ANDREWS, U.S. DISTRICT JUDGE:
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.
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:
(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.
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
'031 patent, claim 1. In the claim language "Compound A" refers to rivastigmine, the "S" enantiomer of the racemic compound RA
The requirements of claim 11 are as follows:
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:
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:
'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,
Id., claim 7.
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 conducted by Novartis's experts does not prove that Watson's ANDA product is an oxidative environment or that it contains a functioning antioxidant.
"Under [35 U.S.C.] § 271(e)(2)(A), a court must determine whether, if the 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.
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.
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.
Butylhydroxytoluene, or BHT, is well known in the art as an antioxidant. (DTX
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 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 of rivastigmine 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 905A/900A adhesive bilayer and measured 0.027 percent BHT. (JTX 41, p. 2; JTX 36). Using these result, Dr. Davies calculated
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.
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) (finding combination of testing and scientific literature sufficient to prove infringement). According to Watson, Novartis must establish the following three elements to prove infringement of the function claims: "(1) rivastigmine oxidatively degrades in Watson's product; (2) BHT is significantly reducing the oxidative degradation of rivastigmine in Watson's product; and (3) the significant reduction of the oxidative degradation of rivastigmine occurs over a prolonged period of time." (D.I.318, p. 13). Here, Novartis has proven that free radical generators create an oxidative environment, that Watson's ANDA products contain three known free radical generators, and that rivastigmine is susceptible to oxidative degradation in the presence of those free radical generators. Despite this oxidative environment, the rivastigmine in Watson's ANDA products undergoes only minimal oxidative degradation over a prolonged period of time. The most logical conclusion is that the BHT in Watson's ANDA products acts as an antioxidant by scavenging free radicals, thereby protecting rivastigmine from oxidative degradation.
Watson's ANDA product is manufactured and stored in an oxidative environment. Oxidative degradation is a type of chemical reaction, caused by the presence of free radicals, "where the substance that is oxidized loses an electron to another substance that is called an oxidant." (Tr. 134:22-135:9). Free radicals are a highly reactive species due to their free or unpaired electrons. (Id. at 135:15-19). Species with paired electrons are more stable, so free radicals take electrons from other molecules to pair their free electrons. (Id. at 135:20-24). Oxygen, peroxides, and other free radical generators, which include residual monomers, are three common sources of free radicals. (Id. at 136:14-137:12). Importantly, chain reactions
Every step of Watson's manufacturing process is carried out in the presence of air, which contains oxygen. Rivastigmine is mixed with the 905A adhesive in ambient air, the 905A casting solution is passed through a filter in ambient air, the 905A casting solution is coated onto the release liner in ambient air, the 905 A-coated release liner is dried in the presence of "filtered and heated air," the backing layer is laminated onto the 905A adhesive in ambient air, the 900A casting solution is coated onto the release liner in ambient air, the 900A-coated release liner is dried in the presence of "filtered and heated air," and the 900A and 905A adhesive layers are laminated together in ambient air. (JTX 56, pp. 1832-37). The individual product patches are also cut and pouched in ambient air. (Id.). Indeed, Dr. Sessler acknowledged during cross-examination that the external environment for each step of the manufacturing process occurs in ambient air. (Tr. 513:4-518:19). It should come as no surprise, therefore, that Dr. Davies found the presence of oxygen inside the pouch containing Watson's ANDA product in a concentration comparable to that of ambient air. (JTX 54, p. 2; Tr. 339:22-330:14).
Watson raises two counterarguments questioning whether the manufacturing process's environment is indicative of the oxygen levels in the ANDA product itself. First, Dr. Sessler emphasized that pressurized nitrogen is used to extrude the 905A and 900A adhesive solutions onto the release liners, thereby forming a "nitrogen-saturated solution." (Tr. 514:10-515:21). Although the nitrogen gas does not stay in the adhesive layer, Dr. Sessler testified that he believed "a blanket of vapor and nitrogen" would form around the adhesive and protect it from oxygen molecules. (Id. at 453:2-23). Dr. Sessler did not provide any support for this argument other than the general scientific principle that gas solubility decreases at higher temperature, which would lead to the "out gassing" of nitrogen from the adhesive. (Id.). Even if Dr. Sessler was correct in his hypothesis about the nitrogen blanket, the nitrogen blanket would only protect the adhesive from oxygen for the steps following extrusion. There would be no nitrogen blanket for any of the previous steps, each of which was conducted in the environment of ambient air.
Second, Watson criticized Dr. Davies for failing to determine whether oxygen is present in the adhesive bilayer itself. (D.I.318, p. 15). Dr. Davies was unable to perform direct testing on the adhesive bilayer both because the bilayer was too thin (on the order of 90 microns thick) and because placing the needle into the bilayer would block the sensor. (Tr. 351:11-22). Novartis did, however, link the oxygen concentration in the pouch to the oxygen concentration in the adhesive bilayer. The backing layer used in Watson's ANDA product is described by the manufacturer as having "high oxygen transmission rates." (JTX 24, p. 2652; Tr. 165:7-15). Dr. Klibanov, another Novartis expert, testified that the oxygen present in the pouch will "readily penetra[te]" the backing film and enter Watson's ANDA product. (Tr. 165:7-166:15). Indeed, Dr. Sessler agreed that these transdermal patches are designed for air to permeate the patch to enhance skin health, which requires that the backing layer allow for the diffusion of oxygen. (Id. at 522:13-22). Therefore, it
Watson's ANDA products also contain peroxides. The peroxide value, or peroxide number, test is a well-known method for detecting peroxides. U.S. Patent No. 6,699,498, 2:58-62 ("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 milliequivalents of active oxygen, the quantity of peroxide contained in 1000 g of the substance." (JTX 47, p. 152). Using this standard experiment, Dr. Davies tested samples of both the 900A and 905A bulk adhesives and found the presence of peroxides. (JTX 53, p. 2 (noting peroxide values of 1.64 and 1.89 for the 900A adhesive and 0.72 and 1.07 for the 905A adhesive); Tr. 353:17-354:20). In addition to Dr. Davies's testing, Novartis relies on two documents from Henkel, Watson's adhesive manufacturer, showing that peroxides are used in the manufacture of the adhesive and might remain after manufacturing is complete. Henkel lists t-amylperoxypivalate ("TAPP"), a known peroxide, as an ingredient in the 900A adhesive whose purpose is to scavenge residual monomers. (JTX 23, p. 1; Tr. 174:13-175:5). Moreover, a Henkel employee informed Watson in an email that the 900A adhesive "contains trace amount[s] of residual initiator, which is a peroxide" when Watson inquired about the 900A components. (JTX 32, p. 285088).
Watson offers three arguments in rebuttal. First, Watson contends that the peroxide test used by Dr. Davies does not measure for peroxides. (D.I.318, p. 17). Watson is technically correct because the peroxide test actually measures the extent to which iodide ions can be oxidized to iodine. However, as Dr. Klibanov explained, the test is conducted under conditions where the measured oxidation is attributable to the presence of peroxides. (Tr. 286:3-287:4 ("Q. So it's a bit of a misnomer to say [the peroxide value test] measures peroxide. It is not directed to peroxides; correct? A. No. I disagree with that. Q. All right. Well, you wouldn't disagree that what it actually measures is the extent to which iodide is oxidized to iodine? A. Yes, but it's done under the conditions where what you measure is a peroxide. That's the test that is described by the United States Pharmacopeia specifically to determine peroxide oxidation number.")). Watson believes this is problematic because there are numerous substances other than peroxides that can oxidize iodide to iodine but that are incapable of oxidizing rivastigmine. (D.I. 318, p. 17; Tr. 429:22-430:16). Despite flagging this as a potential issue, neither Dr. Sessler in his trial testimony, nor Watson in its post-trial briefing, offered any scientific literature in support of its position that this test was applied improperly. Watson's unsubstantiated argument is not persuasive in light of the U.S. Pharmacopeia and a U.S. patent on transdermal devices that both list the peroxide value test as a standard method for determining the quantity of peroxides. (JTX 47, p. 152; '498 patent, 2:58-62; see also Tr. 354:7-11).
Second, Watson asserts the tests Dr. Davies conducted on the samples of bulk 900A and 905A adhesive have no bearing on the peroxide level in Watson's ANDA product. (D.I.318, p. 17). This, too, is unpersuasive because Dr. Davies explained that testing the adhesives themselves prior to their inclusion in the transdermal device is the standard approach. (Tr. 354:21-355:15). Dr. Sessler agreed on cross examination that the method used by Dr. Davies is taught in the '498 patent, which addresses transdermal systems. (Tr.
Finally, Watson disagrees over the import of the Henkel documents cited by Novartis. The fact that Henkel uses TAPP in the manufacturing process proves nothing, according to Watson, because TAPP is used as a monomer scavenger. (D.I.318, p. 20). Monomer scavengers are consumed during the manufacturing process so Watson posits there is no reason to believe that TAPP carries over to the ANDA product,
Residual monomers, a type of free radical generator, are present in Watson's ANDA product. Henkel's specification document for the 900A adhesive states that "residual levels of the starting monomers may be present in the final product" because polymerization "is never 100% efficient." (JTX 23, p. 1). There is a section of the specification titled "Residual Monomers" that lists the maximum specified limits for each monomer that can be present. (Id.). Some of these limits for the individual monomers are as high as 700 ppm, and if all listed monomers were present in their maximum specified amounts it would exceed 1500 ppm. (Id.). Another Henkel document, the certificate of analysis, lists what is actually present in the product, as opposed to the specification which denotes what is permitted in the product. (Tr. 182:3-13). The certificate of analysis for the 900A adhesive identified the presence of four residual monomers at a combined concentration of 606 ppm. (JTX 186, p. 2644; Tr. 182:3-184:12; see also JTX 30, p. 279745 (reporting 388 ppm of residual monomers in a different batch of 900A adhesive)).
Watson does not substantively dispute that residual monomers are present in its ANDA products. Instead, Watson contends the amount of residual monomers is
Novartis also alleges that polymerization initiators are present in Watson's ANDA product. Polymerization initiators are used in the manufacture of polymers, such as the 900A adhesive, and are capable of creating an oxidative environment. (JTX 23, p. 1; Tr. 421:7-19). According to Novartis, the "3M Patent Application shows that, in the absence of washing, residual initiator carries through to the final patches." (D.I. 322, p. 10; see also JTX 17, p. 7 ("Such polymerization reactions result in the formation of a polymer along with some level of unreacted monomers and initiator.")). This argument is not persuasive.
In sum, an oxidizing environment can be created by the presence of oxygen, peroxides, or other free radical generators. In this case, all three types of free radical generators can be found in Watson's ANDA products. Ambient air is not excluded from the manufacturing environment for Watson's ANDA products and was found to be present inside Watson's pouches. Dr. Davies tested the 900A and 905A adhesives and found peroxides, which Dr. Klibanov explained would be carried forward into Watson's ANDA product because no steps were taken to remove these impurities. Similarly, the documentation provided by Henkel shows that residual monomers are present in the 900A adhesive and are not removed prior to the assembly of Watson's ANDA product. The presence of these three free radical
There is no dispute that rivastigmine is susceptible to degradation depending on the particular environment to which it is exposed. (Tr. 522:23-523:3). As discussed above, the environment for Watson's ANDA product contains oxygen, peroxides, and residual monomers. The question becomes whether these substances can oxidatively degrade rivastigmine. The answer to that question is yes, based on the evidence Novartis put forth regarding the individual and collective effects of oxygen, peroxides, and residual monomers on rivastigmine. Each free radical generator's effect on rivastigmine will be discussed in turn.
Rivastigmine oxidatively degrades in the presence of oxygen. The patents in suit teach that rivastigmine in a transdermal device will degrade if exposed to oxygen despite "the formation of an occlusive polymer matrix around compound A [rivastigmine] and its storage in air-tight packaging." '031 patent, 1:22-28 ("It has now been found after exhaustive testing that compound A is susceptible to degradation, particularly in the presence of oxygen."). Novartis's experiments also showed that oxygen caused degradation to rivastigmine in its bulk form. (JTX 85, p. 2403 ("Rivastigmine base as liquid is very sensitive to oxygen (air) and moisture. Degradation is accelerated by the influence of heat.")). Indeed, Watson's own documents acknowledge oxygen's effects on rivastigmine. (JTX 29, p. 29808 ("Rivastigmine is subject to both hydrolytic and oxidative degradation.")).
Watson relies on a two-prong argument articulated by Dr. Sessler: "[F]or oxidative degradation to occur, oxygen must have both the `power' to oxidize rivastigmine and must be present in a sufficient `amount.'" (D.I.318, p. 15). With respect to the first point, Dr. Sessler explained that molecular oxygen alone is insufficient to oxidatively degrade rivastigmine; instead, oxygen must react with another substance, such as a metal ion, to form a reactive oxygen species. (Tr. 443:1-23; id. at 420:1-24). Watson alleges that Novartis's failure to test for these other substances results in a failure to prove oxidative power. (D.I.318, p. 15). Second, the amount of oxygen is important because of its role in the oxidation. Oxygen is not just an initiator; it is consumed in the reaction and incorporated into the ketone degradation product. Watson claims to use pressurized nitrogen gas to extrude the adhesives and a roller to squeeze all of the air from its pouches prior to sealing,
Dr. Sessler's concerns about oxygen's power to oxidize rivastigmine are overstated. Regardless of whether oxygen is labeled as a "strong" or "weak" oxidant in the organic environment, the need to protect the active substance in a transdermal patch from oxygen is well documented in the literature. ('031 patent, 1:22-28; '498 patent, 1:44-47 ("[T]he stability of the
Watson's second argument also misses the mark because the steps Watson took to eliminate air from its ANDA product were verifiably ineffective. There was a large enough volume of gas inside Watson's pouch to form a visible bubble when Dr. Davies rolled up the patch. (Id. at 340:15-341:21). Dr. Davies tested this gas with an oxygen meter and found the presence of oxygen in a concentration similar to that of ambient air. (JTX 54, p. 2; Tr. 340:8-14). It is highly probable the oxygen in the pouch will enter Watson's ANDA product because the patch was designed to be breathable. (Tr. 522:13-22). This is affirmed by Watson's acceleration lifetime studies, which prove that the amount of oxygen in the pouch is sufficient to oxidize rivastigmine because the ketone degradant is detected after 12 weeks of storage under normal conditions.
Peroxides are also capable of oxidatively degrading rivastigmine, but most likely not at the levels measured by Dr. Davies. In order to reduce oxidative degradation, the '498 patent teaches that "an upper peroxide number limit of 20, better still 10, preferably 5, should not be exceeded." '498 patent, 7:16-17. Dr. Davies measured peroxide values of less than 2 in Watson's ANDA product (JTX 53, p. 2), which is well within what Watson describes as the "safe zone" taught by the '498 patent. (D.I.318, p. 19). Novartis responds by pointing to a different section of the '498 patent's specification that states "[a]n additional improvement in stability may be achieved by the addition of antioxidants," even if "the materials are virtually free from peroxides." '498 patent, 7:8-12. Given the diverging opinions from two highly qualified experts (Compare Tr. 189:23-190:13, with Tr. 429:22-430:21), this issue turns on their respective credibility as
The fact that the peroxides, by themselves, likely are not present in sufficient quantities to cause oxidative degradation does not end the inquiry. As Dr. Klibanov noted, all three of the free radical generators discussed can create an oxidative environment that will lead to the oxidative degradation of rivastigmine. (Tr. 189:23-190:13). Peroxides can also react with oxygen and residual monomers to form activated oxygen and monomer radicals, both of which can also degrade rivastigmine. The low level of peroxides, therefore, does not alter the Court's view that rivastigmine is susceptible to degradation in Watson's ANDA product.
Finally, residual monomers, when present with other impurities known to exist in Watson's ANDA product, have the power to oxidize rivastigmine. Dr. Sessler stated this himself. (Tr. 458:10-23). As shown above, residual monomers are present in the 900A adhesive and also in Watson's ANDA product. Watson responds by arguing that the concentration of residual monomers is not sufficient to cause oxidative degradation. (D.I.318, pp. 21-22). The 3M patent application, relied on by both parties, states, "The polymerization reaction product is washed such that the at least two ethylenically unsaturated monomers, if present in the adhesive as unreacted monomers after washing, are reduce[d] to a level of less than 200 ppm of total unreacted monomer, based upon the total weight of the adhesive." (JTX 17, p. 6). The 900A adhesive, which contained 388 and 606 ppm residual monomers in the two certificates of analysis (JTX 186, p. 2644; JTX 30, p. 279745), represents only 34.7% of the total weight of the adhesive. (JTX 56, p. 1823). When the residual monomer concentration is adjusted based on the weight of the total adhesive, as taught in the 3M patent application, the resulting concentrations in the adhesive bilayer are 134 and 210 ppm, respectively.
It is true that the 3M patent application suggests it is desirable to achieve less than 200 ppm of residual monomer by washing the polymerization reaction product. (JTX 17, p. 6). Although it recognizes that some embodiments may be stable after the washing process without the need to add an antioxidant, other embodiments will simply require a lesser amount of antioxidant to attain stability. (Id.). The need for an antioxidant is demonstrated by 3M's own experiments showing 0.95% oxidative degradation of rivastigmine occurred after two months at 60°C in a copolymer with no antioxidant, despite having a residual monomer concentration below the detection limit. (Id., pp. 20-22; D.I. 322, pp. 9-10). Although the parties disagree on whether the level of residual monomers in Watson's ANDA product is sufficient to oxidatively degrade rivastigmine, the Court finds Novartis's position to be more credible.
It is clear that rivastigmine is subject to oxidative degradation in the presence of
Watson's ANDA states that its products exhibit only a "low level of impurities and degradation products" when subjected to stress tests designed to predict degradation over a prolonged period of time. (JTX 56, p. 1826; Tr. 698:24-699:9). Based on its choices of excipients, Watson expected its ANDA product to maintain stability throughout the intended shelf life. (Id.). Watson's ANDA product also contains BHT. Dr. Kibbe, Watson's obviousness expert, admitted that the concentration of BHT claimed in the patents, and present in Watson's ANDA products, falls within what is "typically used in most pharmaceutical formulations." (Tr. 629:11-24; see also DTX 11, p. 47 (listing typical BHT concentrations for various uses)). This belies Watson's contention that "Plaintiffs have not presented any evidence that the small amounts of BHT at the levels detected by Dr. Davies could reduce oxidative degradation of rivastigmine in any formulation, much less in the environment of Watson's ANDA product." (D.I.318, pp. 6-7). Dr. Klibanov offered the following explanation for the low level of degradation:
(Tr. 197:10-198:5).
Watson criticizes Dr. Klibanov's analysis for incorrectly assuming that using an antioxidant and excluding oxygen are the only ways to prevent oxidative degradation in a transdermal product. (D.I.318, p. 24). For example, Watson points to the '498 patent as evidence that the risk of oxidative degradation can be avoided by keeping
Watson relies on the patents in suit for the proposition that trace amounts of free radicals will not negatively affect rivastigmine's stability. '031 patent, 1:44-46 ("The diluent or carrier may contain trace amounts of free radicals without affecting the stability of the pharmaceutical composition."). It follows, according to Watson, that "the presence of some amount of free radicals in a transdermal system does not necessarily lead to an oxidative degradation problem." (D.I.318, p. 24). The Court disagrees. The patents in suit contain an antioxidant, which assists in preventing oxidative degradation. It is more reasonable to conclude that the antioxidant shields rivastigmine from the free radicals' harmful effects than to conclude that free radicals do not create an oxidative environment. See '031 patent, 1:34-36.
Watson also asserts that Novartis should have performed additional testing. (D.I.318, pp. 27-30). This argument is unavailing. The testing and other experimental data Novartis presented are sufficient to prove infringement by a preponderance of the evidence.
Watson's final argument is that Dr. Sessler's "footprint" hypothesis disproves Novartis's theory that BHT is acting as an antioxidant in Watson's ANDA product. Dr. Sessler posits that an antioxidant leaves a characteristic "footprint" involving the ratio of the degradants. According to the theory, rivastigmine degradation results in two main degradants, a styrene degradant and a ketone degradant, in approximately a 1:1 ratio. The styrene degradant forms first, and it can subsequently be oxidized to form the ketone degradant if an oxygen atom source is present. Unlike the styrene degradant, which can be formed via a non-oxidative pathway, the ketone degradant can only be formed through oxidation and consumes an oxygen atom in the process. The presence of an antioxidant will disrupt the oxidation reaction, blocking the ketone degradant's formation in the process. Therefore, the theory predicts the presence of a functioning antioxidant will result in more styrene degradant relative to the ketone degradant. (D.I. 318, p. 25 (citing various portions of Dr. Sessler's trial testimony)).
No experimentation was done to validate the theory,
Even if the "footprint" theory holds, however, its application to Watson's long-term stability test appears to be consistent with the presence of an antioxidant. The presence of an antioxidant, according to the theory, will result in a greater amount of styrene degradant than ketone degradant. In long-term stability testing done on Watson's ANDA product, the styrene and ketone degradant appeared in a 3:2 ratio. (JTX 195, p. 78375 (measuring approximately 0.03% styrene to 0.02% ketone by weight at time points between 26 and 78 weeks)). This is entirely consistent with Novartis's contention that Watson's ANDA product contains an acting antioxidant, namely BHT. Dr. Sessler viewed this study's results differently, contending that the reported weight percentages were at the limits of precision. (Tr. 490:5-24). Because the numbers were so small, Dr. Sessler concluded the ratio at each time point was essentially 1:1 and that no antioxidant was present in the system. (Id. at 490:5-491:4). Without knowing the margin of error in the measurements it is impossible to tell with statistical certainty whether a ratio of 0.03:0.02 is really a 1:1 ratio. But three data points taken after 78 weeks were measured out to the thousandths decimal place and resulted in ratios of 0.029:0.021, 0.030:0.019, and 0.030:0.021. (JTX 195, p. 78375). All three figures after the decimal point are significant in each of those measurements, making it more likely that it is a 3:2 ratio. At the very least, based on the number of significant figures, the Court is not convinced they represent 1:1 ratios, as Dr. Sessler urges.
In sum, the Court reaches the same logical conclusion as Dr. Klibanov did. Rivastigmine, which is susceptible to oxidative degradation, and BHT, an antioxidant, are placed in a demonstrably oxidative environment, yet no significant degradation is observed over a prolonged period of time. The most likely explanation, and an explanation that Novartis has proven by a preponderance of the evidence, is that BHT is acting as an antioxidant to protect rivastigmine from oxidative degradation over a prolonged period of time.
Watson asserts claims 2 and 7 of the '023 patent and claims 3, 7, 13, 16, and 18 of the '031 patent are invalid because the addition of an antioxidant to a rivastigmine transdermal patch would have been obvious to a person having ordinary skill in the art ("PHOSITA") in January 1998-the priority date. (D.I. 311, pp. 2-5; Tr. 34:6-8). This argument is premised on three major pieces of prior art. The first piece of prior art is a British patent application, GB 2
Novartis counters that Watson failed to show by clear and convincing evidence that: a PHOSITA would have chosen GB '040's rivastigmine transdermal formulation as a starting point, rivastigmine was known in the art to be susceptible to oxidative degradation, and the use of an antioxidant would have been a predictable solution to rivastigmine's oxidative degradation problem. (D.I.317, p. 7).
The obviousness inquiry must be conducted from the PHOSITA's point of view. The parties agree the PHOSITA has an advanced degree in pharmaceutics, chemistry, pharmaceutical chemistry, materials engineering, or the like, and at least two years of experience developing pharmaceutical formulations. A PHOSITA could also possess a Bachelor's or Master's degree, provided the PHOSITA has practical experience working in the industry, or academia, for a longer period of time. (Tr. 589:1-590:3; id. at 817:13-818:21).
The presumption that all patents are valid is the starting point for any obviousness determination. 35 U.S.C. § 282 (2012). Under § 103(a), a patent "may not be obtained ... if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art." Id. § 103(a). Obviousness is a question of law that depends on the following factual inquiries: (1) the scope and content of the prior art; (2) the differences between the claims and the prior art; (3) the level of ordinary skill in the relevant art; and (4) any objective considerations such as commercial success, long felt but unsolved need, and the failure of others. See Transocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling USA, Inc., 699 F.3d 1340, 1347 (Fed.Cir.2012). The improvement over the prior art must be "more than the predictable use of prior art elements according to their established functions." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 417, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007).
To prove obviousness, Watson must show that a PHOSITA would be motivated to combine the claimed combinations with a reasonable expectation of success. Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286, 1291 (Fed.Cir.2013). Evidence of obviousness, especially when that evidence is proffered
Watson contends a PHOSITA would have been motivated to develop a rivastigmine transdermal patch based on the teachings of GB '040, the closest piece of prior art to the patents in suit. GB '040 documents rivastigmine's efficacy in the treatment of Alzheimer's disease, and discloses therapeutic benefits that can be obtained through the use of a transdermal formulation. The '807 patent and the Elmalem article disclose the combination of RA
This argument is a logical one, but it overstates the teachings contained in these prior art references. Neither the '807 patent nor the Elmalem article teach a PHOSITA that rivastigmine is susceptible to oxidative degradation. These references certainly disclose that an antioxidant can be added to RA
As discussed briefly above, GB '040 discloses many limitations of the claims at issue. It discusses both the free base and acid addition salt forms of rivastigmine (JTX 97, pp. 281396-97) and recognizes rivastigmine's ability for "marked and selective inhibition of the acetylcholinesterase" (id., p. 281397), which makes it useful for the treatment of Alzheimer's disease. (Id., p. 281395). GB '040 also acknowledges some advantageous aspects of transdermal delivery
A PHOSITA would not have been motivated to include an antioxidant in any formulation unless there was evidence of oxidative degradation. Excipients, including antioxidants, are inactive ingredients of a pharmaceutical composition that are added to ensure the drug performs its function in a desirable fashion. (Id. at 836:22-837:18). The excipients themselves offer no therapeutic benefit. (Id. at 837:11-18). In fact, excipients can be incompatible with the drug or other excipients in the pharmaceutical composition, which could lead to a deleterious effect on the drug's performance. (Id. at 838:22-840:12 (quoting JTX 188, p. 1507)). The compatibility of an excipient with a given pharmaceutical composition cannot be predicted without experimentation because of the numerous possible chemical reactions. (Id. at 841:21-842:3). For this reason, the European Agency for the Evaluation of Medicinal Products — the FDA's European equivalent — instructed, "Antioxidants should only be included in a formulation if it has been proved that their use cannot be avoided." (JTX 105, p. 2).
Moreover, oxidative degradation is not the only degradation pathway; there were many known types of degradation at the time of the invention. These include hydrolysis, reduction, racemization, photolysis, and pyrolysis. (Tr. 812:10-17; id. at 825:21-826:9). But not every drug in every formulation is susceptible to all types of degradation, and, due to the risk of incompatibility discussed above, a PHOSITA would not have added an excipient to prevent each of these types of degradation. A PHOSITA would only be motivated to address and correct known degradation problems. (Id. at 811:19-812:9). Because GB '040 was silent with respect to rivastigmine's instability, this motivation would have had to come from some other prior art reference.
Although the '807 patent does disclose the addition of an antioxidant to RA
At first glance, this statement appears to support the proposition for which Watson cited it: namely, that it teaches a PHOSITA that RA
The Elmalem article also fails to teach a PHOSITA of rivastigmine's susceptibility to oxidative degradation. Elmalem compares the effects of three phenyl carbamate compounds with physostigmine on the morphine-induced respiratory depression in rabbits. (JTX 159, p. 1059). One of the phenyl carbamate drugs tested was RA
Novartis's interpretation of this passage is more nuanced and decisively divergent. According to Dr. Klibanov, the Elmalem article reports the findings of a well-controlled experiment, i.e., one in which any variability that can be eliminated is eliminated. The stated purpose of the Elmalem paper was to compare the effects of three new agents with that of physostigmine. (JTX 159, p. 1059). The simplest way to conduct this experiment would be to prepare aqueous solutions of these four compounds and compare their effects when injected into rabbits. (Tr. 887:20-888:5). The problem with this experiment's design is physostigmine's well-documented lack of stability in aqueous solution. ('807 patent, 1:32-34 ("[Physostigmine] is chemically unstable and must be prepared in solution with an antioxidant, and protected from light."); JTX 148, p. 1266 ("Physostigmine is not stable in aqueous solution."); JTX 159, p. 1059 (recognizing physostigmine's "low chemical stability" as a serious disadvantage); Tr. 888:6-9). The instability can be remedied by adding an antioxidant to the physostigmine solution. (Tr. 888:10-11). If, however, the experiment were conducted with physostigmine and an antioxidant injected into one rabbit, and the other three compounds, without an antioxidant, injected into three other rabbits, there would be no way to determine whether any observed difference in the rabbits' respiratory depression was attributable to the relative chemical activity of the drug or to the presence of the antioxidant. (Id. at 888:15-20). The authors of the Elmalem article addressed this concern by adding an antioxidant to all of the drug formulations, including the saline placebo. (Id. at 889:5-14; id. at 891:6-11). When read in this context, the statement, "All drugs were made up freshly in sterile saline, which included an equal weight of sodium metabisulphite, to prevent oxidation," is better understood as a measure to reduce variability than a teaching that RA
Watson criticizes this "tortuous interpretation" of Elmalem as an attempt to avoid its plain teaching. (D.I.323, pp. 10-11). First, Dr. Klibanov's reading of Elmalem requires both that saline be considered a drug and that an antioxidant be added to the saline as a control. (Id. at 10). Saline is not mentioned as a drug in the "Drugs" section of the paper, and it does not make sense that "[a]ll drugs were made up freshly in sterile saline" if the authors considered saline itself to be a drug. (JTX 159, p. 1060; D.I. 323, p. 10). The article summary in Elmalem, however, states, "Each drug, RA
Second, Watson contends that under Dr. Klibanov's interpretation, the methodology of Elmalem would not be reproducible because a PHOSITA would not know how much antioxidant to add to the saline solution. (D.I.323, pp. 10-11). In fact, Dr. Klibanov testified that he did not know how much antioxidant was used in any of the formulations. (Tr. 933:6-12). To Dr. Kibbe, the sentence, "drugs were made up freshly in sterile saline, which included an equal weight of sodium metabisulphite," instructs a PHOSITA to add an amount of antioxidant to each drug formulation that is equivalent to the weight of the drug in that solution. (Id. at 664:13-665:13). This tells a PHOSITA how much antioxidant to add to each formulation, but it introduces a new variable because a different amount of antioxidant would be present in each of the injectable formulations.
This second issue was hotly contested at trial. One seemingly innocuous sentence has given rise to diametrically opposed interpretations, neither of which is without its criticisms. There does not appear to be an objectively "correct" reading; rather both arguments seem logical and are supported by highly qualified experts in the field. Instead of attempting to explain scientifically why one explanation is superior to the other, the better method for resolving this dispute is based on credibility. To that end, the position advanced by Novartis better comports with the Court's understanding of Elmalem, and the Court credits Novartis's accompanying trial testimony as being more credible. Watson has not convinced the Court, by clear and convincing evidence, that Dr. Klibanov's view of the Elmalem article is incorrect. Therefore, the Court accepts Dr. Klibanov's argument on this point, and adopts it as the Court's finding of fact.
Watson also relies on U.S. Patent No. 5,580,572 ("the '572 patent") and The Handbook of Pharmaceutical Excipients, Second Edition (DTX 7) as prior art references that can be combined with GB '040 to invalidate several of the asserted claims. The '572 patent discloses a transdermal matrix system for delivering hormones. It teaches the inclusion of an antioxidant, within the concentration ranges claimed in the patents in suit, to stabilize the polymer matrix. ('572 patent, 4:47-52, 16:23; Tr. 648:18-649:18). According to Watson, this would have instructed a PHOSITA that antioxidants could be used to stabilize the polymer in a polymer matrix. (D.I.311, p. 15). The '572 patent may indeed teach a PHOSITA that, but Watson has not shown any motivation for the PHOSITA to combine GB '040 with the '572 patent. When discussing the transdermal administration of rivastigmine, GB '040 specifically cites to the hydrophilic polymers described in European Patent Application 0 155 229 ("EP '229"). (JTX 97, p. 281411). The transdermal devices in EP '229 do not suggest using an antioxidant. (JTX 109; Tr. 734:17-22). Additionally, rivastigmine is
The Handbook of Pharmaceutical Excipients provides guidance on what antioxidants are suitable for inclusion in pharmaceutical compositions and suggests typical concentration ranges for each antioxidant. (Tr. 631:5-632:21; see, e.g., DTX 7, p. 12). The Handbook discloses the antioxidants claimed in the patents in suit, in amounts that fall within the claimed concentration ranges. (Tr. 630:14-644:22). Watson asserts a PHOSITA seeking to add an antioxidant to a transdermal rivastigmine formulation would have referred to the Handbook. It is true that the Handbook discloses the antioxidants claimed, but absent a reason to believe an antioxidant was required for a rivastigmine formulation, a PHOSITA would not be motivated to consult the Handbook. Because the Court has concluded that nothing in the prior art disclosed rivastigmine's susceptibility to oxidative degradation, a PHOSITA would have no reason to combine the Handbook's teachings with any other prior art reference.
In conclusion, the obviousness determination in this case turns on whether a PHOSITA in January 1998, looking at all of the prior art, would have known rivastigmine was susceptible to oxidative degradation. If the answer is yes, the asserted claims of the '023 and '031 patents are invalid because the addition of an antioxidant to a pharmaceutical composition that oxidatively degrades is one of several known, obvious solutions. See KSR, 550 U.S. at 421, 127 S.Ct. 1727 ("When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense."). If the answer is no, then the discovery that rivastigmine oxidatively degrades and the solution to that problem are an inventive contribution worthy of patent protection. There can be no motivation to combine prior art references to solve a problem that no one knows exists. Id. at 418, 127 S.Ct. 1727 ("Although common sense directs one to look with care at a patent application that claims as innovation the combination of two known devices according to their established functions, it can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does."). Because I find that a PHOSITA would not have appreciated rivastigmine's susceptibility to oxidative degradation in January 1998, Watson has not proven obviousness by clear and convincing evidence.
Novartis proved Watson's ANDA products infringe claims 2 and 7 of the '023 patent and claims 3, 7, 13, 16, and 18 of the '031 patent by a preponderance of the evidence. Watson failed to prove by clear and convincing evidence that any of the asserted claims of the '023 or '031 patents were invalid. Novartis should submit an agreed upon form of final judgment within two weeks.
