Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 1 of 44 PageID #: 13276
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`Civil Action No. 11-1077-RGA
`(Consolidated)
`
`NOV ARTIS PHARMACEUTICALS
`CORPORATION, NOVARTIS AG,
`NOV ARTIS PHARMA AG, NOV ARTIS
`INTERNATIONAL PHARMACEUTICAL
`LTD., and LTS LOHMANN THERAPIE(cid:173)
`SYSTEME AG,
`
`Plaintiffs,
`
`V.
`
`PAR PHARMACEUTICAL, INC.,
`
`Defendant.
`
`NOV ARTIS PHARMACEUTICALS
`CORPORATION, NOV ARTIS AG,
`NOVARTIS PHARMA AG, NOVARTIS
`INTERNATIONAL PHARMACEUTICAL
`LTD., and LTS LOHMANN THERAPIE(cid:173)
`SYSTEME AG,
`
`Plaintiffs,
`
`Civil Action No. 11-1112-RGA
`
`v.
`
`WATSON LABORATORIES, INC.,
`WATSON PHARMA, INC., and ACTA VIS,
`INC.,
`
`Defendants.
`
`TRIAL OPINION
`
`Michael P. Kelly, Esq., McCARTER & ENGLISH, LLP, Wilmington, DE; Nicholas N. Kallas,
`Esq., FITZPATRICK, CELLA, HARPER & SCINTO, New York, NY; Filko Prugo, Esq.,
`FITZPATRICK, CELLA, HARPER & SCINTO, New York, NY.
`
`Attorneys for Plaintiffs Novartis Pharmaceuticals Corporation, et al.
`
`NOVARTIS EXHIBIT 2002
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 1 of 44
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`

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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 2 of 44 PageID #: 13277
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`Civil Action No. 11-1077-RGA
`
`NOV ARTIS PHARMACEUTICALS
`CORPORATION, NOV ARTIS AG,
`NOV ARTIS PHARMA AG, NOV ARTIS
`INTERNATIONAL PHARMACEUTICAL
`LTD., and LTS LOHMANN THERAPIE(cid:173)
`SYSTEME AG,
`
`Plaintiffs,
`
`V.
`
`PAR PHARMACEUTICAL, INC.,
`
`Defendant.
`
`NOV ARTIS PHARMACEUTICALS
`CORPORATION, NOV ARTIS AG,
`NOV ARTIS PHARMA AG, NOV ARTIS
`INTERNATIONAL PHARMACEUTICAL
`LTD., and LTS LOHMANN THERAPIE(cid:173)
`SYSTEMEAG,
`
`Plaintiffs,
`
`Civil Action No. 11-1112-RGA
`
`V.
`
`WATSON LABORATORIES, INC.,
`WATSON PHARMA, INC., andACTAVIS,
`INC.,
`
`Defendants.
`
`TRIAL OPINION
`
`Michael P. Kelly, Esq., McCARTER & ENGLISH, LLP, Wilmington, DE; Nicholas N. Kallas,
`Esq., FITZPATRICK, CELLA, HARPER & SCINTO, New York, NY; Filko Prugo, Esq.,
`FITZPATRICK, CELLA, HARPER & SCINTO, New York, NY.
`
`Attorneys for Plaintiffs Novartis Pharmaceuticals Corporation, et al.
`
`NOVARTIS EXHIBIT 2002
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 3 of 44 PageID #: 13278
`
`Melanie K. Sharp, Esq., YOUNG CONAWAY STARGATT & TAYLOR, LLP, Wilmington,
`DE; E. Anthony Figg, Esq., ROTHWELL, FIGG, ERNST & MANBECK, P.C., Washington,
`D.C.; C. Nichole Gifford, Esq., ROTHWELL, FIGG, ERNST & MANBECK, P.C., Washington,
`D.C.; Seth E. Cockrum, Esq., ROTHWELL, FIGG, ERNST & MANBECK, P.C., Washington,
`D.C.; Brett A. Postal, Esq., ROTHWELL, FIGG, ERNST & MANBECK, P.C., Washington,
`D.C.
`
`Attorneys for Defendants Watson Laboratories, Inc., et al.
`
`June lK_, 2014
`
`NOVARTIS EXHIBIT 2002
`Noven v. Novartis and LTS Lohmann
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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 4 of 44 PageID #: 13279
`
`Novartis Pharmaceuticals Corporation, Novartis AG, Novartis Pharma AG, Novartis
`
`International Pharmaceutical Ltd., and LTS Lohmann Therapie-Systeme AG (collectively,
`
`"Novartis" or "Plaintiff') brought this suit against Watson Laboratories, Inc., Watson Pharma,
`
`Inc., Watson Pharmaceuticals, Inc. (collectively "Watson" or "Defendant"), and Par
`
`Pharmaceutical, Inc. 1 alleging infringement of U.S. Patent Nos. 6,335,031 ("the '031 patent")
`
`and 6,316,023 ("the '023 patent") (collectively, "the patents in suit"). Both patents share the
`
`same specification. 2 The '031 and '023 patents claim pharmaceutical compositions, transdermal
`
`devices, and methods of stabilizing compositions comprising the drug rivastigmine, which is an
`
`acetylcholinesterase inhibitor, and an antioxidant. (D.I. 310, p. 1 ). Novartis sells an Exelon®
`
`transdermal patch for the treatment of Alzheimer's disease that contains rivastigmine. Novartis
`
`listed the '031 and '023 patents in the Food and Drug Administration's "Approved Drug
`
`Products with Therapeutic Equivalence Evaluations," frequently referred to as the "Orange
`
`Book," as covering the Exelon® patches. Watson's Abbreviated New Drug Application 202,119
`
`("ANDA") seeks approval to engage in the commercial manufacture, importation, use, or sale of
`
`a transdermal patch containing rivastigmine and an antioxidant prior to the expiration of the
`
`patents in suit.
`
`Watson's ANDA product is a transdermal patch that contains a backing film, an adhesive
`
`bilayer comprised of a 905A adhesive and a 900A adhesive, and a protective release liner, a
`
`schematic of which is shown below:
`
`1 Both the Par and Watson defendants were scheduled for trial beginning on August 26, 2013. Par and Novartis
`informed the Court on the morning of the first day of trial that a settlement had been reached. Relying on this
`representation, the Court entered an order staying the action with respect to Par for forty-five days and dismissed Par
`from the trial. (D.I. 293). The settlement later fell through, and a trial for Par and Novartis took place on May 1,
`2014.
`2 Unless otherwise noted, all citations to the specification refer to the '031 patent.
`
`1
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`NOVARTIS EXHIBIT 2002
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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 5 of 44 PageID #: 13280
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`(JTX 56, p. 1822-23). The process for manufacturing Watson's ANDA product can be
`
`summarized as follows: 1) the 905A adhesive and rivastigmine, the active ingredient, are mixed
`
`to form the 905A casting solution; 2) the 905A casting solution is applied to a polyester release
`
`liner, which is subsequently passed through a drying oven; 3) the 900A adhesive is applied to a
`
`polyester release liner and passed through a drying oven; 4) the release liner for the 905A layer is
`
`removed and the exposed 905A layer is laminated onto the 900A layer, thereby forming the
`
`adhesive bilayer; 5) the adhesive bilayer is then cut to size, packaged, and heat sealed into
`
`pouches. (Id., pp. 1832-34). Watson's ANDA product is available in 5 and 10 square centimeter
`
`sizes. (Id.).
`
`Novartis asserts that Watson's ANDA products infringe claims 3, 7, 13, 16, and 18 of the
`
`'031 patent and claims 2 and 7 of the '023 patent. Watson counters that the asserted claims are
`
`obvious under 35 U.S.C. § 103(a) and not infringed. The Court held a four day bench trial from
`
`August 26-29, 2013. (D.I. 306, 307, 308 & 309). As explained below, Novartis proved that
`
`Watson's ANDA products infringe by a preponderance of the evidence, and Watson did not
`
`prove by clear and convincing evidence that the asserted claims were invalid as obvious.
`
`2
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`NOVARTIS EXHIBIT 2002
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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 6 of 44 PageID #: 13281
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`I. INFRINGEMENT
`
`The five asserted claims in the '031 patent depend from non-asserted independent claims
`
`1, 11, and 15, which are drawn to pharmaceutical compositions, transdermal devices, and a
`
`stabilization method, respectively. Claim 1 of the '031 patent recites:
`
`A pharmaceutical composition comprising:
`(S)-N-ethyl-3-{(1-
`amount of
`(a)
`a
`therapeutically
`effective
`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.
`
`'031 patent, claim 1. In the claim language "Compound A" refers to rivastigmine, the "S"
`
`enantiomer of the racemic compound RA1. 3 Claim 3 narrows the pharmaceutical composition
`
`to those in which the antioxidant is "tocopherol, esters thereof, ascorbic acid,
`
`butylhydroxytoluene, butylhydroxyanisole or propyl gallate." Claim 7 recites a "transdermal
`
`device comprising a pharmaceutical composition as defined in claim 1, wherein the
`
`pharmaceutical composition is supported by a substrate."
`
`The requirements of claim 11 are as follows:
`
`A transdermal device comprising a backing layer, a layer comprising a
`therapeutically effective amount of (S)-N-ethyl-3-{(l-dimethylamino)ethyl}-N(cid:173)
`methyl-phenyl-carbamate (Compound A) and an amount of antioxidant effective to
`stabilize Compound A from degradation in a polymer matrix, a release-liner and,
`disposed between the layer comprising Compound A in a polymer matrix and the
`release-liner, a discrete layer of adhesive material for releasably fixing said
`transdermal device to a patient's skin.
`
`3 N-ethyl-3-{(l-dimethylamino)ethyl}-N-methyl-phenyl-carbamate, abbreviated as "RA7," is a racemate. A
`racemate is a compound that is composed of two enantiomers of a chiral molecule, denoted as "S" and "R." The
`two enantiomers are identical in all respects except for the fact that they are mirror images of each other. {Tr. 67: 17-
`69:1).
`
`3
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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 7 of 44 PageID #: 13282
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`Id., claim 11. Claim 13 limits the identity of the antioxidant in the transdermal device to
`
`"tocopherol, esters thereof, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or propyl
`
`gallate."
`
`Claim 15 recites:
`
`A method of stabilizing (S)-N-ethyl-3-{(l-dimethylamino)ethyl}-N(cid:173)
`methyl-phenyl-carbamate in free base or acid addition salt form (Compound A),
`wherein the method comprises forming a composition by combining Compound A
`with an amount of antioxidant effective to stabilize Compound A from degradation.
`
`Id., claim 15. Claim 16 limits the method's antioxidant to "tocopherol, esters thereof, ascorbic
`
`acid, butylhydroxytoluene, butylhydroxyanisole or propyl gallate," and claim 18 limits the
`
`amount of antioxidant to "about 0.01 to about 0.5% by weight based on the weight of the
`
`composition."
`
`Two claims from the '023 patent, claims 2 and 7, are also asserted by Novartis. Claim 2
`
`depends from claim 1, which recites:
`
`A pharmaceutical composition comprising 1 to 40 weight percent of (S)-N(cid:173)
`ethyl-3-[(l-dimethylamino )ethyl]-N-methylphenyl carbamate in the form of a free
`base or acid addition salt, 0.01 to 0.5 weight percent of an antioxidant, and a diluent
`or carrier, wherein the weight percents are based on the total weight of the
`pharmaceutical composition.
`
`'023 patent, claim 1. Claim 2 limits the composition of claim 1 to those where the antioxidant is
`
`"tocopherol, esters of tocopherol, ascorbic acid, esters of ascorbic acid, butylhydroxytoluene,
`
`butylhydroxyanisole, propyl gallate, and combinations thereof" Independent claim 7 requires:
`
`A transdermal device comprising a pharmaceutical composition comprising
`1to40 weight percent of (S)-N-ethyl-3-[(l-dimethylamino)ethyl]-N-methylphenyl
`carbamate in the form of a free base or acid addition salt, 0.01to0.5 weight percent
`of an antioxidant, and a diluent or carrier, wherein the weight percents are based on
`the total weight of the pharmaceutical composition.
`
`Id., claim 7.
`
`4
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`NOVARTIS EXHIBIT 2002
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 8 of 44 PageID #: 13283
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`The claims asserted by Novartis can be broken down into two groups: the "presence"
`
`claims and the "function" claims. Claims 3 and 7 of the '031 patent, as well as claims 2 and 7 of
`
`the '023 patent, constitute the presence claims. These claims require proof that Compound A
`
`and an antioxidant are present. The Court defined "antioxidant" as an "agent that reduces
`
`oxidative degradation." (D.I. 250, pp. 1-2). There is no additional requirement that the
`
`antioxidant function with respect to Compound A because that is specifically required in the
`
`function claims. (Id., p. 2 ("The patents repeatedly disclose the combination of Compound A
`
`and the antioxidant without specifically requiring that the antioxidant affect Compound A. It
`
`would be improper to preclude those embodiments by limiting 'antioxidant' to require that
`
`interaction." (internal citations omitted))).
`
`Claims 13, 16, and 18 of the '031 patent are referred to as the function claims. All three
`
`claims require "an amount of antioxidant effective to stabilize compound A from degradation,"
`
`which the Court construed to mean, "an amount of antioxidant that will significantly reduce
`
`degradation of Compound A over a prolonged period of time." (Id., pp. 2-3). The function
`
`claims, therefore, have an additional requirement that the antioxidant interact with Compound A
`
`to reduce degradation. The Court also construed "stabilizing" to mean "significantly reducing
`
`degradation over a prolonged period of time." (Id., p. 3). These three terms are the only ones at
`
`issue, and the parties agree that the remaining elements of the asserted claims are met. (D.I. 310,
`
`pp. 29-30).
`
`In its post-trial briefing, Watson contends Novartis failed to prove infringement of the
`
`presence claims because those claims have a functional limitation and Novartis never proved that
`
`Watson's product contains an agent that reduces oxidative degradation of any component. (D.I.
`
`318, pp. 1-2). Watson asserts it does not infringe the function claims because the testing
`
`5
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`NOVARTIS EXHIBIT 2002
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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 9 of 44 PageID #: 13284
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`conducted by Novartis's experts does not prove that Watson's ANDA product is an oxidative
`
`environment or that it contains a functioning antioxidant.
`
`A. Legal Standard
`
`"Under [35 U.S.C.] § 271(e)(2)(A), a court must determine whether, ifthe drug were
`
`approved based upon the ANDA, the manufacture, use, or sale of that drug would infringe the
`
`patent in the conventional sense." Glaxo, Inc. v. Novopharm, Ltd., 110 F.3d 1562, 1569 (Fed.
`
`Cir. 1997). The application of a patent claim to an accused product is a fact-specific inquiry.
`
`See Kustom Signals, Inc. v. Applied Concepts, Inc., 264 F.3d 1326, 1332 (Fed. Cir. 2001).
`
`Literal infringement is present only when each and every element set forth in the patent claims is
`
`found in the accused product.4 See Southwall Techs., Inc. v. Cardinal JG Co., 54 F.3d 1570,
`
`1575-76 (Fed. Cir. 1995). The patent owner has the burden of proving infringement by a
`
`preponderance of the evidence. Envirotech Corp. v. Al George, Inc., 730 F.2d 753, 758 (Fed.
`
`Cir. l984)(citingHughesAircraftCo. v. United States, 717F.2d 1351, 1361 (Fed. Cir.1983)).
`
`Infringement can be shown by "any method of analysis that is probative of the fact of
`
`infringement," and, in some cases, "circumstantial evidence may be sufficient." Martek
`
`Biosciences Corp. v. Nutrinova, Inc., 579 F.3d 1363, 1372 (Fed. Cir. 2009).
`
`B. Findings of Fact
`
`1. Butylhydroxytoluene ("BHT") is a well-known antioxidant.
`
`2. BHT is present in Watson's ANDA product.
`
`3. BHT is present in an amount between 0.01 and 0.5 percent by weight.
`
`4. Rivastigmine is subject to oxidative degradation in an oxidative environment.
`
`5. The presence of oxygen, peroxides, or other free radical generators creates an
`oxidative environment.
`
`4 There are no assertions of infringement by the doctrine of equivalents.
`
`6
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`NOVARTIS EXHIBIT 2002
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`6. Oxygen, peroxides, and other free radical generators are present in Watson's
`ANDA product.
`
`7. Watson's ANDA products show only minimal degradation ofrivastigmine
`over a prolonged period of time.
`
`8. BHT acts as an antioxidant to protect rivastigmine from oxidative degradation.
`
`9. Watson's ANDA product infringes all asserted claims of the '023 and '031
`patents.
`
`C. Conclusions of Law
`
`1. The Presence Claims
`
`a. The presence claims do not require a functioning antioxidant
`
`The three limitations of the presence claims are: Compound A, a certain weight percent
`
`of antioxidant, and a diluent or carrier. See, e.g., '031 patent, claim 1. Unlike the function
`
`claims, nowhere in the presence claims is any function of the antioxidant mentioned. Compare
`
`id. (requiring Compound A and "about 0.01 to about 0.5 percent by weight of an antioxidant"),
`
`with id., claim 11 (reciting Compound A "and an amount of antioxidant effective to stabilize
`
`Compound A from degradation" (emphasis added)). The Court cautioned in its claim
`
`construction opinion that it would be "improper to impute the antioxidant's stabilizing effect on
`
`Compound A, explicitly claimed in some claims [i.e., the function claims], into claims that do
`
`not contain that explicit limitation [i.e., the presence claims]." (D.I. 250, p. 2). Despite this clear
`
`statement, Watson maintains that "antioxidant," as used in the patents in suit, "requires the
`
`presence of an agent that reduces oxidative degradation of some component in the claimed
`
`composition." (D.I. 318, pp. 12-13 ("The definition of 'antioxidant' adopted by the Court, 'an
`
`agent that reduces oxidative degradation,' plainly recognizes that the term is a functional
`
`limitation that requires a reduction of oxidative degradation in the claimed composition.")). This
`
`argument is rejected as being inconsistent with the Court's claim construction.
`
`7
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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 11 of 44 PageID #: 13286
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`b. Watson's ANDA products meet every limitation of the presence claims
`
`The parties agree that Watson's ANDA product contains Compound A (PTX 311, p.
`
`1603) and a diluent/carrier. (JTX 56, p. 1823). Only the second limitation requiring "0.01 to 0.5
`
`weight percent" of an antioxidant is in dispute. 5
`
`Butylhydroxytoluene, or BHT, is well known in the art as an antioxidant. (DTX 11, p.
`
`47; PTX 17, p. 203; JTX 184, p. 1261; JTX 19, p. 441; DTX 55, p. 263). The patents in suit also
`
`identify BHT as an antioxidant in the specification and claim BHT as an antioxidant in the
`
`asserted claims. '031patent,4:11-14 ("The applicant has found that an effective stabilising
`
`effect is surprisingly achieved when the antioxidant is selected from ... butylhydroxytoluene.");
`
`id., claim 3 ("A pharmaceutical composition according to claim 1 wherein the antioxidant is ...
`
`butylhydroxytoluene."). Novartis's infringement expert, Dr. Davies, performed tests6 on
`
`Watson's ANDA products that identified the presence ofBHT. (Tr. 312:15-21). Watson's
`
`expert, Dr. Sessler, admitted that Watson's ANDA products contain BHT (Tr. 398:21-399:1),
`
`and Watson itself conceded that BHT may have been introduced into its product by an upstream
`
`supplier. (D.I. 318, p. 6 n.2 ("It appears that BHT may have been added to the tackifier
`
`component by one ofHenkel's suppliers upstream in the polymer manufacturing process and that
`
`small amounts ofBHT were carried over into Watson's ANDA product as an unreactive
`
`impurity.")). This evidence proves that BHT, a well-known antioxidant, is present in Watson's
`
`ANDA products.
`
`BHT is present in Watson's ANDA products within the claimed ranges: 0.01 to 0.5
`
`percent by weight of the composition. Dr. Davies tested the 905A adhesive in isolation using gas
`
`5 Claim 1 of the '031 patent requires "about" 0.01 to "about" 0.5 percent by weight. This difference is immaterial
`because, as shown below, the measured amount of antioxidant falls within the 0.01 to 0.5 weight percent range.
`6 The tests Dr. Davies utilized were gas chromatography and gas chromatography coupled with mass spectrometry.
`(Tr. 311:21-312:21).
`
`8
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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 12 of 44 PageID #: 13287
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`chromatography and found BHT at a level of 447 parts per million, which is 0.045 percent. (JTX
`
`41, p. 2; JTX 36; Tr. 320:7-20). After the addition ofrivastigmine to the 905A adhesive layer,
`
`the BHT concentration is decreased to 0.032 percent. (JTX 41, p. 2; Tr. 320:10-321:17). Dr.
`
`Davies then performed the same tests on the 905N900A adhesive bilayer and measured 0.027
`
`percent BHT. (JTX 41, p. 2; JTX 36). Using these result, Dr. Davies calculated7 the amount of
`
`BHT in the drug-containing 905A layer in two scenarios: 1) all of the BHT remains in the 905A
`
`layer but the rivastigmine becomes distributed throughout the 905N900A adhesive bilayer via
`
`diffusion;8 and 2) BHT and rivastigmine both diffuse and become evenly distributed in the
`
`905N900A adhesive bilayer. (JTX 41, pp. 1-2). The amount ofBHT in the 905A layer under
`
`those two scenarios is 0.036 and 0.023 percent by weight, respectively. (Id., p. 2; Tr. 113:15-
`
`120:6). In response to criticism from Dr. Sessler, Dr. Davies repeated his experiments using
`
`high performance liquid chromatography and ultraviolet spectroscopy. (Tr. 329: 13-330:8).
`
`These additional tests showed "excellent agreement" with the gas chromatography results and
`
`confirmed his earlier findings. (Id. at 330:4-14; JTX 51).
`
`In addition to Dr. Sessler' s criticism, Watson advances several other arguments in
`
`support of its non-infringement position. Watson points out that "BHT is not identified in any of
`
`Watson's product development reports for the formulation used in Watson's ANDA product, and
`
`BHT is not mentioned anywhere in Watson's ANDA." (D.I. 318, p. 6). The fact that those
`
`reports did not detect and quantify BHT does not mean no BHT is present. Novartis has shown,
`
`7 Dr. Davies was not able to measure the diffusion ofBHT experimentally because the BHT level is below the
`instrument's limit of detection. (Tr. 328:10-16). Nonetheless, there are several reasons to believe that BHT will
`diffuse. First, there is no barrier to diffusion between the 905A and 900A adhesive layers. Second, Dr. Davies
`experimentally confirmed that rivastigmine diffuses through the bilayer. Third, BHT is a smaller molecule than
`rivastigmine which, generally speaking, means it will more readily diffuse. (Tr. 121 :17-122:22).
`8 The adhesive bilayer is a highly diffusible system, allowing the rivastigmine to travel from the 905A layer through
`the 900A layer and into the patient's skin. (Tr. 323:15-324:7). Dr. Davies confirmed the diffusion ofrivastigmine
`experimentally through Raman spectroscopy. (Tr. 323: 15-329:3; JTX 38).
`
`9
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`Case 1:11-cv-01077-RGA Document 414 Filed 06/18/14 Page 13 of 44 PageID #: 13288
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`and Watson now appears to admit (id., p. 6 n.2), that Watson's ANDA products contain BHT.
`
`How the BHT entered Watson's product and why previous reports did not quantify the amount
`
`ofBHT is irrelevant for purposes of infringement. Watson also asserts that Novartis should have
`
`conducted additional testing for "BHT daughter products" to prove that the BHT in Watson's
`
`ANDA product actually functioned as an antioxidant. (Id., pp. 29-30). This line of testing is not
`
`necessary because, as discussed above, the presence claims do not add a functional limitation
`
`vis-a-vis the antioxidant.
`
`In summary, the amount of BHT, a known antioxidant, present in both scenarios
`
`evaluated by Dr. Davies falls within the amount required in the asserted claims. Watson does not
`
`dispute that its ANDA product meets the other claim limitations. (D.I. 310, p. 30). Therefore,
`
`Novartis has proven by a preponderance of the evidence that Watson's ANDA product infringes
`
`the presence claims of the patents in suit.
`
`2. The Function Claims
`
`As explained by the Federal Circuit, patentees are permitted to prove infringement by
`
`"any method of analysis that is probative of the fact of infringement, and circumstantial evidence
`
`may be sufficient." Martek Biosciences Corp., 579 F.3d at 1372-73 (internal citation omitted)
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`(finding combination of testing and scientific literature sufficient to prove infringement).
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`According to Watson, Novartis must establish the following three elements to prove
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`infringement of the function claims: "(1) rivastigmine oxidatively degrades in Watson's product;
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`(2) BHT is significantly reducing the oxidative degradation of rivastigmine in Watson's product;
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`and (3) the significant reduction of the oxidative degradation of rivastigmine occurs over a
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`prolonged period of time." (D.I. 318, p. 13). Here, Novartis has proven that free radical
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`generators create an oxidative environment, that Watson's ANDA products contain three known
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`free radical generators, and that rivastigmine is susceptible to oxidative degradation in the
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`presence of those free radical generators. Despite this oxidative environment, the rivastigrnine in
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`Watson's ANDA products undergoes only minimal oxidative degradation over a prolonged
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`period of time. The most logical conclusion is that the BHT in Watson's ANDA products acts as
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`an antioxidant by scavenging free radicals, thereby protecting rivastigrnine from oxidative
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`degradation.
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`a. Watson's ANDA product is an oxidizing environment
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`Watson's ANDA product is manufactured and stored in an oxidative environment.
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`Oxidative degradation is a type of chemical reaction, caused by the presence of free radicals,
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`"where the substance that is oxidized loses an electron to another substance that is called an
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`oxidant." (Tr. 134:22-135:9). Free radicals are a highly reactive species due to their free or
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`unpaired electrons. (Id. at 135: 15-19). Species with paired electrons are more stable, so free
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`radicals take electrons from other molecules to pair their free electrons. (Id. at 135:20-24).
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`Oxygen, peroxides, and other free radical generators, which include residual monomers, are three
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`common sources of free radicals. (Id. at 136:14-137:12). Importantly, chain reactions do not
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`require large quantities of free radicals. (See, e.g., JTX 188, p. 1507 ("Only a very small amount
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`of oxygen is required to initiate a chain reaction."); Tr. 136:22-137:4). Watson's ANDA product
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`is exposed to all three categories of free radical generators, which creates an oxidative
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`environment. The presence of each free radical generator will be discussed in turn.
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`Every step of Watson's manufacturing process is carried out in the presence of air, which
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`contains oxygen. Rivastigrnine is mixed with the 905A adhesive in ambient air, the 905A
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`casting solution is passed through a filter in ambient air, the 905A casting solution is coated onto
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`the release liner in ambient air, the 905A-coated release liner is dried in the presence of "filtered
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`and heated air," the backing layer is laminated onto the 905A adhesive in ambient air, the 900A
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`casting solution is coated onto the release liner in ambient air, the 900A-coated release liner is
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`dried in the presence of "filtered and heated air," and the 900A and 905A adhesive layers are
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`laminated together in ambient air. (JTX 56, pp. 1832-37). The individual product patches are
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`also cut and pouched in ambient air. (Id.). Indeed, Dr. Sessler acknowledged during cross(cid:173)
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`examination that the external environment for each step of the manufacturing process occurs in
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`ambient air. (Tr. 513:4-518:19). It should come as no surprise, therefore, that Dr. Davies found
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`the presence of oxygen inside the pouch containing Watson's ANDA product in a concentration
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`comparable to that of ambient air. (JTX 54, p. 2; Tr. 339:22-330:14).
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`Watson raises two counterarguments questioning whether the manufacturing process's
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`environment is indicative of the oxygen levels in the ANDA product itself. First, Dr. Sessler
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`emphasized that pressurized nitrogen is used to extrude the 905A and 900A adhesive solutions
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`onto the release liners, thereby forming a "nitrogen-saturated solution." (Tr. 514:10-515:21).
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`Although the nitrogen gas does not stay in the adhesive layer, Dr. Sessler testified that he
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`believed "a blanket of vapor and nitrogen" would form around the adhesive and protect it from
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`oxygen molecules. (Id. at 453:2-23). Dr. Sessler did not provide any support for this argument
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`other than the general scientific principle that gas solubility decreases at higher temperature,
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`which would lead to the "out gassing" of nitrogen from the adhesive. (Id.). Even if Dr. Sessler
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`was correct in his hypothesis about the nitrogen blanket, the nitrogen blanket would only protect
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`the adhesive from oxygen for the steps following extrusion. There would be no nitrogen blanket
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`for any of the previous steps, each of which was conducted in the environment of ambient air.
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`Second, Watson criticized Dr. Davies for failing to determine whether oxygen is present
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`in the adhesive bilayer itself. (D.I. 318, p. 15). Dr. Davies was unable to perform direct testing
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`on the adhesive bilayer both because the bilayer was too thin (on the order of 90 microns thick)
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`and because placing the needle into the bilayer would block the sensor. (Tr. 351: 11-22).
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`Novartis did, however, link the oxygen concentration in the pouch to the oxygen concentration in
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`the adhesive bilayer. The backing layer used in Watson's ANDA product is described by the
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`manufacturer as having "high oxygen transmission rates." (JTX 24, p. 2652; Tr. 165:7-15). Dr.
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`Klibanov, another Novartis expert, testified that the oxygen present in the pouch will "readily
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`penetra[te]" the backing film and enter Watson's ANDA product. (Tr. 165:7-166:15). Indeed,
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`Dr. Sessler agreed that these transdermal patches are designed for air to permeate the patch to
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`enhance skin health, which requires that the backing layer allow for the diffusion of oxygen. (Id.
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`at 522:13-22). Therefore, it is a logical conclusion that the gases in the pouch, which include
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`oxygen, will enter into Watson's ANDA product.
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`Watson's ANDA products also contain peroxides. The peroxide value, or peroxide
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`number, test is a well-known method for detecting peroxides. U.S. Patent No. 6,699,498, 2:58-
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`62 ("the '498 patent") ("The peroxide content is commonly expressed by means of the so-called
`
`peroxide number."). As described in the U.S. Pharmacopeia, the test "expresses, in
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`milliequivalents of active oxygen, the quantity of peroxide contained in 1000 g of the substance."
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`(JTX 47, p. 152). Using this standard experiment, Dr. Davies tested samples of both the 900A
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`and 905A bulk adhesives and found the presence of peroxides. (JTX 53, p. 2 (noting peroxide
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`values of 1.64 and 1.89 for the 900A adhesive and 0. 72 and 1.07 for the 905A adhesive); Tr.
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`353:17-354:20). In addition to Dr. Davies's testing, Novartis relies on two documents from
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`Henkel, Watson's adhesive manufacturer, showing that peroxides are used in the manufacture of
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`the adhesive and might remain after manufacturing is complete. Henkel lists t(cid:173)
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`amylperoxypivalate ("TAPP"), a known peroxide, as an ingredient in the 900A adhesive whose
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`purpose is to scavenge residual monomers. (JTX 23, p. 1; Tr. 174:13-175:5). Moreover, a
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`Henkel employee informed Watson in an email that the 900A adhesive "contains trace amount[ s]
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`of residual initiator, which is a peroxide" when Watson inquired about the 900A components.
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`(JTX 32, p. 285088).
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`Watson offers three arguments in rebuttal. First, Watson contends that the peroxide test
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`used by Dr. Davies does not measure for peroxides. (DJ. 318, p. 17). Watson is technically
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`correct because the peroxide test actually measures the extent to which iodide ions can be
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`oxidized to iodine. However, as Dr. Klibanov explained, the test is conducted under conditions
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`where the measured oxidation is attributable to the presence of peroxides. (Tr. 286:3-287:4 ("Q.
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`So it's a bit of a misnomer to say [the peroxide value test] measures peroxide. It is not directed
`
`