michniak-Kohn). For these reasons, the Court finds that Effing, as well as

other prior art of record, would have led a POSA to formulate a granisetron transdermal patch

using a permeation enhancer. See Trial Tr. Day 5 (2/7/2018 AM) at 59:22–24; 60:2–9 (Enscore).

In view of these teachings, the Court finds that the prior art as a whole would

have directed a POSA away from the invention of claim 22 of the ’282 Patent. Further, as discussed

above, because claim 22 depends directly from claim 1, this claim incorporates each and every

limitation of claim 1. Therefore, for the same reasons as discussed above, the prior art does not

teach or suggest the subject matter of claim 22 of the ’282 Patent, and therefore this claim is not

obvious under 35 U.S.C. § 103 (pre-AIA).

In summary, Actavis’s obviousness analysis is based almost wholly on

hindsight and selective portions from various references to support its obviousness theory. See

Trial Tr. Day 5 (2/7/2018 AM) at 66:6–14 (Enscore). More specifically, Actavis’s analysis ignores

many components within the very references it cites that explicitly prove such references simply

cannot fall within the limits of the adhesive in claim 1 of the ’282 Patent because they contain

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ingredients that affect the basic and novel properties of the invention disclosed in the ’282 Patent.

See Trial Tr. Day 5 (2/7/2018 AM) at 66:6–14 (Enscore). Further, only four of the cited

references—Effing, Lee, Kamiyama, and Braun—even relate to 5-HT3 antagonists and, as

explained above, these references clearly teach away from the surprising discovery made by the

inventors of the ’282 Patent. See Trial Tr. Day 5 (2/7/2018 AM) at 66:17–67:11 (Enscore). For

these reasons, and because of additional secondary considerations of non-obviousness discussed

below, the asserted claims of the ’282 Patent would not have been obvious to a POSA. See Trial


c) Secondary Considerations

As set forth below, several objective indicia of non-obviousness (also called

“secondary considerations”) are relevant to the question of whether the asserted claims of the ’282

Patent would have been obvious to a POSA, and further establish that the ’282 Patent is not

obvious.

(1) Granisetron Permeation Compared to Other Acrylic

Adhesives

Superior unexpected result is an evidentiary factor pertinent to the legal

conclusion of obviousness of the claims at issue. The claimed invention of the ’282 Patent is not

obvious because it shows superior unexpected results. See Trial Tr. Day 5 (2/7/2018 AM) at 67:25–

68:5 (Enscore). First and foremost, Actavis’s expert’s analysis on unexpected results is improper,

as she ignored any consideration of the basic and novel properties of the ’282 Patent, i.e., increased

permeation and the complete release of granisetron, in her invalidity analysis, but yet she

considered such properties in her secondary considerations analysis. See Trial Tr. Day 5 (2/7/2018

AM) at 149:11–25 (Michniak-Kohn). Nonetheless, as explained below, the claimed invention is

not obvious.

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The ’282 Patent explicitly discloses that the carboxylic acid (-COOH)

functional group materially decreases granisetron transdermal flux compared to non-acidic

hydroxyl (-OH) functional group. See Trial Tr. Day 5 (2/7/2018 AM) at 67:25–68:25 (Enscore).

Table 2, col. 9, ll. 1–10 of the ’282 Patent discloses granisetron transdermal permeation of DT

2052, DT 2353, and DT 2287. See JTX-001.

DT 2052 and DT 2353 both include carboxylic acid (-COOH) functional

groups. DT 2287 includes only non-acidic hydroxyl (-OH) functional groups. At hours 3 and 6,

the granisetron transdermal permeation of DT 2287 is more than thirty times higher than that of

DT 2052, and more than a hundred times higher than that of DT 2353. The comparisons of DT

2287, DT 2052, and DT 2353 show that the functional group of carboxylic acid (-COOH)

materially decreases the granisetron transdermal permeation. See Trial Tr. Day 5 (2/7/2018 AM)

at 67:25–68:25 (Enscore). As admitted by Actavis’s expert Dr. Michniak-Kohn, all of the Duro-

Tak® adhesives are prior art. See Trial Tr. Day 5 (2/7/2018 AM) at 146:10–22 (Michniak-Kohn).

Therefore, contrary to Actavis’s belief, Plaintiffs’ expert, Dr. Enscore, did compare the claimed

acrylic adhesive to the closest prior art. As discussed above, the prior art cited by Actavis fails to

provide any teaching or suggestion that acrylic adhesives containing granisetron and non-acidic

hydroxyl functional groups would exhibit superior skin permeation compared to adhesives that

include granisetron and either a carboxylic acid functional group, or no functional group. See Trial

Tr. Day 5 (2/7/2018 AM) at 69:1–70:10 (Enscore). Indeed, Actavis’s own expert conceded that

Effing does not disclose any permeation data for granisetron because the patches in Effing did not

include granisetron. See Trial Tr. Day 5 (2/7/2018 AM) at 147:1–12 (Michniak-Kohn).

Furthermore regarding, Lee, which Actavis has asserted is the closest prior art to the ’282 Patent,

Actavis’s expert conceded that Lee discloses granisetron in patches with acidic functional groups

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whereas the ’282 Patent compares granisetron patches having hydroxyl groups with patches

including acidic groups. See Trial Tr. Day 5 (2/7/2018 AM) at 146:10–22 (Michniak-Kohn).

Therefore, as discussed in the ’282 Patent, a POSA would have viewed these results as unexpected.

See Trial Tr. Day 5 (2/7/2018 AM) at 70:11–13 (Enscore).

(2) Other Attempts to Develop a Transdermal Product to

Deliver a 5-HT3 Receptor Antagonist

The patent applications that led to the ’282 Patent were first filed in 2003

and 2004, and the ’282 Patent eventually issued in 2009. See JTX-001 at 1; see JTX-002. The

NDA that would become Sancuso® (NDA No. 22-198) was approved by the FDA in 2008. See

JTX-022. Sancuso® was the first transdermal product approved by FDA and marketed in the

United States that contains a 5-HT3 receptor antagonist. See, e.g., JTX-068 at 18; Trial Day 2

(2/2/2018 PM) at 13:2–5 (Walther); Trial Tr. Day 1 (2/1/2018 AM) at 82:1–82:25; 98:23–99:1

(Paolillo); Trial Day 5 (2/7/2018 AM) at 145:15–18 (Michniak-Kohn). Based on prior art cited in

the ’282 Patent and by Actavis, at the time the inventors developed the invention claimed in the

’282 Patent that would become the Sancuso® product, various others had attempted and failed to

develop a product for the transdermal delivery of various 5-HT3 receptor antagonists, including

granisetron. See Trial Tr. Day 5 (2/7/2018 AM) at 70:20–71:20 (Enscore). Dr. Michniak-Kohn

admitted that the prior art references she relies upon on in her obviousness analysis, such as Lee,

Effing, Braun, and Kamiyama, show that others were working on transdermal patches for

antiemetic agents, but failed to develop a patch that was capable of delivering a physiologically

effective amount of granisetron through the skin. See Trial Tr. Day 4 2/6/2018 PM at 95:16–19);

Trial Tr. Day 5 (2/7/2018 AM) at 143:11–15; 144:8–145:14.

As described in the ’282 Patent, in the 1990s, 3M (Minnesota Mining &

Manufacturing Co.) was actively researching various methods for the transdermal delivery of 5-

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HT3 receptor antagonists. See JTX-001 at 5, 2:13–26 (discussing U.S. Patent No. 5,372,819); see

also DTX0061; see Trial Tr. Day 5 (2/7/2018 AM) at 71:5–12 (Enscore). Plaintiffs are not aware

of any research and development at 3M related to the transdermal administration of 5-HT3 receptor

antagonists (such as tropisetron, lerisetron, or granisetron) that progressed past the initial

experimental phases, let alone developed into an Investigational New Drug Application, NDA, or

commercialized product containing a 5-HT3 receptor antagonist. See DTX0061; DTX0139; see

Trial Tr. Day 5 (2/7/2018 AM) at 71:5-12 (Enscore). This is further emphasized by the fact that

3M now manufactures Sancuso® for ProStrakan. See Trial Tr. Day 5 (2/7/2018 AM) at 146:1–7

(Enscore).

There is also evidence that Cygnus Inc. was actively developing

transdermal delivery devices for a wide range of active pharmaceutical ingredients in the 1990s.

See JTX001 at 5, 2:13–26 (discussing Int’l Patent Pub. No. WO 94/07468); see also JTX-017;

JTX-018; see Trial Tr. Day 5 (2/7/2018 AM) at 71:13–20 (Enscore).

Prior art publications cited during prosecution of the ’282 Patent also show

that other companies were active in the area of developing transdermal products for various 5-HT3

receptor antagonists, including Samyang Corp. (based in South Korea), LTS Lohmann

TherapieSysteme AG (based in Germany), and Novosis AG (based in Germany). See JTX-002 at

187–215 (Int’l Patent Pub. No. WO 00/47208), 272–288 (Int’l Patent Pub. No. WO 01/74338),

324- 330 (EP 1 064 939 A2).

The fact that Sancuso® was the first and only transdermal product for a 5-

HT3 receptor antagonist where it is clear that many others attempted to develop such a product but

ultimately failed, is evidence that the claimed invention of the ’282 Patent would have been non-

obvious to a POSA. See Trial Tr. Day 5 (2/7/2018 AM) at 71:21–72:2 (Enscore).

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(3) Attempted Design Around

As set forth above, Actavis’s Accused Product is a matrix-type transdermal

system consisting of three consecutive layers: (1) a translucent backing layer composed of

polyester/EVA laminate; (2) a drug/adhesive matrix of granisetron and acrylic adhesive; and (3) a

release liner which protects the drug reservoir layer during storage and is removed immediately

prior to application. (JTX-006 at 3; see Trial Tr. Day 1 (2/1/2018 PM) at 53:11–25; 70:2–16;

77:21–78:7 (Enscore); Trial Tr. Day 2 (2/2/2018 AM) at 87:13–88:19 (Rifaat).

Actavis’s Accused Product has a rectangular shape with rounded corners

and has a surface area of 52 cm2. See JTX-006 at 3; see Trial Tr. Day 1 (2/1/2018 PM) at 52:18–

53:7; 62:2–9 (Enscore). Actavis’s Accused Product includes 34.3 mg of granisetron per patch (or

660 µg/cm2) and provides a nominal dose of 3.1 mg/24 hours. See JTX-006 at 3; JTX-026; see

Trial Tr. Day 1 (2/1/2018 PM) at 52:18–53:7; 62:2–9 (Enscore); see Trial Tr. Day 2 (2/2/2018

PM) at 27:18–28:5 (Walther); Trial Tr. Day 2 (2/2/2018 PM) at 94:8–23 (Tan). These

characteristics of Actavis’s Accused Product are summarized in the following table:

JTX-006 at 3.

Like Sancuso®, Actavis’s Accused Product is also formulated in Duro-

Tak® 387- 2287. See JTX-001 at 9–10, 9:42–10:51; JTX-006 at 4; supra § (I)(G)(2)(a); see also

Trial Tr. Day 2 (2/2/2018 PM) at 95:6–96:4 (Tan); Trial Tr. Day 5 (2/7/2018 AM) at 73:18–74:9

(Enscore). Prior to arriving at this final formulation for its proposed generic version of Sancuso®,

Actavis performed research that included numerous in vitro skin permeation studies that utilized a

range of standard acrylic adhesives and various permeation enhancers. See JTX005 at 5; see Trial

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Tr. Day 2 (2/2/2018 AM) at 64:23–71:3 (Rifaat); Trial Tr. Day 5 (2/7/2018 AM) at 73:9–74:9

(Enscore). As set forth in Actavis’s Formulation Transfer Report:

Adhesives investigated include Duro-Tak 87-2051, DuroTak 87- 2054, Duro-Tak

87-900A, Duro-Tak 87-2196, Duro-Tak 87-2677, Duro-Tak 9301, Duro-Tak 2287

(and blends of aforementioned adhesives), silicone adhesive (sufficient drug did

not dissolve), and PIB-PB adhesive (sufficient drug did not dissolve). Skin

permeation enhancers investigated include Oleyl Alcohol and Isopropyl Myristate

(IPM). The formulation used in the Exhibit batches contains Duro-Tak 87-2287

adhesive, as discussed in the following summary. JTX-005 at 5.

Actavis was able to develop two formulations that potentially would not

infringe the claims of the ’282 Patent. Specifically, Actavis’s internal report states that:

The formulation with Duro-Tak 87-9301 adhesive had comparable skin permeation

when compared to the brand, however this adhesive is not typically used for long-

term (i.e. 7-days) wear times based on vendor recommendations. The formulation

with Duro-Tak 87-900A adhesive and drug yielded 85% of the brand skin

permeation value as shown below in study 1784-072214-HN. Skin permeation

enhancers (IPM, Oleyl Alcohol, and a combination) were therefore added to

increase the skin permeation as shown below in study 1784-072214-HN. The

formulation with Duro-Tak 87-900A and a combination of IPM and Oleyl Alcohol

yielded skin permeation comparable to that of the brand product as shown below in

study 1784-072214-A-HN. JTX-005 at 5 (emphasis added).

Duro-Tak® 87-9301 and Duro-Tak® 87-900A are acrylate copolymers

having no monomers that include functional groups (e.g., -OH groups), contain no vinyl acetate,

and no crosslinker. See JTX-004 at 2. The latter adhesive required a permeation enhancer in order

to achieve transdermal permeation of granisetron comparable to Sancuso®. See JTX-005 at 5–7.

Trial mixes of one potentially non-infringing formulation having

comparable skin permeation to Sancuso® were manufactured, but the casting solution required a

re-mixing step before laminate coating and a continuous mixing step during laminate coating. See

id. at 5–7; Trial Tr. Day 5 (2/7/2018 AM) at 73:18–74:9 (Enscore); Trial Tr. Day 2 (2/2/2018 AM)

at 88:20–24 (Rifaat). Despite Actavis’s capabilities to perform these manufacturing steps, a

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formulation requiring fewer manufacturing steps was instead selected. See JTX-005 at 5–7; see

Trial Tr. Day 5 (2/7/2018 AM) at 73:18–74:9 (Enscore).

Actavis also reverse engineered Sancuso®. See JTX-005 at 16; see Trial Tr.

Day 2 (2/2/2018 AM) at 62:7–14 (Rifaat); Trial Tr. Day 5 (2/7/2018 AM) at 82:3–10 (Enscore);

Trial Tr. Day 5 (2/7/2018 AM) at 153:5–10 (Michniak-Kohn). In sum, despite developing two

potentially non-infringing formulations that exhibited comparable skin permeation to Sancuso®,

Actavis chose instead to use a transdermal formulation that includes precisely the same polymer

as Sancuso® (Duro-Tak® 87-2287 / 387-2287) and drug in the same concentrations. See Trial Tr.

Day 5 (2/7/2018 AM) at 73:18–74:9 (Enscore); Trial Tr. Day 5 (2/7/2018 AM) at 153:5–10;

153:14-17; 154:12-15 (Michniak-Kohn). Notably, Actavis was not required by the FDA to use the

same adhesive as the Sancuso® product, but Actavis specifically chose to copy the claimed

invention of the ’282 Patent. See Trial Tr. Day 5 (2/7/2018 AM) at 74:10–11 (Enscore). For this

additional reason, the claimed invention of the ’282 Patent would not have been obvious to a

POSA.

I. Facts Relating to Inequitable Conduct

Actavis asserts applicants, specifically Peter Altenschöpfer and Adam

Charles Watkinson, failed to disclose material information and made affirmative

misrepresentations to the PTO during the prosecution of the application that led to the ’282 Patent.

Specifically, Actavis alleges that applicants failed to disclose information regarding the specific

and complete formulation(s) claimed in the ’282 Patent while repeatedly making misleading

statements about the advantages of the formulation(s). Further, Actavis alleges that the applicants

included inaccurate data in the application that led to the ’282 Patent concerning the performance

of an Example formulation, specifically the DT 4098 formulation, by underrepresenting the

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permeation values, which allowed applicants to make misleading statements and arguments to the

PTO regarding the alleged advantages of its inventive formulations as compared thereto.

Actavis must prove both elements of inequitable conduct by clear and

convincing evidence: (1) that omissions and/or misrepresentations by applicants to the PTO were

material to patentability; and (2) that such misrepresentations were made with an intent to deceive.

Actavis fails to meet its burden on both elements. Actavis’s alleged evidence of materiality relies

on discrepancies between permeation data presented in an example of the ’282 Patent and the

Sancuso® NDA. However, there is no evidence that any of the permeation data presented in the

’282 Patent was material to the PTO’s allowance of the ’282 Patent. Moreover, even assuming that

the data in the ’282 Patent was material to patentability, Actavis has no evidence—either express

or inferred—that anyone associated with the prosecution of the ’282 Patent—including the named

inventors—intended to deceive the PTO. Instead, Actavis alleges that the only reasonable

inference is that these misrepresentations and omissions were made and committed by the patent

applicants with the intent to deceive the PTO. Based on the record presented, the Court finds that

Actavis has not met its high burden to prove that the ’282 Patent is unenforceable for inequitable

conduct.

1. The Teachings of the ʼ282 Patent

a) The Claims and Specification of the ʼ282 Patent Require Only

a Specific Adhesive—Not a Permeation Enhancer

Claim 1—the sole independent claim of the ’282 Patent—is directed to an

“adhesive patch” and lacks any limitation concerning the presence or absence of a “permeation

enhancer” in the claimed formulations. JTX-001 at 10, 12:52–65; see Trial Tr. Day 3 (2/5/2018

AM) at 41:13–18 (Tan); Trial Tr. Day 5 (2/7/2018 AM) at 115:25–116:25 (Enscore). Indeed,

because claim 1 uses the transitional phrase “comprising” this claim is open-ended and can further

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include ingredients, such as permeation enhancers. See Trial Tr. Day 5 (2/7/2018 AM) at 115:25–

116:21 (Enscore). The Court notes that claim 22 of the’282 Patent is the only claim of the ’282

Patent that is specifically directed to a patch “incorporating no plasticizers or permeation

enhancers.” JTX-001 at 11, 14:13–14.

Exemplary embodiments of the inventive granisetron transdermal patches

are presented at Examples 1-3 of the ’282 Patent. Id. at 8, 8:45–55.

The ’282 Patent is wholly silent concerning whether a permeation enhancer

is present in any of the transdermal formulations of Example 1. See Trial Tr. Day 1 (2/1/2018 PM)

at 133:10–23 (Enscore); Trial Tr. Day 5 (2/7/2018 AM) at 96:9–12 (Enscore). The purpose of

Example 1 (and Table 1) of the ’282 Patent is to compare granisetron permeation and flux through

mouse skin from pressure sensitive adhesives having different functional groups. See Trial Tr. Day

1 (2/1/2018 PM) at 34:23–35:6 (Enscore). In discussing the formulations presented in Example 1

and Table 1 of the ’282 Patent, there is no mention as to whether any formulation contained a

permeation enhancer. See Trial Tr. Day 1 (2/1/2018 PM) at 133:10–23 (Enscore); Trial Tr. Day 5

(2/7/2018 AM) at 96:9–12 (Enscore).

Table 2 of the ’282 Patent, shown below, discloses the in vitro permeation

of granisetron from those four formulations through mouse skin as a function of time (i.e., from 0

to 48 hours):

JTX-001 at 9, 9:1–10.

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In explaining the above permeation data in Table 2 (Example 1), the ’282

Patent states that:

(Id. at 8:62–67). The ’282 Patent further explains that “[p]ermeation from the adhesives containing

acidic moieties was very much lower than that from the adhesive with no functionality” (Id. at 9,

9:12–14) and that:

(Id. at 9, 9:44–57).

Concerning the data in Table 2, the ’282 Patent states that the “levels of

[granisetron] flux from DT 2287 [were] 30x greater than those obtained with the nonnucleophilic

and electroneutral DT 4098. The reason for the convergence at higher levels is owing to the

depletion of drug from the adhesive in DT 2287.” Id. at 8, 8:62–67; see also id. at 9, 9:1–10

(comparing flux data from DT 2287 and DT 4098 at 3 hours (31.7 μg/cm2 vs. 1 μg/cm2) and 6

hours (92.0 μg/cm2 vs. 2.9 μg/cm2). Thus, contrary to Actavis’s assertions, Example 1 of the ’282

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Patent purports to show increased granisetron permeation based on the functional group present in

the acrylic adhesive—namely, a non-acidic hydroxyl group. Moreover, the ’282 Patent

specification discloses unequivocally that it is the combination of granisetron with the claimed

acrylic adhesive having a non-acidic hydroxyl group that is the invention. See id. at 1 (Abstract),

at 6, 3:43–46, 3:54–64, at 8-9, 8:35–9:57.

In contrast, Actavis alleges that the ’282 Patent is replete with misleading

statements about the advantages of the formulation(s) of the ’282 Patent because the inventive

formulations do not contain a permeation enhancer. However, while the ’282 Patent explains that

“[t]he adhesive patches of the present invention are effective without having to incorporate any

plasticisers or permeation enhancers,” Id. at 6, 4:32–34, the ’282 Patent does not teach this as being

a requirement. See Trial Tr. Day 1 (2/1/2018 PM) at 133:10–23 (Enscore).

In addition to Example 1, transdermal patch formulations embodying the

claimed invention (i.e., prepared using Duro-Tak® 387-2287) are presented in Example 2 (JTX-

001 at 9, 10:12–21 (FIG. 3)) and Example 3 (see id. at 9-10, 10:41–11:50) of the ’282 Patent. Like

Example 1, Example 2 of the ’282 Patent is also silent as to whether the formulations included a

permeation enhancer. See id. at 9, 9:59–10:39. Only Example 3 of the ’282 Patent discloses a

detailed manufacturing process to teach that a permeation enhancer is not present. Specifically,

Example 3 teaches that:

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JTX-001 at 9-10, 10:43–11:6.

In sum, regardless of whether a permeation enhancer is present, granisetron

patch formulations in Examples 1-3 prepared using DT 2287 acrylic adhesive (i.e., DuroTak®

387-2287) are embodiments of the claimed inventive transdermal patch. See Trial Tr. Day 1

(2/1/2018 PM) at 132:1–4 (Enscore); Trial Tr. Day 4 (2/6/2018 AM) at 75:5–11 (Stratford).

Further, it is undisputed that the commercial embodiment of the ’282 Patent (i.e., Sancuso®) does

not contain a permeation enhancer. See Trial Tr. Day 1 (2/1/2018 PM) at 25:11–14 (Enscore); Trial

Tr. Day 2 (2/2/2018 AM) at 59:17–18, 59:20, 93:6–9 (Rifaat); Trial Tr. Day 3 (2/5/2018 PM) at

69:8–10 (Duguid); Trial Tr. Day 5 (2/7/2018 AM) at 67:17–19 (Enscore). For these reasons, the

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Court finds that while formulations lacking a permeation enhancer may be preferred embodiments

of the ’282 Patent, aside from claim 22, this is not a requirement.

The named inventors of the ’282 Patent are Peter Altenschöpfer and Adam

Charles Watkinson. See JTX-001 at 1. Dr. Watkinson is a former employee of ProStrakan (see

JTX-058), who left the company in 2005, but voluntarily testified by deposition in London, UK,

on August 9, 2017. The other named inventor, Dr. Altenschöpfer, worked for Novosis AG, which

ProStrakan hired to assist in the development of an anti-emetic patch. See Trial Tr. Day 4 (2/6/2018

AM) at 22:12–16, 46:15–19, 52:17–23 (Stratford); see also JTX-022 at 2. As Dr. Watkinson

testified, it was Dr. Altenschöpfer who prepared the transdermal formulations and conducted the

experiments that were presented in the ’282 Patent. See Trial Tr. Day 3 (2/5/2018 PM) at 74:11–

20 (Watkinson); Trial Tr. Day 4 (2/6/2018 AM) at 52:17–23, 71:8–73:16 (Stratford). However,

there is no testimony in the record from Dr. Altenschöpfer, who was not deposed during fact

discovery. Thus, Dr. Watkinson’s testimony is the only record outside of the prosecution history

of the ’282 Patent concerning the preparation and prosecution of the ’282 Patent. Further, other

than submitting signed declarations shortly after the ’282 Patent was filed, there is no evidence

that either inventor was involved in prosecuting of the ’282 Patent.

b) The Patent Office Only Allowed the Claims of the ʼ282 Patent

Based on Amendments to Claim 1 that Require a Specific Acrylic

Adhesive

Actavis alleges several instances during prosecution of the ’282 Patent in

which applicants argued the patentability of their invention based on the lack of a permeation

enhancer. However, Actavis can point to no evidence from the prosecution history of the ’282

Patent or Dr. Watkinson’s testimony that the alleged omissions or errors in Tables 1 and 2 of the

’282 Patent were material to the patentability of the claims. Indeed, the presence or absence of a

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permeation enhancer in the transdermal formulations of the ’282 Patent was not relevant to the

PTO’s decision to issue the ’282 Patent. For example, the Patent Office recognized that the claimed

transdermal patch may include a permeation enhancer:

In response to applicant’s argument that the references fail to show certain features

upon which applicant relied (i.e., matrix patch, or an adhesive matrix patch, another

form of patch, may not be suitably employed in the present invention because it can

carry only limited amounts of an anti-vomiting agent and a soluble skin penetration

enhancer in its adhesive layer) are not recited in the rejected claim(s).

See JTX-002 at 628, 644. Indeed, the PTO was steadfast in rejecting all of applicants’ arguments

of record, and repeatedly found the claims (at the time) anticipated or obvious over the prior art.

See id. at 555–60, 598–609, 633–45. It was only through amendments to the claims that any of the

PTO’s rejections over the prior art were overcome. See id. at 566–92, 594, 610–29, 648–54.) Thus,

the absence of a permeation enhancer was simply not relevant to the PTO’s decision to allow the

claims of the ’282 Patent to issue.

Instead, the PTO only allowed the ’282 Patent to issue after an amendment

to the claims was entered to overcome prior art rejections of Effing (DTX0061). Nothing in the

PTO’s reasons for allowing the claims of the ’282 Patent to issue concerned the specific amounts

of granisetron permeation from any patches, but instead concerned the use of an acrylic adhesive

that contained specific monomers and the resulting drug stability that resulted from its use with

granisetron. See JTX-002 at 654.

In response, applicants submitted the comments on the Patent Office’s

reasons for allowance, which sought to clarify that amendment to claim 1 of the ’282 Patent

introduced the transitional phrase “consisting essentially of,” as opposed to “consisting of.” Id. at

686–87. After the agreed upon amendment to claim 1 that introduced the transitional phrase

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“consisting essentially of” to limit the monomer composition of the claimed adhesive, the ’282

Patent issued on October 27, 2009. See JTX-001 at 1; Docket No. 110 at 8, 14.

2. The Sancuso® NDA

More than four-and-one-half years after the earliest priority date of the ’282

Patent, on June 29, 2007, ProStrakan filed NDA No. 022198 seeking FDA-approval to market

Sancuso® (the “Sancuso® NDA”). See PTX-094 at 3.

The Sancuso® NDA included a summary of “investigations” of various

transdermal formulations conducted in conjunction with the development of Sancuso®, along with

information concerning the formulations such as the maximum transdermal flux, amount of

granisetron permeated, and whether crystals were observed to form in the formulations. See JTX-

022 at 2–6. Data related to several of the formulations is provided below in Table 2 of the

Sancuso® NDA:

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As shown above, Table 2 in the Sancuso® NDA does not include

permeation data hours at 3, 6, 12, 14, or 36. See id. This data instead is presented in Tables 3 and

4 of the Sancuso® NDA:

Id. at 7 (Sancuso® NDA). However, Table 4 of the Sancuso® NDA discloses the cumulative

granisetron permeation from the DT 87-4098 formulation (allegedly corresponding to batch 28) as

being 129.8 μg/cm2, as opposed to the value of 174.6 μg/cm2 disclosed in Table 2. The same

permeation value of 129.8 μg/cm2 for the DT 87-4098 formulation appears in Table 2 of the ’282

Patent.

Neither Dr. Watkinson nor ProStrakan’s witnesses could explain the origin

of this discrepancy between the granisetron permeation values at 48 hours for the DT 87-4098

formulation between, on the one hand, Table 2 of the Sancuso® NDA, and, on the other hand,

Table 2 of the ’282 Patent (and Table 4 of the Sancuso® NDA). As Dr. Watkinson testified, the

permeation data in Table 4 of the Sancuso® NDA and Table 2 of the ’282 Patent appear to be “the

same or similar.” Trial Tr. Day 3 (2/5/2018 PM) at 92:1–3 (Watkinson). However, no testimony

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of record confirms that the data reported in Table 2 of the ’282 Patent in fact comes from the same

transdermal formulations as the data of Tables 2 and 4 of the Sancuso® NDA. See Trial Tr. Day 3

(2/5/2018 PM) at 57:2–12 (Duguid); Trial Tr. Day 4 (2/6/2018 AM) at 92:7–14 (Stratford).

Further, Actavis failed to solicit any testimony from Dr. Altenschöpfer, who was the inventor who

actually prepared the formulations and performed the testing of those formulations.

Despite this lack of evidence, Actavis asks this Court to infer that the

applicants intentionally changed the granisetron permeation value for the DT 87-4098 formulation

listed in Table 2 of the ’282 Patent from the allegedly “correct” value of 174.6 μg/cm2 to the

falsified value of 129.8 μg/cm2.

It should be noted that, both the permeation value of 129.8 µg/cm2 (that

appears in Table 4 of the Sancuso® NDA and Table 2 of the ’282 Patent), and the allegedly correct

permeation value of 174.6 µg/cm2 (that appears only in Table 2 of the Sancuso® NDA), are

considerably lower than the granisetron permeation from DT 387-2287 at 48 hours (290.4 µg/cm2)

reported in both the Sancuso® NDA and the ’282 Patent. See JTX001 at 9, 9:1–10; JTX-022 at 6.

Further, Actavis has no evidence that an admixture of 3% “LD” would have increased (or

decreased) the granisetron permeation in batch 28 (i.e., from the DT 87-4098 formulation), or to

what degree it would have increased or decreased. See Trial Tr. Day 5 (2/7/2018 AM) at 150:18–

151:9 (Michniak-Kohn); see also DTX0139 at 6 (Table 1).

3. Any Omissions or Errors in the ʼ282 Patent Were Not Material

Based on the information presented in Table 2 of the Sancuso® NDA,

Actavis alleges at least two misrepresentations or omissions in Tables 1 and 2 of the ’282 Patent

that compel this Court to reach a finding of inequitable conduct. First, Actavis alleges that

applicants intentionally and affirmatively misrepresented that three of the transdermal

formulations of Example 1 and Table 1 of the ’282 Patent did not contain a permeation enhancer.

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Second, Actavis alleges that applicants intentionally falsified the permeation data at 48 hours in

Table 2 of the ’282 Patent for the formulation prepared from DT 87-4098. Further, Actavis alleges

that, but for these alleged misrepresentations, the PTO would not have allowed the ’282 Patent to

issue.

The Court finds that, assuming that there were omissions of the complete

formulation details for three of the transdermal formulations in Example 1 of the ’282 Patent, such

omissions were not material to the patentability of the claims of the ’282 Patent. As discussed

above, the inventors surprisingly found that the combination of granisetron with an acrylic

adhesive having a non-acidic hydroxyl group provided superior permeation. The Court finds that

whether or not three of the formulations in Table 2 of the ’282 Patent further included a 3%

“Admixture” of lauric acid diethanolamide was not material to patentability because claim 1 does

not specifically omit, and applicants never stated, that a permeation enhancer is excluded from the

claimed invention. Indeed, claim 1 of the ’282 Patent includes the transitional phrase

“comprising,” which is open ended and does not exclude additional ingredients. See JTX-001 at

10, 12:52–65.) Therefore, the use or exclusion of a permeation enhancer would not have been

material to the PTO in evaluating the claims of the ’282 Patent, and the Court disagrees that the

applicants failed to disclose information regarding the entire composition of the adhesive in the

claimed patch formulation. Indeed, it was only through an amendment to claim 1 focused on a

specific combination of monomers in the acrylic adhesive that led to the Patent Office’s issuance

of the ’282 Patent.

The Court further finds that discrepancies between permeation data

presented in Table 2 of the ’282 Patent and Tables 2 and 4 of the Sancuso® NDA were not material

to the patentability of the claims of the ’282 Patent. The Court notes that the granisetron permeation

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from the DT 387-2287 formulation (290.4 µg/cm2) is consistently reported as being higher than

permeation values reported for DT 87-4098—whether in the ’282 Patent or the Sancuso® NDA

(129.8 µg/cm2 and 174.6 µg/cm2). As discussed above, there is no evidence of record as to which

data is actually “correct.” Dr. Enscore stated that the most valid comparisons between the

adhesives in Table 2 occur at hours 3 and 6 given that the DT 2287 formulation releases the

granisetron so quickly, and a majority of the drug content by hour 12. See JTX-001 at 9, 9:1–10;

Trial Tr. Day 1 (2/1/2018 PM) at 33:4–35:20, 120:23–121:9 (Enscore); Trial Tr. Day 5 (2/7/2018

AM) at 17:16–24, 21:2–11, 68:16–25 (Enscore).

As Dr. Michniak-Kohn admitted, nor is there any evidence of record

concerning whether the addition of 3% lauric acid diethanolamide to the DT 87-4098 formulation

would have resulted in increased granisetron permeation, and to what degree permeation would be

increased. See Trial Tr. Day 5 (2/7/2018 AM) at 150:18–151:9 (Michniak-Kohn); see also

DTX0139 at 6 (Table 1). Further, the Court finds that this data was merely exemplary and not

material to the patentability of the claims of the ’282 Patent, which, as discussed above, were

allowed to issue based on an amendment to claim 1.

For the same reasons, the Court finds that applicants made no material

misrepresentations to the PTO during prosecution of the ’282 Patent. Indeed, the prosecution

history is consistent with the specification of the ’282 Patent in that it is devoid of any admission

that a permeation enhancer is either required or specifically omitted from the claimed formulations.

At most, the prosecuting attorney argued that a permeation enhancer is “not necessary” in order

“to achieve desirable performance properties.” See JTX-002 at 575, 618; Trial Tr. Day 5 (2/7/2018

AM) at 115:25–116:12 (Enscore). The prosecuting attorney also stated “the combination of

adhesive having non-acidic hydroxyl moieties and granisetron provides numerous advantages,

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e.g., -the combination has been found remarkably stable; -the combination has been found to have

surprisingly good drug release properties; and -the combination has been found to have

surprisingly good skin flux properties.” JTX-002 at 575, 618. Such attorney argument during

prosecution of the ’282 Patent—particularly because it was not effective in overcoming any prior

art rejection—does not constitute a material misrepresentation.

Finally, the Court does not agree with Actavis that it would have been

material to have in their possession the other batch data from the Sancuso® NDA besides the four

Duro-Tak® adhesives in Table 2 of the ’282 patent. Applicants are not required to disclose every

study conducted during development of a product. Further, it was reasonable to create a

comparative table using four Duro-Tak® adhesives.

In sum, the Court finds that the alleged misrepresentations or omissions by

the inventor(s) were not material to the patentability of the ’282 Patent. As noted, the formulations

and permeation data presented in Example 1 of the ’282 Patent were not relevant to the Patent

Office’s decision to issue the ’282 Patent. Instead, it was applicants’ decision to amend claim 1 to

specifically claim the combination of granisetron with an acrylic adhesive having a non-acidic

monomer that led to issuance of the ’282 Patent.

4. No Evidence of Intentional Misrepresentation or Omission

The Court analyzes intent and materiality separately and will not infer intent

solely from materiality. Actavis has failed to put forth any evidence—either express or inferred—

that one or both of the inventor(s) intentionally omitted or falsified information in the ’282 Patent.

Therefore, the Court disagrees with Actavis’s conclusory allegation that the inventors or applicants

acted with the intent to deceive the PTO and somehow modified a data point reported to the PTO

in the patent application to reflect a lower permeation value than Plaintiffs reported to the FDA in

their NDA for the same testing.

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At the deposition of Dr. Watkinson stated that he did not remember anything

about the inclusion or lack of inclusion of permeation enhancers in the formulations. See Trial Tr.

Day 3 (2/5/2018 PM) at 104:6–105:12 (Watkinson). Dr. Watkinson was never asked about the

difference in the data points between the Sancuso® NDA and the ’282 Patent regarding DT 87-

4098. However, when asked if he believed the data that is reported in Table 2 for DT 2287 at hours

36 and 48 to be “erroneous”, Dr. Watkinson answered, “No.” See Trial Tr. Day 3 (2/5/2018 PM)

at 96:16–22 (Watkinson).

Further, neither Dr. Watkinson nor Plaintiffs’ corporate designees knew

why only the four Duro-Tak® adhesives were chosen to exemplify the invention in Tables 1 and

2 in the ’282 Patent. See Trial Tr. Day 3 (2/5/2018 PM) at 55:1–6 (Duguid); Trial Tr. Day 3

(2/5/2018 PM) at 89:21–90:18, 92:16-20 (Watkinson); Trial Tr. Day 4 (2/6/2018 AM) at 63:21–

23 (Stratford). Further, Dr. Watkinson did not know why the full Table 2 of the Sancuso® NDA

was not included in the application for the ’282 Patent. See Trial Tr. Day 3 (2/5/2018 PM) at

103:12–23.

Moreover, Actavis failed to elicit any testimony whatsoever from Dr.

Altenschöpfer—the inventor who actually performed the permeation testing—or anyone else at

Novosis AG who actually performed the adhesive permeation studies. See Trial Tr. Day 3

(2/5/2018 PM) at 74:11–20, 75:14–76:12, 87:14–88:1 (Watkinson); Trial Tr. Day 4 (2/6/2018 AM)

at 52:17–23, 71:8–73:16 (Stratford).

Neither of Plaintiffs’ corporate designees, Dr. Ian Duguid or Dr. Tom

Stratford, had an explanation for the difference in data points between the table in the NDA

document and the table in the ’282 Patent. See Trial Tr. Day 3 (2/5/2018 PM) at 58:2–12, 58:22–

59:3 (Duguid); Trial Tr. Day 4 (2/6/2018 AM) at 88:19–91:14 (Stratford). Dr. Stratford also stated

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that he believed that the data in Table 2 of the ’282 Patent to be accurate. See Trial Tr. Day 4

(2/6/2018 AM) at 77:11–15 (Stratford).

Having no testimony from any inventors or Plaintiffs’ corporate designees

that demonstrates the inventor(s) had any knowledge of the allegedly withheld information,

Actavis cannot show that the inventor(s) had any specific intent to withhold this information or

deceive the PTO, or deliberately made a decision to include only the data for the four adhesive

formulations to the exclusion of other data. The Court disagrees that, allegedly, the applicants

deliberatively chose to withhold data, affirmatively misrepresented formulations including a

permeation enhancer, or manipulated a data point to make misleading statements and deceive the

PTO.

Actavis has put forth no evidence that the inventors, prosecuting attorney,

or any other employee of Plaintiffs knew that any information in the patent was in any way

different than that found in the NDA, intentionally withheld material information, or made

knowingly false misrepresentations. Indeed, the only sworn testimony elicited on whether any

inventor believed the data in Table 2 for DT 2287 in the ’282 Patent were false or erroneous is Dr.

Watkinson’s resounding “No”. See Trial Tr. Day 3 (2/5/2018 PM) at 96:16–18. The Court also

does not find any basis as to any inferred intent based on the information allegedly withheld or

misrepresented.

II. CONCLUSIONS OF LAW

A. Jurisdiction

[CL1] This Court has subject matter jurisdiction over Actavis’s counterclaim

action for declaratory judgment pursuant to 35 U.S.C. § 271(e)(5); 28 U.S.C. §§ 1331, 1337(a),

1338, 2201, and 2202; and/or 21 U.S.C. § 355(j), based on an actual controversy between Actavis

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and ProStrakan arising under the patent laws of the United States, 35 U.S.C. §§ 101 et seq., and

specifically under 35 U.S.C. § 271(e)(2)(A).

[CL2] The Court has personal jurisdiction over ProStrakan based on its filing of

this lawsuit in this District and because it is doing business in this District.

[CL3] Actavis did not contest personal jurisdiction or raise objections to the

propriety of venue for the limited purposes of the present matter only.

B. Infringement

1. Legal Standard

[CL4] “Patent infringement, whether literal or by equivalence, is an issue of fact,

which the patentee must prove by a preponderance of the evidence.” Siemens Med. Sols. USA, Inc.

v. Saint-Gobain Ceramics & Plastics, Inc., 637 F.3d 1269, 1279 (Fed. Cir. 2011).

[CL5] Determining infringement requires a two-step analysis: (1) the patent claims

must be construed to ascertain their scope and meaning; and (2) the claims, as properly construed,

must be compared to the accused method or product. SmithKline Diagnostics, Inc. v. Helena Labs.

Corp., 859 F.2d 878, 889 (Fed. Cir. 1988).

[CL6] Under 35 U.S.C. § 271(e)(2)(A), Actavis’s submission of ANDA No.

208726 to the FDA constituted infringement of the ’282 Patent. Although no traditional patent

infringement has occurred until a patented product is made, used, or sold, under the Hatch-

Waxman framework, the filing of an ANDA itself constitutes a technical act of infringement for

jurisdictional purposes. 35 U.S.C. § 271(e)(2)(A); Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661,

676-78 (1990).

[CL7] Direct infringement under 35 U.S.C. § 271(a) is established if an accused

product or method meets every limitation of a claim either literally or under the doctrine of

equivalents. Pfizer, Inc. v. Teva Pharm., USA, Inc., 429 F.3d 1364, 1376 (Fed. Cir. 2005).

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“Because drug manufacturers are bound by strict statutory provisions to sell only those products

that comport with the ANDA’s description of the drug, an ANDA specification defining a

proposed generic drug in a manner that directly addresses the issue of infringement will control

the infringement inquiry.” Abbott Labs. v. TorPharm, Inc., 300 F.3d 1367, 1373 (Fed. Cir. 2002);

see Sunovion Pharm., Inc. v. Teva Pharm. USA, Inc., 731 F.3d 1271, 1279-80 (Fed. Cir. 2013)

(categorizing an ANDA compound that “meets the limitations of an asserted claim” as one where

there “is almost never a genuine issue of material fact that the claim is infringed” because the

manufacturer must comport with the ANDA specification). Thus, “if a product that an ANDA

applicant is asking the FDA to approve for sale falls within the scope of an issued patent, a

judgment of infringement must necessarily ensue.” Sunovion, 731 F.3d at 1278.

2. Discussion

[CL8] The Court finds that Actavis’s proposed generic granisetron extended

release transdermal film product, 3.1 mg/24 hours, meets all of the limitations of the asserted

claims, and thus Actavis’s manufacture, use, offer for sale, sale, or importation of its proposed

generic granisetron extended release transdermal film product, 3.1 mg/24 hours, literally infringes

the ’282 Patent. See FOF ¶¶ 68-90, 142-67.

a) Actavis’s Accused Product Meets the Basic and Novel

Properties of the Claimed Invention of the ʼ282 Patent

[CL9] The Court construed “consisting essentially of” in Claim 1 as “including the

listed ingredient and open to unlisted ingredients that do not materially affect the basic and novel

properties of the invention, the basic and novel properties of the invention being 1) increased

transdermal delivery of granisetron, 2) granisetron stability in the patch, and 3) the complete

release of granisetron from the patch.” Docket No. 62 at 7. Accordingly, the basic and novel

properties become part of the scope of the claims. See AK Steel Corp. v. Sollac & Ugine, 344 F.3d

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1234, 1240 (Fed. Cir. 1988) (limiting to “no more than 0.5% silicon by weight” because “silicon

in excess of 0.5% by weight would materially alter the basic and novel properties of the

invention”); see also Horizon Pharma Ireland Ltd. v. Actavis Labs., UT, Inc., No. 14-7992, 2016

WL 4408990, at *7 (D.N.J. Aug. 17, 2016) (“The Court agrees with [defendant] that the basic and

novel properties are part of the scope of the claim, and as such are part and parcel of the claims.”).

[CL10] The Court finds that Actavis’s Accused Product meets the basic and novel

properties of the claimed invention of the ’282 Patent. See FOF ¶¶ 91-109. Actavis only disputes

that its Accused Product meets the property of complete release of granisetron from the patch. The

definition of “complete release” is defined in the specification. See AK Steel, 344 F.3d at 1239

(Fed. Cir. 2003) (“To determine these [basic and novel] properties, we need look no further than

the patent specification.”). The Court therefore finds, as defined by the specification of the ’282

Patent and testified to by Dr. Enscore, that “complete release” means “complete depletion,” to the

point that there is no lasting interaction between the drug and the adhesive. See FOF ¶¶ 95-100.

[CL11] Further, the specification of the ’282 Patent describes the “complete

release” of granisetron as being measured by in vitro testing. Indeed, both Dr. Enscore and Dr. Tan

relied on Example 1 of the ’282 Patent for their definitions of “complete release,” and both agreed

that the “complete release” was observed through in vitro drug permeation tests. See FOF ¶ 103.

The ’282 Patent does not contain any in vivo data on the complete release of granisetron. See FOF

¶ 106. Therefore, as demonstrated in Example 1 (Table 2) of the ’282 Patent, the Court finds that

“complete depletion” is determined by in vitro testing using, for example, a Franz cell with no

specific time period or type of skin required. See FOF ¶¶ 102-106. Moreover, Dr. Tan admitted

that at some point, Actavis’s Accused Product would become completely depleted of granisetron

by either in vitro or in vivo testing. See FOF ¶ 108.

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[CL12] The Court credits Dr. Enscore’s undisputed testimony that Actavis’s ANDA

includes results of in vitro testing that show Actavis’s Accused Product completely releases the

granisetron content over 168 hours (seven days). See FOF ¶¶ 107-109. Accordingly, Actavis’s

Accused Product exhibits the basic and novel properties required by the ’282 Patent, namely an

increased rate of transdermal delivery of granisetron, granisetron stability, and complete release of

granisetron.

b) Additional Components Do Not Materially Affect the Basic

and Novel Properties of the Claimed Invention of the ʼ282 Patent

[CL13] The question of what constitutes a “material effect” in considering the term

“consisting essentially of” is a question of fact relating to infringement. See PPG Indus. v.

Guardian Indus. Corp., 156 F.3d 1351, 1354 (Fed. Cir. 1998) (holding that it was proper for the

district court to instruct the jury that “an ingredient has a material effect on the characteristics . . .

if the effect is of importance or of consequence to those of ordinary skill in the art . . . .”); see also

Kim v. Earthgrains Co., No. 01C3895, 2010 WL 625220, at *4 (N.D. Ill. Feb. 18, 2010)

(“[A]dditional active ingredients which improve the performance of the basic claim formula, but

do not otherwise change its function, do not materially alter the ‘basic and novel’ characteristics

of the invention.”).

[CL14] The specification of the ’282 Patent is silent on what constitutes a material

effect on the basic and novel characteristics of the granisetron patch. See AK Steel, 344 F.3d at

1240–41. The Court finds that the definition of “material effect” was provided by Plaintiffs’ expert

Dr. Enscore and, as unrebutted, relies on this definition. The Court therefore finds that a material

effect is a large enough effect that would project that a POSA could make a reasonable size

granisetron transdermal patch based on that transdermal permeation. Further, the Court finds that

in the context of “complete release,” a material effect is one that would prevent the drug from

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leaving the patch. Finally, in the context of drug stability, a material effect is one that causes

significant drug degradation such that the patch would not be suitable for pharmaceutical use. See

FOF ¶ 111.

(1) Vinyl Acetate

[CL15] As construed by the Court, the term “consisting essentially of” merely

requires that no additional components present in the acrylic adhesive have a material effect on the

basic and novel properties of the claimed invention. See Docket No. 62. Actavis alleges that vinyl

acetate and glycidyl methacrylate in Actavis’s Accused Product materially affect the basic and

novel properties of the claimed invention of the ’282 Patent. Actavis did not assert that any

additional unlisted ingredients such as ethanol, ethyl acetate, the release liner, or backing layer

used in Actavis’s Accused Product materially affect the basic and novel properties of the claimed

patch.

[CL16] The Court finds, as Dr. Enscore testified, that vinyl acetate is a copolymer

that has a modifying effect on bulk properties such as tack, adhesion, elasticity, and cohesive

strength— not to change transdermal delivery, “complete release,” or for stability purposes. See

FOF ¶ 116. The prior art confirms this, as relevant prior art such as Lee, Effing, Braun, and Li

PCT all discuss polymers that contain vinyl acetate, but do not state that vinyl acetate affected the

drug delivery in any way. See id.

[CL17] Further, the amount of vinyl acetate in Actavis’s Accused Product is within

the ranges disclosed by the ’282 Patent, demonstrating that the inventors believed that such

amounts would not materially alter the basic and novel properties of the invention. See FOF ¶ 118.

As the ’282 Patent states, “[t]ypical levels of . . . the modifying monomer [in adhesives], such as

vinyl acetate . . . is typically present in an amount of about 10 to 40% w/w.” See JTX-001 at 6, 4:

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20–23. Further, the inventors never sought to include vinyl acetate in claim 1, even when amending

the claim from “comprising” to “consisting essentially of.” See, e.g., JTX-002 at 686–87.

However, the inventors did put a different monomer between 0.5 and 20% w/w because it affected

the basic and novel properties. See JTX-001. Accordingly, given that the vinyl acetate at 26.5%

(w/w) is within the range given in the specification, this further demonstrates that it has no material

effect on the basic and novel properties of the claimed invention. See AK Steel, 344 F.3d at 1240.

[CL18] The Court credits Dr. Enscore who testified that the comparative examples

set forth in the ’282 Patent would similarly lead to a conclusion that the vinyl acetate present in

Duro-Tak® 387-2287 does not materially affect the transdermal delivery of granisetron. See FOF

¶¶ 119-21. A comparison of granisetron patches prepared using the adhesives DT 2052 and DT

2287 shows that for two adhesives that each contain vinyl acetate, the vinyl acetate was a non-

factor in the transdermal flux of granisetron. See FOF ¶¶ 119-20. Notably, the ’282 Patent in FIG.

1 and Table 2 shows that DT 2287 has a transdermal granisetron flux more than thirty times higher

than DT 2052 at hours 3 and 6. See id. As described in the ’282 Patent, the non-acidic hydroxyl

functional group appeared to play a substantial role in increasing the transdermal delivery of

granisetron. See id.

[CL19] Dr. Enscore made a second comparison between two acrylic adhesives that

each include a monomer having a carboxylic acid functional group (DT 2052 and DT 2353), with

one being a copolymer with vinyl acetate (DT 2052) and the other lacking vinyl acetate as a

comonomer (DT 2353). See FOF ¶ 121. Both adhesives are characterized by very low granisetron

flux compared to that for the formulation prepared using Duro-Tak® 2287, particularly at hours 3

and 6. See id. Thus, vinyl acetate had no material effect on increasing the transdermal drug delivery

in these exemplary acrylic adhesives loaded with 3% granisetron. See id. Accordingly, the

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exemplary embodiments disclosed in the ’282 Patent lead to the conclusion that vinyl acetate has

no material effect on the transdermal delivery of granisetron. See FOF ¶¶ 119-121.

[CL20] Dr. Enscore further testified that Actavis’s own empirical data from its

Formulation Transfer Report demonstrates that vinyl acetate does not materially affect the

transdermal delivery of granisetron from the claimed inventive patch. See FOF ¶¶ 122-23. During

development of Actavis’s Accused Product, Actavis tested several formulations against Sancuso®

for transdermal granisetron flux across human skin in vitro. See FOF ¶ 122. Two specific

formulations included pressure sensitive adhesives that contain vinyl acetate and granisetron, the

only difference being that the former system includes a functional monomer containing non-acidic

hydroxyl (-OH) groups whereas the latter system includes a functional monomer containing

carboxylic acid (-COOH) groups. See FOF ¶ 123. Notably, the formulation containing non-acidic

hydroxyl (-OH) had more than five times the cumulative transdermal granisetron permeation of

the formulation containing carboxylic acid (-COOH) groups, proving that the non-acidic hydroxyl

moiety is the factor that materially increased transdermal delivery of granisetron and consistent

with what the inventors found as novel—not vinyl acetate. See id.

[CL21] Based on the transdermal permeation data set forth in the ’282 Patent, the

testimony of Dr. Enscore, and a review of studies conducted by Actavis, the Court finds that vinyl

acetate does not materially affect the transdermal delivery of granisetron from the claimed

inventive patch where a POSA would make a reasonable size granisetron transdermal patch

focusing on the use of vinyl acetate.

[CL22] The Court also finds that vinyl acetate does not materially affect the final

two properties: granisetron stability in the patch and complete release of granisetron from the

patch. Both the ’282 Patent and Actavis’s ANDA disclose the granisetron stability in the patches

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formulated with Duro-Tak® 387-2287. See FOF ¶¶ 125–27. That is, the stability data reported in

the ’282 Patent and for Actavis’s Accused Product (measured for adhesives containing vinyl

acetate), meet the stability limitation of claim 1 of the ’282 Patent. See FOF ¶¶ 125–27.

Accordingly, crediting the testimony of Dr. Enscore on this issue, the Court does not find that vinyl

acetate materially affects the chemical stability of granisetron in the claimed inventive patch

causing the drug to degrade.

[CL23] Finally, as discussed, the ’282 Patent discloses that the granisetron is

completely released through murine skin in vitro after 24 hours. See FOF ¶¶ 102–109. As a result

of the Court finding that the proper measure of “complete release” is in vitro and demonstrated by

the in vitro data of Table 2 of the ’282 Patent for the fact that the Sancuso® (Duro-Tak® 387-

2287) patch had completely released its granisetron drug content, vinyl acetate had no material

effect on the “complete release,” i.e., depletion, of the granisetron from the patch. See FOF ¶¶ 127–

28. Moreover, Actavis’s Formulation Transfer Report discloses that Actavis’s Accused Product

was tested using human skin in vitro and also shows “complete release.” See FOF ¶¶ 102–109,

127–28.

[CL24] Therefore, vinyl acetate does not materially affect the complete release of

granisetron from the claimed inventive patch causing the drug to no longer chemically interact

with the adhesive, preventing the drug from leaving the patch.

[CL25] The Court gives little to no weight to Dr. Tan’s testimony and finds it

conclusory and non-persuasive. Dr. Tan cited to no documentary evidence in reaching his

conclusions or the percentage of monomers in other Duro-Tak® adhesives and provided no data

that vinyl acetate is anything other than a bulking modifying monomer or materially affects any

property. See Velander v. Garner, 348 F.3d 1359, 1371 (Fed. Cir. 2003) (according “little weight

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to broad conclusory statements that it determined were unsupported by corroborating references”);

Lemelson v. United States, 752 F.2d 1538, 1551 (Fed. Cir. 1985) (according “no weight to the

series of conclusory statements offered by [plaintiff’s] expert witness” since there was no

demonstrable assertion that the accused device met “claim 1’s manipulation means”); see also

Apple Inc. v. Samsung Elecs. Co., Ltd., 839 F.3d 1034, 1066 n.3 (Fed. Cir. 2016) (Reyna, J.,

dissenting) (“A court may not treat a conclusory answer without any context as evidence.” (citing

Telemac Cellular Corp. v. Topp Telecom, Inc., 247 F.3d 1316, 1329 (Fed. Cir. 2001)); Ashland

Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 294 (Fed. Cir. 1985) (lacking “factual

support for [an] expert opinion going to factual determinations . . . may render the testimony of

little probative value in a validity determination”). Moreover, Dr. Tan’s analysis was based on an

incorrect assumption that granisetron base is hydrophilic and that vinyl acetate is hydrophobic,

which was contradicted by both Dr. Enscore and Dr. Michniak-Kohn, and the prior art of record.

See FOF ¶ 117.

[CL26] Accordingly, the Court determines that vinyl acetate does not materially

affect any of the basic and novel properties of Actavis’s Accused Product.

(2) Glycidyl Methacrylate

[CL27] Glycidyl methacrylate is also present in Duro-Tak® 387-2287, but not

recited in claim 1 of the ’282 Patent. The Court credits Dr. Enscore’s testimony in finding that

glycidyl methacrylate does not materially affect any of the basic and novel properties of the

invention of the ’282 Patent. The Court again gives little to no weight to Dr. Tan’s testimony, as

he cited no documentary evidence to support his conclusions and provided no data that glycidyl

methacrylate materially affects any property of Actavis’s Accused Product. Plaintiffs have met

their burden that even if glycidyl methacrylate has some effect or even if a residual amount of

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glycidyl methacrylate were to crosslink, it does not reach the threshold of a material effect on the

basic and novel properties of the invention of the ’282 Patent according to Dr. Enscore’s definition

that the Court adopts.

[CL28] The Court finds that although glycidyl methacrylate may be used as a

crosslinking monomer at an appropriate concentration, as Dr. Enscore testified, the concentration

of glycidyl methacrylate in the adhesive of Actavis’s Accused Product at 0.15% (w/w) is too low

to produce any crosslinking characteristic for Actavis’s Accused Product unless a separate

crosslinking agent is added to the adhesive to react with the glycidyl methacrylate moieties. See

FOF ¶ 133. The record is replete with examples that Duro-Tak® 387-2287 contains no crosslinking

agent and is described as non-curing. See FOF ¶¶ 132–33. Actavis’s other expert, Dr. Michniak-

Kohn, also testified that Duro-Tak® 387-2287 does not contain a crosslinker, and certain other

prior art also describe Duro-Tak® 387-2287 as containing no crosslinking agent. See FOF ¶ 133.

As Dr. Enscore explained, the glycidyl methacrylate in Actavis’s Accused Product is there to

provide a site for crosslinking if an additional crosslinking agent is added to the polymer for it to

react with, which Actavis’s Accused Product does not contain. See id.

[CL29] The Court credits Dr. Enscore’s testimony that the comparative examples

set forth in the ’282 Patent show that the glycidyl methacrylate present in Duro-Tak® 387-2287

does not materially affect the transdermal delivery of granisetron. See FOF ¶ 134. Both DT 2287

and DT 2353 include glycidyl methacrylate, but the difference between DT 2287 and DT 2353 is

that DT 2287 includes a functional monomer of non-acidic hydroxyl (-OH) groups, and DT 2353

includes a functional monomer containing carboxylic acid (-COOH) groups. See id.. Table 2 of

the ’282 Patent shows that the patch prepared using DT 2287 exhibited cumulative granisetron

permeation over a hundred times higher at hours 3 and 6 than that achieved using the acrylic

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adhesive DT 2353, thus showing that glycidyl methacrylate had no effect on the transdermal flux

of granisetron. See id. Instead, the non-acidic hydroxyl functional group appeared to play a much

more substantial role in increasing the transdermal flux of granisetron. See id. The Court therefore

finds that glycidyl methacrylate does not materially affect the transdermal delivery of granisetron

in Actavis’s Accused Product.

[CL30] The Court finds that glycidyl methacrylate also does not materially affect

the “complete release” or stability of granisetron in the patch. As explained above, Actavis’s

Formulation Transfer Report also proves the granisetron stability in the patch of Actavis’s Accused

Product. See FOF ¶ 135. Actavis’s ANDA also includes the results of tests of exhibit batches

demonstrating that Actavis’s Accused Product provides for the complete release of granisetron

from the patch. See id.

[CL31] Finally, the specification of the ’282 Patent leads to the conclusion that the

inventors did not believe glycidyl methacrylate to have a material effect on the basic and novel

properties of the invention. See FOF ¶ 136. As the ’282 Patent states, the adhesive may contain

glycidyl methacrylate at levels between 0.05 and 1% (w/w). See JTX-001 at 6, 4:28–30. The

inventors did not seek to amend claim 1 to include glycidyl methacrylate, even when they amended

the claim from “comprising” to “consisting essentially of.” See, e.g., JTX002 at 686–87. Given

that the glycidyl methacrylate in the adhesive used in Actavis’s ANDA Product (at 0.15% (w/w))

is within the range described in the ’282 Patent, this further demonstrates that it has no material

effect on the basic and novel properties of the claimed invention. See AK Steel, 344 F.3d at 1240.

[CL32] Thus, a concentration of 0.15% (w/w) glycidyl methacrylate included in

DuroTak® 387-2287 of Actavis’s Accused Product does not materially affect, or even have any

affect at all, any of the basic and novel properties of the invention, neither increased transdermal

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delivery of granisetron, nor granisetron stability in the patch, nor the complete release of

granisetron from the patch.

[CL33] Actavis’s reliance on Kim v. ConAgra Foods is misplaced, as the law does

not require Plaintiffs to prove infringement by scientific testing. Kim v. ConAgra Foods, Inc., 465

F.3d 1312 (Fed. Cir. 2006). Rather, the Federal Circuit has no “general rule requiring one who

alleges infringement of a claim containing functional limitations to perform actual tests or

experiments on the accused product or method. Instead [the Federal Circuit] stated only that ‘Kim

did not prove infringement because she presented no testimony based on the accused products

themselves that supported a finding of infringement.’” Martek Biosciences Corp. v. Nutrinova,

Inc., 579 F.3d 1363, 1374 (Fed. Cir. 2009); see Endo Pharm. Inc. v. Actavis Labs. UT, Inc., No.

2:13-CV-192-JRG, 2015 WL 12910639, at *31 (E.D. Tex. Aug. 27, 2015) (presenting evidence,

without experimental testing, “that the presence or absence of water in the inventive formulations

. . . effect[s] . . . the properties of the product” is sufficient to prove that water “materially affects

the basic and novel properties of the inventions” even though the FDA filing did “not state that

water has an effect on the properties of the product”); Allergan, Inc. v. Athena Cosmetics, Inc., No.

07-1316, 2013 WL 12141346, at *6 (C.D. Cal. Mar. 5, 2013) (arguing “that there is a genuine

issue of fact because no testing proves that bimatoprost isopropyl ester stimulates hair growth”

was unavailing because “actual hair growth” was not a functional limitation of the patent).

[CL34] The Court concludes that no experimental studies are required here because

the data in the ’282 Patent and in Actavis’s own formulation work confirm that vinyl acetate does

not materially affect the basic and novel properties of the invention of the ’282 Patent that are also

present in Actavis’s Accused Product. (See FOF ¶ 123.) Plaintiffs presented testimony from two

experts, each of whom conceptually analyzed Actavis’s Accused Product and how it satisfies each

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limitation of the asserted claims, including the basic and novel properties, and that the product

contains no unlisted ingredient that materially affects those properties of the invention.

c) Indirect Infringement

[CL35] 35 U.S.C. § 271(b) provides that “[w]hoever actively induces infringement

shall be liable as an infringer.” “[I]nducement requires that the alleged infringer knowingly

induced infringement and possessed specific intent to encourage another’s infringement.”

AstraZeneca LP v. Apotex Inc., 633 F.3d 1042, 1056 (Fed. Cir. 2010) (quoting DSU Med. Corp. v.

JMS Co., 471 F.3d 1293, 1306 (Fed. Cir. 2006)). According to the Supreme Court of the United

States, “[e]vidence of active steps . . . taken to encourage direct infringement, such as advertising

an infringing use or instructing how to engage in an infringing use, shows an affirmative intent

that the product be used to infringe . . . .” Metro-Goldwyn-Mayer Studios, Inc. v. Grokster, Ltd.,

545 U.S. 913, 915 (2005). Consistent with this guidance, the Federal Circuit has found defendants

liable for induced infringement based on product labeling that would encourage others to use the

associated drug product in an infringing manner. See, e.g., AstraZeneca, 633 F.3d at 1060-61

(finding specific intent to induce infringement when “the proposed label instructs users to perform

the patented method” and here, “[defendant] included instructions in its proposed label that will

cause at least some users to infringe the asserted method claims” while “proceed[ing] with its plan

to distribute the drug despite being aware that the label presented infringement problems”).

[CL36] In addition to Actavis’s direct infringement, Actavis’s offer for sale or sale

of its proposed generic granisetron extended release transdermal film product, 3.1 mg/24 hours,

with its proposed package insert, will induce infringement of the claim 26 of the ’282 Patent.

[CL37] Actavis’s proposed generic granisetron extended release transdermal film

product, 3.1 mg/24 hours, meets all of the formulation elements of the asserted method claims. See

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FOF ¶¶ 84–90, 165–67. Actavis intends to sell its Accused Product in the United States

accompanied by Actavis’s proposed Prescribing Information. See FOF ¶¶ 165-67. Dr. Tan agreed

that Actavis’s proposed Prescribing Information provides instructions to a medical professional as

to how the product is to be used. See id. Thus, healthcare professionals, patients, and others

administering Actavis’s Accused Product, in accordance with Actavis’s proposed Prescribing

Information, will practice all of the limitations of the asserted method claims. See FOF ¶ 168.

Accordingly, Actavis will induce healthcare professionals, patients, and others to directly infringe

the claims of the ’282 Patent by marketing its proposed generic granisetron extended release

transdermal film product, 3.1 mg/24 hours, with its proposed Prescribing Information.

AstraZeneca, 633 F.3d at 1060-61.

C. Validity

[CL38] An issued patent is presumed valid under 35 U.S.C. § 282, and “[t]he burden

of establishing invalidity of a patent or any claim thereof shall rest on the party asserting such

invalidity.” Abbott Labs. v. Sandoz, Inc., 544 F.3d 1341, 1346 (Fed. Cir. 2008) (citing 35 U.S.C.

§ 282). Accordingly, a defendant raising an invalidity defense bears a “‘heavy burden of

persuasion,’ requiring proof of the defense by clear and convincing evidence.” Microsoft Corp. v.

i4i Ltd. P’ship, 564 U.S. 91, 102 (2011) (quoting Radio Corp. of Am. v. Radio Eng’g Labs, 293

U.S. 1, 8 (1934)); see Finnigan Corp. v. Int'l Trade Comm’n, 180 F.3d 1354, 1365 (Fed. Cir. 1999)

(“The burden is on the party asserting invalidity to prove it with facts supported by clear and

convincing evidence.” (quoting another source)).

1. Enablement

[CL39] Actavis has not shown by clear and convincing evidence that the asserted

claims of the ’282 Patent are invalid for lack of enablement.

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[CL40] 35 U.S.C. § 112, first paragraph, which sets forth the enablement

requirement, states: “The specification shall 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 is most nearly connected,

to make and use the same, and shall set forth the best mode contemplated by the inventor or joint

inventor of carrying out the invention.”

[CL41] “[T]his statutory language mandates satisfaction of two separate and

independent requirements: an applicant must both describe the claimed invention adequately and

enable its production and use.” Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1307-08 (Fed. Cir.

2015) (quoting Alcon Research Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1188 (Fed. Cir. 2014)). “A

patent need not disclose what is well known in the art.” In re Wands, 858 F.2d 731, 735 (Fed. Cir.

1988). Questions of law, such as whether a claim satisfies the enablement requirement, are for the

judge to decide. Allergan, 796 F.3d at 1309.

[CL42] “To prove that a claim is invalid for lack of enablement, a challenger must

show by clear and convincing evidence that a person of ordinary skill in the art would not be able

to practice the claimed invention without ‘undue experimentation.’ ” Id. (quoting Wands, 858 F.2d

at 736-37). As detailed in Plaintiff’s findings of fact and explained above, see FOF ¶¶ 170–86, the

unrebutted clear and convincing evidence at trial proved the asserted claims of the ’282 Patent are

not invalid for lack of enablement under 35 U.S.C. § 112, first paragraph (pre-AIA).

[CL43] Whether practicing the invention requires undue experimentation “is not a

single, simple factual determination, but rather is a conclusion reached by weighing many factual

considerations.” ALZA Corp. v. Andrx Pharm., LLC, 603 F.3d 935, 940 (Fed. Cir. 2010) (quoting

Wands, 858 F.2d at 737). “Factors to be considered in determining whether a disclosure would

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require undue experimentation . . . include (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.” Wands, 858 F.2d

at 737. Although illustrative, these factors are not mandatory. See Amgen, Inc. v. Chugai Pharm.

Co., 927 F.2d 1200, 1213 (Fed. Cir. 1991); see also Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d

1362, 1371 (Fed. Cir. 1999). A court need not review all of the factors before making an

enablement determination. Biochem, Inc., 188 F.3d at 1371.

[CL44] The test for whether a person of ordinary skill in the art would not be able

to practice the claimed invention without undue experimentation “is not merely quantitative, since

a considerable amount of experimentation is permissible, if it is merely routine, or if the

specification in question provides a reasonable amount of guidance with respect to the direction in

which the experimentation should proceed.” Wands, 858 F.2d at 737; see also PPG, 75 F.3d at

1565 (“Where the specification provides ‘guidance in selecting the operating parameters that

would yield the claimed result,’ it is fair to conclude that the experimentation required to make a

particular embodiment is not ‘undue.’ ” (internal citation omitted)). Further, “extensive

experimentation does not necessarily render the experiments unduly extensive where the

experiments involve repetition of known or commonly used techniques.” Cephalon, Inc. v. Watson

Pharm., Inc., 707 F.3d 1330, 1338 (Fed. Cir. 2013).

[CL45] Actavis has not proven by clear and convincing evidence that the asserted

claims of the ’282 Patent are invalid for lack of enablement under 35 U.S.C. § 112. The crux of

Actavis’s enablement argument rests on whether the asserted claims enable a POSA to practice

the in vivo “complete release of granisetron from the patch” as required by the ’282 Patent. FOF

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¶ 170. However, this Court agrees with Dr. Enscore’s testimony that Actavis places far too rigid

of a definition on the term “complete release” by requiring 100% of the granisetron to be depleted

from the claimed patch during its therapeutically useful clinical application to a human subject.

See FOF ¶¶ 171–73, 182. This is because a POSA would have known in 2003-2004 that, in

practice, no matrix patch was known to undergo the complete release of an active agent during the

period of its clinical use. See FOF ¶¶ 170, 181. Actavis’s definition is also not supported by this

Court’s claim construction, which does not require “the complete release of granisetron” to occur

within seven days of being applied to a patient’s upper arm to prevent nausea and vomiting. See

FOF ¶ 182.

[CL46] Also, contrary to Actavis’s assertions, the specification of the ’282 Patent

discloses to a POSA reviewing the specification what is meant by the “complete release” of

granisetron from the claimed patch. Here, as set forth in Example 1, the term “complete release”

refers to the “complete depletion” of granisetron from the inventive patch, which “indicates that it

is very unlikely that any lasting interaction occurred between the drug and this adhesive.” JTX-

001 at 9, 9:49–51; see FOF ¶¶ 173–74. Based on this description, a POSA would understand

“complete release” to mean there is no interaction between the granisetron and the claimed acrylic

adhesive that prevents the granisetron from being released from the patch. See FOF ¶ 173.

[CL47] Further, the Court agrees with Dr. Enscore’s opinion that based on the

specification of the ’282 Patent, a POSA would have no reason to conclude that the “complete

release” of granisetron is required to be measured by in vivo testing of patches on human subjects.

See FOF ¶¶ 179–182. Rather, a POSA would understand that “complete release” of granisetron

could be examined by in vitro tests such as that described in Example 1 of the ’282 Patent. See

FOF ¶¶ 170–71, 174–78. The fact that Dr. Tan opines in vivo testing is the only testing that should

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be applied to determine “complete release” is without merit, as Dr. Tan himself only relies on

Example 1 and Table 2 of the ’282 Patent to support his strict definition of “complete release,”

while it is clear the experiments of Example 1 and Table 2 are based on in vitro data. See id.

[CL48] Contrary to Actavis’s position, a POSA would understand the data disclosed

in Example 1, and specifically Table 2 of the ’282 Patent, and would therefore be able to apply the

data disclosed to formulate the “complete release” of the patch. Indeed, as admitted by Dr. Tan,

Example 1 actually shows the “complete release” of granisetron from the patch within 24 hours.

See id. Further, Dr. Tan confirmed the Franz cell testing demonstrated in the ’282 Patent is the

exact type of experimentation that is routinely used to select a particular drug formulation. See id.

Indeed, Actavis used the same methodology to develop its Accused Product. See FOF ¶¶ 175–77.

Therefore, as Dr. Enscore and Dr. Tan testified, any variability in the data set forth in the ’282

Patent is of a degree of variability expected when using Franz cells, and similar to the variability

Actavis itself observed in its own in vitro testing. See JTX-005 at 9–10; PTX-219; see id.

[CL49] Finally, contrary to Actavis’s assertions, a POSA would have understood

that the data disclosed in Example 2 of the ’282 Patent would eventually achieve “complete

release” from the claimed formulation. This is confirmed by Dr. Tan, who admitted that even in

vivo, the patch would eventually demonstrate “complete release,” see FOF ¶¶ 170, 177, and

Actavis’s own testing of Sancuso® and its own granisetron patches that were examined under

experimental conditions similar to the in vitro skin permeation testing set forth in Example 2 (FIG.

3) of the ’282 Patent. See JTX-005; FOF ¶ 175. More specifically, the in vitro data provided in

Actavis’s ANDA using human skin which confirms that after seven days, there is a “complete

release” of granisetron from the Duro-Tak® 387-2287 patches tested. See FOF ¶ 177.

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[CL50] For all of the reasons set forth above, including the discussion above,

Actavis has not met its burden to provide clear and convincing evidence that the asserted claims

of the ’282 Patent are invalid for lack of enablement under 35 U.S.C. § 112. The claims of the ’282

Patent are fully enabled and do not require undue experimentation.

2. Indefiniteness

[CL51] A claim can only be held invalid for indefiniteness when “read in light of

the specification and prosecution history, it fails to inform those skilled in the art about the scope

of the invention with reasonable certainty.” Exmark Mfg. Co. v. Briggs & Stratton Power Prods.

Grp., LLC, 879 F.3d 1332, 1345 (Fed. Cir. 2018) (citing Nautilus, Inc. v. Biosig Instruments, Inc.,

134 S.Ct. 2120, 2129 (2014)).

[CL52] Actavis puts forth no evidence regarding whether the ’282 Patent is invalid

for indefiniteness. When Actavis attempted to offer evidence in the record through its expert Dr.

Tan, Dr. Tan questioned Actavis’s counsel, “[w]hat [does] ‘indefinite’ mean?”, at which point

Actavis’s counsel halted any further questioning regarding indefiniteness. FOF ¶ 187. Thus, there

is no dispute that Actavis has not presented sufficient evidence, or at the very least any evidence,

to meet its burden of establishing by clear and convincing evidence that the ’282 Patent is invalid

for indefiniteness.

3. Anticipation

[CL53] Notably, the burden of establishing invalidity is even greater where, as here,

the prior art relied upon was considered by the PTO during prosecution. See, e.g., Tokai Corp. v.

Easton Enters., Inc., 632 F.3d 1358, 1367 (Fed. Cir. 2011) (“[A]lthough the standard of proof does

not depart from that of clear and convincing evidence, a party challenging validity shoulders an

enhanced burden if the invalidity argument relies on the same prior art considered during

examination by the . . . PTO[.]”). Actavis failed to meet this burden by applying an improper

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obviousness and anticipation analysis that contradicts both this Court’s and the Federal Circuit’s

precedent. Even if this Court looked past this misapplication of the patent law, the Court still finds

that Actavis has failed to meet this heightened burden.

[CL54] This Court and the Federal Circuit have emphasized the importance of

consistency for claims to “be interpreted and given the same meaning for purposes of both validity

and infringement analyses.” Amazon.com, Inc. v. Barnseandnoble.com, Inc., 239 F.3d 1343, 1351

(Fed. Cir. 2001); Sterner Lighting, Inc. v. Alied Elec. Supply, Inc., 431 F.2d 539, 544 (5th Cir.

1970) (“A patent may not, like a ‘nose of wax,’ be twisted one way to avoid anticipation and

another to find infringement.” (citing White v. Dunbar, 119 U.S. 47, 51 (1886))); see also Source

Search Techs., LLC v. Lending Tree, LLC, 588 F.3d 1063, 1075 (Fed. Cir. 2009); AK Steel, 344

F.3d at 1241–45. However, Actavis’s infringement and validity analyses are far from consistent.

On the one hand, Actavis’s infringement analysis focuses on where its Accused product fails to

meets the basic and novel properties of the ’282 Patent. See FOF ¶¶ 91–109. On the other hand,

for the purposes of invalidity, Actavis’s expert Dr. Michniak-Kohn acknowledged the prior art

must disclose all of the basic and novel properties of the ’282 Patent; however, Dr. Michniak-Kohn

did not analyze, nor was she asked to analyze, whether PEG monomers, or any other monomers,

in Lee’s adhesives, or any other prior art adhesives for that matter, materially affect the basic and

novel properties of the ’282 Patent. See FOF ¶¶ 196, 217.

[CL55] Setting aside this flaw in its arguments, the Court rejects Actavis’s

anticipation and obviousness arguments on a substantive level as well. A patent claim is invalid

as “anticipated” under 35 U.S.C. § 102 if it is determined that all of the limitations of the claim are

described in a single prior art reference. The standard for anticipation is one of strict identity. See

Homeland Housewares, LLC v. Whirlpool Corp., 865 F.3d 1372, 1381 (Fed. Cir. 2017) (relying

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on general background does not establish anticipation when the limitations are neither shown in

the prior art nor references within the prior art). To invalidate a patent by anticipation, a prior art

reference must disclose each and every limitation of the claim. Merck & Co., Inc. v. Teva Pharm.

USA, Inc., 347 F.3d 1367, 1372 (Fed. Cir. 2003). Federal Circuit decisions have repeatedly

emphasized that anticipation is established only if all the elements of an invention, as stated in a

patent claim, are identically set forth in a single prior art reference. Id.; see also Xerox Corp. v.

3Com Corp., 458 F.3d 1310, 1322 (Fed. Cir. 2006) (“[I]nvalidity by anticipation requires that the

four corners of a single, prior art document describe every element of the claimed invention. . . .”

(quoting Advanced Display Sys., Inc. v. Kent State Univ., 212 F.3d 1272, 1282 (Fed. Cir. 2000)));

Teleflex, Inc. v. Ficosa N. Am. Corp., 299 F.3d 1313, 1335 (Fed. Cir. 2002) (“As we have

repeatedly stated, anticipation requires that each limitation of a claim must be found in a single

reference.”) Furthermore, “[b]ecause the hallmark of anticipation is prior invention, the prior art

reference—in order to anticipate under 35 U.S.C. § 102—must not only disclose all elements of

the claim within the four corners of the document but must also disclose those elements ‘arranged

as in the claim.’ ” Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 (Fed. Cir. 2008)

(quoting Connell v. Sears, Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir. 1983)) (“In such

instances, a reference that discloses all of the claimed ingredients, but not in the order claimed,

would not anticipate. . . .”) The Federal Circuit stated “that the ‘arranged as in the claim’

requirement applies to all claims and refers to the need for an anticipatory reference to show all of

the limitations of the claims arranged or combined in the same way as recited in the claims, not

merely in a particular order.” Id. at 1370; In re Chudik, 851 F.3d 1365, 1372 (Fed. Cir. 2017);

Summit 6, LLC v. Samsung Elecs. Co., Ltd., 802 F.3d 1283, 1294 (Fed. Cir. 2015).

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[CL56] However, a prior art reference may anticipate when the claim limitation or

limitations not expressly found in that reference are nonetheless inherent. Eli Lilly & Co. v. Zenith

Goldline Pharm., Inc., 471 F.3d 1369, 1375 (Fed. Cir. 2006); see, e.g., In re Omeprazole Patent

Litig., 483 F.3d 1364, 1371–73 (Fed. Cir. 2007) (finding “inherent anticipation” from “credible

. . . evidence of in situ formation” of a separating layer when a certain combination of ingredients

are used); Schering Corp. v. Geneva Pharm., Inc., 339 F.3d 1373, 1377 (Fed. Cir. 2003)

(illustrating that “a skilled artisan [does not need] to recognize the inherent characteristic [of DCL

formation] in the prior art” in order for the prior art to anticipate the patent at issue). If a limitation

is not explicitly disclosed in an allegedly anticipating prior art reference, Actavis bears the burden

of showing that the limitation is inherently disclosed by the reference. See, e.g., Glaxo Inc. v.

Novopharm Ltd., 52 F.3d 1043, 1047 (Fed. Cir. 1995) (finding “Novopharm had not carried its

burden of proving by clear and convincing evidence that practice of Example 32 of the ’658 patent

always produced Form 2 ranitidine hydrochloride,” and therefore “Form 2 was not inherently

disclosed by Example 32”); Electro Med. Sys., S.A. v. Cooper Life Scis., Inc., 34 F.3d 1048, 1052

(Fed. Cir. 1994) (failing to disclose the inherent feature, “unpressurized flow[,]” is present in the

Ruemelin patent and “would be so recognized by persons of ordinary skill”).

[CL57] To establish inherency, the anticipatory feature or result must be consistent,

necessary, and inevitable, not simply possible or probable, and it should be clear that it would be

so recognized by persons of ordinary skill. See Atofina v. Great Lakes Chem. Corp., 441 F.3d 991,

1000 (Fed. Cir. 2006) (disclosing a preferred embodiment temperature range was insufficient to

demonstrate, “with sufficient specificity[,]” anticipation when the prior art and patent ranges were

different yet overlapped); In re Robertson, 169 F.3d 743, 745 (Fed. Cir. 1999) (holding a POSA

would not understand that the disposable absorbent garment limitation inherently “include[s] a

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third fastening means for disposal of the diaper”). That is, inherency “may not be established by

probabilities or possibilities”, and “[t]he mere fact that a certain thing may result from a given set

of circumstances is not sufficient” to show inherency. Robertson, 169 F.3d at 745 (quoting

Continental Can Co. v. Monsanto Co., 948 F.2d 1264, 1268 (Fed. Cir. 1991)). In fact, “inherency

does not follow even from a very high likelihood that a prior art method will result in the claimed

invention.” In re Montgomery, 677 F.3d 1375, 1384 (Fed. Cir. 2012). Rather, “[t]he keystone of

the inherency doctrine is inevitability.” Id. (“Our precedent has been steadfast in this strict

requirement of inevitability.”) Accordingly, “[t]he very essence of inherency is that one of ordinary

skill in the art would recognize that a reference unavoidably teaches the property in question.”

Agilent Techs., Inc. v. Affymetrix, Inc., 567 F.3d 1366, 1383 (Fed. Cir. 2009).

[CL58] As explained above, Actavis has failed to meet its burden to prove by clear

and convincing evidence, let alone its heighted burden, that Lee anticipates any of the asserted

claims of the ’282 Patent.

[CL59] First and foremost, Lee is referenced under the “References Cited,” as a

“Foreign Patent Document” on the front page of the ’282 Patent, which means the Patent Examiner

considered the Lee reference during the prosecution of the ’282 Patent and still allowed the patent

to proceed to issuance. See FOF ¶ 191. This alone suggests the claims of the ’282 Patent are not

anticipated over Lee. See Glaxo Grp. Ltd. v. Apotex, Inc., 376 F.3d 1339, 1348 (Fed. Cir. 2004)

(“This burden [of showing invalidity by clear and convincing evidence] is ‘especially difficult’

when . . . the infringer attempts to rely on prior art that was before the patent examiner during

prosecution.”) (internal citation omitted.)) Nonetheless, as explained in further depth above,

Actavis has failed to prove otherwise through the opinions of Dr. Michniak Kohn.

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[CL60] This is especially true where Dr. Michniak-Kohn’s analysis as a whole

misapplies the standard for proving anticipation. The Federal Circuit clarified the test for proving

anticipation in Net MoneyIN, when it reversed the district court’s finding of anticipation that was

based on combining two separate examples within a single prior art reference and confirmed the

appropriate analysis is to show that all limitations of the claims are described in a single example

of a prior art reference. Dr. Michniak-Kohn has offered a similar analysis to the analysis rejected

by the Court in Net MoneyIN. Indeed, when asked whether the prior art elements she previously

discussed were disclosed “in a single specific example in Lee or [if they were] disclosed in Lee

[as a] single reference,” Dr. Michniak-Kohn admitted that the prior art elements she discussed are

only “disclosed in Lee as a single reference.” Trial Tr. Day 4 (2/6/2018 PM) 54:8–15 (Michniak-

Kohn). The Court rejects Actavis’s anticipation arguments as improperly selecting from various

disclosures in Lee, which the Federal Circuit has found improper under Net MoneyIN. See 545

F.3d at 1369.

[CL61] As proven by Plaintiffs, Lee does not teach or suggest the basic and novel

properties of the ’282 Patent because: (1) Lee does not disclose a patch containing the claimed

acrylic adhesive recited in the ’282 Patent (FOF ¶¶ 191–97); (2) Lee does not disclose any

transdermal patch that contains a physiologically effective amount of granisetron, nor does Lee

disclose such a patch in combination with the acrylic adhesive of claim 1 without requiring a POSA

to modify Comparative Example 16 in Lee (FOF ¶¶ 198–203); and (3) Lee does not disclose a

patch having the claimed granisetron stability because the acrylic adhesives included in Lee are

not “inherently stable.” See FOF ¶¶ 204–206. Indeed, Dr. Michniak-Kohn admitted that Lee’s only

examples of patches with granisetron include ingredients that Lee shows materially affect those

basic and novel properties, namely drug permeation and stability. See FOF ¶ 203 (admitting the

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only examples of granisetron disclosed in Lee as part of a patch are adhesive Examples 1(A) and

1(I) which include PEG side chains and/or an acidic functional group). Regarding whether Lee

discloses a physiologically effective amount, Actavis’s experts could not even agree as to whether

the appropriate data to consider should be in vivo or in vitro testing. See FOF ¶ 200. Certainly,

Actavis cannot expect this Court to find Lee anticipates this limitation in the ’282 Patent when

such a discrepancy exists. Finally, this Court also finds the acrylic adhesives disclosed in Lee

cannot be “inherently stable” based on Dr. Tan’s opinion that the stability of a drug in a particular

adhesive is unpredictable. See FOF ¶ 206. Of all experts offered by the parties in this case, Dr.

Tan, an experienced formulator, is the most qualified to opine on this issue, and his opinion refutes

Actavis’s position. Therefore, the asserted claims of the ’282 Patent are not anticipated by Lee.

4. Obviousness

[CL62] A finding of obviousness requires an analysis of: (1) the scope and content

of the prior art; (2) the level of ordinary skill in the art; (3) the differences between the claimed

invention and the prior art; and (4) whether those differences are such that the claimed invention

as a whole would have been obvious to a person having ordinary skill at the time the invention

was made. KSR v. Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2005); Graham v. John Deere Co.

of Kansas City, 383 U.S. 1, 17-18 (1966). Secondary considerations of obviousness also must be

considered. Transocean Offshore Deepwater Drilling, Inc. v. Maersk Contractors USA, Inc., 617

F.3d 1296, 1305 (Fed. Cir. 2010); Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1323

(Fed. Cir. 2005). All of these factors weigh in favor of a determination of nonobviousness with

respect to the asserted claims of the ’282 Patent.

[CL63] In an obviousness analysis, “where the prior art, at best, ‘[gives] only

general guidance as to the particular form of the claimed invention or how to achieve it,’ relying

on an ‘obvious-to-try’ theory to support an obviousness finding is ‘impermissible.’ ” In re

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Cyclobenzaprine Hydrochloride Extended Release Capsule Patent Litig., 676 F.3d 1063, 1073

(Fed. Cir. 2012) (quoting In re Kubin, 561 F.3d 1351, 1359 (Fed. Cir. 2009)).

[CL64] “[A] combination is only obvious to try if a person of ordinary skill has ‘a

good reason to pursue the known options.’ ” Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352,

1361 (Fed. Cir. 2011) (citing KSR, 550 U.S. at 421). “When a field is ‘unreduced by direction of

the prior art,’ and when prior art gives ‘no indication of which parameters were critical or no

direction as to which of many possible choices is likely to be successful,’ an invention is not

obvious to try.” Id. (quoting Bayer Schering Pharm. AG v. Barr Labs., Inc., 575 F.3d 1341, 1347

(Fed. Cir. 2009)).

[CL65] Even where there was a desire for a claimed invention, absent evidence that

the skilled artisan would have known how to achieve the claimed invention, it is not obvious. See

Cardiac Pacemakers, Inc. v. St. Jude Med., Inc., 381 F.3d 1371, 1377 (Fed. Cir. 2004)

(“Recognition of a need does not render obvious the achievement that meets that need. . . .

Recognition of an unsolved problem does not render the solution obvious.”).

[CL66] “[T]o establish a prima facie case of obviousness based on a combination

of elements in the prior art, the law requires a motivation to select the references and to combine

them in the particular claimed manner to reach the claimed invention.” Eli Lilly v. Zenith, 471 F.3d

at 1380.

[CL67] Secondary considerations must be considered in evaluating the obviousness

of a claimed invention. Transocean, 617 F.3d at 1305. “[E]vidence of secondary considerations

may often be the most probative and cogent evidence in the record. It may often establish that an

invention appearing to have been obvious in light of the prior art was not. It is to be considered as

part of all the evidence, not just when the decisionmaker remains in doubt after reviewing the art.”

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Ruiz v. A.B. Chance Co., 234 F.3d 654, 667 (Fed. Cir. 2000) (quoting Stratoflex, Inc. v. Aeroquip

Corp., 713 F.2d 1530, 1538 (Fed. Cir. 1983)).

[CL68] Secondary considerations that provide evidence of non-obviousness

include, inter alia: unexpected results, failure of others, and copying. KSR, 550 U.S. at 399, 401,

406. For example, evidence of failed attempts by others supports a finding that the patented

invention would not have been obvious. Compare Advanced Display, 212 F.3d at 1285 (failing to

develop cholesteric visible material “for a long time”), and Cyclobenzaprine, 676 F.3d at 1081

(failing to develop an extended-release formulation), with Mylan Institutional LLC v. Aurobindo

Pharma Ltd., No. 2:16-CV-491-RWS-RSP, 2016 WL 7587325, at *20 (E.D. Tex. Nov. 21, 2016)

(failing “to develop a reliable method for synthesizing isosulfan blue” did not weigh against a

finding of obviousness because the claimed invention specifically involved “a method of preparing

isosulfan blue using silver oxide”). Moreover, “[u]nexpected superior properties of an invention

suggest that the invention was not obvious to one of ordinary skill in the art at the time of the

claimed invention, because ‘that which would have been surprising to a person of ordinary skill in

a particular art would not have been obvious.’ ” Asetek Danmark A/S/ v/ CMI USA, Inc., 100 F.

Supp. 3d 871, 885 (N.D. Cal. 2015) (quoting In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995)); see

Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 997 (Fed. Cir. 2009) (surprising,

low dose effectiveness, illustrating “superior properties of risedronate” demonstrate that the results

were unexpected and could not have been predicted).

[CL69] Also, “[t]he copying of an invention may constitute evidence that the

invention is not an obvious one. This would be particularly true where the copyist had itself

attempted for a substantial length of time to design a similar device and had failed.” Vandenberg

v. Dairy Equip. Co., a Div. of DEC Int’l, Inc., 740 F.2d 1560, 1567 (Fed. Cir. 1984) (internal

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citation omitted); see Merck Sharp & Dohme Corp. v. Hospira, Inc., 874 F.3d 724, 731 (Fed. Cir.

2017) (trying five different alternative formulations as an attempt to avoid copying the patent at

issue lends weight toward nonobviousness).

[CL70] As stated previously, Actavis initially relied on Lee, Effing, and Kamiyama

as its primary references to support its obviousness argument, however at trial, Actavis chose to

focus almost entirely on Lee, citing Tan and Xia as secondary references. See FOF ¶ 224.

Nevertheless, Actavis did not prove by clear and convincing evidence that the asserted claims are

obvious over any combination of references.

[CL71] Notably, the common thread in Actavis’s invalidity arguments is Lee, which

was considered by the Patent Office during prosecution of the ’282 Patent (FOF ¶ 196), and this

Court has already determined is largely irrelevant to the inventions claimed in the ’282 Patent.

Further, the only other reference that specifically discusses granisetron in a transdermal patch

(Effing) was also considered by the Patent Office. See FOF ¶ 234. The remainder of Actavis’s

obviousness arguments can be summarized by the Court’s finding that Dr. Michniak-Kohn’s

reliance on secondary prior art references such as Kamiyama, Xia, Li PCT, and the National Starch

Product Selection Guide can only be the result of hindsight, as these references have nothing to do

with granisetron and only have in common the disclosure of Duro-Tak® 2287. See FOF ¶¶ 229–

31, 237–41. The use of such hindsight in an obviousness analysis is improper.

[CL72] The Court also finds that Plaintiffs mustered secondary indicia of

nonobviousness that further indicates the inventions claimed in the 282 Patent would not have

been obvious to a POSA. FOF ¶¶ 259–74. The 282 Patent shows that granisetron patches having

non-acidic hydroxyl groups surprising have superior granisetron permeation compared to patches

that include acidic functional groups. FOF ¶¶ 260-63. While Actavis asserts the ’282 Patent shows

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no surprising results over the prior art relied upon in Dr. Michniak-Kohn’s analysis, Dr. Michniak-

Kohn conceded that Lee, which Actavis has asserted as the closest prior art to the ’282 Patent,

discloses granisetron in patches with acidic functional groups whereas the ’282 Patent compares

granisetron patches having hydroxyl groups with patches including acidic groups. See FOF ¶¶

261–62. The Court also disagrees with Actavis’s assertion that Dr. Enscore did not compare the

Duro-Tak® 2287 permeation data to the closest prior art based on Dr. Michniak-Kohn’s

acknowledgment that all of the adhesives listed in Table 1 of the ’282 Patent are prior art adhesives.

See FOF ¶ 262.

[CL73] Further, the prior art of record shows that other companies such as 3M were

working to develop transdermal products that contained a 5-HT3 antagonist such as granisetron

but were not successful in ever developing an FDA-approved product. See FOF ¶¶ 263-66. What

is more, Actavis’s contentions that such companies were successful is contradicted by the fact that

Effing and Braun, which are both patents from 3M, include no in vivo data showing that those

patches could deliver a physiologically effective amount of granisetron to a human subject. FOF

¶¶ 226, 245–46. Further, 3M, which owns the Effing and Braun patents, is now the contract

manufacturer of Sancuso®. See FOF ¶ 264.

[CL74] Finally, the Court finds evidence that Actavis copied the Sancuso®

formulation in developing its Accused Product. FOF ¶¶ 265-71. While copying may not be

probative in the context of a patent that covers an active pharmaceutical ingredient, such a fact can

be highly probative of non-obviousness where, as here, a generic drug manufacturer is free to use

a noninfringing formulation so long as other FDA requirements (e.g., bioequivalence) are satisfied.

See Merck Sharp, 874 F.3d at 731 (“The Act does not . . . require the generic manufacturer to copy

the NDA holder’s process of manufacturing the drug.”); but see Allergan, Inc. v. Teva Pharm.

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USA, Inc., No. 2:13-cv-1455, 2017 WL 4803941, at *50 (E.D. Tex. Oct. 16, 2017) (citing Bayer

Healthcare Pharm., Inc. v. Watson Pharm., Inc., 713 F.3d 1369, 1377 (Fed. Cir. 2013)) (copying

a brand-name biologic for ANDA purposes, “in order to facilitate [a] . . . showing of

bioequivalence” is not probative of nonobviousness). Thus, under the HatchWaxman Act, the

ANDA applicant is only required to show the FDA evidence of copying of the brand drug’s active

ingredients, route of administration, dosage form, strength, and bioequivalency—not the inactive

ingredients. See 35 U.S.C. §§ 355(j)(2)(A)(ii)-(iv).

[CL75] According to Actavis’s ANDA, Duro-Tak® 387-2287 is the inactive

ingredient of Actavis’s Accused Product. See DTX-156 at 1. Indeed, Actavis’s analytical

deformulation of Sancuso® and in vitro granisetron transdermal flux experiments related to

finding a different adhesive to demonstrate bioequivalence. In fact, Actavis found multiple non-

infringing formulations using different adhesives that had comparable skin permeation to that of

Sancuso® (Duro-Tak® 87-9301, Duro-Tak® 87-900A). See JTX-005 at 5–7; see FOF ¶¶ 269–77.

Yet, after the different formulations were tested during development See JTX-005 at 5–7; PTX-

012; see FOF ¶¶ 270–74, Actavis selected the formulation where its Accused Product contains the

same amount of granisetron, same pressure sensitive adhesive (Duro-Tak® 387-2287), and the

same surface area of drug loaded adhesive matrix as Sancuso®. See FOF ¶¶ 269–71, 274. The

Court therefore finds that the copying of the Duro-Tak® 387-2287 is probative of nonobviousness

as the inactive ingredients in Actavis’s ANDA Product are unrelated to demonstrating that

Actavis’s generic Sancuso® product met FDA requirements for approval of its ANDA. See The

Medicines Co. v. Mylan Inc., No. 11-cv-1285, 2014 WL 2464732, at *4-5 (N.D. Ill. June 2, 2014)

(after consideration of Bayer, copying, in the ANDA context, “was not relevant or compelling

evidence of nonobviousness” unless aspects of the drug, such as inactive ingredients, are

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“unrelated to demonstrating bioequivalency” and are copied, therefore “hav[ing] some

relevance”).

[CL76] In summary, Actavis has not shown that the prior art references, alone or in

combination, render the ’282 Patent obvious. In fact, as discussed herein, the prior art cited by

Actavis would have led one of skill in the art away from the claimed invention and does not provide

any reasonable expectation of success in making the invention. Further, the Court finds that

Actavis’s arguments in support of obviousness are grounded in hindsight, and do not properly

consider the state of the art as a whole as of February 2003. See Sanofi-Synthelabo v. Apotex, Inc.,

550 F.3d 1075, 1088 (Fed. Cir. 2008) (“Only with hindsight knowledge that the dextrorotatory

enantiomer has highly desirable properties, can Apotex argue that it would have been obvious to

select this particular racemate and undertake its arduous separation. The application of hindsight

is inappropriate where the prior art does not suggest that this enantiomer could reasonably be

expected to manifest the properties and advantages that were found for this particular

dextrorotatory isomer.”); see also KSR, 550 U.S. at 421 (recognizing “hindsight bias” and “ex post

reasoning” as inappropriate in determination of obviousness).

[CL77] Moreover, Plaintiffs have presented evidence of secondary considerations

that Actavis failed to successfully rebut.

[CL78] For all of the reasons set forth above, including the discussion above, See

FOF ¶¶ 217–274, Actavis has not met its burden to provide clear and convincing evidence that the

asserted claims of the ’282 Patent are invalid as obvious under 35 U.S.C. § 103 (pre-AIA).

D. Inequitable Conduct

[CL79] Actavis has not met its burden to provide clear and convincing evidence that

the ’282 Patent is unenforceable for inequitable conduct.

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[CL80] “Inequitable conduct is an equitable defense to patent infringement that, if

proved, bars enforcement of a patent.” Therasense, Inc. v Becton, Dickinson & Co., 649 F.3d 1276,

1285 (Fed. Cir. 2011). However, “[t]o prevail on the defense of inequitable conduct, the accused

infringer must prove that the applicant misrepresented or omitted material information with the

specific intent to deceive the PTO.” Id. at 1287 (citing Star Scientific Inc. v. R.J. Reynolds Tobacco

Co., 537 F.3d 1357, 1365 (Fed. Cir. 2008)). In other words, a finding of inequitable conduct

requires the accused infringer to prove both elements—materiality and intent to deceive. See id.

[CL81] To show specific intent, “the accused infringer must prove by clear and

convincing evidence that the applicant knew of the reference, knew that it was material, and made

a deliberate decision to withhold it.” Id. at 1290. “[T]o meet the clear and convincing evidence

standard, the specific intent to deceive must be ‘the single most reasonable inference able to be

drawn from the evidence.’ ” Id. (citing Star, 537 F.3d at 1366). As such, “when there are multiple

reasonable inferences that may be drawn, intent to deceive cannot be found.” Id. at 1290–91 (citing

Scanner Techs. Corp. v. ICOS Vision Sys. Corp., 528 F.3d 1365, 1376 (Fed. Cir. 2008)).

[CL82] With regard to materiality, “as a general matter, the materiality required to

establish inequitable conduct is but-for materiality.” Id. at 1291. “When an applicant fails to

disclose prior art to the PTO, that prior art is but-for material if the PTO would not have allowed

a claim had it been aware of the undisclosed prior art.” Id.

[CL83] “[A] prosecuting attorney is free to present argument in favor of

patentability without fear of committing inequitable conduct.” Rothman v. Target Corp., 556 F.3d

1310, 1328-29 (Fed. Cir. 2009). Statements “which consist of attorney argument” do not constitute

affirmative misrepresentations of material fact.” Young v. Lumenis, Inc., 492 F.3d 1336, 1349 (Fed.

Cir. 2007). Applicants may advocate for a particular interpretation, “which the Examiner [is] free

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to accept or reject.” See Life Techs., Inc. v. Clontech Labs., Inc., 224 F.3d 1320, 1326 (Fed. Cir.

2000). Indeed, “[a]fter Therasense, an accused infringer cannot drop the ‘atomic bomb’ by mere

conjecture that the prosecution attorney’s zealous arguments were inequitable conduct. Attorneys

prosecuting a patent should be able to correct mistakes, change their opinion, or adjust their

argument to convince the examiner without risking invalidation of the patent by a later finding of

inequitable conduct. As devastating as inequitable conduct can be, pleading the charge should

require more.” Human Genome Sci., Inc. v. Genentech, Inc., No. 2:11-cv-6519, 2011 WL 7461786,

at *6 (C.D. Cal. Dec. 9, 2011).

[CL84] Actavis has failed to meet its burden to prove both of the Federal Circuit’s

requirements to satisfy a claim for inequitable conduct: (1) materiality and (2) intent.

[CL85] As a preliminary matter, the Court agrees with Plaintiffs that: (1) on its face,

the patent does not teach the exclusion of a permeation enhancer as a requirement, see FOF ¶¶

275–86, and (2) the prosecution history is consistent with the specification of the ’282 Patent and

lacks any admission that a permeation enhancer is either specifically required or excluded in the

claimed formulation See JTX-002; see FOF ¶¶ 287–89. Nonetheless, for purposes of completeness,

the Court discusses the core of Actavis’s argument below.

[CL86] In reality, the crux of Actavis’s “evidence” of materiality relies on

discrepancies between permeation data presented in an example of the ’282 Patent and the

Sancuso® NDA. See FOF ¶¶ 290-96. However, the Court does not find any support in the evidence

presented that any of the permeation data disclosed in the ’282 Patent was material to the PTO’s

allowance of the ’282 Patent. See FOF ¶¶ 297-303. Absent such evidence, the mere fact that alleged

discrepancies exist in Example 1 of the ’282 Patent and Tables 2 and 4 of the Sancuso® NDA do

not provide any insight that such information was material to issuance of the ’282 Patent. This

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holds true regardless of whether the alleged discrepancy was a mistake or an accurate depiction, a

distinction which Actavis’s evidence does not adequately show for this Court to make a

determination regardless. See FOF ¶¶ 297–303. In reality, the permeation data that appears in Table

4 of the Sancuso® NDA and Table 2 of the ’282 Patent, and is allegedly fabricated according to

Actavis, and the allegedly correct permeation data that appears only in Table 2 of the Sancuso®

NDA, are still lower than the granisetron permeation from DT 387-2287® at 48 hours that is

reported in both the Sancuso® NDA and the ’282 Patent. See JTX-001 at 9, 9:1–10; JTX-022 at

6; see FOF ¶¶ 297–303. Further, Actavis has no evidence that an admixture of 3% “LD” would

have increased the granisetron permeation in batch 28 (i.e., the DT 87-4098 formulation), or to

what degree it would have increased, as Dr. Michniak-Kohn ultimately admitted during her cross-

examination. See FOF ¶ 296, 300. Accordingly, Actavis has failed to provide any direct or implied

evidence that the alleged misrepresentations or omissions by the inventor(s) were material to the

patentability of the ’282 Patent. Since both materiality and intent must be proven to establish a

claim of inequitable conduct, Actavis’s inequitable conduct defense fails.

[CL87] However, even assuming that the data in the ’282 Patent was material to

patentability, Actavis has no evidence—either express or inferred—that anyone associated with

the prosecution of the ’282 Patent—including the named inventors—intended to deceive the PTO.

See FOF ¶ 300–07. This lack of evidence was clear in light of the lack of testimony from any

inventors or Plaintiffs’ corporate designees possessing any knowledge of the allegedly withheld

information. See FOF ¶¶ 304–10. Notably, since Therasense, the Federal Circuit has inferred intent

when there is a combination of evidence of knowledge of misrepresentation and credibility

findings/legal misconduct found at the district court level. See, e.g., Aventis Pharma S.A. v.

Hospira, Inc., 675 F.3d 1324 (Fed. Cir. 2012) (intent affirmed based on rejection of excuses and

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adverse credibility findings); Intellect Wireless, Inc. v. HTC Corp., 732 F.3d 1339 (Fed. Cir. 2013)

(intent affirmed based on a pattern of misleading statements and adverse credibility findings);

Apotex Inc. v. UCB, Inc., 763 F.3d 1354 (Fed. Cir. 2014) (intent affirmed based on actions

“evidencing a pattern of lack of candor,” including directing counsel to boost misrepresentations

being made by submitting a declaration on behalf of an expert who was never informed of the

entire truth); see also Regeneron Pharms., Inc. v. Merus N.V., 864 F.3d 1343 (Fed. Cir. 2017)

(affirming intent found based on “widespread litigation misconduct”). The evidence presented by

Actavis here is far from the egregious circumstances of these other cases. Such scant evidence

certainly cannot rise to a level that would enable this Court to infer intent based on the information

allegedly withheld or misrepresented.

[CL88] For all of the reasons set forth above, see FOF ¶¶ 275–310, Actavis has not

met its burden to provide clear and convincing evidence that the ’282 Patent is unenforceable for

inequitable conduct.

[CL89] The statements above constitute the Court’s findings of fact and conclusions

of law in accordance with Rule 52(a) of the Federal Rules of Civil Procedure. The Court finds

that Actavis literally infringes and induces infringement of the ʼ282 patent and that Actavis has

not shown by clear and convincing evidence that the asserted claims of the ʼ282 patent are invalid

for lack of enablement, indefiniteness, anticipation or obviousness or that the ʼ282 patent is

unenforceable on the basis of inequitable conduct.

____________________________________ROBERT W. SCHROEDER IIIUNITED STATES DISTRICT JUDGE

So ORDERED and SIGNED this 28th day of September, 2018.

in the united states district court for the eastern … · 2019-12-18 · backing and a membrane,...

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