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ABBOTT LABORATORIES v. BAXTER PHARMACEUTICAL PRODUCTS

September 26, 2005.

Abbott Laboratories, et al., Plaintiff,
v.
Baxter Pharmaceutical Products, Inc., et al. Defendants.



The opinion of the court was delivered by: RONALD GUZMAN, District Judge

AMENDED BENCH OPINION

This case involves U.S. Patent Number 5,990,176 (the "`176 Patent" or "Patent"), which claims compositions and methods of preventing the degradation of a widely used anesthetic, sevoflurane, by adding an effective or sufficient amount of certain specific Lewis acid inhibitors, one of which is water.*fn1 Water is used in the production of sevoflurane, and so there is nothing novel about having a combination of the two. In fact, because sevoflurane naturally absorbs water and there is always some humidity in the atmosphere, it is practically impossible to produce completely dry sevoflurane. FACTS

Ironically, sevoflurane was invented by Baxter scientists. (Tr. at 1478, Dr. Lessor.) The original compound patent for sevoflurane was applied for and granted in the 1970s. (Id. at 1476-77, Dr. Lessor; DX 46.) The original patent expired in 1989. (Tr. 1478, Dr. Lessor.)

  Sevoflurane is a useful anesthetic because it has a sweet smell and is a drug that acts and wears off quickly:
Sevoflurane was a very fast-acting drug. You could put it on a mask, have a patient breathe into it. It had a very sweet smell; it wasn't a pungent odor. Many of the other inhalation agents are difficult for a patient to breathe in. So it made it particularly useful to use in pediatrics, which, you know, masking a child into anesthesia when they're frightened and combative. Oftentimes you don't have an intravenous line to get an anesthetic in, so that was a very compelling attribute of the drug.
But probably one of the most compelling one was that it was a very fast-acting agent. It worked very quickly to take effect, and it wore off very quickly when you stopped the drug.
(Id. at 859.)

  Abbott first began to sell sevoflurane, a product it labeled as Ultane, in glass bottles beginning in 1995. (Id. at 860.) In January 1995, the food and drug administration (FDA) approved the new drug application Abbott had submitted for Ultane. (Id. at 819, Leticia Delgado.) Abbott did not, however, commercialize the product until June 1995. (Id.) Thus, the five-year market exclusivity that accompanied the FDA's approval of Abbott's new drug application did not expire until June 2000. (Id. at 1483, Dr. Lessor.) Between June 1995 and January 26, 1996, Abbott sold 79,000 bottles of sevoflurane with water from 23 different lots. In late 1996, Abbott discovered that some bottles of sevoflurane from one lot had begun to degrade. (Id. at 1133.) The product in these bottles had developed a very pungent odor and murkiness. (Id.)

  The degraded sevoflurane created a grave problem because it produced a harmful byproduct, hydrofluoric acid. (Id. at 25.) Hydrofluoric acid is very dangerous because if inhaled, it can cause death. (Id.) As a result, that particular lot was recalled. (Id. at 132, 1150.)

  Abbott immediately investigated, and Dr. Keith Cromack, one of its scientists, concluded that the degradation of sevoflurane occurred because of a rusty valve, or valves, in the stainless steel shipping containers ("tycons") that were used to transport sevoflurane from Central Glass of Japan, which manufactures all of the sevoflurane for Abbott. (Id. at 69-85.) Reports explaining Dr. Cromack's findings regarding the origin of the degradation of Abbott's sevoflurane are found in PXs 411, 21 and 315. (Id. at 1139-46.)

  Dr. Cromack concluded that the sevoflurane degradation was caused by exposure to Lewis acids. (Id. at 1145.) Lewis acid is simply defined as any chemical species that has a deficiency of electrons. "In a broad sense, Lewis acid is anything that is electron-deficient. It's looking for electrons to bind with, essentially." (Id. at 65, Dr. David Loffredo; PX 572.) Lewis acid inhibitors have the ability to donate electrons to bind with Lewis acids thereby neutralizing the Lewis acid. (Tr. at 44.) Sevoflurane contains two extra electrons on one of its oxygen atoms that seek to bind to Lewis acids. (Id. at 224-25.) When Lewis acid binds to sevoflurane, it causes the sevoflurane to break down, degrade, into a wide variety of products, some of which are harmful to humans. (Id. at 87-88, 226.) Because there are so many different potential pathways for these binding interactions to occur during the degradation process, the process is considered a complex chemical reaction. (Id. at 82-83, 226; PX 518.)

  Lewis acids can be found almost anywhere in the environment. The most common source of Lewis acids are metals. (Id. at 65.) When metals get oxidized the resulting metal oxides are Lewis acids. (Id.) Rust is a common example of a material that is Lewis acidic. (Id. at 223.) So any place containing metals that are exposed to the air and can be oxidized can contain Lewis acids. (Id.) Rust typically will not degrade sevoflurane because the rust molecules are neutralized by moisture from the air. (See id. at 299.) If, however, the rust is exposed to heat or acid, the water is driven off and the rust may become an activated Lewis acid. (Id. at 778.) Before Abbott's investigation in the Fall of 1996, it was unknown that Lewis acids would increase sevoflurane degradation. (Id. at 82-83, 231-32.)

  In the fall of 1997, some ten or eleven months after the application for the `176 patent had been filed, Abbott again recalled its sevoflurane product. (Id. at 132, 892; DX 136.) During its second recall investigation, Abbott discovered that its glass container was involved in the chemical reaction that was causing the degradation. (Tr. at 133.) Hydrofluoric acid, it was found, has the ability to etch glass. (Id. at 232.) Acidic etching of glass can expose and activate further Lewis acid species (silicon fluorides) within the glass itself. (Id.; see id. at 498-99.) This can cause what is called a cascading reaction in which the Lewis acid released from the glass container itself causes further degradation of the sevoflurane which in turn produces more hydrofluoric acid which causes even more etching thereby releasing more Lewis acid. (Id. at 95-96.) The cascading reaction has not been seen in any other (non-glass) container. (Id. at 151.) In fact, Abbott presently does not use a glass container. (Id. at 67.) It has developed and patented a container made of Polyethylene naphthoate, referred to as a "PEN," container which contains no Lewis acid in its makeup. (Id.)

  During the recall investigation, Abbott scientists discovered that they could solve the degradation problem by neutralizing Lewis acids by exposing them to water. (Id. at 98, Dr. Loffredo.) Water interacts with Lewis acids by forming a chemical bond between the acids and the empty oxygen orbital on the water molecule. (Id. at 232-33, Dr. Jung.) This inhibits degradation by deactivating Lewis acids which would otherwise attack sevoflurane at its ether and halogen linkages and release hydrofluoric acid into the anesthetic. Abbott Labs. v. Baxter Pharm. Prods., Inc., 334 F.3d 1274, 1275 (Fed. Cir. 2003). In the words of Abbott witness and patent inventor Dr. Loffredo: "You could put a certain amount of water in and cut off the degradation process, and this was — I think the significance of this was to show that if you had an inadvertent introduction of Lewis acids, this idea of sprinkling in, okay, that certainly the water present at an appropriate level would stop that from causing a reaction to proceed." (Tr. at 116, Dr. Loffredo.) Based upon this finding, Abbott filed for the `176 Patent on January 27, 1997, which issued on November 23, 1999. (Id. at 1041); see Abbott, 334 F.3d at 1275.

  Prior to this discovery, Abbott had always sought to minimize the amount of water contained in its sevoflurane product.

 
Q. Prior to your work in the fall of 1996 with Dr. Cromack and the others, did you have any understanding as to the role of water in the Abbott sevoflurane product?
A. Yes, I did.
Q. And what was that understanding? A. My understanding is that there was a desire to minimize the amount of water, to bring down the water level in sevoflurane.
(Tr. at 98, Dr. Loffredo.)

  Five chemical compounds other than water were also found potentially to have the same useful effect and are listed in claim numbers 1 and 6 of the `176 patent. Water was chosen because it posed no possible risk of harm to humans and would not require any complicated regulatory approval. (Id. at 102.)

  In April 1998, Ohmeda, Inc. sought to bring their new sevoflurane product, containing less than 130 parts per million ("ppm") of water, to market by filing an Abbreviated New Drug Application ("ANDA") with FDA. Baxter acquired Ohmeda, Inc. in April 1998. (Id. at 1487.) After placing the sevoflurane project on hold for a few months, Baxter decided to bring sevoflurane to market. (Id. at 1488.) An amended ANDA was filed with the FDA on January 26, 2001, which differed from the original application because it sought to manufacture sevoflurane in Baxter's aluminum epoxy phenolic resin-lined container. (Id. at 1534; DX 271, Revised ANDA.) In its application to the FDA, Baxter made a paragraph IV certification that its sevoflurane product does not infringe the `176 patent. Abbott, 334 F.3d at 1275. The filing of the initial ANDA by Baxter led Abbott to file an infringement action in this Court. DISCUSSION

  Claim Construction

  At issue is whether Baxter's sevoflurane product, containing no more than 130 ppm of water, falls within the claims of Abbott's `176 Patent. Claim 1 of the Patent states:
What is claimed is:
1. An anesthetic composition comprising:
a quantity of sevoflurane; and
a Lewis acid inhibitor in an amount effective to prevent degradation by a Lewis acid of said quantity of sevoflurane, said Lewis acid inhibitor selected from the group consisting of water, butylated hydroxytoluene, methylparaben, propylparaben, propofol, and thymol.
(PX 1, `176 Patent, Claim 1, Col. 11, Lines 21-28.)

  In its review of this Court's construction of that claim, the Federal Circuit held that the phrase "in an effective amount" means "the amount of Lewis acid Inhibitor that will prevent the degradation of sevoflurane by a Lewis acid." Abbott, 334 F.3d at 1277-78. Thus, this Court is left with the task of construing the phrase "to prevent degradation" to determine whether the Baxter product has a sufficient amount of water to prevent degradation and, therefore, infringes Abbott's `176 patent.

  When construing a claim, intrinsic evidence — the language of the patent and its prosecution history — is considered first. Metabolife Labs., Inc. v. Lab. Corp. of Am. Holdings, 370 F.3d 1354, 1360 (Fed. Cir. 2004) ("In most cases, the best source for discerning the proper context of claim terms is the patent specification wherein the patent applicant describes the invention.") The Court gives the words of the claim the ordinary and customary meaning that they "would have to a person of ordinary skill in the art in question at the time of the invention," Phillips v. AWH Corp., 415 F.3d 1303, 1312-13 (Fed. Cir. 2005), unless it appears from the specification or the file history that they were used differently by the inventor. Carroll Touch, Inc. v. Electro. Mech. Sys. Inc., 15 F.3d 1573, 1577 (Fed. Cir. 1993).

  Sometimes, "the ordinary meaning of claim language as understood by a person of skill in the art may be readily apparent even to lay judges." Phillips, 415 F.3d at 1314. In other cases, like this one, "determining the ordinary and customary meaning of the claim requires examination of terms that have a particular meaning in a field of art." Id. To divine the ordinary meaning of claim language in those cases, courts may use "those sources available to the public that show what a person of skill in the art would have understood disputed claim language to mean," including "extrinsic evidence concerning relevant scientific principles, the meaning of technical terms, and the state of the art." Id. (quotation omitted).

  If the meaning of a disputed term is clear from the intrinsic evidence, as informed by evidence about the relevant technology, then no extrinsic evidence as to the proper claim construction may be used. Key Pharms. v. Hercon Labs. Corp., 161 F.3d 709, 715 (Fed. Cir. 1998). If, however, intrinsic evidence does not fully illuminate the meaning of a claim, a trial court may rely on extrinsic evidence, including expert testimony. Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1583 (Fed. Cir. 1996).

  The phrase "to prevent degradation" is not defined in the Patent. Thus, we must determine what a person of ordinary skill in the art would have understood that term to mean at the time the application for the `176 Patent was filed. It is clear that the word prevent, as used in the phrase "to prevent degradation" is a term of art. In laymen's terms, "to prevent" means "to keep from happening." See WEBSTER'S NEW WORLD DICTIONARY 1067 (3rd College ed. 1988). But Drs. Loffredo and Jung, both of whom are skilled in the art, agree that it is impossible to stop all degradation of sevoflurane. Dr. Loffredo testified:
Q. When you did your analysis and concluded that Claim 1 of the Abbott water patent covered the Baxter product with 130 parts per million of water, did you assume that the use of the word "prevent" meant that all degradation must be prevented in order for the amount of water to be effective?
A. In this context, the word "prevent," you can never prevent all degradation. There will always be some level of degradation in any product.
(Tr. at 435, Dr. Loffredo.) Similarly, Dr. Jung testified:
[To] slow down, essentially, and inhibit, make it slower. You never get zero degradation. The likelihood of having something which is 99.999 percent pure is extremely low. There's always some degradation. And so what "prevent degradation" means is to slow it down so that the material is not very degraded. That is, it is inhibited the degradation process. . . . [I]t's very had to get any compound with no degradation. It's essentially impossible.
(Id. at 239.) If it is not possible to prevent all degradation, then the term "prevent degradation" as used in the patent must mean to prevent degradation past a certain point.

  The next step then, must be to determine what that point is. In other words at what level is degradation so great that the amount of Lewis acid inhibitor has not been sufficient to "prevent degradation." Or to put it another way, when, according to the teachings of the patent to one of ordinary skill in the art is sevoflurane deemed to be degraded. Dr. Jung says the term is illuminated by the experiments described in examples 1-6 in the Patent. Those experiments were performed by Abbott during its investigation to determine if sevoflurane degraded after being exposed to a Lewis acid.

  Abbott used activated alumina in its tests. Activated alumina is made using a chemical called aluminum oxide. If you take aluminum oxide and heat it or treat it with hydrochloric acid, you can activate the Lewis acid by driving off the water molecules that are normally present. Thus activated, the alumina will cause the sevoflurane to degrade. Abbott chose alumina as the Lewis acid with which to conduct its tests because it was what Abbott's scientists thought would be present in many circumstances and was certainly present in the glass container itself.

  The test described in example 1 of the Patent involved sprinkling alumina into a container of sevoflurane and then incubating it to accelerate the reaction which, without incubation, would take six to nine months to occur. After heating the mixture, Abbott looked for degradation. Next, Abbott added water to the mix and did the same experiment to see if the water was effective in preventing degradation. In this first example, Abbott took 20, 10 and 50 milligrams, respectively, of the Lewis acid and added it to sevoflurane, incubated the mixtures and then analyzed them. The results, according to Dr. Loffredo, demonstrated the Lewis acid-inhibiting quality of water:
You could put a certain amount of water in and cut off the degradation process, and this was — I think the significance of this was to show that if you had an inadvertent introduction of Lewis acids, this idea of sprinkling in, okay, that certainly the water present at an appropriate level would stop that from causing a reaction to proceed.
(Id. at 116, Dr. Loffredo.) Another experiment, reflected in example 2 of the Patent, involved putting sevoflurane into a glass ampule that was flame-sealed to cause the formation of Lewis acid sites. Once formed, the Lewis acid sites caused the sevoflurane to degrade. Abbott did the same thing with another flame-sealed glass ampule, but the sevoflurane in this ampule was saturated with water. Abbott then heated both of the ampules at a high temperature. The results: the non-saturated sevoflurane degraded while the sevoflurane saturated with water did not. Dr. Loffredo referred to this as "sort of an on-and-off mechanism. . . . You've introduced an active Lewis acid site, and you've stopped that site from degrading sevoflurane by the addition of the inhibitor." (Id. at 118, Dr. Loffredo.)

  Abbott expanded on its second experiment in the test described in example 3. Instead of using one ampule, it used multiple ampules with varying levels of water and varying levels of heat. The results showed that a water level of 595 ppm produced a pH of 5 and very low levels of degradation. With water levels of 303 ppm, 206 ppm, and 109 ppm, respectively, the results showed high levels of degradation.

  Example 4 of the Patent describes additional ampule experiments at what Dr. Loffredo testified was a more reasonable temperature range, i.e., 60 degrees for 144 hours and 40 degrees for 200 hours, as depicted in Table 3. Under these conditions, sevoflurane with 109 ppm of water had a pH of zero, indicating a high acid concentration, and large quantities of degradants. The degradation was minimized when more water was added. Example 4 suggests that as the temperature increases, the amount of water required to inhibit the degradation of sevoflurane will also increase. The experiment described in example 5 is similar to the first experiment. It was designed to assess what happened in an actual bottle that Abbott used to package its sevoflurane. Abbott took glass containers that had been previously etched, so the surface was known to be Lewis acid activated, and added sevoflurane with water to them to demonstrate that a Lewis acid inhibitor would inhibit the degradation that had occurred in the glass bottles of sevoflurane that Abbott had previously recalled. The tests showed that sevoflurane in previously etched bottles would degrade, but the degradation was inhibited by adding 400 ppm of water.

  In example 7, Abbott rolled a previously etched glass container in saturated sevoflurane and then tested it in the same way as in example 5. The idea was to coat the etched glass with water to see if the coating would prevent degradation. The result was that the sevoflurane experienced virtually no degradation. Dr. Jung says that this example demonstrates not only that coating a container with a Lewis acid inhibitor decreases degradation, but that the container itself can be a Lewis acid inhibitor. (Tr. at 247.)

  According to Dr. Jung, a person of ordinary skill in the art would conclude from the patent examples that degradation as it is used in Claim 1 means sevoflurane with total impurities of 4000 ppm or more. (Id. at 287.) Conversely, a person of ordinary skill in the art would understand that sevoflurane with less than 4000 ppm of degradants is not degraded. (Id. at 241.)

  Dr. Jung based this conclusion primarily on his reading of example 6 of the patent. When asked how the `176 patent defines degradation, Dr. Jung replied by referencing Table 6 (columns 9 and 10), which reflects the results of example 6. (Id. at 239-40.) Dr. Jung said that Table 6 shows that when only 20 ppm of water is added to sevoflurane that had been introduced to Lewis acid, large amounts of degradation — from 4100 to 6500 ppm of impurities — resulted. (Id.) However, when 400 ppm of water was added to the sevoflurane, the number of degradants was reduced to a range of approximately 100 to 600 ppm. (Id.)

  According to Dr. Jung, Figures 4 and 5 of the Patent, which are bar graphs of the impurity levels in the sevoflurane tested in examples 5 and 6, also demonstrate that degradation of sevoflurane is inhibited by the addition of water at 400 ppm. (Id. at 240.) Dr. Jung says the graphs in Figures 4 and 5 show no impurities in the sevoflurane with 400 ppm of water tested in example 6 and at least 4100 ppm of impurities in the sevoflurane with only 20 ppm of water. (Id.) From these graphs, Dr. Jung concludes that a person of ordinary skill in the art would interpret the word degraded as it is used in the `176 Patent to mean sevoflurane with no less than 4000 ppm of degradants. (Id. at 239-40, Dr. Jung.)

  But the Patent does not say that the study group with 400 ppm of water is not degraded. Rather, it says that Figures 4 and 5 "demonstrate that the degradation of sevoflurane is inhibited by the addition of water at 400 ppm." (PX 1, Col. 10, Lines 38-40.) In fact, at column 10, line 25, the Patent states that the HFIP concentration, which indicates the presence of hydrofluoric acid, of that study group is "quite high and suggests that the glass surfaces were still somewhat active." This language directly contradicts Dr. Jung's contention that the study group is not degraded.

  Moreover, even a cursory examination of the graphs in Figures 4 and 5 reveals that they cannot bear the weight that Dr. Jung ascribes to them. Based on the visual representations of the bar graphs in Figures 4 and 5, Dr. Jung equates "inhibited," as it is used to describe those Figures, with eliminated: "[I]f you look at those bar graphs and you see bar graphs going off scale for the control group and you see zero bar graph for the other, that tells me this is undegraded." (Tr. at 290, Dr. Jung.) The visual representations, however, are clearly imprecise. They are extremely small — occupying no more than a few inches in the center of an 8½ × 11 inch page — and measure impurities by the thousands of parts per millions. It is impossible to tell from these tiny, summary graphs precisely what level of impurities was found in any bottle tested.

  Moreover, the conclusion that Dr. Jung draws from these graphs contradicts other portions of testimony. At one point, Dr. Jung testified that a person skilled in the art would understand the word degradation to refer to the pH level of the sevoflurane. (Id. at 243.) In his view, sevoflurane with a pH level of 1.5 is highly degraded. (Id.) Dr. Loffredo, who performed the tests described in the Patent, said that bottle 1 in Example 6, had a pH level of 1.5. (Id. at 500.) ...


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