STANLEY R. CHESLER, District Judge.
Plaintiffs Bausch Health Companies Inc., Progenics Pharmaceuticals, Inc., Salix Pharmaceuticals, Inc., and Wyeth LLC (collectively, "Plaintiffs") bring this action for patent infringement against Defendant Actavis Laboratories FL, Inc. ("Actavis.") Plaintiffs own U.S. Patent No. 8,524,276 ("the '276 patent"), which is listed in the Orange Book as protecting Plaintiffs' oral methylnaltrexone bromide tablet formulation, marketed under the brand name Relistor®. Plaintiffs complain that, by filing Abbreviated New Drug Application ("ANDA") No. 209615 with the United States Food and Drug Administration, Defendant has infringed the '276 patent. A bench trial on both infringement and Actavis' patent invalidity defenses to infringement was held for 4 days, beginning on May 6, 2019, and ending on May 9, 2019. Upon hearing the evidence presented at trial, this Court finds that Plaintiffs have proven that claim 2 is infringed, and Actavis has not proven that claims 2 and 5 of the '276 patent are invalid.
Just before trial, the parties submitted the following stipulation, which the Court entered:
MNTX is methylnaltrexone. SDS is sodium dodecyl sulfate; SLS is sodium lauryl sulfate; SDS and SLS are alternate names for the same compound. OIC is opioid-induced constipation. APC is apparent octanol/water partition coefficient. "Quaternary ammonium compounds" ("QAC") is a genus of chemical compounds of which MNTX is a species. A POSA is a person of ordinary skill in the pertinent art.
The parties stipulated to the following facts in the Final Pretrial Order ("FPO"):
28. Methylnaltrexone bromide is a pharmaceutically acceptable salt of methylnaltrexone.
29. Sodium lauryl sulfate is an amphiphilic pharmaceutically acceptable excipient.
30. Sodium lauryl sulfate is a surfactant.
32. Sodium lauryl sulfate comprises a sulfate (—OSO
33. Sodium lauryl sulfate is also known as sodium dodecyl sulfate.
61. Actavis Laboratories FL, Inc. submitted to the United States Food and Drug Administration ("FDA") Abbreviated New Drug Application ("ANDA") No. 209615 seeking approval to engage in the commercial manufacture, use or sale of methylnaltrexone bromide tablets for oral use ("Actavis's ANDA No. 209615 product" or "Actavis's generic methylnaltrexone product" or the like).
70. Actavis's ANDA No. 209615 product contains 28.57% methylnaltrexone bromide by weight of the composition.
71. Actavis's ANDA No. 209615 product contains 9.73% sodium lauryl sulfate by weight of the composition.
76. Dr. Elder conducted testing intended to replicate the test method that Dr. Koleng used to determine the apparent octanol/water partition coefficient for methylnaltrexone in Actavis's ANDA No. 209615 product at a pH of about 1.1 and measured values of 0.051 and 0.053 respectively for two of Actavis's tablets from Actavis's ANDA No. 209615 exhibit batch lot number 4056R0013A.
77. Without conceding that the documents below anticipate or render obvious any of the claims of the '276 patent, the following documents are prior art, as the term prior art is defined under 35 U.S.C. § 102:
78. On April 24, 2008, the FDA approved an injectable Relistor® product, a singleuse vial containing 12 mg/0.6 mL solution for subcutaneous injection, under NDA No. 021964 for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.
What follows is selected excerpts from the testimony of the witnesses appearing in court at trial:
Dr. Koleng was qualified as an expert witness in the field of pharmaceutical formulation and drug delivery, product development and operations. (Tr. 80:5-12.) Dr. Koleng stated that the terms SDS and SLS are used interchangeably and refer to the same compound. (
In the first experiment, testing of the three exhibit batches produced APC results of .936, .944, and 1.0. (
In the second experiment, SSCI created a "tablet blend" that duplicated the composition of the Actavis tablet product, but without SLS. (
In the third experiment, SSCI used the shake-flask procedure with the Actavis exhibit batch tablets, but measured the resultant concentration of MNTX and SLS in the octanol phase. (
On cross-examination, Dr. Koleng stated that, prior to being retained by Plaintiffs, he had never used the shake-flask method to determine the APC for an active pharmaceutical ingredient within a tablet. (
Other than in this litigation, Dr. Koleng had never determined whether an ion pair had formed in a solution. (
After the examination finished, the Court asked Dr. Koleng why he concluded that the increase in APC in the first experiment was evidence of ion pairing, but he did not know about the cause of the increase in APC in the second experiment. (
Dr. Chambliss was qualified as an expert in the fields of pharmaceutical sciences and pharmaceutical formulations. Dr. Chambliss did not agree with Dr. Koleng that Actavis' ANDA product infringed claim 2. (
Dr. Chambliss said that Dr. Koleng used scientifically inappropriate comparisons when he compared the APC for MNTX alone with the APC for the Actavis tablet. (
Dr. Chambliss stated that he reviewed the testing done by Dr. Elder, who attempted to replicate SSCI's testing method at different pH levels. (
Dr. Chambliss stated that claims 2 and 5 are obvious in view of the prior art. (
Sanghvi '899 discloses methods of treating constipation with oral formulations of MNTX in all three types (immediate, delayed, extended.) (
Dr. Chambliss stated that the POSA would have understood the Accordingly Phrase
Whitehead 2007 is titled, "Safe and effective permeation enhancers," and studied 51 enhancers. (
WO '352 was published in 2008 and describes the classes of excipients that could be used with MNTX. (
As to claim 5, Dr. Chambliss stated that the subject matter would have been obvious as of March 2010, in view of 2006 Handbook, WO '352, and Sanghvi '899. (
As to claim 2, a formulator who used MNTX and SLS in a composition would expect ion pairing to occur in solution. (
On cross-examination, Dr. Chambliss stated that the prior art recognized that ion pairing was controversial, and that he would not know whether MNTX and SLS would ion pair in any formulation without doing a test. (
Heimbecher '504 does not disclose any quaternary ammonium compound or APC coefficient. (
Dr. Davies was qualified as an expert in the field of chemistry. Dr. Davies stated that SLS is a long chain, 12-carbon chain compound, and is the same as SDS. (Tr. 296:19-25.) The 12 refers to the number of carbon atoms in a straight chain. (
Dr. Davies disagreed with Dr. Chambliss' opinions regarding Heimbecher '504, which does not relate to quaternary ammonium compounds. (
A POSA who wanted to increase the lipophilicity of MNTX could have used one of a very large number of carboxylic acids and make esters from them. (
On cross-examination, Dr. Davies stated that Example 4 in the '276 patent does not state that an MNTX-lauryl sulfate salt is an ion pair; it describes a process in which that salt is put in solution and forms ion pairs. (
On redirect examination, Dr. Davies said that the concept of Galvani potential difference is not an accepted explanation for an apparent partition coefficient increase, and that he had not come across this hypothesis other than in the papers just discussed. (
Dr. Rauck was qualified as a medical expert in the field of pain management and in the treatment of the side effects of pain management, including opioid-induced constipation. Before March of 2010, both immediate release and enteric-coated forms of oral MNTX were known in the art. (
Clinical study 105 compared enterically-coated spheroids in capsules to enterically-coated tablets. (
Dr. Williams was qualified as an expert in the field of the design, evaluation, and formulation of drug products encompassing pharmaceutical formulation and pharmaceutical development. Dr. Williams stated that a POSA would understand the dissolution conditions in claim 5 to describe an immediate release tablet. (
Dr. Williams disagreed with Dr. Chambliss' opinion that a POSA would have been motivated to improve the absorption and bioavailability of oral formulations of MNTX. (
In Table 1, the van Hoogdalem reference discloses classes of enhancers for intestinal drug absorption, including SLS. (
A skilled pharmaceutical formulation scientist would be skeptical about using permeation enhancers, including SLS, in oral formulations of SLS. (
On cross-examination, Dr. Williams agreed that permeability is the ability of a drug to access an intestinal cell, and said that lipid solubility is an indicator of permeability. (
Dr. Taft was qualified as an expert in the fields of pharmaceutics (but not formulations), pharmacokinetics, and pharmacodynamics. Dr. Taft stated that "the first step for a drug to be bioavailable is it has to be able to permeate into the intestine itself." (Tr. 540:2-3.) "When I define bioavailability, I don't define it as absorption into the bloodstream." (
Yuan 1997 would not motivate the POSA to increase permeation of MNTX, because it found no correlation between effectiveness and plasma levels. (
As to the Accordingly Phrase, the POSA would understand it to reflect that the inventors "started with the prior art best-performing formulation, and unexpectedly found that it didn't work." (
There were experiments in the prior art that were designed to evaluate the effect of SLS on the absorption of quaternary ammonium compounds, and showed that SLS did not work to improve the absorption of quaternary ammonium compounds. (
Dr. Taft disagreed with Dr. Chambliss about the Whitehead 2007 reference. (
Aungst 1993 reviews potential approaches to improving bioavailability that a POSA might consider. (
Aungst 2000 states: The drug and the absorption promotor must be delivered to the absorption site simultaneously and a sufficient concentration of the absorption promoter must be achieved and maintained there. (
On cross-examination, Dr. Taft agreed that, in the prior art, Yuan 2000 Enteric was the only enteric study. (
The 1115 study clearly shows the inventors developed an effective formulation with SLS, but it was not due to increased bioavailability. (
Dr. Chambliss said that the POSA would know that in vitro studies, using the Caco-2 cell, are frequently and routinely used to determine the permeability of almost every compound. (
A POSA would consider a lauryl sulfate to be a sulfate salt. (
Generally, one would not make an enteric formulation unless one needed to, especially for a laxative, where an enteric coating would keep the tablet in the stomach for several hours before the possibility of any effect. (
Claims 2 and 5 of the '276 patent, which depend from independent claim 1, are at issue:
The '276 patent descends from provisional application No. 61/313,018, filed on March 11, 2010 (the "Critical Date.")
The Federal Circuit has summarized the fundamental principles of the law of obviousness as follows:
The parties agree on many basic facts. In the relevant art, prior to the Critical Date, MNTX was known as an opioid receptor antagonist useful as a pharmaceutical for the treatment of OIC. The "Background of the Invention" section of the '276 patent recites the following key points in the history of MNTX, which has been studied since the 1970s. '276 patent, col.1 ll.62-3. U.S. Patent No. 6,559,158 (the "'158 patent"), filed in 2000, claims use of MNTX for the treatment of OIC, including in an oral enterically-coated dosage form. The '158 specification reports a study in which intravenous administration of MNTX to patients with OIC produced immediate laxation. '158 patent, col.8 ll.52-64. The '276 specification also reports that MNTX subcutaneous injection has been clinically approved in the United States, and the specification reports that certain subcutaneous doses induced laxation within four hours in a significant number of patients treated. '276 patent, col.2 ll.19-26.
The '276 patent then summarizes a number of prior art references dealing with oral dosage forms of MNTX. U.S. Patent No. 6,419,959 (the "'959 patent") disclosed a controlledrelease oral dosage form, designed to deliver MNTX across the entire GI tract, but did not report data about the efficacy of the formulation. '276 patent, col.2 ll.27-41. U.S. Patent No. 6,274,591 (the "'591 patent") claimed a method of treating OIC by orally administering an enteric-coated MNTX dose, but did not report data about time to laxation. '276 patent, col.2 ll.42-49. The '158 patent claims, inter alia, both enterically-coated and immediate release oral dosage forms, and reported a study of the immediate release oral dosage form in which the fastest response was found in the subjects receiving the highest dose, with an average time to laxation of about five hours. '276 patent, col.2 ll.50-60.
After setting forth this background to the invention, the '276 specification states the Accordingly Phrase: "Accordingly, the need exists for bioavailable oral dosage formulations comprising methylnaltrexone." '276 patent, col.2 ll.61-62.
Because both claim 2 and claim 5 are dependent claims, and both depend on independent claim 1, to prove that either claim 2 or claim 5 is obvious requires proof that claim 1 is obvious. This Court thus begins its obviousness inquiry with claim 1, which covers the combination of MNTX and SLS in a tablet for oral administration. Actavis builds its obviousness case from the following propositions: 1) all the elements of the asserted claims were in the prior art; 2) a POSA would have been motivated to combine MNTX and SLS in a tablet, and would have had a reasonable expectation of success; and 3) Plaintiffs have not proven any secondary indicia of nonobviousness. As to claim 1, Actavis builds its case for the second proposition, regarding motivation to combine, from the following propositions: 1) MNTX was known to have poor permeability and bioavailability and SLS was known to improve both; and 2) the prior art did not teach away from the use of SLS.
The proposition that all the elements of claim 1 were in the prior art appears to be undisputed. Oral pharmaceutical formulations of MNTX were known in the art,
The terms "permeability" and "bioavailability" have fundamental importance in this case. The relationship between permeability and bioavailability appears to be a complex subject that was sometimes simplified and sometimes blurred in discussions at trial. Dr. Taft presented a demonstrative to help explain "the complicated process of what bioavailability ultimately is." (Tr. 539:2.) Once a drug is in the GI tract, the first step involves permeating the intestine itself. (Tr. 540:2-3.) Natural barriers in the intestine may prevent that, leading to drug efflux, which prevents drug absorption. (Tr. 540:4-12.) Even if a drug permeates into the intestine, intestinal enzymes may break it down, if the drug is susceptible to drug metabolism. (Tr. 540:13-16.) It is only after passing this series of obstacles that a drug may be absorbed into the bloodstream: "to penetrate into the intestine, to be able to liberate itself from the intestine and avoid intestinal metabolism, now we say it's in the bloodstream, but that is not bioavailability because we have something called the first pass effect." (Tr. 540:17-24.) The bloodstream takes the drug to the liver, where it may or may not be metabolized. (Tr. 541:1-7.) To become bioavailable, the drug must escape metabolism in the liver. (Tr. 541:8-14.) Plaintiffs summarized this process as follows: "Oral bioavailability (systemic exposure) is a complicated concept and, modelled mathematically, depends on the fraction of the dose absorbed into the intestine, the fraction of dose absorbed into the intestine that escapes intestinal metabolism, and the fraction of the dose absorbed into the bloodstream that escapes first-pass hepatic metabolism." (Pls.' FOF ¶ 122.)
It appeared, however, that the witnesses and the parties used the terms "bioavailability" and "permeability" in ways that suggested varying meanings.
As to claim 1, the parties strongly dispute whether a POSA would have been motivated to combine MNTX and SLS in a tablet. Actavis begins its argument with the proposition that MNTX was known to have poor permeability and poor bioavailability. At the outset, the Court notes that the choice of adjective here matters: "poor" implies deficiency and a problem to be solved, whereas "low" does not. This has great relevance to the analysis of motivation. From a semantic perspective alone, "low" value on some dimension is unlikely, without more, to suggest a problem that might motivate a quest for a solution.
Plaintiffs provide support for this semantic analysis by pointing to the evidence at trial demonstrating the following proposition: "Drugs with high potency can elicit a pharmacologic response even if they have low permeability—meaning low permeability is not always a problem." (Pls.' Br. ¶ 131.) Dr. Taft stated that "the potency of a drug is how much concentration do you need to elicit a certain effect." (Tr. 565:20-22.) Plaintiffs also point to the definition in the Pandit treatise: "The potency of a drug is the dose needed to produce a certain defined response in an individual." (P-262.076) Dr. Taft pointed to this teaching of Foss 2001:
(Tr. 566:11-15, citing Foss 2001, D-40.003.) Dr. Taft also stated that the prior art clinical studies taught that, because MNTX was potent, it was sufficiently permeable to be effective. (Tr. 567:15-17.) Plaintiffs point also to the testimony of Dr. Chambliss, who agreed that "a drug with high potency but poor permeability can still elicit a pharmacologic response . . ." (Tr. 240:12-15.) Based on this evidence, the Court finds that low permeability would not, without more, present the POSA with a problem to be solved.
Actavis contends that the experts on both sides agreed that a POSA would have known that MNTX had poor permeability and poor bioavailability. Actavis first cites Dr. Chambliss' testimony that MNTX "was known to have permeability issues." (Tr. 180:2-3.) In support, Dr. Chambliss cited the second paragraph on page 2 of D-74, the Yuan 1997 reference. (Tr. 184:10-185:1.) What this paragraph states, however, does not support Dr. Chambliss' assertion:
(D-74.002.) This paragraph states that antagonists such as naltrexone are "fairly lipid-soluble" and methylnaltrexone has "lower lipid solubility" relative to antagonists like naltrexone. This does not characterize the lipid solubility in any absolute sense but, instead, simply contends that MNTX is less soluble than compounds that are fairly lipid-soluble.
Dr. Chambliss then cited a statement on page 7 of Yuan 1997: "As a charged compound, methylnaltrexone's absorption in the gut may be limited, contributing in part to low bioavailability of oral methylnaltrexone." (Tr. 185:2-9; D-74.007.) This statement contains two assertions. The first is that the absorption of MNTX in the gut may be limited, which might conceivably support Actavis' position, but neither Yuan 1997 nor Dr. Chambliss defined "absorption," and there is no basis to conclude that it is a synonym for permeation.
Next, Dr. Chambliss cited the finding in Yuan 1997 that a relatively high oral dose of 19.2 mg/kg did not produce high blood levels. (Tr. 185:14-25.) Dr. Chambliss finished his discussion of Yuan 1997 with this statement of what the POSA would understand that Yuan 1997 taught with regard to the permeability of MNTX: "That methylnaltrexone has poor permeability for developing an oral formulation. You need to address that." (Tr. 186:3-7.) The Court finds that Dr. Chambliss' opinion about the teachings of Yuan 1997 is not supported by the text of that reference. Actavis has pointed to nothing in Yuan 1997 that teaches that there was a problem with the permeation of MNTX into the opioid receptors in the GI tract.
Next, Actavis cites this testimony from the cross-examination of Dr. Williams:
(Tr. 484:14-17.) This quote appears to say exactly what Actavis contends it says, but the Court makes several observations. First, the question was asked without any clear qualification as to the time frame. There is no way to know whether Dr. Williams' answer addressed the understanding of the POSA before the critical date or after. Second, Dr. Williams was not asked to articulate the basis for his statement. Third, because there was no development of this point, it is not clear what Dr. Williams meant by "poor." Cross-examination of Dr. Williams did not elicit any clear statement that the prior art understood that the permeability of MNTX was poor to the extent that it was an obstacle to effectiveness and needed remediation. Moreover, the Court considers this testimony together with the rest of Dr. Williams' testimony. On direct examination, Dr. Williams stated clearly that he disagreed with Dr. Chambliss that a person of ordinary skill in the art would have been motivated to improve the absorption and bioavailability of oral formulations of MNTX. (Tr. 452:9-15.) Dr. Williams then stated that, for a POSA, "the goal would not be to improve absorption and bioavailability" of MNTX. (Tr. 452:20-23.) Given those very clear statements, the Court does not find this unclear statement to deserve any weight.
Next, Actavis cites this testimony from the cross-examination of Dr. Taft:
(Tr. 645:24-646:2.) Dr. Taft did not agree that MNTX was known to have poor permeability, but that it had low permeability. As already discussed, low permeability does not imply a problematic characteristic in need of remedy. Dr. Taft, in fact, stated this clearly on direct examination:
(Tr. 585:7-18.) Dr. Taft clearly stated that the prior art did not indicate that permeation was a problem for oral MNTX. Dr. Taft's testimony does not support the proposition that the prior art believed that MNTX had poor permeability such that it was a problem to be solved.
Next, Actavis points to Dr. Chambliss' opinion that MNTX was known to have a positive charge, and that, generally, drugs with a positive charge have poor permeability. (Tr. 183:7-20.) Dr. Chambliss did not state, nor was he asked, whether or not the prior art understood MNTX as conforming to this general rule. It was directly after Dr. Chambliss stated this that counsel asked him whether there were any references in the prior art that discuss the poor permeability, and this led to his testimony about Yuan 1997, as just discussed. (Tr. 183:21-25.) As already discussed, this Court finds that Yuan 1997 does not support Dr. Chambliss' permeability opinions.
Next, Actavis points to the specification and the Accordingly Phrase, contending:
(Defs.' FOF ¶ 125.) This is unpersuasive, as Actavis has failed to explain what in the specification is consistent with Dr. Chambliss' testimony. The "Background of the Invention" section of the specification does not use the words "permeability" or "permeation." Later in the specification, when describing certain embodiments, the patent states: "The amphiphlic [sic] pharmaceutically acceptable excipient increases the lipophilicity of the composition thereby allowing for increased transport through the unstirred diffusion layer in the GI tract, resulting in increased permeation through biological membranes." '276 patent, col.13 ll.58-63. This demonstrates that the patentees knew how to specify permeation through membranes when they chose to do so, and they did not choose to do so in presenting the Background of the Invention. The descriptions of the prior art patents in that subsection make no reference to concepts of permeability, or even bioavailability, with the exception of the Accordingly Phrase.
At trial, the parties debated the meaning and significance of the Accordingly Phrase. The bottom line issue concerns what is essentially an attempt by Actavis to rewrite the sentence by inserting the word "more" before "bioavailable." The Court makes a few observations about the phrase, which is the terminal sentence in the Background of the Invention subsection. First, its antecedent foundation is unclear at best. As stated, there is no reference in the subsection, outside of the Accordingly Phrase, to bioavailability. The closest it comes is in the description of the '158 patent, with a reference only to average peak plasma levels. '276 patent, col.2 ll.15-17.
Second, given the lack of antecedent reference to bioavailability, the meaning of the word "bioavailable" in the Accordingly Phrase is unclear, and so this Court considers the context to understand its meaning. The Background of the Invention subsection starts by describing the use of opioids for the treatment of pain, and the side effect of constipation, "which can be debilitating and often cause patients to refuse the use of opioid analgesics." '276 patent, col.1 ll.27-29. The subsection then discusses the problem this can cause in the treatment of postsurgical pain. Next, it points to the problem of opioid receptor antagonists that cross the bloodbrain barrier, and then turns to MNTX. It then surveys the prior art use of MNTX as a treatment for OIC.
The Court finds no antecedent to illuminate the meaning of the Accordingly Phrase and concludes that it is too ambiguous to be read as a significant statement about anything. Given the context, the Background of the Invention subsection, and the lack of clarity about its meaning, the Court can only conclude that the Accordingly Phrase indicates the general view of the inventors that the prior art demonstrated a need for a more effective oral MNTX formulation. The Court thus understands the Accordingly Phrase to be an unremarkable transitional statement, and not more. There is no basis to consider this to be a detailed statement of specific teachings of the prior art.
Because the Accordingly Phrase is not a specific statement about the teachings of the prior art, the Court need not strain to interpret the meaning of "bioavailable." There is nothing in the Background of the Invention subsection that supports Actavis' attempt to rewrite "bioavailable" as "more bioavailable." Actavis has not pointed to any language in the subsection that would justify such an interpretation.
Nor does this Court agree with Actavis that the Accordingly Phrase constitutes a binding admission regarding the prior art, within the meaning of
The interpretation of the Accordingly Phrase is a key building block in Actavis' obviousness case, and the Court's determination that it does not mean what Actavis proposes leaves Actavis with a major hole in its case.
Next, Actavis quotes the testimony of one of the inventors, Dr. Al-Shareffi, contending that it corroborates that a POSA would have wanted to improve the bioavailability of MNTX. This is problematic for several reasons. First, an inventor's insights are not part of the prior art. Second, in the quoted testimony, Dr. Al-Shareffi made a general observation that all formulators want to make a formulation that has better bioavailability. This is not a statement about MNTX, or about the prior art; it is a statement about the general motivations of formulators. Third, as Dr. Taft opined in his testimony, and as will be discussed in detail below, the prior art taught that plasma levels should be kept low to avoid side effects like orthostatic hypertension, and the invention claimed in the '276 patent did not increase bioavailability. For all these reasons, the Court concludes that Dr. Al-Shareffi's statements do not, as Actavis argues, corroborate or support the proposition that a POSA would have wanted to improve the bioavailability of MNTX.
Plaintiffs contend that there was no motivation to increase the permeability of MNTX in the prior art. Dr. Williams testified that he did not agree with Dr. Chambliss that a POSA would have been motivated to improve the absorption and bioavailability of oral formulations of methylnaltrexone. (Tr. 452:9-15.) As already discussed, Dr. Taft stated that prior art clinical studies taught that, because MNTX was potent, it was sufficiently permeable to be effective. (Tr. 566:11-567:17.)
Plaintiffs next contend that the prior art recognized that, when orally administered drugs have a local site of action:
(Pls.' Br. ¶ 136.) Dr. Taft testified that the prior art taught that "it was preferred to keep the systemic levels, the plasma levels, low because of the known side effects or expected side effects of methylnaltrexone systemically, including orthostatic hypertension." (Tr. 556:17-557:3.) Dr. Rauck agreed that "elevated . . . plasma levels of methylnaltrexone, can produce orthostatic hypotension." (Tr. 382:11-21.)
Plaintiffs then argue:
(Pls.' Br. ¶ 137.) In support, Plaintiffs cite to a number of pieces of evidence, but the evidence supports this argument only in part. It is undisputed that oral MNTX acts locally, not systemically, to relieve OIC, and it is clear that MNTX in the plasma can cause undesirable side effects. Moss 2008 states:
(P-258.003.) In support, Moss cites the Yuan 2000 Enteric study. The Yuan 2000 Enteric study states that the tested enteric formulation was designed "to achieve lower plasma levels of the compound." (P-275.002.) In discussing the results, the Yuan 2000 Enteric study stated: "results from this study showed that administration of enteric-coated methylnaltrexone prevents gastric absorption of the compound, resulting in lower plasma levels." (P-275.006.) Moss 2008 and Yuan 2000 Enteric support the proposition that the prior art believed that low plasma concentrations of MNTX were desirable.
Furthermore, the passage from Moss 2008 just quoted teaches that "[n]o correlation exists between drug effect and plasma concentrations after doses of 3.2 mg/kg or 6.4 mg/kg of enteric-coated MNTX." Dr. Taft confirmed that this means what it says: plasma levels do not correlate with drug effects. (Tr. 560:6-12.) Yuan 2000 RL taught that, at three dosage levels at 3.0 mg/kg and below, low plasma levels indicated that MNTX acted directly in the GI tract. (D-374.007.) Since Moss 2008 taught that increasing plasma concentration with doses above 3.2 mg/kg does not affect drug effect, the two references together teach that there is no significant relationship between plasma level and drug effect, and thus that increasing plasma level of MNTX does not increase the drug effect. Similarly, Foss 2001 found "no correlation between changes in transit time and the MNTX plasma concentrations over a 3-hour period." (D-40.004.) The prior art of record does not teach that oral MNTX formulations with improved bioavailability were needed in order to improve treatment efficacy, and Actavis has not pointed to any prior art reference that teaches otherwise.
Actavis contends that Yuan 2000 RL taught that increases in plasma levels were associated with increases in efficacy (decreased time to laxation), and thus that time to laxation decreases as bioavailability increases. In support, Actavis cites the testimony of Dr. Taft: "Dr. Taft agreed that data from the Yuan 2000 Research Letter shows that as the bioavailability of MNTX increases, the average time to laxation decreases." (D's FOF ¶ 171.) This statement is not supported by the record:
(Tr. 613:3-614:2.) The cross-examination refers to a demonstrative exhibit which Actavis had created, based on Yuan 2000 RL. The exhibit shows, correctly, that plasma levels of MNTX were undetectable in the four patients in lowest dosage group, detectable in one of four patients in the middle dosage group, and detectable in three of four patients in the highest dosage group. (D's. Post-Trial Br. 63.) Contrary to Actavis' argument, the transcript shows that Dr. Taft expressly disagreed with the conclusion that Actavis now contends he agreed with. Furthermore, Yuan 2000 RL, in discussing the results, absolutely did not find that increases in bioavailability are associated with decreased time to laxation. (D-374.007.) To the contrary, the concluding paragraph states: "The low methylnaltrexone plasma levels observed in our study suggest that this charged compound acts directly in the gut." (
The evidence clearly supports the inference that the POSA, when creating an orally administered MNTX formulation at the critical date, would have sought to minimize plasma levels of MNTX. The evidence does not establish, however, a key step in Plaintiffs' argument: the proposition that the POSA would have therefore believed that increasing permeation was undesirable. The evidence clearly shows that the POSA would have believed that increasing plasma levels was undesirable, but it does not show what effect this belief had on beliefs about increasing permeation. Dr. Taft stated that Clinical Study 3200A3-115 demonstrated that the invention of the '276 patent, an SLS formulation, did not show different bioavailability than the same formulation without SLS. (Tr. 576:1-9.) Dr. Taft also stated that the 1115 Study showed that the inventors' formulation was effective, but not due to increased bioavailability. (Tr. 575:22-24; 633:20-22.) This suggests that permeation may, in fact, be increased without a concomitant increase in bioavailability.
In its responsive brief, Actavis appears to raise a common-sense proposition: it is better to use less of a drug than more, and cites Aungst 1993 in support. Indeed, Aungst 1993 states that low bioavailability leads to waste:
(D-36.001.) Actavis has neither argued nor presented evidence that MNTX is expensive to produce. This Court has no basis to infer that cost-effectiveness would have motivated a POSA in designing an MNTX oral formulation. Instead, the Court has significant evidence that the likelihood of increased serious side effects would have motivated a POSA to not increase the bioavailability of MNTX. This record does not support any other inference.
In the responsive brief, Actavis argues that Plaintiffs have offered no evidence of concern about the side effect of orthostatic hypertension. This is incorrect. In addition to the expert testimony on this subject already discussed, Foss '591 states:
'591 patent, col.7 ll.47-62. The Court finds that the prior art recognized the need to minimize systemic levels of MNTX to minimize side effects like orthostatic hypotension. Actavis contends that the art, as of the critical date, taught that oral formulations of MNTX did not achieve an adequate time to laxation, citing this statement in Moss 2008: "Methylnaltrexone has also been developed in a subcutaneous formulation designed to avoid the long delay associated with oral dosing." (P-258.004.) This statement appears right after a discussion of Yuan 2000 RL which, at the highest oral dose, reported a mean time to laxation of about 5 hours. (D-374.006.) This evidence supports the inference that the prior art, as of the critical date, recognized a need to find a treatment that worked faster, and this appears likely to be a correct statement. It does not support any inference about how to achieve the goal of faster constipation relief. Actavis has shown that the prior art recognized a need for treatments providing faster constipation relief, and that existing oral formulations were not fast enough, but not more.
The Court's uncertainty about what the prior art understood about whether permeation could be increased without a concomitant increase in bioavailability does not weaken Plaintiffs' argument that there was no motivation to increase the permeability of MNTX in the prior art. Having considered the parties' arguments and the evidence of record, the Court finds that Actavis has only the unsupported and conclusory opinions of Dr. Chambliss to support its contention that a POSA, prior to the critical date, would have had the motivation to find an oral formulation of MNTX that improved permeability. Dr. Chambliss stated that he based his opinion on Yuan 1997, but, as discussed, not only does Yuan 1997 not support the assertions Dr. Chambliss made about it, its findings differed markedly from Dr. Chambliss' statements about it. The Court concludes that, on this subject, Dr. Chambliss has low credibility, and his testimony is given little weight both because of his low credibility and the lack of evidentiary support. The other evidence cited by Actavis is even weaker. Significantly, Actavis has not pointed to any piece of prior art that states what Actavis argues was well-known.
Even if Actavis had proven that a POSA would have been motivated to improve the permeability of MNTX to improve the efficacy of oral formulations, Actavis would still fail to show that it would have been obvious to combine MNTX and SLS in a tablet. The prior art cited by Actavis disclosed a wide array of options for a POSA faced with the purported permeability problem, with no reason to pick out SLS, which appears to be just one whitecap in a sea of choices.
Given the absence of evidence to support the inference that the prior art recognized a problem of poor permeability in oral MNTX formulations, there is a strong risk that Actavis' theory relies on hindsight. A case with important similarities is
(
The next key proposition for Actavis' obviousness argument is that a POSA, having recognized that MNTX had poor permeability in oral formulations, would have selected SLS to improve the permeability of MNTX. Given the factual finding that the prior art did not recognize the permeability of MNTX as a problem to be solved, nor as a characteristic in need of improvement, this proposition cannot be proven: if there is no motivation to look for a permeation enhancer, it cannot be obvious to select a particular permeation enhancer to combine with MNTX. Nonetheless, for the sake of completeness, the Court will consider Actavis' argument in support of this proposition. The Court finds significant problems in addition to the lack of foundation.
The missing foundation is the proposition that the prior art recognized the poor permeability of MNTX as a problem to be solved by improving permeability. Even if the Court had decided that factual issue in favor of Actavis, however, there are big gaps in the road that Actavis contends leads to the selection of SLS. Actavis' next step on that road is to cite Dr. Chambliss' testimony about Table 1 in Aungst 1993. Table 1 is titled, "Categories of Oral Bioavailability Problems, Methods to Identify those Problems, and Formulation Approaches." (D-36.002.) Actavis does not explain why a POSA, faced with the challenge of improving the permeability of MNTX, would have looked to Table 1. As already established, the prior art did not believe that there was any problem with the bioavailability of MNTX. Moreover, the prior art taught that increasing bioavailability increased the risk of side effects such as orthostatic hypotension. Actavis' use of Table 1 is hindsight-driven: the predicate appears to be that the POSA would disregard the fact that Aungst 1993 primarily addresses bioavailability problems and that the title of Table 1 expressly states that it concerns bioavailability problems, but look there nonetheless to address a permeation problem because one of the listed problems is "poor membrane permeation." (
Why, in fact, would a POSA seeking to improve oral MNTX formulations have looked at Aungst 1993 at all? Consider the first sentence of Aungst 1993: "Bioavailability is the fraction or percentage of a dose that reaches the systemic circulation intact, when not directly injected into the circulation." (D-36.001.) As established, the prior art did not seek to increase the amount of MNTX that reaches systemic circulation. A reference teaching ways to increase how much drug reaches systemic circulation would not have been relevant to a POSA seeking to improve an oral MNTX formulation. Actavis' use of Aungst 1993 appears to be hindsight-driven cherry-picking.
Moreover, those problems aside, even if the POSA found a way to Aungst 1993 and to the section of Table 1 that Actavis has picked out, Table 1 lists 3 subcategories of permeation problems: "poor partitioning," "low diffusivity," and "binding to mucus or membrane." (
According to the Actavis theory, which skips over the subcategories, the POSA then looks at the "Possible Solutions" column in Table 1 which, for the "Poor membrane permeation" category, lists these solutions: "permeation enhancers," "ion pairing," "complexation," and "lipid or surfactant vehicles." (
(Tr. 190:11-17.) Here, Dr. Chambliss discards without explanation two of the solutions, complexation and lipid vehicle, and selects three for consideration. Dr. Chambliss then jumps the logical gap to selecting the permeation enhancer option. Neither Actavis nor Dr. Chambliss explain why this is the obvious choice from the five options. Actavis acknowledges that Table I states a number of solutions to the problem of poor permeability, and quotes Dr. Williams in support of the idea that the POSA would likely have worked on "several formulation strategies simultaneously," one being the use of permeation enhancers. (D's FOF ¶ 130; Tr. 484:18-25.) The next step on the path to SLS is unclear from Defendant's post-trial brief. Defendant jumps ahead to what the POSA would know about SLS and MNTX. But there is a big gap here: Actavis proposed that the POSA would work on several formulation strategies simultaneously. Actavis does not clearly articulate the path to the selection of SLS as the obvious choice.
Actavis next points to the evidence that SLS was known in the prior art both as a pharmaceutical excipient and as a permeation enhancer. This is undisputed; Table II in Whitehead 2007 lists SLS as the fifth most safe and effective permeation enhancer of the 51 reviewed. (D-49.004.) Actavis has one paragraph in its brief, number 138, that appears to be intended to bridge the gap, stating a set of criteria that the POSA would have used to find a permeation enhancer (still leaving unexplained why permeation enhancers would have been the obvious choice, given the group of options in Table 1 and the other teachings of Aungst 1993). The key question is: out of the universe of permeation enhancers
(Def.'s Br. ¶ 138.) These criteria are roughly similar to those stated by Dr. Chambliss: 1) an excipient that is a permeation enhancer; 2) anionic surfactant; 3) has the potential for ion pairing; 4) safe and effective for use in oral formulations; 5) compatible with MNTX. (Tr. 190:18-191:5.
Dr. Chambliss listed these criteria, and then stated:
(Tr. 191:6-12.)
Actavis' post-trial brief does not refer to Dr. Chambliss' "top of mind" principle but, as quoted above, simply says that SLS was the obvious choice because it satisfied all the criteria.
The Chambliss List is akin to a magic black box: you put in diverse teachings of the prior art, and it gives you SLS. Defendant's use of the Chambliss List is very problematic, and it attempts to cover over a big gap in the obviousness theory. First, consider the last step, selection of SLS. Actavis contends that the application of these factors leads to SLS, but this depends at least on establishing the factual predicate that, given those criteria, there was only one compound that fit them. Actavis did not establish this predicate. The record contains no evidence about how many compounds would have fit the criteria in the Chambliss List. Actavis has pointed to no evidence that supports the inference that SLS is the only one.
Second, Actavis skips over the creation and assembly of the Chambliss List itself. This is especially problematic because the Chambliss List — at work inside the black box — does the work of selecting and combining the various prior art elements, but away from scrutiny. Crucially, neither Dr. Chambliss nor Actavis have made any case that it would have been obvious for the prior art POSA to combine the prior art to assemble this schema of the five criteria. What is the evidence that the POSA, prior to the critical date, would have put together this list of criteria? It is not enough to show that each one of these, individually, is a teaching or a sensible inference from the prior art — not that Actavis has shown even that. The Chambliss List itself is a combination of prior art teachings, unsupported by any analysis.
If the Court accepted this approach, it would be allowing an end run around the center of the obviousness inquiry. The obviousness inquiry here focuses on the motivation to
In short, Actavis has failed to demonstrate that, even if the foundation proposition had been proven, it would have been obvious to a POSA to select SLS as the solution to the problem. Actavis has failed to propose a complete theory to explain how a POSA looking at Table 1 of Aungst 1993 would have selected SLS as the obvious choice.
Actavis also points to WO '352 as a prior art reference that teaches the use of SLS as an excipient with MNTX. This is correct but incomplete: WO '352 teaches the use of SLS as an excipient with MNTX, but as a lubricant, and not as anything else, such as a permeation enhancer. (D-73.023.) Actavis has not explained how use as a lubricant might have played any role in the selection of SLS as a permeation enhancer.
The Court finds that, even if the prior art had recognized that MNTX had poor permeability in oral formulations, Actavis has failed to show, by clear and convincing evidence, that the choice of SLS as the solution to those problems would have been obvious to a POSA.
Plaintiffs argue that the prior art taught away from using SLS with a quaternary ammonium compound like MNTX. The parties agree that MNTX belongs to a genus of chemical compounds termed "quaternary ammonium compounds" ("QAC.") Plaintiffs contend that prior art studies showed that SLS failed at increasing absorption of QACs, and point to the Kakemi and Langguth references. Dr. Chambliss agreed that a POSA creating an oral MNTX formulation would look to other QACs. (Tr. 237:7-10.)
Kakemi is a 1969 journal article reporting on a research study which investigated, inter alia, the effect of SLS on rectal absorption of poorly absorbable compounds, including three QACs. (P-253.001, P-253.005.) Kakemi reported: "no absorption of strong quaternary ammonium compounds could be detected." (P-253.004.)
Langguth is a 1987 journal article reporting on a research study which investigated, inter alia, the effect of various counterions, including n-alkyl sulfates, on the permeation of the quaternary ammonium compound trospium across rat intestine and human abdominal epidermis. (P-254.004.) Langguth reported these results:
(P-254.006-.007.) The parties do not dispute that SLS has a chain length of 12. Langguth thus teaches that n-alkyl sulfates like SLS, which has a chain length of 12, are associated with only slightly increased permeation of the QAC trospium, and that it is n-alkyl sulfates with a chain length of 7 or 9 that maximally increase permeation.
Plaintiffs also point to the statements of the examiner in the Notice of Allowability during prosecution of the '276 patent. What follows is the "Reasons for allowance" section in its entirety:
(P-11.731.) The examiner thus made clear that the decision relied significantly on the teachings of Langguth.
Plaintiffs also point out, correctly, that Actavis has misinterpreted the meaning of Table IV in Aungst 1993. As previously stated, Aungst 1993 is a journal article titled, "Novel Formulation Strategies for Improving Oral Bioavailability of Drugs with Poor Membrane Permeation or Presystemic Metabolism." (D-36.001.) The article reviews the relevant literature. Table IV is titled, "Some Examples of the Application of Ion Pairing to Increase GI Absorption." (D-36.005.) One row in Table IV presents these elements: additives of n-alkyl sulfates, the drug trospium, the result being "increased flux," and a citation to reference 48, which is Langguth. Actavis has cited Table IV as evidence in support of the proposition that the prior art knew that n-alkyl sulfates increased GI absorption of the QAC trospium. Plaintiffs point out that this is incorrect. Aungst 1993 is a review of literature. Table IV refers the reader to Langguth. Table IV cannot be understood to teach something contrary to the teachings of the study it cites.
Actavis contends that the prior art did not teach away from combining SLS with MNTX. Actavis argues first that the testimony of Plaintiff's experts on this subject does not apply to claim 5, which does not require ion pairing. While it is correct that claim 5 does not require ion pairing, it does require, since it depends on claim 1, a formulation comprising MNTX and SLS. The key question at this point in the obviousness inquiry is whether the prior art provided a motivation to combine MNTX and SLS. Evidence of teaching away from that combination is relevant to the obviousness inquiry into both claims 2 and 5.
Actavis argues that Langguth and Kakemi do not reflect the state of the art as of the Critical Date, and that a POSA would have relied on two more recent references, Aungst 1993 and Whitehead 2007.
"A reference may be said to teach away when a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant."
Plaintiffs contend that formulations embodying the claimed invention showed unexpectedly superior efficacy. "[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art."
The clinical study evidence supports Dr. Rauck's assessment that the inventive formulation showed a dramatic improvement in efficacy. The enteric-coated formulations in study 105 showed no statistically significant reduction in time to laxation from predose to postdose, while the immediate release formulations without SLS in study 1115 had a median time to laxation of about 8 hours. The performance of the immediate release formulation with SLS in study 1115, with a median time to laxation of .76 hours, is markedly superior to the performance of any of the tested formulations similar to prior art oral formulations.
Dr. Chambliss opined that the performance of the inventive formulation was not unexpected. (Tr. 668:6-8.) Dr. Chambliss supported this opinion by saying that SLS was a known permeation enhancer. (Tr. 668:9-12.) There is no dispute that SLS was known in the prior art as a permeation enhancer but, in the context of the evidence of record, this is a weak argument. As discussed, Plaintiffs have cited the Langguth and Kakemi references as teaching that SLS would not be effective in increasing the absorption of MNTX. Given those references, this Court looks for evidence of teachings in the prior art that SLS would be effective in increasing the absorption of MNTX, with reason to expect a dramatic increase in efficacy. Actavis has not persuaded that a POSA would have had a reasonable basis for discounting the teachings of Kakemi and Langguth and for having an expectation that SLS would have increased the absorption of MNTX, much less with such dramatic impact.
The Court finds that formulations embodying the claimed invention showed superior efficacy to prior art formulations, both enteric-coated and immediate release. The immediate release formulations disclosed in Yuan 2000 RL are the closest prior art, but this determination is not material. Plaintiffs have shown that a POSA examining the prior art would not have expected these results, and Actavis has failed to rebut this.
The Federal Circuit has set forth these fundamental principles regarding the role of unexpected results in the obviousness inquiry:
Actavis argues on several grounds that Plaintiffs have failed to demonstrate unexpected results. These arguments share a common form — they purport to show defects in Plaintiffs' presentation — and suffer from a common problem: Actavis misapprehends the burden of proof.
As to Actavis' critiques of Plaintiffs' evidence of unexpected results, the Court observes that the research studies showing the performance of oral MNTX formulations in the prior art are in the record, and that it might have been a simple matter to point to a prior art result that was not left in the dust by the mean time to laxation of the inventive formulation in study 1115 — if such existed. The "Background of the Invention" section summarizes the results of a number of studies of oral MNTX formulations:
'276 patent, col.2 ll.27-60.
The present record also includes the following studies of oral MNTX formulations:
Defendants also cite as prior art references Sanghvi '899 (D-44) and WO '352 (D-73), which do not report any clinical study results. The record thus shows only one prior art oral MNTX study which reports time to laxation, and the fastest mean time to laxation found was 5.2 hours. Actavis itself states that Yuan 2000 RL is the only oral MNTX study in the prior art to report time to laxation data. (D.'s FOF ¶ 169.) The fastest time to laxation reported in Yuan 2000 RL was for the group administered a dose of 3mg/kg. An average 150 pound person, then, is 68 kg, and the dosage would be 204 mg. Given a rough average time to laxation of 5 hours at the 204 mg dose, what would have been the expectation of the POSA for a lower dose (150 mg) with SLS? Actavis does not articulate any reason why a POSA would have expected that a 25% reduction in dosage, formulated with SLS, would have led to an 80% reduction in time to laxation. Rather, Actavis' entire argument is contained in this sentence: "Indeed, the POSA would have had an expectation that the addition of SLS to an immediate release formulation would lead to improved efficacy because SLS was a known permeation enhancer." (D's FOF ¶ 199.) This Court, however, has already determined that the Kakemi and Langguth references taught away from the use of SLS to increase GI absorption of QACs like MNTX, and Aungst 1993 and Whitehead 2007 do not undermine this finding. In view of this determination, Actavis cannot succeed with the argument that a POSA would have expected superior results from a formulation containing SLS because of general knowledge that SLS enhanced permeation.
Furthermore, compared to the best average time to laxation observed in Yuan 2000 RL, the time to laxation for the inventive composition found in study 1115 shows marked superiority. As evidence of this, Moss 2008, reviewing Yuan 2000 RL and other studies, characterized the prior art oral formulations as having "long delays." (P-258.004.) Study 1115 found an average time to laxation for the inventive formulation of roughly 45 minutes, which is a markedly shorter delay.
Actavis also argues that Plaintiffs have failed to show that the results were unexpected compared with the closest prior art, since studies 105 and 1115 are confidential and not in the prior art. Yuan 2000 RL is in the prior art, however, and Actavis admits that it is the only prior art study of oral MNTX that reported data on time to laxation. Furthermore, Actavis states: "As Dr. Rauck explained, the clinically relevant endpoint for studies of OIC treatments is time to laxation." (D's Post-Trial Br. 68-69.) As just established, under well-settled Federal Circuit law, Actavis bears the burden of showing the lack of unexpected results. The argument that the proper study for comparison is one which supports a finding of unexpectedly superior efficacy on the clinically relevant endpoint does not help Actavis meet that burden.
The Court finds that the performance of the inventive formulation, as reported in study 1115, is markedly superior to that of any oral formulation for which time to laxation data is available in the prior art. Actavis has not shown that any prior art formulation came anywhere close to the performance of the inventive formulation. Thus, when Actavis asserts that "plaintiffs' evidence of unexpected results must fail," that is the incorrect legal conclusion: it is Actavis that has failed to establish the lack of unexpected results.
Plaintiffs have established that the superior performance of the inventive formulation was unexpected. "[W]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious."
In conclusion, Defendant's obviousness theory has at least two large holes. The first hole is the failure to establish the fundamental proposition that the prior art believed that MNTX had poor permeability such that it was a problem to be solved. The second hole is the failure to show how it would have been obvious to the POSA, following the teachings of Table 1 of Aungst 1993, to select SLS to combine with MNTX in an oral formulation. Lastly, Plaintiffs have shown, and Actavis has not disproven, that the prior art taught away from the inventive formulation, and that the inventive formulation produced unexpected results, supporting a conclusion of nonobviousness.
"An inference of nonobviousness is especially strong where the prior art's teachings undermine the very reason being proffered as to why a person of ordinary skill would have combined the known elements."
Actavis' obviousness case unsuccessfully tries to bridge the gap between the teachings of the prior art about oral formulations of MNTX to treat OIC and the inventive formulation. In largest part, Defendant has tried to build this bridge on the pillars of the Accordingly Phrase and the Aungst 1993 reference. Actavis contends that the Accordingly Phrase should be interpreted as an admission by the inventors that the prior art recognized the need to increase the bioavailability of MNTX in oral formulations, and that Aungst 1993 taught that bioavailability may be increased by the use of permeation-enhancing excipients. A known problem is thus connected to a known solution, Actavis argues. There are two main defects in this argument. First, the Accordingly Phrase is ambiguous and, in any case, neither the Accordingly Phrase nor the '276 patent contradict the teachings of the prior art that low bioavailability was an advantageous property of oral MNTX, rather than a problem. Contrary to Defendant's thesis, the prior art did not teach that low bioavailability was a problem to be solved. Second, Aungst 1993 teaches the use of permeation-enhancing excipients as a possible solution only to problems of bioavailability. Actavis proposes that the POSA would consider low bioavailability to be a problem to be solved and, therefore, would look to Aungst 1993 in the quest for a solution, but the evidence does not support this. Because the evidence shows that the prior art taught that bioavailability was unrelated to an oral MNTX formulation's efficacy, and that increasing plasma levels was undesirable because of the risk of side effects, Aungst 1993 fails to be relevant to the search of the hypothetical POSA wanting to improve on the efficacy of prior art oral MNTX formulations. Aungst 1993 can serve as a connector in Actavis' theory only if Defendant's interpretation of the Accordingly Phrase is correct, but it is not. Actavis has thus failed to connect the teachings of the prior art to the inventive use of a permeation-enhancing excipient. Without this essential bridge, Actavis has failed to show an obvious path to the invention.
Actavis has failed to prove that independent claim 1 of the '276 patent is invalid as obvious. Because claims 2 and 5 depend on claim 1, Actavis cannot prove that claims 2 and 5 are obvious. Actavis has failed to prove that claims 2 or 5 are invalid for obviousness.
The parties stipulated to a finding of infringement of claim 5, and so only the question of infringement of claim 2 is at issue. The parties do not dispute that Actavis' proposed ANDA product contains MNTX and SLS in quantities that meet the limitations of independent claim 1. The question of infringement of claim 2 turns on the question of whether Plaintiffs have proven, by a preponderance of the evidence, that the MNTX and SLS in the proposed ANDA product "form an ion pair when dissolved in solution," as required by claim 2.
Plaintiffs offered the testimony of Dr. Koleng, who oversaw a series of chemical tests on the ANDA product and a related mixture. Plaintiffs argue that this evidence is sufficient to prove, by a preponderance of the evidence, that it is more likely than not that the MNTX and SLS in the proposed ANDA product form an ion pair when dissolved in solution.
Dr. Koleng testified about three experiments which were executed by commercial laboratory SSCI. The shake-flask method was used to determine the APC of MNTX in solution.
Actavis argues that the experiments do not prove infringement of claim 2 on several grounds. First, Actavis contends that ion pairing is not the only explanation for why the APC of MNTX in the proposed ANDA product might show an increase. Actavis contends that another possible explanation is the Galvani potential difference. In support, Actavis cites the testimony of Plaintiffs' expert, Dr. Davies, and two journal articles, Lombardo 2008 and Bouchard 2001. In short, the cited evidence does not support Actavis' contention. In the cited testimony, Dr. Davies made clear that the Galvani potential difference theory "only applies with an excess of the anion present." (Tr. 352:3-7.) Dr. Davies repeated this and stated: "it's only applicable . . . to cases where there's an excess of the anion, which we don't have." (Tr. 347:19-21.) He further explained that the Lombardo and Bouchard references dealt with the situation in which an excess of the anion was present. (Tr. 352:2-7.) Dr. Davies also testified:
(Tr. 342:18-25.) Dr. Davies thus clearly did not, as Actavis claims, testify that the Galvani potential difference is another possible explanation for an increase in APC as observed in the context of this case. To the contrary, he stated clearly that ion pairing was the only explanation he could think of for an increase in APC as observed in this case. Dr. Davies also explained that an increase in measured APC shows that ion pairing has occurred. (Tr. 317:4-15.)
Actavis also cites the testimony of Dr. Williams in support of the proposition that an increase in APC does not demonstrate ion pairing. Dr. Williams did indeed agree that the '276 patent leaves open whether or not the explanation for the increase in APC is due to the formation of ion pairs. (Tr. 506:16-20.) Dr. Williams was not, however, asked to explain his opinion on this point, and the Court does not find it to be consistent with the teachings of the '276 patent. For example, the specification states:
'276 patent, col.14 ll.21-29. This is a very clear statement that, in certain embodiments, ion pairing results in an increase in measured APC of MNTX. This Court does not see how it leaves the explanation open.
Actavis also cites similar testimony from Dr. Williams:
(Tr. 507:2-5.) This interchange is best described as cryptic: it is entirely unclear what Dr. Williams meant, but it seems likely that he was giving some kind of qualified response which received no further investigation. In light of the fact that Dr. Williams was neither offered nor qualified as an expert in chemistry, but rather as a formulator, as well as the inconclusive nature of this testimony, the Court finds that it does not significantly weaken the conclusions of Dr. Davies.
Actavis also cites inconsistency in Dr. Koleng's testimony on whether an increase in APC is necessarily due to ion pairing. As Actavis contends, Dr. Koleng admitted that he had no experience with ion pairing and that he did not consult any scientific literature on ion pairing to educate himself on the subject. (Tr. 108:17-109:11.) His statements about ion pairing will be given no weight.
In sum, Actavis cites the testimony of Drs. Koleng, Davies, Chambliss and Williams in support of the proposition that an increase in APC does not demonstrate ion pairing. Dr. Koleng's testimony is given no weight. The cited testimony of Dr. Chambliss is only a conclusory statement that there are other explanations, without giving any other possible explanations.
Actavis next argues that APCs cannot be determined for ingredients within tablets. In support, it points to the testimony of Dr. Chambliss and the deposition testimony of Dr. Diorio, one of the inventors. As Actavis contends, Dr. Chambliss and Dr. Koleng agreed that neither knew of any report in the literature in which the shake-flask method was used to determine an APC in a tablet, as opposed to a pure compound.
While Actavis' post-trial brief clearly contends that APCs cannot properly be determined for tablets, it never states any underlying principle to support this. What exactly is the problem with using the shake-flask method to determine the APC of MNTX in a tablet? At some points, Actavis suggests that skilled artisans determine APCs of pure compounds, never stating, however, that this is a limiting rule. It is clear, however, that such cannot be the case, since the '276 patent specification states: "The composition includes methylnaltrexone and an amphiphilic pharmaceutically acceptable excipient that form an ion pair or salt with methylnaltrexone when dissolved in solution, thereby increasing the octanol/water partition coefficient of methylnaltrexone." '276 patent, col.5 ll.62-66. This requires that an APC can be determined for a composition of MNTX and an excipient. Since that is clearly a predicate for that patent disclosure, what exactly is the line that Actavis proposes? Why would it be proper to use the shake-flask method to determine the APC of MNTX in some compositions, such as the one cited in the specification, but not tablet compositions? Actavis has no explanation, save for Dr. Chambliss' carrying theory, which will be discussed further below.
Actavis next points to the fact that there is only one example of the shake-flask method in the '276 patent, and that it was performed on a pure compound, not tablets. This refers to Example 4, which discloses determination of the APC through use of the shake-flask method with three MNTX salts. '276 patent, col.31 ll.28-46. This argument is not persuasive. Actavis does not contend that Example 4 was intended to be a comprehensive and exclusive set of rules for determination of APCs using the shake-flask method. Example 4 is, as the patent states, an example.
Actavis cites the excerpted deposition testimony of Dr. Diorio, who stated that he did not know how to measure the partition coefficient of MNTX in a composition, or whether one could determine the partition coefficient of MNTX in a composition. (D-380, Diorio Tr. 126:7-20.) Without more, the Court cannot assess what this means. The Court has no way to know whether this means that Dr. Diorio has no expertise in the details of APC measurement procedures, or something else. Was he a clinician and not a chemist? Given that the '276 patent specification teaches the measurement of APCs in compositions, this testimony does not appear to be significant.
Actavis also cites the testimony of Dr. Chambliss, who did state that he believed that Dr. Koleng's use of the APC measurement was not proper. The weight to be given to this testimony must be reduced because of the lack of support Dr. Chambliss offered. Dr. Chambliss stated: "I don't think you can use this test to determine the partition coefficient, and then you cannot infer from that that it's ion pairing. You don't know why a drug has gone from one phase to the other." (Tr. 154:4-8.) This one aspect of his opinion could have merit: a finding that the APC of MNTX in a composition with multiple excipients changed may leave questions about the reason for the change. But it was Dr. Chambliss' attempt at explanation of this opinion that was unpersuasive:
(Tr. 156:15-157:5.) The only explanation that Dr. Chambliss gave for his opinion that using the shake-flask method with the ANDA product was improper concerned the role of the insoluble excipients. According to Dr. Chambliss, because they are insoluble, they float around, going from one phase to the other. Dr. Chambliss speculates that, in that process, an insoluble excipient might "carry" the active ingredient from one phase to the other. Actavis has not shown that the theory has any relevance to the issues before the Court. The carrying theory proposes that insoluble excipients carry MNTX from the aqueous phase into the octanol phase. It would appear that the design of the first and second experiments controls for that. The compositions tested contained the same insoluble excipients. Actavis has argued only that the manufacturing process differed (plus, of course, the presence or absence of SLS.) There is no reason to believe that the effect of "carrying," if any, would not be the same in the two tests, since the test material had the same insoluble components in both. The carrying theory has no power to explain the difference between the measured APCs in the first and second experiments.
The Court finds that Dr. Chambliss' opinions about the use of the shake-flask method to measure the APC of MNTX in a composition deserve weight only in part. Dr. Chambliss raised a question which has value: if one observes a change in the APC of MNTX in a composition, how does one account for the change with confidence, given the presence of multiple excipients? This question will be explored in detail below. As for Dr. Chambliss' carrying theory, the Court finds that it is unsupported by the evidence of record, and the Court will give it no weight. The evidence of record does not support the proposition that Plaintiffs' experimental evidence is invalid because the APC of a compound in a tablet composition cannot be validly determined. The '276 patent specification clearly teaches the measurement of APCs in compositions, and Actavis has offered no persuasive explanation of why this cannot apply to tablets.
Actavis next challenges Plaintiffs' reasoning about the interpretation of the results of the three experiments with two arguments. First, Actavis challenges the comparison of the APC for a tablet, from the first experiment, with the APC for the loose tablet blend without SLS, from the second experiment. Actavis argues that the presence of SLS is not the sole difference between the tested materials: the tablet had undergone a manufacturing process, while the loose tablet blend had not undergone that manufacturing process. This is factually correct, but it is not sufficient to show that Plaintiffs' analysis is invalid. Actavis points out that, under these circumstances, the difference in APC could be due to the difference in manufacturing process, rather than the presence of SLS in the formulation. While this is a valid point, without more, it raises no more than a metaphysical doubt. Actavis has offered no evidence that the difference in manufacturing process would have changed the measured APC of MNTX.
Second, Actavis challenges Plaintiffs' reasoning about the third experiment. Actavis observes, correctly, that the third experiment did not assess the levels of excipients other than SLS in the octanol phase, and so another excipient might have also had a 1:1 molar ratio with MNTX. This appears to be a fragment of an argument, and the Court does not discern its significance.
Actavis next argues that the SSCI test results are unreliable because "they differed dramatically from what was disclosed in the '276 patent." (Pls.' FOF ¶ 91.) Actavis points to the fact that SSCI reported an APC for MNTX bromide of .002, while the patent reports an APC for MNTX of .025. Actavis does not address the fact that Example 4 in the patent does not state that .025 is the APC for MNTX bromide, but says only that it is for MNTX. '276 patent, col.31 1.45. The table in Example 4 discloses that three different MNTX salts had vastly different APCs — from roughly 2 to 32. '276 patent, col.31 ll.50-55. Actavis has not persuaded that there is any significance to the fact that the APC for MNTX bromide that SSCI reported differs from the APC for unspecified MNTX stated in the patent.
Furthermore, the specification contains an express definition of "apparent partition coefficient," which, inter alia, states:
'276 patent, col.10 ll.27-40. Note that the specification makes two statements about the procedures to be used for determination of the APC, and that both use the phrase, "may be determined by." Note as well that the first statement specifies the plural, "procedures." This indicates that the method to be used to determine the APC is not limited to one particular method.
Note as well that the patentees observed that the APC may be determined under various conditions. This fits with the testimony of Dr. Davies:
(Tr. 318:8-12.) Dr. Davies stated that changes in the relative ratio of concentrations will change the APC. Dr. Williams agreed that APC values can vary with pH. (Tr. 507:10-20.) All of this evidence supports the inference that a particular compound has no absolute APC value, and that the measured APC for a particular compound may vary based on a number of conditions, including testing method used, relative concentration ratio, and pH.
Actavis next argues that Dr. Elder's test results show that there was no ion pairing. As noted, stipulated fact number 76 states that Dr. Elder attempted to replicate SSCI's APC measure of MNTX in the ANDA tablets in solution at a different pH and obtained measurements of approximately .05. Actavis contends that this shows that the MNTX and SLS will not form ion pairs at a pH of 1. Dr. Chambliss testified that this shows that the ANDA product does not infringe claim 2. (Tr. 172:20-23.) This argument is problematic. The premise of Dr. Elder's testing is that pH changes the APC measured. Dr. Elder's testing is evidence that, indeed, the pH changed the APC measured, but the Court has no evidence about how to interpret that change given that SSCI's other measurements were all at a different pH. There is no evidence that Dr. Elder also determined the APC of MNTX bromide at pH 1.1. Because APC values vary based on many conditions, including pH, the statement that a particular value was obtained at a particular pH does not, without more, support any inference about ion pairing. Dr. Elder's APC measurement of MNTX in the ANDA tablet does not support any inference about the presence or absence of ion pairing. Dr. Elder's experiment confirmed what is undisputed: pH affects measured APC.
Actavis next argues that Plaintiffs have offered no evidence that the Actavis ANDA product will infringe when it is used by patients, as the issue is what will happen after patients have ingested the tablet and it is in the stomach. This argument is a non-starter.
This Court has considered Actavis' challenges to Plaintiffs' infringement case and has rejected everything but one point, which is the general caution that changes in the APC of MNTX in a composition with multiple excipients may leave questions about the explanation for the change. With that in mind, the Court considers the SSCI experiments.
SSCI measured the APC of MNTX in the ANDA product as approximately 1.0, the APC of MNTX bromide alone as .002, and the APC in the tablet blend without SLS as .01. Actavis has failed to persuade the Court that the fact that the tablet blend had not undergone the same manufacturing process as the tablet materially impacted these results. Plaintiffs have presented unrebutted evidence that, when SLS is removed from the tablet blend, the measured APC drops substantially. The Court has determined that, in the context of this case, the only explanation for this change is the presence or absence of ion pairing. Plaintiffs have also presented unrebutted evidence that the MNTX and SLS in the ANDA tablet, dissolved in solution, appear in the octanol phase in a 1:1 molar ratio. This supports the inference that the MNTX and SLS have formed ion pairs. Actavis has presented no useful experimental evidence.
Actavis has, at best, persuaded that the SSCI testing is not the perfect testing for an airtight scientific case. The evidentiary standard here is not, however, beyond a reasonable doubt: it is a preponderance of the evidence standard. Actavis has not persuaded that the possible imperfections in the SSCI testing render it valueless as evidence. Furthermore, Actavis has not persuaded that any of the imperfections substantially reduces the weight this Court should give to the SSCI test evidence. Actavis could have conducted tests which demonstrated that, when its ANDA product is in solution, the MNTX does not ion pair with SLS, but it did not.
The Court finds that Plaintiffs' evidence of infringement deserves significant weight. Plaintiffs have presented experimental evidence that the APC of MNTX in the ANDA tablet is significantly greater than the APC of MNTX in the tablet blend without SLS. The tablet blend experiment is not the perfect control, since, as Actavis contends, the tablet blend has not undergone the tablet manufacturing process. Actavis did not present, however, any basis to find that the manufacturing difference can account for the difference in APC value. The only evidence to the contrary was the opinion of Dr. Chambliss, which the Court found unsupported and unpersuasive. The Court concludes that the observed difference in the APC of MNTX between the ANDA tablet and the tablet blend without SLS is explained solely by the presence and absence of SLS. There is no evidence that other excipients played any role. The Court also concludes that the observed increase in APC value can only be accounted for by the formation of ion pairs between MNTX and SLS.
Actavis presented the opinion of Dr. Chambliss that the shake-flask method could not be used on a tablet composition, but, again, the Court finds the opinion of Dr. Chambliss to be unsupported and not persuasive. At most, Actavis persuaded this Court that the presence of multiple excipients requires caution in interpretation, as well as adequate experimental control, to have confidence in the inference that the addition or removal of one particular excipient accounts for observed changes in APC. The Court finds that Plaintiffs' experiments adequately controlled for the presence of multiple excipients, and that, in view of the applicable evidentiary standard, the experimental evidence supports the inference that it is more likely than not that the presence or absence of SLS alone accounts for the difference in APC measurements.
The Court concludes that Plaintiffs have proven, by a preponderance of the evidence, that the MNTX and SLS in the Actavis ANDA product form an ion pair when dissolved in solution. Plaintiffs have proven, by a preponderance of the evidence, that the proposed ANDA product will infringe claim 2. Actavis has failed to prove, by clear and convincing evidence, that claims 2 or 5 of the '276 patent are invalid as obvious. Judgment will be entered in favor of Plaintiffs on their claims that the proposed ANDA product infringes claims 2 and 5 of the '276 patent.
Pursuant to FED. R. CIV. P. 52(a), the Court presents its findings of fact and conclusions of law.
I. This Opinion incorporates by reference all stipulated facts set forth in the Final Pretrial Order.
II. Based on the evidence presented at trial, this Court now makes the following findings of fact:
An appropriate Order follows.
