KNOBBE, MARTENS, OLSON & BEAR, LLP UNITED STATES...

Filed: November 13, 2014

Filed on behalf of: Mylan Pharmaceuticals Inc.

By: Joseph M. Reisman Jay R. Deshmukh KNOBBE, MARTENS, OLSON & BEAR, LLP 2040 Main Street, 14th Floor Irvine, CA 92614 Ph.: (949) 760-0404 Fax: (949) 760-9502 E-mail: [email protected]

UNITED STATES PATENT AND TRADEMARK OFFICE __________________________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD

__________________________________

MYLAN PHARMACEUTICALS INC., Petitioner

v.

NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG, Patent Owners

Case No. TBD Patent 6,335,031

PETITION FOR INTER PARTES REVIEW OF U.S. PATENT 6,335,031

TABLE OF CONTENTS

Page No.

i

EXHIBIT LIST ........................................................................................................ vi

I. MANDATORY NOTICES ............................................................................. 1

A. Real Party-In-Interest ............................................................................ 1

B. Related Matters ...................................................................................... 1

C. Lead and Back-Up Counsel ................................................................... 3

D. Service Information ............................................................................... 3

II. GROUNDS FOR STANDING ........................................................................ 4

III. IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE PRECISE RELIEF REQUESTED ............................................................................. 4

IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW .............. 4

V. STATEMENT OF REASONS FOR THE RELIEF REQUESTED ............... 5

A. Level of Ordinary Skill in the Art ......................................................... 6

B. Claim Construction ................................................................................ 7

C. Scope and Content of the Prior Art ..................................................... 11

1. Rivastigmine Was Being Developed for the Treatment of Alzheimer’s Disease ................................................................ 11

2. Rosin Taught the Use of Antioxidants in Compositions Comprising RA7 (Racemic Rivastigmine) ............................. 12

3. Elmalem Taught Adding Antioxidants to a Compositions Comprising RA7 to Prevent Oxidation .................................. 13

4. Enz Taught Transdermal Rivastigmine Compositions ........... 14

5. Ebert Taught a Transdermal Drug Delivery System For Liquid, Oxidizable Drugs ........................................................ 15

TABLE OF CONTENTS (cont’d)

Page No.

ii

6. Sasaki Taught Using the Antioxidant Tocopherol to Promote Storage Stability of the Active Ingredient in Transdermal Compositions ........................................................................... 17

7. The Handbook of Pharmaceutical Excipients Detailed Common Antioxidants Used in Approved Pharmaceutical Compositions ........................................................................... 18

D. Ground 1: Claim 15 is Unpatentable as Anticipated by Elmalem ..... 19

E. The Challenged Claims are Unpatentable as Obvious Over the Prior Art ........................................................................................................ 23

1. There was Motivation to Select Rivastigmine and Modify Existing Rivastigmine Treatments .......................................... 23

2. Ground 2: Claims 16 and 18 are Unpatentable as Obvious Over Elmalem and the Handbook ........................................... 25 (1) No Secondary Considerations Support Non- Obviousness 28

3. Ground 3: Claims 1, 2, 7, 15, and 18 are Obvious Over Enz and the Handbook, Optionally in View of Rosin and/or Elmalem and/or Ebert .............................................................. 31

4. Ground 4: Dependent Claims 3 and 16 are Unpatentable as Obvious Over Enz and the Handbook and/or Rosin and/or Ebert ........................................................................................ 42

5. Ground 5: The Challenged Claims Are Unpatentable As Obvious over Enz and Sasaki .................................................. 44

VI. CONCLUSION .............................................................................................. 52

TABLE OF AUTHORITIES

Page No(s).

-iii-

Asyst Techs., Inc. v. Emtrak, Inc., 544 F.3d 1310 (Fed. Cir. 2008) .......................................................................... 30

In re Geisler, 116 F.3d 1465 (Fed. Cir. 1997) .......................................................................... 38

In re Kao, 639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 30

KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ............................................................................................ 31

MeadWestVaco Corp. v. Rexam Beauty & Closures, Inc., 731 F.3d 1258 (Fed. Cir. 2013) .......................................................................... 29

Merck & Co. v. Teva Pharms. USA, Inc., 395 F.3d 1364 (Fed. Cir. 2005) .................................................................... 29, 30

In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003) ...................................................................passim

Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 28

OTHER AUTHORITIES

35 U.S.C. § 102 .................................................................................................passim

35 U.S.C. § 103 .......................................................................................................... 4

35 U.S.C. § 311 .......................................................................................................... 1

35 U.S.C. § 312 .......................................................................................................... 1

35 U.S.C. § 313 .......................................................................................................... 1

35 U.S.C. § 314 ...................................................................................................... 1, 4

TABLE OF AUTHORITIES (cont’d)

Page No(s).

iv

35 U.S.C. § 315 .......................................................................................................... 1

35 U.S.C. § 316 .......................................................................................................... 1

35 U.S.C. § 317 .......................................................................................................... 1

35 U.S.C. § 318 .......................................................................................................... 1

35 U.S.C. § 319 .......................................................................................................... 1

37 C.F.R. § 42 ............................................................................................................ 1

37 C.F.R. § 42.6 ......................................................................................................... 4

37 C.F.R. § 42.10 ....................................................................................................... 1

37 C.F.R. § 42.15 ....................................................................................................... 1

37 C.F.R. § 42.100 et seq. .......................................................................................... 1

37 C.F.R. § 42.104 ..................................................................................................... 3

Mylan v. Novartis IPR Petition - U.S. Pat. 6,335,031

Exhibit List, Page v

EXHIBIT LIST

Exhibit No. Description

Ex. 1001 U.S. Patent No. 6,335,031, issued January 1, 2002

Ex. 1002 UK Patent Application GB 2,203,040 A, to Enz, published October 12, 1988 (“Enz”)

Ex. 1003 Handbook of Pharmaceutical Excipients, A. Wade and P. J. Weller (eds.) 1994, 2nd Edition, The Pharmaceutical Press London (the “Handbook”)

Ex. 1004 Japanese Patent Application Publication No. JP 59-184121 to Sasaki et al., published October 19, 1984

Ex. 1005 Certified English Translation of Japanese Patent Application Publication No. JP 59-184121 to Sasaki et al. (“Sasaki”)

Ex. 1006 PCT Publication No. WO 95/024172 to Ebert et al, published September 14, 1995 (“Ebert”)

Ex. 1007 Carey & Sundberg, ADVANCED ORGANIC CHEMISTRY, 2nd ed. Part A: Structure and Mechanism, Plenum Press, New York, 1984, pp. 652

Ex. 1008 U.S. Patent 4,948,807 (“Rosin”)

Ex. 1009 Elmalem et al. 1991, Neuropharmacology 30: 1059-1064 (“Elmalem”)

Ex. 1010 Declaration of Agis Kydonieus, Ph.D.

Ex. 1011 Declaration of Christian Schöneich, Ph.D.

Ex. 1012 “Safety/Tolerability Trial of SDZ ENA 713 in Patients with Probable Alzheimer’s Disease,” John J. Sramek et al., Life Sciences, Vol. 58, No. 15, pp. 1201-1207 (1996) (“Sramek”)


Exhibit List, Page vi


Ex. 1013 “New acetylcholinesterase inhibitor shows promise in largest Alzheimer’s trial to date,” Formulary, Vol. 32, Dec. 1997 (“Formulary Article”)

Ex. 1014 ICH Topic Q 1 A, Stability Testing Guidelines: Stability Testing of New Drug Substances and Products (CPMP/ICH/380/95)

Ex. 1015 Connors, Amidon, & Stella, Oxidation and Photolysis in Chemical Stability of Pharmaceuticals – A Handbook for Pharmacists (2nd Edition), John Wiley & Sons, NY (1986), pp. 82-114

Ex. 1016 Howard C. Ansel, Introduction to Pharmaceutical Dosage Forms, 4th Edition, Lea & Febiger, Philadelphia (1985), pp. 83-116

Ex. 1017 Ho-Leung Fung, Chapter 7 – Chemical Kinetics and Drug Stability in MODERN PHARMACEUTICS (G.S. Banker and C.T. Rhodes, eds.), Marcel Dekker, NY (1978), pp. 227-62

Ex. 1018 Miguel-Hidalgo, J., 2000, Current Opinion in CPNS Investigations Drugs, 2000 2(4):438-453

Ex. 1019 Boccardi G. et al. Photochemical Iron(III)-Mediated Autoxidation of Dextromethorphan. Chemical & Pharmaceutical Bulletin. Vol. 37, 308–310 (1989)

Ex. 1020 Bateman, L., Olefin Oxidation, Quarterly Review (1954) Vol. 8, pp. 147–167

Ex. 1021 Linnell, R.H., The Oxidation of Nicotine. I. Kinetics of the Liquid Phase Reaction Near Room Temperature. Tobacco Science, Vol. 4, pp. 89–90 (1960)

Ex. 1022 Resume/Curriculum Vitae of Agis Kydonieus, Ph.D.


Exhibit List, Page vii


Ex. 1023 Resume/Curriculum Vitae of Christian Schöneich, Ph.D.

Ex. 1024 U.S. Patent No. 5,602,176, issued Feb. 11, 1997


1

Pursuant to 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42, Mylan

Pharmaceuticals Inc. (“Petitioner” or “Mylan”) petitions for Inter Partes Review

(“IPR”) of claims 1-3, 7, 15, 16, and 18 of U.S. Patent No. 6,335,031 to Asmussen

et al., titled “TTS containing an antioxidant” (“the ’031 patent,” Ex. 1001).

Concurrently filed herewith is a Power of Attorney pursuant to 37 C.F.R. § 42.10(b).

The Office is authorized to charge Deposit Account 11-1410 for the fee set forth in 37

C.F.R. § 42.15(a), and is authorized to charge any additional fees to the same account.

I. MANDATORY NOTICES

A. Real Party-In-Interest

Mylan Inc., Mylan Technologies Inc., and Mylan Pharmaceuticals Inc. are

the real parties-in-interest for Petitioner.

B. Related Matters

The ’031 patent is being asserted in the following patent infringement

lawsuits: Novartis Pharm. Corp. et al. v. Mylan Inc. et al., 1:14-cv-00777 (D. Del.);

Novartis Pharm. Corp. et al. v. Mylan Inc. et al., 1:14-cv-00106 (N.D. W.Va.);

Novartis Pharm. Corp. et al. v. Noven Pharm. Inc., 1:13-cv-00527 (D. Del.);

Novartis Pharm. Corp. et al. v. Noven Pharm. Inc., 1:14-cv-00111 (D. Del.);

Novartis Pharm. Corp. et al. v. Par Pharm. Inc. et al., 1:11-cv-01077 (D. Del.);

Novartis Pharm. Corp. et al. v. Watson Labs. Inc. et al., 1:11-cv-01112 (D. Del.);

Novartis Pharm. Corp. et al. v. Alvogen Pine Brook Inc. et al., 1:13-cv-00052 (D.


2

Del.); Novartis Pharm. Corp. et al. v. Alvogen Pine Brook Inc. et al., 1:13-cv-00370

(D. Del.); Novartis Pharm. Corp. et al. v. Actavis, Inc. et al., No. 1:13-cv-00371 (D.

Del.); Novartis Pharm. Corp. et al. v. Par Pharm. Inc. et al., No. 1:13-cv-01467 (D.

Del.); Novartis Pharm. Corp. et al. v. Zydus Noveltech Inc. et al., No. 1:14-cv-

05405 (D. N.J.); Novartis Pharm. Corp. et al. v. Zydus Noveltech Inc. et al., No.

1:14-cv-01104 (D. Del.); Par Pharm. Inc. et al. v. Novartis Pharm. Corp. et al.,

1:14-cv-00843 (D. Del.); Watson Labs Inc. v. Novartis Pharm. Corp et al., 14-1799

(C.A.F.C.); Novartis Pharm. Corp et al. v. Par Pharm. Inc. et al, 15-1061

(C.A.F.C.); Novartis Pharm. Corp et al. v. Par Pharm. Inc. et al, 15-1062

(C.A.F.C.); Par Pharm. Inc. v. Novartis Pharm Corp. et al., 15-1120 (C.A.F.C.); and

Par Pharm. Inc. v. Novartis Pharm Corp. et al., 15-1121 (C.A.F.C.).

The ’031 patent is also the subject of Inter Partes Review IPR2014-00550,

filed by Noven Pharmaceuticals, Inc. on April 2, 2014 (“the Noven IPR”) and

instituted on three of five proposed grounds of invalidity on October 14, 2014.

Mylan has submitted herewith a Motion for Joinder, requesting that upon

institution of this Petition, the present IPR be joined with the Noven IPR pursuant

to 35 U.S.C. § 315(c) as to the three instituted grounds.

The ’031 patent is the parent to U.S. Application 09/747,519, now U.S.

Patent 6,316,023 (“the ’023 patent”). The ’023 patent is also asserted in each of

the above-listed lawsuits. The ’023 patent is also the subject of a petition for Inter


3

Partes Review, IPR2014-00549, filed on April 2, 2014 by Noven Pharmaceuticals

Inc. Concurrent with this petition, Mylan is also filing a petition for Inter Partes

Review of the ’023 patent.

C. Lead and Back-Up Counsel

Lead Counsel Back-up Counsel Joseph M. Reisman (Reg. No. 43,878) KNOBBE, MARTENS, OLSON & BEAR, LLP 2040 Main Street, 14th Floor Irvine, CA 92614 Ph.: (949) 760-0404 Fax: (949) 760-9502 E-mail: [email protected]

Jay R. Deshmukh (Reg. No. 34,507) KNOBBE, MARTENS, OLSON & BEAR, LLP 2040 Main Street, 14th Floor Irvine, CA 92614 Ph.: (949) 760-0404 Fax: (949) 760-9502 E-mail: [email protected]

D. Service Information

Please direct all correspondence to lead counsel at the contact information

above. Petitioner consents to service by electronic mail at

[email protected].


4

II. GROUNDS FOR STANDING

As required by 37 C.F.R. § 42.104(a), Petitioner certifies that the ’031

patent is available for IPR and that the Petitioner is not barred or estopped from

requesting IPR on the grounds identified herein.

III. IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE PRECISE RELIEF REQUESTED

Petitioner requests inter partes review and cancellation of claims 1-3, 7, 15,

16, and 18 of the ’031 patent on one or more of the grounds under 35 U.S.C. §§

102 and 103 set forth herein. Petitioner’s detailed statement of the reasons for the

relief requested is set forth below in the section titled “Statement of Reasons for

Relief Requested.” In accordance with 37 C.F.R. § 42.6(c), copies of the exhibits

are filed herewith. In addition, this Petition is accompanied by the declarations of

Agis Kydonieus, Ph.D. (Ex. 1010) and Christian Schöneich, Ph.D. (Ex. 1011).

IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW

A petition for inter partes review must demonstrate “a reasonable likelihood

that the petitioner would prevail with respect to at least 1 of the claims challenged

in the petition.” 35 U.S.C. § 314(a). This Petition meets this threshold. As

explained below, for each of the grounds of unpatentability proposed below, there

is a reasonable likelihood that Petitioner will prevail with respect to at least one of

the challenged claims.


5

V. STATEMENT OF REASONS FOR THE RELIEF REQUESTED

The challenged claims of the ’031 patent are generally directed to pharmaceutical

compositions, including transdermal devices, comprising rivastigmine and a specified

amount of antioxidant.

Prior to the ’031 patent, the compound rivastigmine was patented. The use of

rivastigmine to treat Alzheimer’s disease was patented. Compositions containing

rivastigmine, including transdermal devices, were also patented. The sole alleged

advance claimed in the ’031 patent is adding an antioxidant to compositions containing

rivastigmine. The ’031 patent asserts that the inventors were the first to recognize that

rivastigmine was subject to oxidative degradation and that compositions containing

rivastigmine required an antioxidant. (Ex. 1001 at 1:22-24; 4:8-10.) But as will be

discussed, that was not so.

Compositions containing an antioxidant and a racemic mixture that includes

rivastigmine were described in the prior art, as were methods of combining rivastigmine

with antioxidant per some of the challenged claims, demonstrating that it was known

that rivastigmine was susceptible to oxidative degradation. Further, one of ordinary skill

in the art would have recognized, based on the chemical structure of rivastigmine, that it

was susceptible to oxidative degradation. The person of ordinary skill would have

reasonably expected that this oxidative degradation could be addressed with antioxidants,

and would have been motived to use conventional amounts of antioxidants taught in the


6

prior art, which overlap with the claimed range. Accordingly, the person of ordinary

skill would have been motivated to combine rivastigmine with the claimed amount of

antioxidant in a pharmaceutical composition, and thus the claimed subject matter as a

whole would have been obvious to a person of ordinary skill in the art at the time of the

alleged invention.

A. Level of Ordinary Skill in the Art

The subject matter of the ʼ031 patent draws from several disciplines, and as

such, the patent is directed to a collaborative team of individuals in which each

person would have been able to draw upon the experiences and knowledge of the

others. In particular, the person of ordinary skill in the art at the time of the alleged

invention would have been a chemist, chemical engineer, polymer chemist or

pharmaceutical chemist working to develop pharmaceutical formulations, including

transdermal drug delivery systems. The person of ordinary skill would have been

familiar with testing that accompanies the development of any pharmaceutical

formulation, including testing for efficacy and stability. The person of ordinary

skill would have been familiar with excipients typically employed in

pharmaceutical formulations, including transdermal devices. The person of

ordinary skill would have had knowledge of organic chemistry, or would have

collaborated with a person having knowledge of organic chemistry, and would have


7

been able to predict the physical properties of a compound based on its chemical

structure. (Ex. 1010 ¶ 9.)

B. Claim Construction

Claim 1 of the ’031 patent reads:

1. A pharmaceutical composition comprising

(a) a therapeutically effective amount of (S)-N-ethyl-3-

{(1-dimethylamino) ethyl}-N-methyl-phenyl carbamate in free

base or acid addition salt form (Compound A),

(b) about 0.01 to about 0.5 percent by weight of an

antioxidant, based on the weight of the composition, and

(c) a diluent or carrier.

Claim 2 depends from claim 1 and adds that the amount of Compound A in

the pharmaceutical composition is between 1 and 40% by weight. Claim 3 depends

from claim 1 and identifies specific antioxidants. Claim 7 depends from claim 1

and is directed to a transdermal device, wherein the pharmaceutical composition is

supported by a substrate.

Independent claim 15 is directed to a method of stabilizing Compound A

comprising forming a composition by combining Compound A with an amount of

antioxidant effective to stabilize Compound A from degradation. Claim 16

depends on claim 15 and identifies specific antioxidants. Claim 18 depends on


8

claim 15 and specifies that the antioxidant is present in an amount of from about

0.01–0.5% by weight based on the weight of the composition.

The terms in the challenged claims are presumed to take on their ordinary

and customary meaning based on the broadest reasonable interpretation of the

claim language in view of the specification. Under this standard, the Patentee has

not acted as its own lexicographer for any of the claim terms, nor has it attributed

any special meaning to the any of the claim terms.

For example, when the broadest reasonable interpretation is applied, the

term “pharmaceutical composition” means a composition suitable for

pharmaceutical use, e.g., for administration to a patient. (See, e.g., Ex. 1001 at col.

3, line 60–col. 4, line 4; col. 4, lines 35–54.) The composition may be designed for

administration to a subject in any acceptable way, e.g., orally, parenterally (e.g. by

injection), or topically (including via transdermal administration). It would be

inappropriate to limit claim 1 to transdermally-administered compositions because

nothing in the claim language or specification requires such a construction, and

further, such a construction would render claims 1 and 7 identical in scope.

The term “antioxidant” means a compound that reduces or prevents the

oxidative decomposition of other compounds. (See, e.g., Ex. 1001 at col. 4, lines

20–30; Ex. 1010 ¶ 15.) In the context of the challenged claims, which are directed


9

to compositions comprising rivastigmine, the antioxidant reduces the amount of

oxidative decomposition of rivastigmine relative to a composition which does not

contain said compound. (See, e.g., Ex. 1001 at col. 1, lines 29–33.)

The term “diluent or carrier” means inactive ingredient(s) of the

pharmaceutical composition that aid(s) in the administration of the drug. (See, e.g.,

id. at col. 1, line 44 – col. 2, line 9.)

The term “transdermal device” means medical device for systemic drug

administration through skin. (See, e.g., id. at col. 5, lines 31–37 and col. 6, lines

59–62.)

The term “substrate” means a backing layer providing structural support for

the pharmaceutical composition. (See, e.g., id. at col. 5, lines 55–59.)

The term “adhesive layer” means layer of adhesive.

The term “stabilizing” means reducing degradation. (See, e.g., id. at col. 4,

lines 5–30.)

The term “amount of antioxidant effective to stabilize Compound A from

degradation” means an amount of antioxidant that reduces the oxidative

degradation of Compound A. (See, e.g., id. at col. 1, lines 29-33.)

For clarity, the term “(S)-N-ethyl-3-{(1-dimethylamino) ethyl}-N-

methylphenyl carbamate” refers to rivastigmine, which has the following

chemical structure:


10

Rivastigmine is the S-enantiomer of a racemic compound known as RA7. (Ex.

1010 ¶ 15; Ex. 1002 at 3.) As a racemate, RA7 is comprised of an equal mixture of

rivastigmine and its enantiomer ent-rivastigmine, or (R)-rivastigmine:

(Id.)

In addition, each of the challenged claims contains the transition

“comprising.” Accordingly, while the claims require the presence of rivastigmine,

they do not exclude other components from the claimed composition, including

ent-rivastigmine. The challenged claims do not recite a degree of optical purity,

nor does the specification suggest that the claims be limited to a single isomer. As

such, the claims embrace compositions containing both rivastigmine and its

enantiomer, including compositions containing racemic RA7.


11

Petitioner’s positions regarding the scope of the claims should not be

construed as an assertion regarding the appropriate claim scope in other

adjudicative forums, where a different claim interpretation standard may apply.

C. Scope and Content of the Prior Art

1. Rivastigmine Was Being Developed for the Treatment of Alzheimer’s Disease

At the time of the alleged invention, the person of ordinary skill in the art

would have been aware of the compound rivastigmine (also known as ENA 713),

and that it was being developed as a treatment for Alzheimer’s disease. (See, e.g.,

“Safety/Tolerability Trial of SDZ ENA 713 in Patients with Probable Alzheimer’s

Disease,” John J. Sramek et al., Life Sciences, Vol. 58, No. 15, pp. 1201-1207,

1996 (“Sramek,” Ex. 1012 at 1); “New acetylcholinesterase inhibitor shows

promise in largest Alzheimer’s trial to date,” Formulary, Vol. 32, Dec. 1997 (the

“Formulary Article,” Ex. 1013 at 3); see also Ex. 1010 ¶26.) Both Sramek and the

Formulary Article are prior art under 35 U.S.C. § 102(b), and were not of record

during the ’031 patent prosecution.

Rivastigmine was reportedly well-tolerated, with the majority of patients

experiencing only mild-to-moderate adverse events. (Ex. 1012 at 6; Ex. 1013 at 3.)

Rivastigmine was characterized as an improvement over tacrine, a first-generation

acetylcholinesterase inhibitor used to treat Alzheimer’s disease. (Ex. 1012 at 1-2.)


12

2. Rosin Taught the Use of Antioxidants in Compositions Comprising RA7 (Racemic Rivastigmine)

U.S. Patent 4,948,807 (“Rosin,” Ex. 1008), titled “Phenyl Carbamates,”

issued on August 14, 1990 and is prior art under 35 U.S.C. § 102(b).

Rosin discloses a genus of acetylcholinesterase inhibitors, with one of the

seven preferred species being RA7.1 (Ex. 1008 at, e.g., 5:44-45, 14:17-19, 10:9-27;

see also Ex. 1010 ¶¶ 28-29.) Rosin teaches that these compounds are superior to

physostigmine, a known acetylcholinesterase inhibitor, because they have, e.g.,

greater in vivo activity, slower metabolic degradation, higher lipid solubility, and

more efficient absorption. (Id. at 11:28-35.)

Rosin teaches that the compounds may be administered by conventional

methods, and that when they are administered orally or parenterally (e.g., by

injection), they may be combined with conventional excipients such as carriers,

binders, preservatives, and stabilizers. (Id. at 7:15-26.) Rosin also teaches that

“[b]uffers, preservatives, antioxidants and the like can be incorporated as required,”

and identifies sodium metabisulphite and ascorbic acid as “preferred antioxidants.”

(Id. at 7:45-53.)

1 As noted above, RA7 is a racemic mixture that includes rivastigmine. (Ex.

1010 ¶ 15.)


13

3. Elmalem Taught Adding Antioxidants to a Compositions Comprising RA7 to Prevent Oxidation

Elmalem is an article titled “Antagonism of Morphine-Induced Respiratory

Depression by Novel Anticholinesterase Agents,” by Ester Elmalem and others,

published in 1991 in Neuropharmacology 30:1059-1064 (“Elmalem,” Ex. 1009).

Elmalem is prior art under 35 U.S.C. § 102(b), and was not of record during the

’031 patent prosecution.

Elmalem describes experiments designed to compare three drugs, RA6, RA7,

and RA15, to physostigmine with respect to the drugs’ ability to counteract

morphine-induced respiratory depression in rabbits. (Ex. 1009 at 1; see also Ex.

1010 ¶¶ 30-31.) The authors prepared aqueous solutions of physostigmine, RA6,

RA7, and RA15 with sodium metabisulphite. (Ex. 1009 at 2.) Elmalem explicitly

states that the sodium metabisulphite was added to prevent oxidation of the drug:

“All drugs were made up freshly in sterile saline, which included an equal weight

of sodium metabisulphite, to prevent oxidation.” (Id.) (emphasis added).2

2 To avoid the clear teaching in Elmalem that the function of the antioxidants

in the drug solutions was to “prevent oxidation,” the Patentees may argue that a

person of ordinary skill in the art would have understood that physostigmine (one

of the other tested drugs) required an antioxidant, and therefore an antioxidant had

to be added to all other test compositions, including the saline placebo, as a control.


14

4. Enz Taught Transdermal Rivastigmine Compositions

Enz is U.K. Patent 2,203,040 to Albert Enz, titled “Phenyl carbamate,”

published on October 12, 1988 (“Enz,” Ex. 1002). Enz is prior art under 35 U.S.C.

§ 102(b).

Enz teaches that the (-) enantiomer of the racemic compound RA7 is useful

to treat cognitive diseases including Alzheimer’s disease. (Ex. 1002 at 10; see also

Ex. 1010 ¶ 32.) Enz also teaches that the (-) enantiomer is superior to both the

racemic mixture and the (+) enantiomer. (Ex. 1002 at 6.) Enz teaches that the (-)

enantiomer can be obtained by converting the racemic RA7 into the diastereomeric

tartrate salts, followed by selective crystallization of the (-) enantiomer. (Id. at 3,

11.)

Enz teaches that rivastigmine, either as the free base or acid addition salt,

may be advantageously administered transdermally. (Id. at 4-9.) Enz teaches that

the pharmacokinetic profile from transdermal administration is superior to that of

either oral or subcutaneous administration. (Id. at 15-16.)

Enz discloses an exemplary composition of rivastigmine suitable for

transdermal administration. (Id. at 20, Example 2.) Rivastigmine tartrate

This argument is contrary to Elmalem’s clear statement that the antioxidant was

added to the drugs to prevent oxidation. (Ex. 1009 at 2.)


15

(“Compound A”) is combined with Eudragit E 100 (a hydrophilic polymer),

Durotack 280-2416 (an acrylic adhesive), and Brij 97 (a plasticizer) in a volatile

organic solvent. (Id.) The viscous composition is spread on a polyester foil and

the solvent is allowed to evaporate at room temperature. (Id.)

5. Ebert Taught a Transdermal Drug Delivery System For Liquid, Oxidizable Drugs

PCT Publication WO 95/24172, entitled “Drug-containing adhesive

composite transdermal delivery device,” lists Charles D. Ebert and others as

inventors, and published on September 14, 1995 (“Ebert,” Ex. 1006). It is prior art

under 35 U.S.C. § 102(b), and was not of record during the ’031 patent prosecution.

Ebert is directed to a transdermal drug delivery device for nicotine and other

drugs. (Ex. 1006 at 3; see also Ex. 1010 ¶ 36.)3 Ebert teaches that conventional

methods of preparing transdermal devices containing drugs such as nicotine are

problematic for a variety of reasons. For example, Ebert teaches that because

nicotine is volatile, it can evaporate if a drying step is employed, leading to reduced

and uneven concentrations of the drug throughout the composition. (Id. at 5.)

To solve this problem, Ebert describes the preparation of a transdermal

3 As discussed below (pages 35 to 38), nicotine, which is susceptible to

oxidation, is a good model for the susceptibility of rivastigmine to oxidation. See

also Dr. Schöneich’s declaration, Ex. 1011, at paragraphs 56 to 57.


16

device that avoids the use of drying. (Id. at 7.) The drug, in gel form, is extruded

onto one or two adhesive layers, one of which has an impermeable backing layer

and the other of which has a peelable layer. The layers are then laminated together

to produce the transdermal drug delivery system. (Id. at 7-8.) A schematic of the

device is reproduced below:

(Id. at 1.)

Ebert teaches that nicotine was known to oxidize readily in the presence of

light and air, and that to minimize oxidation, the transdermal device should be kept

in the dark and under an inert atmosphere. (Id. at 21.) Ebert also teaches that

oxidation during manufacturing may be further reduced by adding an antioxidant to

the active gel, and that the most preferred antioxidant is butylated hydroxytoluene

(BHT) in a range of 0.05-0.2% by weight. (Id.) Ebert teaches that other

antioxidants such as butylated hydroxyanisole (BHA), sodium metabisulfite,

14 = drug impermeable backing layer

18 = drug containing composite

19 = distal adhesive layer 20 = proximal adhesive layer

21 = gelled drug layer

22 = drug impermeable release layer


17

EDTA, and α-tocopherol are also useful. (Id.)

Although the exemplified device is described with respect to nicotine (id. at

3), Ebert explicitly teaches that the device is suitable for any chemical or biological

material that may be delivered transdermally. (Id. at 10-11 and 15.)

6. Sasaki Taught Using the Antioxidant Tocopherol to Promote Storage Stability of the Active Ingredient in Transdermal Compositions

Japanese Patent Application Publication No. JP 59-184121 to Sasaki et al.,

titled “Acrylic Plaster,” published on October 19, 1984 (“Sasaki”). The original

Japanese language document is Exhibit 1004, and a certified translation is Exhibit

1005. Sasaki is prior art under 35 U.S.C. § 102(b). Sasaki was not of record

during the ’031 patent prosecution.

Sasaki is directed to methods of stabilizing pharmaceutical compounds in

transdermal compositions. Sasaki teaches that when an active ingredient is

combined with an acrylic adhesive, the drug will often oxidatively degrade upon

long term (2-3 years) storage. (Ex. 1005 at 1; see also Ex. 1010 ¶ 40.) Sasaki

notes that this degradation often cannot be prevented by protecting the composition

from light by using aluminum packaging, and that certain drugs, especially those

drugs “having a phenolic hydroxyl group or an amino group,” are especially

susceptible to oxidative degradation over this time frame. (Id. at 1.)

Sasaki teaches that blending a tocopherol antioxidant into the composition


18

prevents the drug from degrading. (Id. at 2.) Sasaki discloses using an amount of

tocopherol of 0.005–5% by weight relative to the acrylic adhesive of the patch, and

a preferred amount of 0.05–1 wt%. (Id.)

7. The Handbook of Pharmaceutical Excipients Detailed Common Antioxidants Used in Approved Pharmaceutical Compositions

The Handbook of Pharmaceutical Excipients (2nd Ed. 1994, Wade, A. and

Weller, P.J., Eds., the “Handbook”) published in 1994. Excerpts of the Handbook

are marked as Ex. 1003. The Handbook is prior art under 35 U.S.C. § 102(b), and

was not of record during the ’031 patent prosecution.

The Handbook is a reference textbook that lists inactive ingredients and their

physical and chemical properties. (Ex. 1010 ¶ 42.) Persons of ordinary skill in the

art routinely consult the Handbook to determine what excipients had been

previously approved for use in pharmaceuticals and food products, and in what

amounts. (Id.)

The Handbook provides an overview of antioxidants (including ascorbic

acid, butylated hydroxytoluene (BHT), α-tocopherol, and ascorbyl palmitate)

suitable for use in products intended for human use, and the concentrations at

which they are commonly employed, as shown in Table 1:


19

Antioxidant Concentration Typically Used in

Pharmaceutical Products

Citation in the

Handbook (Ex. 1003)

Ascorbic acid In aqueous formulations, 0.01–0.1 %

w/v

p. 8

BHT In IV injections, 0.0009–0.002 % w/v

In topical formulations, 0.0075–0.1 %

w/w

pp. 19-20

α-tocopherol 0.001 to 0.05 wt% pp. 5-6

Ascorbyl

palmitate

Not provided pp. 12-13

BHA In IV injections, 0.0002-0.0005 % w/v

In topical formulations, 0.005-0.02 %

w/w

pp. 17-18

Propyl gallate ≤0.1% % w/v pp. 21-23

Table 1: Excerpt of Antioxidant Information from the Handbook of

Pharmaceutical Excipients

D. Ground 1: Claim 15 is Unpatentable as Anticipated by Elmalem

In the Elmalem reference, the authors report making two different

compositions of RA7: one comprising 1 mg/kg RA7 and 1 mg/kg sodium

metabisulphite in sterile saline, and the other comprising 2 mg/kg RA7 and 2 mg/kg


20

sodium metabisulphite in sterile saline. (Ex. 1009 at 2.) Elmalem explicitly states

that the sodium metabisulphite was added to prevent oxidation of the drug: “All

drugs were made up freshly in sterile saline, which included an equal weight of

sodium metabisulphite, to prevent oxidation.” (Id.)

Independent claim 15 is directed to a method of stabilizing Compound A

comprising forming a composition by combining Compound A with an amount of

antioxidant effective to stabilize Compound A from degradation. Elmalem meets

every limitation of this claim. In Elmalem, two solutions of RA7 with an equal

weight of antioxidant were reported. RA7 is comprised of an equal mixture of

rivastigmine and its enantiomer ent-rivastigmine, or (R)-rivastigmine. (Ex. 1010 ¶

15.) Accordingly, the ratio of rivastigmine to antioxidant on a wt/wt basis was

0.5:1, or 67% antioxidant. Elmalem taught that this amount of rivastigmine was

added to prevent oxidation (Ex. 1009 at 2), and indeed the Patentee discloses that a

much smaller amount of antioxidant (0.01 to 0.5%) in a pharmaceutical

composition comprising rivastigmine is sufficient to prevent oxidation. (Ex. 1001

at 4:15–19.) Accordingly, in preparing the solutions described in Elmalem, the

authors necessarily practiced a method of stabilizing rivastigmine by forming a

composition by combining rivastigmine with an amount of antioxidant effective to

stabilize rivastigmine from degradation, which meets every limitation of claim 15,

as shown in the below claim chart:


21

Claim 15 Support

A method of stabilizing

(S)-N- ethyl-3-{(1-

dimethylamino)ethyl}-

N-methyl-phenyl-

carbamate in free base

or acid addition salt

form (Compound A),

wherein the method

comprises

In the Elmalem reference, the authors report making

two different solutions of RA7, which is N-ethyl, N-

methyl-3[1-(dimethylamino)ethyl] phenyl carbamate

HCl. (Ex. 1009 at 2.) RA7 is comprised of an equal

mixture of rivastigmine hydrochloride salt (i.e.,

Compound A) and its enantiomer ent-rivastigmine, or

(R)-rivastigmine. (Ex. 1010 ¶ 15.)

forming a composition

by combining

Compound A with an

amount of anti-oxidant

effective to

In the Elmalem reference, the authors report making

two different solutions of RA7, one comprising 1

mg/kg RA7 and 1 mg/kg sodium metabisulphite in

sterile saline, and the other comprising 2 mg/kg RA7

and 2 mg/kg sodium metabisulphite in sterile saline.


22

Claim 15 Support

stabilize Compound A

from degradation.

(Ex. 1009 at 2.) Elmalem explicitly states that the

sodium metabisulphite was added to prevent oxidation

of the drug: “All drugs were made up freshly in sterile

saline, which included an equal weight of sodium

metabisulphite, to prevent oxidation.” (Id.) (emphasis

added).

In the Elmalem solutions, the ratio of RA7 to

antioxidant on a wt/wt basis was 1:1. Thus the ratio of

rivastigmine to antioxidant was 0.5:1, or 67%

antioxidant. Elmalem taught that this amount of

rivastigmine was added to prevent oxidation (Ex. 1009

at 2), and indeed the Patentee discloses that a much

smaller amount of antioxidant (0.01 to 0.5%) in a

pharmaceutical composition comprising rivastigmine

is sufficient to prevent oxidation. (Ex. 1001 at 4:15–

19.)


23

Claim 15 Support

In Elmalem, the authors necessarily combined

rivastigmine (Compound A) with an amount of

antioxidant effective to stabilize rivastigmine from

degradation.

Claim 15 is therefore unpatentable as anticipated by Elmalem (Ex. 1009).

E. The Challenged Claims are Unpatentable as Obvious Over the Prior Art

As detailed herein, each of the limitations of the challenged claims is

disclosed in the prior art, and a person of ordinary skill in the art would have been

motivated to combine teachings in prior art references to arrive at the claimed

subject matter.

1. There was Motivation to Select Rivastigmine and Modify Existing Rivastigmine Treatments

In co-pending litigation to which Petitioner is not a party, the Patentees have

asserted that as a starting point for an obviousness analysis, a patent challenger

must prove that a person of ordinary skill in the art would have selected

rivastigmine over other available compounds for treating Alzheimer’s disease, and

would have selected a transdermal device for the development of a treatment for

Alzheimer’s disease. Although Petitioner disagrees with the Patentees’ proposed


24

legal framework, it here addresses why there was motivation to select rivastigmine

and the rivastigmine transdermal device taught in the prior art as a starting point.

As of January 1998, it was known that Novartis had filed for FDA approval

of a rivastigmine twice-daily treatment for Alzheimer’s disease (Ex. 1013 at 3), and

that rivastigmine was effective, well-tolerated, and had benefits over tacrine, a

competing Alzheimer’s treatment. (Id.; Ex. 1012 at 2.) The prior art also indicated

that another competing Alzheimer’s treatment, donepezil, was given once a day

(Ex. 1013 at 3), thus providing motivation for a person of ordinary skill in the art to

reduce the dosing frequency of the rivastigmine treatment, e.g., through a

transdermal patch like that taught in Enz. (Ex. 1010 ¶ 48.)

Further, Enz taught that compared to its racemate, rivastigmine exhibits

particularly marked and selective acetylcholinesterase inhibition (Ex. 1002 at 3),

that it can be prepared using known techniques (id.), and that it can be formulated

into pharmaceutical compositions (id. at 11; see also Ex. 1010 ¶ 47). Enz

exemplified a transdermal device that contains 20% Compound A (i.e.,

rivastigmine tartrate, see Ex. 1002 at 3), together with polymers and a plasticizer.

(Id. at 20, Example 2.) Enz also taught that transdermal administration of

rivastigmine is particularly advantageous, because it “induces a long-lasting and

constant inhibition of acetylcholinesterase activity as indicated in standard tests,

with a slow onset of action, which is particularly advantageous with respect to the


25

tolerability of these compounds.” (Id. at 14.) In view of the prior art, from a

technical standpoint, a person of ordinary skill in the art would have been

motivated to select both rivastigmine and a transdermal device containing

rivastigmine as starting points for further development.

2. Ground 2: Claims 16 and 18 are Unpatentable as Obvious Over Elmalem and the Handbook

Claim 16: Claim 16 depends from independent claim 15. Claim 15 is

directed to a method of stabilizing Compound A comprising forming a composition

by combining Compound A with an amount of antioxidant effective to stabilize

Compound A from degradation. In Elmalem, two solutions of RA7 each containing

an equal weight of antioxidant were reported. (Ex. 1009 at 2.) RA7 is comprised of

an equal mixture of rivastigmine and its enantiomer ent-rivastigmine, or (R)-

rivastigmine. (Ex. 1010 ¶ 15.) Thus the ratio of rivastigmine to antioxidant was

0.5:1, or 67% antioxidant. Elmalem taught that this amount of rivastigmine was

added to prevent oxidation (Ex. 1009 at 2), and indeed the Patentee discloses that a

much smaller amount of antioxidant (0.01 to 0.5%) in a pharmaceutical

composition comprising rivastigmine is sufficient to prevent oxidation. (Ex. 1001

at 4:15–19.) Accordingly in preparing the solutions described in Elmalem, the

authors necessarily practiced a method of stabilizing rivastigmine by forming a


26

composition by combining rivastigmine with an amount of antioxidant effective to

stabilize rivastigmine from degradation, which meets every limitation of claim 15.

Claim 16 further specifies that the antioxidant is selected from tocopherols,

ascorbic acid, BHT, BHA, and propyl gallate. Elmalem reported using sodium

metabisulfite, a reducing agent, to prevent oxidation. (Ex. 1009 at 2.) A person of

ordinary skill in the art would have known that other antioxidants such as ascorbic

acid also function as reducing agents to prevent oxidation. (Ex. 1011 ¶ 50.) A

person of ordinary skill in the art also would have known that other antioxidants

such as α-tocopherol, BHT, BHA, and propyl gallate, which function as chain

terminators, can also prevent or reduce oxidation. (Id.) A person of ordinary skill

in the art would have been motivated to use any of these well-known antioxidants,

as they were known and commonly used in pharmaceuticals and other products

used in humans. The Handbook provides information on antioxidants (including α-

tocopherol, ascorbic acid, BHT, and ascorbyl palmitate) suitable for use in products

intended for human use, and the concentrations at which they are commonly

employed. (Ex. 1003; Ex. 1010 ¶ 51.) Accordingly, it would have been prima

facie obvious to modify the composition taught in Elmalem by substituting another

known antioxidant, which would have resulted in the subject matter of claim 16.

(Ex. 1010 ¶ 51.)


27

Claim 18: Claim 18 depends on claim 15, and specifies that the antioxidant

is present in an amount of about 0.01 to 0.5% by weight of the composition. This

range overlaps with the antioxidant ranges taught in the prior art. For example, the

Handbook details antioxidants suitable for use in pharmaceutical compositions

(including ascorbic acid, butylated hydroxytoluene (BHT), α-tocopherol, ascorbyl

palmitate, butylated hydroxyanisole (BHA), and propyl gallate), and the

concentrations at which they are typically employed, as shown in Table 1 above.

Similarly, Ebert discloses compositions containing 0.01–1.0% antioxidant by

weight of the pharmaceutical composition, preferably 0.03–0.3%, and most

preferably 0.05–0.2%. (Ex. 1006 at 21.)

Because the claimed range of antioxidant was taught in the prior art, the

subject matter of claim 18 would have been obvious. See In re Peterson, 315 F.3d

1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists

when the ranges of a claimed composition overlap the ranges disclosed in the prior

art.”). The specification of the ʼ031 patent does not provide evidence of any

criticality of the antioxidant concentration recited in claim 18, nor did the applicant

allege any such criticality during prosecution. The person of ordinary skill could

have easily determined the optimal antioxidant concentration by preparing a series

of compositions with varying antioxidant levels and determining which

composition had the best combination of properties, which was a typical approach


28

at the time of the alleged invention. (Ex. 1010 ¶ 53.) Accordingly, it would have

been prima facie obvious to modify the composition taught in Elmalem by adding

an antioxidant in the amounts specified in the Handbook, which would have

resulted in the subject matter of claim 18.

(1) No Secondary Considerations Support Non- Obviousness

To overcome Petitioner’s strong showing of prima facie obviousness, the

Patentees have the burden of establishing any secondary considerations of

nonobviousness. Although secondary considerations must be taken into account,

they do not control the analysis where, as here, there is an otherwise strong case of

obviousness. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007).

Petitioner reserves the right to supplement its positions regarding secondary

considerations in response to any allegations Patentees raise in this proceeding.

The Patentees may assert that because the Exelon® Patch, an alleged

commercial embodiment of the claims, is the first and remains the only transdermal

treatment for Alzheimer’s disease in the U.S., this supports non-obviousness.

Petitioner disagrees. First, the challenged claims (other than claim 7) are not

limited to transdermal devices. Since 1997, rivastigmine capsules have been

available in Europe. (Ex. 1018 at 3.) Accordingly, the lack of any other

transdermal formulations is irrelevant to these claims because this fact is not


29

commensurate with the scope of these claims. See MeadWestVaco Corp. v. Rexam

Beauty & Closures, Inc., 731 F.3d 1258, 1264-65 (Fed. Cir. 2013) (“The district

court’s analysis of the secondary considerations of non-obviousness involved only

fragrance-specific uses, but the claims now at issue are not fragrance-specific, and

objective evidence of non-obviousness must be commensurate in scope with the

claims which the evidence is offered to support.”) (internal citations and quotations

omitted).

Moreover, that no rivastigmine transdermal patch appeared on the market

before the Patentees decided to commercialize one is entirely unsurprising. As the

Federal Circuit has recognized, the financial incentive to develop a product

protected by a blocking patent is virtually non-existent. See, e.g., Merck & Co. v.

Teva Pharms. USA, Inc., 395 F.3d 1364, 1376-77 (Fed. Cir. 2005). Here, other

patents listed in the FDA’s Orange Book for Exelon® transdermal, capsule, and

oral solution products blocked others from developing any rivastigmine product,

including transdermal devices.

For example, claims 3 and 4 of U.S. Patent 4,948,807 (the Rosin patent

discussed above, Ex. 1008), which recently expired on August 14, 2012, claim RA7

and use of the same to treat diseases and disorders including Alzheimer’s disease.

U.S. Patent 5,602,176 (Ex. 1024) (the U.S. counterpart to the Enz patent application

(Ex. 1002) discussed above) claims rivastigmine per se, pharmaceutical


30

compositions containing this drug (specifically including transdermal patches), and

methods of treating Alzheimer’s disease using the same. This patent expired even

more recently, on February 11, 2014. In view of these blocking patents, the fact

that the Exelon® Patch is the first and only transdermal treatment for Alzheimer’s

disease in the U.S. is not probative of non-obviousness. Merck & Co., 395 F.3d at

1376-77.

The Patentees may also assert that the Exelon® Patch has garnered industry

praise as an effective treatment option for patients with Alzheimer’s disease, with

the potential for improving compliance. However, to be probative of

nonobviousness, the Patentees must prove that any alleged industry praise is due to

the merits of the claimed invention beyond what was available in the prior art.

Asyst Techs., Inc. v. Emtrak, Inc., 544 F.3d 1310, 1316 (Fed. Cir. 2008). Here, the

alleged praise is directed to use of a transdermal patch to treat Alzheimer’s disease.

But this is exactly the subject matter taught in Enz. (Ex. 1002 at, e.g., 4- 9, 10,

20.) Accordingly, there is no nexus between the alleged praise and the merits of

the claimed invention. Asyst Techs., Inc. 544 F.3d at 1316; see also In re Kao, 639

F.3d 1057, 1068 (Fed. Cir. 2011) (“Where the offered secondary consideration

actually results from something other than what is both claimed and novel in the

claim, there is no nexus to the merits of the claimed invention. If commercial

success is due to an element in the prior art, no nexus exists.”).


31

In view of the above, claims 16 and 18 of the ’031 patent are unpatentable as

obvious over Enz (Ex. 1002) and the Handbook (Ex. 1003). See KSR Int’l Co. v.

Teleflex Inc., 550 U.S. 398, 419-20 (2007) (“One of the ways in which a patent’s

subject matter can be proved obvious is by noting that there existed at the time of

invention a known problem for which there was an obvious solution encompassed

by the patent’s claims.”).

3. Ground 3: Claims 1, 2, 7, 15, and 18 are Obvious Over Enz and the Handbook, Optionally in View of Rosin and/or Elmalem and/or Ebert

Claim 1: Claim 1 of the ’031 patent is directed to pharmaceutical

compositions comprising a therapeutically effective amount of rivastigmine; a

diluent or carrier; and 0.01–0.5 weight percent of an antioxidant.

Enz teaches a rivastigmine composition that meets every limitation of claim

1, except the antioxidant limitation. For example, Enz’s Example 2 teaches a

pharmaceutical composition (a limitation of claim 1) comprising the hydrogen

tartrate salt of rivastigmine (“Compound A,” see Ex. 1002 at 2-4), Eudragit E 100

(a hydrophilic polymer), Durotack 280-2416 (an acrylic adhesive), and Brij 97 (a

plasticizer). (Id. at 20; Ex. 1010 ¶ 56.)

Enz specifies a daily dosage of from about 0.1 to about 25 mg of

rivastigmine, together with solid or liquid carriers or diluents. (Ex. 1002 at 10.)

Enz’s Example 2 further specifies an example composition containing 20%


32

rivastigmine, together with Eudragit E 100 (a hydrophilic polymer) and Durotack

280-2416 (an acrylic polymer adhesive), both of which are diluents or carriers. (Id.

at 20.) These disclosures meet the limitations of claim 1 that require a

therapeutically effective amount of rivastigmine (“Compound A”) and a diluent or

carrier. (Ex. 1010 ¶ 57.)

As noted, Enz does not disclose that the rivastigmine pharmaceutical

compositions contain an antioxidant. However, although Enz provides a starting

point for those interested in formulating a rivastigmine drug product,4 a person of

ordinary skill in the art would not have viewed Enz as the end of the inquiry. (Ex.

1010 ¶ 58.) For example, Enz lacks certain information a person of ordinary skill

in the art would have needed to produce a viable transdermal patch, such as data

from testing the patches on human skin. (Id.) Additionally, the example patches

lack a release liner, which a person of ordinary skill in the art would have known is

needed, e.g., to address practical considerations such as convenient manufacture

and transport of a transdermal patch. (Id.) Enz also lacks any stability data,

including with respect to oxidation, which is one of the first considerations

4 To the extent necessary, the discussion above (in section D.1) regarding

motivation to select rivastigmine as a starting point is incorporated herein by

reference.


33

addressed in early drug product development. (Ex. 1010 ¶ 58.)

In this regard, Enz is a starting point, and the fact that his patches did not

expressly contain an antioxidant does not teach away from the claimed invention or

deprive one of a motivation to investigate the stability of a rivastigmine

transdermal patch. As noted, one of the first steps a person of ordinary skill in the

art would have taken when formulating a drug product is to investigate the stability

of the active component. (Ex. 1010 ¶ 59.) From Elmalem (Ex. 1009), the person of

ordinary skill would have learned that RA7 had been combined with an antioxidant

to prevent oxidative degradation. (Ex. 1009 at 2; Ex. 1010 ¶ 59.) Similarly, Rosin

suggested adding antioxidants such as sodium metabisulphite and ascorbic acid to

compositions containing RA7. (Ex. 1008 at 7:45-53.) A person of ordinary skill

would have concluded from these references that RA7 was susceptible to oxidative

degradation. (Ex. 1010 ¶ 60.) 5 The person of ordinary skill would have known

that there would be little or no difference between rivastigmine and RA7 with

5 The Patentees may argue that this conclusion is erroneous because Rosin

states that RA7 is more stable than physostigmine. (Ex. 1008 at 11:29.) This

statement, however, cannot reasonably be read to mean that RA7 is stable. To the

contrary, Rosin expressly teaches that the formulator should consider adding an

antioxidant to compositions of RA7 as required. (Id. at 7:45-50.)


34

respect to oxidation. (Ex. 1010 ¶ 60.)

The Patentees may argue that Rosin and Elmalem are irrelevant because they

relate to aqueous compositions, whereas the ’031 patent relates to transdermal

compositions. This argument is wrong for several reasons. First, none of the

challenged claims (other than claim 7) are limited to transdermal compositions, but

instead cover any composition, including aqueous compositions of rivastigmine

such as those disclosed by Rosin and Elmalem. Second, one of ordinary skill would

have considered Rosin and Elmalem relevant prior art even when designing a

rivastigmine transdermal patch, including because the drug substance in

transdermal compositions may remain in solution or suspension in the finished

product, e.g. in a reservoir-type transdermal system. (Ex. 1010 ¶ 61.)

Even leaving aside Rosin and Elmalem (which unambiguously teach that

racemic rivastigmine is susceptible to oxidative degradation), a person of ordinary

skill in the art would have considered the chemical stability of rivastigmine, both on

its own, and with excipients, early in the development process. (Ex. 1010 ¶ 62.)

This includes considering the mechanisms of degradation of the drug substance,

identifying functional groups and labile centers, and considering how the drug

substance behaves under external factors such as pH, temperature, humidity, and

light. ( Ex. 1010 ¶ 23.) Indeed, regulatory guidelines in effect as of January 1998

recommended that applicants perform stability tests on both the drug substance and


35

drug product. (Id.; see also ICH Topic Q 1 A, Stability Testing Guidelines:

Stability Testing of New Drug Substances and Products (CPMP/ICH/380/95) (Ex.

1014), at 3-9.) The guidelines suggested performing routine stress testing on the

drug substance to determine its intrinsic stability and degradation pathways

(including testing for oxidative degradation), as well as formal studies on the drug

substance to show that it will remain within specification during the re-test period

if stored under the recommended storage conditions. (Id. at 3, 13.) Further, one of

ordinary skill would have known that the free base form of rivastigmine would

have been more susceptible to oxidation than the salt form disclosed in Enz’s

Example 2, and that the free base would have been more useful in a transdermal

device, thus providing even more motivation to use an antioxidant in a transdermal

delivery system. (Ex. 1010 ¶ 62.)

Accordingly, a person of ordinary skill in the art would have investigated the

stability of rivastigmine in the ordinary course of formulating the drug, and in doing

so, would have reasonably expected, based on the molecular structure of the drug,

that rivastigmine would be susceptible to oxidative degradation. (Ex. 1010 ¶ 63;

see generally Ex. 1011 ¶¶ 52-59.) For example, a person of ordinary skill in the art

would have recognized the similarities in the structure of rivastigmine with that of

other drugs like nicotine. (Ex. 1011 ¶¶ 56-60.) As shown in Figure 1 below,

nicotine and rivastigmine each have a carbon that is both adjacent to an aromatic


36

ring (indicated as a benzylic carbon) and bonded to nitrogen (N):

Figure 1. Comparison of the structures of rivastigmine (top) and nicotine (bottom).

(Ex. 1011 ¶ 57.) Further, in both molecules the nitrogen bonded to the benzylic

carbon is a tertiary nitrogen (a tertiary amine). (Id.) As Dr. Schöneich explains, a

person of ordinary skill in the art would have recognized that for nicotine and

rivastigmine, the presence of a C–H bond on the carbon adjacent to the aromatic

ring would stabilize a radical at this carbon and thus make that radical easier to

form. (Id.) The tertiary amine functional group would also have contributed to

degradation of both molecules. (Ex. 1011 ¶ 59.) For these reasons, a person of

ordinary skill in the art would have expected that rivastigmine would be susceptible


37

to oxidative degradation at the benzylic C-H bond and the adjacent tertiary amine

via similar mechanisms as nicotine and to roughly the same extent as nicotine.

(Id.)

A person of ordinary skill in the art, aware of rivastigmine’s susceptibility to

oxidative degradation, would have been motivated to use an antioxidant, as taught,

e.g., in Rosin, Elmalem, and Ebert, to protect against such degradation. (Ex. 1010 ¶

63; Ex. 1011 ¶ 61.) Antioxidants are compounds that can reduce or prevent the

oxidative decomposition of other compounds. (Ex. 1010 ¶ 63; Ex. 1011 ¶ 50.)

They are (and were at the time of the alleged invention) commonly used in

pharmaceutical products, including in transdermal devices, to protect the drug

and/or excipients from oxidative degradation. For example, Ebert taught that

nicotine was known to readily oxidize in the presence of light and air, and that

adding an antioxidant such as BHT, BHA, sodium metabisulfate, EDTA, or α-

tocopherol to the patch and during manufacture could reduce that oxidation. (Ex.

1006 at 19; see also Ex. 1010 ¶ 63; Ex. 1011 ¶ 50; Ex. 1008 at, e.g., 5:44-45, 14:17-

19, 7:45-53 (teaching the use of antioxidants with RA7); Ex. 1009 at 2 (teaching the

use of antioxidants to prevent oxidation of RA7); Ex. 1005 at 1-2 (teaching the use

of the antioxidant tocopherol to reduce oxidative degradation of the drug in

transdermal compositions).) Accordingly, a person of ordinary skill in the art

would have had a reasonable expectation of success that adding an antioxidant to a


38

rivastigmine composition, including rivastigmine compositions within a

transdermal patch, would protect rivastigmine against oxidative degradation. (Ex.

1010 ¶ 63; Ex. 1011 ¶ 61.)

In view of the above, a person of ordinary skill in the art would have been

motivated to modify the rivastigmine compositions disclosed in Enz by adding

antioxidants to avoid the anticipated degradation of rivastigmine. (Ex. 1010 ¶ 64.)

One of ordinary skill in the art could have easily determined the optimal

antioxidant and its concentration by referencing the Handbook (Ex. 1003) and

through routine experimentation. (Ex. 1010 ¶ 64; see also In re Geisler, 116 F.3d

1465, 1470 (Fed. Cir. 1997) (“[I]t is not inventive to discover the optimum or

workable ranges by routine experimentation.”). Further, the antioxidant range of

0.01 to 0.5 weight percent of the composition recited in claim 1 overlaps with the

antioxidant ranges taught in the prior art. (See Table 1, above; Ex. 1003 at 5-6, 8,

12-13, 17-23; Ex. 1006 at 21; Ex. 1005 at 2; Ex. 1010 ¶ 64; see also Peterson, 315

F.3d at 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists

when the ranges of a claimed composition overlap the ranges disclosed in the prior

art.”).) Accordingly it would have been prima facie obvious to modify the

rivastigmine compositions taught in Enz by adding an antioxidant in the amounts

specified in the Handbook or Ebert, which would have resulted in the subject

matter of claim 1.


39

Claim 2: Claim 2 depends on claim 1 and further specifies that the

pharmaceutical composition contains 1 to 40% by weight of Compound A

(rivastigmine) in free base or acid addition salt form. Rivastigmine comprises 20%

of the pharmaceutical composition disclosed in Enz’s Example 2, which falls

within the limitation of claim 2 that requires 1–40% weight percent of rivastigmine

in the pharmaceutical composition. (Ex. 1002 at 20; Ex. 1010 ¶ 66.)


pharmaceutical composition is part of a transdermal device and is supported by a

substrate. Enz’s Example 2 discloses a transdermal device that comprises a

backing layer (aluminum foil), which corresponds to claim 7’s substrate that

supports the pharmaceutical composition. (Ex. 1002 at 20; Ex. 1010 ¶ 67.)

Claim 15: Independent claim 15 is directed to a method of stabilizing

Compound A (rivastigmine) comprising forming a composition by combining

Compound A with an amount of antioxidant effective to stabilize Compound A

from degradation. For the reasons discussed above in connection with claim 1

(pages 31 to 38, which are incorporated here by reference), a person of ordinary

skill in the art would have been motivated to modify the rivastigmine compositions

disclosed in Enz by adding antioxidants (such as those taught in the Handbook or

Ebert) to avoid the anticipated degradation of rivastigmine. (Ex. 1010 ¶ 68.)

Indeed, Ebert teaches that oxidation during manufacturing may be reduced by


40

mixing the drug with antioxidants such as BHT, BHA, sodium metabisulfite,

EDTA, and α-tocopherol. (Id.; Ex. 1006 at 21.) This would have resulted in the

person of ordinary skill in the art practicing the method of claim 15, which requires

only forming a composition by combining Compound A with an amount of

antioxidant effective to stabilize Compound A from degradation.


is present in an amount of about 0.01 to 0.5% by weight of the composition. For

the reasons discussed above in connection with claims 1 and 15 (pages 31-40,

which are incorporated here by reference), a person of ordinary skill in the art

would have been motivated to modify the rivastigmine compositions disclosed in

Enz by adding antioxidants (such as those taught in the Handbook or Ebert) to

avoid the anticipated degradation of rivastigmine. (Ex. 1010 ¶ 69.)

The antioxidant range specified in claim 18 overlaps with the antioxidant

ranges taught in the prior art. For example, the Handbook details antioxidants

suitable for use in pharmaceutical compositions (including ascorbic acid, butylated

hydroxytoluene (BHT), α-tocopherol, ascorbyl palmitate, butylated hydroxyanisole

(BHA), and propyl gallate), and the concentrations at which they are typically

employed, as shown in Table 1 above. Similarly, Ebert discloses mixing the drug

with 0.01–1.0% antioxidant by weight of the pharmaceutical composition,

preferably 0.03–0.3%, and most preferably 0.05–0.2%. (Id.; Ex. 1006 at 21.)


41

Because the claimed range of antioxidant was taught in the prior art, the

subject matter of claim 18 would have been obvious. See Peterson, 315 F.3d at

1329 (“A prima facie case of obviousness typically exists when the ranges of a

claimed composition overlap the ranges disclosed in the prior art.”). The

specification of the ʼ031 patent does not provide evidence of any criticality of the

antioxidant concentration recited in claim 18, nor did the applicant allege any such

criticality during prosecution. The person of ordinary skill could have easily

determined the optimal antioxidant concentration by preparing a series of

compositions with varying antioxidant levels and determining which composition

had the best combination of properties, which was a typical approach at the time of

the alleged invention. (Ex. 1010 ¶ 71.)

No secondary considerations support non-obviousness. As discussed

above with respect to Ground 2 (see pages 28 to 31), Petitioner is not aware of any

secondary considerations supporting non-obviousness.

Accordingly, a person of ordinary skill in the art would have reasonably

expected that one or more of the antioxidants described in the Handbook and/or

Rosin and/or Ebert could be successfully employed in a composition containing

rivastigmine (such as taught in Enz), rendering claims 1, 2, 7, 15, and 18 of the

’031 patent unpatentable as obvious over Enz (Ex. 1002) and the Handbook (Ex.

1003) and/or Rosin (Ex. 1008) and/or Ebert (Ex. 1006).


42

4. Ground 4: Dependent Claims 3 and 16 are Unpatentable as Obvious Over Enz and the Handbook and/or Rosin and/or Ebert

Dependent claim 3 contains all of the limitations of claim 1, and further

specifies that the antioxidant is selected from a group that includes tocopherol,

esters thereof, ascorbic acid, BHT, BHA, and propyl gallate. Dependent claim 16

contains all of the limitations of claim 15, and further specifies that the antioxidant

is selected from a group that includes tocopherol, esters thereof, ascorbic acid,

BHT, BHA, and propyl gallate. For the reasons discussed above in Ground 3 with

respect to claims 1 and 15 (pages 31 to 40, which are incorporated herein by

reference), a person of ordinary skill in the art would have been motivated to

modify the rivastigmine compositions disclosed in Enz by adding an antioxidant.

The additional matter in claims 3 and 16 is merely a list of common antioxidants.

Many of the antioxidants in these claims are listed in the Handbook. (Ex.

1003 at 3-23.) A person of ordinary skill in the art would have been motivated to

select one of these antioxidants from the Handbook, since inclusion in the

Handbook indicates that that antioxidant has previously been used in approved

pharmaceuticals and foodstuffs. (Ex. 1010 ¶ 74.)


43

Further, Rosin taught that ascorbic acid is a preferred antioxidant to stabilize

racemic rivastigmine. (Ex. 1008 at, e.g., 5:44-45, 7:51-53.) Although the

properties of enantiomers and racemates can differ in certain situations, e.g., with

respect to biological activity, in the context of an aqueous solution or dispersion in

a polymer, each enantiomer will behave the same. (Ex. 1010 ¶ 75.) Accordingly a

person of ordinary skill in the art would have been motivated to select ascorbic

acid, with a reasonable expectation that it would act as an antioxidant with

rivastigmine in pharmaceutical compositions. (Id.)

Further, Ebert taught that antioxidants including BHT, BHA, and tocopherol

could be used to prevent degradation of nicotine during manufacture of transdermal

devices. (Ex. 1006 at 21.) Because nicotine and rivastigmine share structural

features pertinent to oxidative degradation (as discussed above at pages 35-38), a

person of ordinary skill in the art would have been motivated to select BHT, BHA,

or tocopherol, with a reasonable expectation that these compounds would act as an

antioxidant with rivastigmine in pharmaceutical compositions. (Ex. 1010 ¶ 76; Ex.

1011 ¶ 61.)


above with respect to Ground 2 (pages 28-31), Petitioner is not aware of any

secondary considerations supporting non-obviousness.

Accordingly, a person of ordinary skill in the art would have reasonably


44

expected that one or more of the antioxidants described in the Handbook and/or

Rosin and/or Ebert could be successfully employed in a composition containing

rivastigmine, rendering claims 3 and 16 of the ’031 patent unpatentable as obvious

over Enz (Ex. 1002) and the Handbook (Ex. 1003) and/or Rosin (Ex. 1008) and/or

Ebert (Ex. 1006).

5. Ground 5: The Challenged Claims Are Unpatentable As Obvious over Enz and Sasaki

Claims 1 and 7: Claim 1 of the ’031 patent is directed to pharmaceutical

compositions comprising a therapeutically effective amount of rivastigmine; a

diluent or carrier; and 0.01–0.5 weight percent of an antioxidant. Claim 7 depends

from claim 1 and further specifies that the pharmaceutical composition is part of a

transdermal device and is supported by a substrate.

Enz teaches a rivastigmine composition that meets every limitation of claims

1 and 7, except the antioxidant limitation. For example, Enz’s Example 2 teaches a

transdermal pharmaceutical composition comprising the hydrogen tartrate salt of

rivastigmine (“Compound A,” see Ex. 1002 at 2-4), Eudragit E 100 (a hydrophilic

polymer), Durotack 280-2416 (an acrylic adhesive), and Brij 97 (a plasticizer). (Id.

at 20; Ex. 1010 ¶ 79.) The transdermal device of Example 2 also comprises a

backing layer (aluminum foil), which corresponds to claim 7’s substrate that

supports the pharmaceutical composition. (Ex. 1002 at 20; Ex. 1010 ¶ 80.)


45

Enz specifies a daily dosage of from about 0.1 to about 25 mg of

rivastigmine, together with solid or liquid carriers or diluents. (Ex. 1002 at 10.)

Enz’s Example 2 further specifies an example composition containing 20%

rivastigmine, together with Eudragit E 100 (a hydrophilic polymer) and Durotack

280-2416 (an acrylic polymer adhesive), both of which are diluents or carriers. (Id.

at 20.) These disclosures meet the limitations of claim 1 that require a

therapeutically effective amount of rivastigmine (“Compound A”) and a diluent or

carrier. (Ex. 1010 ¶ 81.)

As noted, Enz does not disclose that the rivastigmine pharmaceutical

compositions contain an antioxidant. However, although Enz provides a starting

point for those interested in formulating a rivastigmine drug product,6 a person of

ordinary skill in the art would not have viewed Enz as the end of the inquiry. (Ex.

1010 ¶ 82.) For example, Enz lacks certain information a person of ordinary skill

in the art would have needed to produce a viable transdermal patch, such as data

from testing the patches on human skin. (Id.) Additionally, the example patches

lack a release liner, which a person of ordinary skill in the art would have known is

6 To the extent necessary, the discussion above (in section D.1) regarding

motivation to select rivastigmine and rivastigmine transdermal patches as a

starting point is incorporated herein by reference.


46

needed, e.g., to address practical considerations such as convenient manufacture

and transport of a transdermal patch. (Id.) Enz also lacks any stability data, which

is one of the first considerations addressed in early drug product development. (Ex.

1010 ¶ 82.)

In this regard, Enz is a starting point, and the fact that his patches did not

expressly contain an antioxidant does not teach away from the claimed invention or

deprive one of a motivation to investigate the stability of a rivastigmine

transdermal patch. As noted, one of the first steps a person of ordinary skill in the

art would have taken when formulating a drug is to investigate the stability of the

active component. (Ex. 1010 ¶ 83.)

Regarding stability of active components, Sasaki discloses that drugs

formulated with acrylic polymer adhesives in transdermal patches can undergo

oxidative degradation upon long term (2–3 years) storage, even when shielded

from light using aluminum laminate packaging. (Ex. 1005 at 1; Ex. 1010 ¶ 84.)

Sasaki teaches that drugs “having a phenolic hydroxyl group or an amino group”

are susceptible to this oxidative degradation. (Ex. 1005 at 1.) Sasaki teaches that

adding a tocopherol antioxidant to the patch prevents breakdown of the drug. (Id.

at 2.) Sasaki teaches using 0.005–5% tocopherol by weight relative to the acrylic

adhesive of the patch, and specifies a preferred range of 0.05–1 wt%. (Id. at 2.)


47

A person of ordinary skill in the art would have been motivated to combine

Enz with Sasaki. Enz discloses a transdermal patch comprising rivastigmine and

the acrylic adhesive Durotack 280-2416. (Ex. 1002 at 20; Ex. 1010 ¶ 85.) Enz

does not disclose any stability data. However, Sasaki teaches that compounds that

have an amino group (like rivastigmine, see Ex. 1011 ¶ 12) can undergo oxidative

decomposition over the shelf life of the product when the product contains an

acrylic adhesive. (Ex. 1005 at 1; Ex. 1010 ¶ 85.) Based on Sasaki, a person of

ordinary skill in the art would have expected that rivastigmine transdermal patches

like that disclosed in Enz’s Example 2, which contained an acrylic adhesive

(Durotack 280-2416), would be unstable during long-term storage of two to three

years. (Ex. 1010 ¶ 85.)

As persons of ordinary skill in the art generally strive to develop stable

pharmaceutical products with a commercially viable shelf life, they would have

been motivated to apply Sasaki’s solution of adding tocopherol, to maintain the

stability of the Enz patch over 1–2 years. (Ex. 1010 ¶ 86.) Antioxidants are (and

were at the time of the alleged invention) commonly used in pharmaceutical

products, including in transdermal devices, to protect the drug and/or excipients

from oxidative degradation. (Ex. 1010 ¶ 86; Ex. 1011 ¶ 50; Ex. 1008 at, e.g., 7:45-

53, 5:44-45, 14:17-19 (teaching the use of antioxidants with RA7); Ex. 1009 at 2

(teaching the use of the antioxidant sodium metabisulphite to prevent oxidation of


48

RA7); Ex. 1006 at 21 (teaching the use of antioxidants such as BHT, sodium

metabisulfite, EDTA, and α-tocopherol to reduce oxidative degradation in nicotine

transdermal patches); Ex. 1004 at 1-2 (teaching the use of the antioxidant

tocopherol to reduce oxidative degradation of the drug in transdermal

compositions).) Given Sasaki’s teaching that his solution is particularly useful

with amine-based compounds—of which rivastigmine is one—a person of ordinary

skill in the art would have had a reasonable expectation of success that this solution

would result in a stable rivastigmine transdermal composition. (Ex. 1010 ¶ 86.)

Sasaki teaches to add 0.005–5 wt% tocopherol, and preferably 0.05 to 1

wt%, relative to the acrylic adhesive. (Ex. 1005 at 2.) Enz discloses a patch

containing 44% acrylic adhesive (Durotack 280-2416) by weight. (Ex. 1002 at

20.) One of ordinary skill, applying Sasaki’s ranges to Enz’s patch, would have

been motivated to add tocopherol in a range of 0.0022–2.2 wt% relative to the

total weight of the pharmaceutical composition in Enz, and applying Sasaki’s

preferred range, would have been motivated to add tocopherol in a range of

0.022–0.44 wt% relative to the total weight of the pharmaceutical composition

in Enz. (Ex. 1010 ¶ 87.) Thus, the amounts of antioxidant taught by Sasaki

encompass the amounts recited in claim 1, and Sasaki’s preferred range overlaps

with the range specified in claim 1.


49

The specification of the ʼ031 patent does not provide evidence of any

criticality of the antioxidant concentration recited in the claims, nor did the

applicant allege any such criticality during prosecution. In view of the above,

claims 1 and 7 are unpatentable as obvious over Enz (Ex. 1002) and Sasaki (Ex.

1005). See Peterson, 315 F.3d 1329 (“A prima facie case of obviousness typically

exists when the ranges of a claimed composition overlap the ranges disclosed in the

prior art.”).


pharmaceutical composition contains 1 to 40% by weight of Compound A in free

base or acid addition salt form. For the reasons discussed above in connection with

claim 1 (pages 44-49, which are incorporated here by reference), a person of

ordinary skill in the art would have been motivated to modify the rivastigmine

compositions disclosed in Enz by adding antioxidant as taught in Sasaki.

Rivastigmine comprises 20% of the pharmaceutical composition disclosed in Enz’s

Example 2, which falls within the limitation of claim 2 that requires 1-40% weight

percent of rivastigmine in the pharmaceutical composition. (Ex. 1002 at 20; Ex.

1010 ¶ 88.)

Claim 15: Independent claim 15 is directed to a method of stabilizing

Compound A comprising forming a composition by combining Compound A with

an amount of antioxidant effective to stabilize Compound A from degradation. For


50

the reasons discussed above in connection with claim 1 (pages 44-49, which are

incorporated here by reference), a person of ordinary skill in the art would have

been motivated to modify the rivastigmine compositions disclosed in Enz by

adding antioxidant as taught in Sasaki. This would result in the person of ordinary

skill in the art practicing the method of claim 15, which requires only forming a

composition by combining Compound A with an amount of antioxidant effective to

stabilize Compound A from degradation.


is present in an amount of about 0.01 to 0.5% by weight of the composition. For

the reasons discussed above in connection with claims 1 and 15 (pages 44-50,

which are incorporated here by reference), a person of ordinary skill in the art

would have been motivated to modify the rivastigmine compositions disclosed in

Enz by antioxidant as taught in Sasaki.

Sasaki teaches to add 0.005–5 wt% tocopherol relative to the acrylic

adhesive. (Ex. 1005 at 2.) Enz discloses a patch containing 44% acrylic adhesive

(Durotack 280-2416) by weight. (Ex. 1002 at 20.) One of ordinary skill, applying

Sasaki’s ranges to Enz’s patch, would have been motivated to add tocopherol in a

range of 0.0022–2.2 wt% relative to the total weight of the pharmaceutical

composition in Enz. (Ex. 1010 ¶ 90.) Thus, the amounts of antioxidant taught by

Sasaki encompasses the amounts recited in claim 18.


51

The specification of the ʼ031 patent does not provide evidence of any

criticality of the antioxidant concentration recited in the claims, nor did the

applicant allege any such criticality during prosecution. Because the claimed

concentration of antioxidant was taught in Sasaki, claim 18 is unpatentable as

obvious over Enz (Ex. 1002) and Sasaki (Ex. 1005). See Peterson, 315 F.3d at

1329 (“A prima facie case of obviousness typically exists when the ranges of a

claimed composition overlap the ranges disclosed in the prior art.”).

Claims 3 and 16: Dependent claim 3 contains all of the limitations of claim

1, and further specifies that the antioxidant is selected from a group that includes

tocopherol, esters thereof, ascorbic acid, BHT, BHA, and propyl gallate.

Dependent claim 16 contains all of the limitations of claim 15, and further specifies

that the antioxidant is selected from a group that includes tocopherol, esters

thereof, ascorbic acid, BHT, BHA, and propyl gallate. The discussions above with

respect to claims 1 and 15 (pages 44-50) are incorporated herein by reference.

Because Sasaki teaches the use of tocopherol (Ex. 1005 at 2), one of ordinary skill

would have been motivated to use this antioxidant. (Ex. 1010 ¶ 92.)


above with respect to Ground 2 (pages 28-31), Petitioner is not aware of any

secondary considerations supporting non-obviousness. Accordingly, claims 3 and

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