AstraZeneca LP v. Breath Ltd.

Citations: 88 F. Supp. 3d 326; 2015 WL 777460Docket: Civil Action No. 08-1512 (RMB/AMD)

Court: District Court, D. New Jersey; February 12, 2015; Federal District Court

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The Court, upon remand from the Federal Circuit, addresses further proceedings related to U.S. Patent No. 7,524,834 ('834 Patent), which pertains to sterile budesonide compositions. AstraZeneca LP and AstraZeneca AB are pursuing a consolidated patent infringement action against defendants Breath Limited, Watson Laboratories, Inc., Sandoz, Inc., and Apotex Corp./Apotex, Inc., based on their Abbreviated New Drug Applications (ANDAs). Prior claims of infringement regarding U.S. Patent Nos. 6,899,099 and 6,598,603 were dismissed due to invalidity, as affirmed by the Federal Circuit.

The Court finds that the '834 Patent is also invalid as obvious, as the defendants demonstrated that a person of ordinary skill in the art (POSA) would have reasonably expected to create a sterile budesonide composition using established methods. Consequently, judgment is entered in favor of the defendants. 

The relevant claims of the '834 Patent include independent claims 1 and 50, which describe a micronized powder composition and a suspension with at least 98.5% pure budesonide, respectively, both meeting specific sterility criteria. Dependent claims 2 and 51 reiterate the purity requirement. Following a Markman hearing, the Court defined 'micronized powder composition' as a product-by-process claim, specifically referring to 'heat-sterilized finely divided dry particles.' The trial centered on AstraZeneca's heat sterilization process, linked to another unrelated patent.

The Federal Circuit reversed the lower court's claim construction of 'micronized powder composition,' defining it as 'finely divided dry particles' without necessitating a specific sterilization process. This broader interpretation opened the patent to potential invalidity challenges based on a wider range of prior art. On remand, the court clarified that 'pharmaceutically acceptable' retains its plain meaning, indicating suitability for pharmaceutical administration. Furthermore, it determined that the term regarding sterility aligns with the U.S. Pharmacopoeia's criteria and is simply defined as 'sterile.' The court consolidated a preliminary injunction hearing with the main trial for judicial efficiency, leading to a 13-day bench trial. Following extensive post-trial briefs, closing arguments were presented. Currently, the claim analysis on remand includes independent claims specifying a sterile, pharmaceutically acceptable composition of finely divided dry particles comprising at least 98.5% by weight, with dependent claims stipulating that this composition contains pure budesonide.

AstraZeneca claims that the Defendants' submissions of Abbreviated New Drug Applications (ANDAs) for generic Pulmicort Respules® budesonide inhalation suspension constitute infringement of the '834 Patent. To prove infringement, AstraZeneca must demonstrate that each element of the patent claims is present in the accused products, a burden it meets by a preponderance of the evidence. The Defendants do not dispute that their products fulfill all claimed elements, including being pharmaceutically acceptable, consisting of a micronized powder composition, containing at least 98.5% pure budesonide or a related compound, and being suspended in an aqueous solution. Initially, Defendants argued against infringement due to lack of evidence for sterility, but this argument was dismissed as they later conceded that their products are sterile. Consequently, the Court concludes that AstraZeneca has established infringement.

In their defense, the Defendants raise several invalidity arguments: obviousness, anticipation, lack of written description, and lack of enablement. The Court references the established definition of a person of ordinary skill in the art (POSA), which includes specific educational and experiential qualifications relevant to treating asthma in children and related fields.

The 'critical date' for the '834 patent is established as November 11, 1997, which is one year prior to its earliest U.S. filing date. AstraZeneca claims to have reduced its invention to practice by at least March 1997, and certainly by July 1997, to address prior art references from Leuschner and Harris. The court has not yet ruled on this matter. To establish priority, a party must demonstrate either an earlier reduction to practice or a prior conception followed by diligent reduction to practice. Actual reduction to practice requires the inventor to show: (1) construction of an embodiment or performance of a process meeting all limitations of the interference count, and (2) determination that the invention works for its intended purpose. The inventor must also recognize contemporaneously that the embodiment functions as intended and meets all interference count limitations. The patentee must provide evidence supporting an earlier invention date, while the defendant must prove by clear and convincing evidence that the patentee's date does not precede the cited prior art. AstraZeneca references laboratory reports from March 1997 indicating that heating a substance at 110°C for 60 minutes achieves over a 7 log reduction in Bacillus subtilis spores, which meets the standard for a sterilizing process. Testimonies from experts Dr. George Zhanel and inventor Dr. Cheryl Larrivee-Elkins support that a six or seven log reduction indicates a 1/1 million sterility assurance level, and that a person of ordinary skill in the art would recognize the experiment's efficacy in achieving a sterile product.

Defendants’ expert, Dr. Scott Sutton, indicated that the data presented only showed spore reduction, not sterility, and admitted he was not qualified to link spore reduction to sterility. Despite documents suggesting that heating at 110°C for 60 minutes would yield over a 7 log reduction, evidence (PTX 1034) showed that samples were not subjected to this process. To establish reduction to practice, an inventor must demonstrate actual preparation of the composition, as noted in Estee Lauder Inc. v. L’Oreal, S.A. PTX 1527 also lacked information on the sterility of heat-treated samples, which were not tested for sterility. Dr. Elkins noted that initial attempts to confirm the data were “unsuccessful and concerning,” and by April 1997, validation of the cycle was reported to be problematic. Nevertheless, by May 1997, AstraZeneca believed it could produce a sterile product and began preparing to inform the FDA. AstraZeneca claimed to have produced a sterile batch of Pulmicort Respules® on May 10, 1997, but Defendants argued that no testimonial evidence supported this claim and that sterility tests were not conducted until late June. Defendants incorrectly interpreted Medichem, S.A. v. Rolabo, S.L. as requiring corroboration for every piece of evidence rather than for general claims of reduction to practice. The Court acknowledged the manufacturing of a budesonide suspension on May 10, 1997, but noted that sterility test results were not recorded until June 24, 1997, with impurity analyses occurring in July. Consequently, until those tests, AstraZeneca did not confirm if its budesonide suspension met all claim limitations. Although evidence was limited regarding the powder composition’s reduction to practice, the Court found Defendants did not provide clear evidence that AstraZeneca had not achieved this prior to the critical date of the '834 Patent. Thus, AstraZeneca demonstrated sufficient evidence of reduction to practice by July 9, 1997, emphasizing that successful testing must be recognized by the inventor.

A patent is presumed valid, but an accused infringer can challenge this presumption by providing clear and convincing evidence of invalidity. The burden to prove this lies with the party asserting invalidity. A patent may be deemed invalid for obviousness if the differences between the claimed invention and prior art would have been apparent to a person of ordinary skill in the field at the time of the invention. The determination of obviousness involves analyzing four factors: the scope and content of prior art, the skill level in the art, differences between the prior art and the claims, and secondary considerations such as commercial success. The inquiry requires establishing whether a skilled person would have had both a reason to combine prior art teachings and a reasonable expectation of success in achieving the claimed invention. Importantly, absolute predictability of success is not necessary; only a reasonable expectation suffices. The Supreme Court emphasized that this analysis should be expansive and flexible, considering that a skilled person is creative and capable of making inferences rather than merely following precise teachings. If a known technique improves one device and is applicable to similar devices, its use is considered obvious unless beyond the skill of the artisan. Additionally, if a known problem had an obvious solution reflected in the patent claims, this can also indicate obviousness. An invention may be "obvious-to-try" if it emerges from pursuing known options among a limited set of predictable solutions.

Defendants argue that the claims in question are obvious based on prior art presenting five established sterilization techniques, which a Person of Ordinary Skill in the Art (POSA) could have reasonably expected to use to achieve the claimed products. The Court will examine each technique individually, beginning with the motivation for a POSA in 1997 to develop the sterilized budesonide compositions at issue. By 1997, AstraZeneca was actively marketing PULMICORT, an aqueous suspension of highly pure, micronized budesonide powder in Europe, which meets all claim limitations of claims 50 and 51, except for sterility. Additionally, the Pulmicort® Turbuhaler, a dry powder inhaler introduced by AstraZeneca, also disclosed a highly pure micronized budesonide composition, covering all elements of claims 1 and 2, except sterility.

The key question is whether it would have been obvious for a POSA to create a sterilized budesonide composition. Both Defendants and AstraZeneca agree that, due to FDA and industry expectations regarding sterility for pharmaceutical products, a POSA would have been motivated to prepare sterile budesonide powders and suspensions. Although the FDA's proposed rule at that time specifically addressed only aqueous-based solutions, expert testimony indicated that the rule was understood to apply to all aqueous inhalation products, including suspensions. Dr. Kenneth H. Muhvich, who contributed to drafting the Proposed Rule, clarified that his intention was for the term "solutions" to encompass all aqueous-based nebulization products, including suspensions, citing the rule's origins in response to contamination issues with inhalation solutions.

Health risks associated with contaminated aqueous-based inhalation products are comparable for both solutions and suspensions. The FDA’s Final Rule from May 26, 2000, mandated that all aqueous-based drug products for oral inhalation must be manufactured sterile, encompassing both types of products. During a prior trial, Dr. Muhvich testified regarding a comment on the Rule suggesting it should explicitly cover inhalation suspensions, which he attributed to a misunderstanding on the commentator's part. AstraZeneca later revealed that this comment was authored by Dr. Muhvich himself, leading them to question his credibility. However, the Court rejected AstraZeneca's request to disregard Dr. Muhvich's testimony based on this revelation, noting that they had previously possessed the comment letter but chose not to question him about it during his deposition due to mistrust of the potential responses. The Court concluded that Dr. Muhvich's earlier testimony regarding the intended broad scope of the Proposed Rule was consistent with the comment letter and that he had simply forgotten his authorship during questioning. Furthermore, both parties' experts agreed that the industry trend was towards requiring all aqueous-based inhalation products to be sterile, a sentiment echoed by FDA communications dating back to 1994 and reinforced in a meeting with AstraZeneca in 1996, where the expectation for sterile products for both solutions and suspensions was clearly stated.

Dr. Zhanel's testimony aligns with prior witnesses, confirming that in 1997, the FDA advised AstraZeneca to ensure the sterility of suspensions, consistent with industry standards. He acknowledges the FDA's directive to AstraZeneca but expresses uncertainty about communications to others in the field. The trial evidence indicates that sterile parenteral and ophthalmic products were already available, with the FDA mandating sterility due to the heightened contamination risks associated with administration methods that bypass natural bodily defenses. Kenneth Avis’s publication emphasizes the necessity of sterility for parenteral products due to their invasive nature.

Mr. Zaccheo, an expert for the defendants, affirmed that a person of ordinary skill in the art (POSA) would recognize the advantages of sterilizing inhaled products, as they similarly bypass body defenses. Consequently, the Court concludes that both the Proposed Rule and FDA communications provided a compelling incentive for a POSA to create a sterilized budesonide composition.

The claims under scrutiny are not confined to any specific sterilization method, meaning that if any conventional sterilization technique was obvious for producing the claimed product, the claims could be deemed invalid. At the time of the '834 Patent, five established sterilization techniques for steroids like budesonide were recognized: sterile filtration with aseptic crystallization, moist heat, dry heat, ethylene oxide, and irradiation. Although each method has its drawbacks, a POSA had multiple options available to address these issues. The Court will evaluate all relevant evidence, including secondary considerations, before determining the obviousness of the asserted claims, even though the organization of the discussion places secondary considerations after the analysis of sterilization techniques.

Defendants argue that a person of ordinary skill in the art (POSA) would reasonably expect success in producing the claimed sterilized budesonide compositions using conventional sterile filtration and crystallization combined with standard aseptic processing. They claim the asserted patent claims are invalid due to obviousness when compared to existing references, including the IPPL, European Pulmicort, Pulmicort® Turbuhaler, and the 1994 FDA Inspection Guide, along with secondary sources like Lachman, Ansel, Remington 1995, and optionally Steckel or Harris.

The 1994 FDA Inspection Guide outlines essential steps for inspecting manufacturers of sterile drug substances, emphasizing the process of converting a non-sterile drug into a sterile form. Key steps include: dissolving the non-sterile substance in a solvent, sterilizing the solution, aseptic precipitation or crystallization, aseptic isolation via centrifugation or filtration, and aseptic drying, milling, blending, sampling, and packaging. The guide mandates that these operations occur in closed systems with minimal handling by operators, noting the common use of sterile filtration combined with aseptic processing by 1997.

Defendants provided evidence indicating that, by 1997, a POSA would understand the necessary steps to create sterile budesonide, starting with highly pure, pharmaceutically acceptable budesonide, which was commercially available at that time. Both parties' experts concurred that budesonide is readily soluble in various organic solvents, a fact well-known by 1997. They referenced U.S. Patent No. 5,556,964, which describes a method for manufacturing budesonide. The experts also agreed that a POSA would know to use a 0.2 micron sterilizing filter to eliminate all microorganisms and larger particles.

A POSA in 1997 would recognize that solutions could be filter-sterilized, as testified by Dr. Zhanel. Hofstraat indicates that a POSA could recrystallize budesonide from a solution to obtain pure budesonide with a 1:1 isomer ratio. This process could involve adding an antisolvent, such as water, through a sterilization filter, and could occur in a sterile reactor, consistent with FDA guidelines. A June 1997 article by H. Steckel et al. taught that budesonide could be dissolved in an organic solvent and crystallized into fine particles without compromising purity or morphology. AstraZeneca's claim that Steckel does not disclose micronized budesonide with greater than 99% purity is challenged; Dr. Zhanel acknowledged that Steckel utilized pharmaceutical-grade budesonide with over 99% purity. Other witnesses from AstraZeneca corroborated this understanding, confirming that the materials used in Steckel's experiments were of high purity. Dr. Robert O. Williams, III, also supported that Steckel's methods for micronization using supercritical carbon dioxide were credible and achievable.

The evidence accepted in the document indicates that Steps 3 and Jp of the FDA Inspection Guide, which involve aseptic isolation and processing of sterile substances, were standard practices for a Person of Ordinary Skill in the Art (POSA) at the time of the '834 Patent. AstraZeneca's expert, Dr. James Akers, confirmed that a POSA would have the knowledge to effectively dry, mill, and blend budesonide into a finely-divided, dry powder. Additionally, prior art references supported aseptic methods for these processes.

Dr. Michael J. Akers' 1997 publication explained procedures for aseptically discharging dried sterile substances and emphasized the importance of designing sterilization processes to reduce contamination risks. Both parties acknowledged that creating a sterile, pharmaceutically acceptable suspension of micronized budesonide from sterile powder was routine as of 1997.

Mr. Zaccheo opined that following the FDA Inspection Guide would reasonably lead a POSA to prepare sterile budesonide compositions. He also asserted that it was obvious to a POSA in 1997 to prepare these sterile compositions based on Lachman's 1986 teachings, which identified sterile filtration as the preferred method for heat-sensitive substances. Lachman noted that sterile filtration is commonly used in the pharmaceutical industry and is essential for aseptic filling processes. The document further delineates two methods for producing sterile products: terminal sterilization and aseptic processing, explaining the distinctions between them.

Aseptic conditions denote the absence of living organisms, essential for maintaining sterility during pharmaceutical processes. Sterile filtration can only be performed on solutions and is not effective for suspensions without additional steps under aseptic conditions. Aseptic processing aims to exclude microorganisms after filtration, necessitating a strictly controlled environment and technique to manage the challenges of maintaining aseptic conditions. While aseptic processing is not a sterilization method per se, it is crucial for products that cannot undergo terminal sterilization after being sealed.

A person of ordinary skill in the art (POSA) understands that optimizing sterilization processes is routine and varies based on the specific characteristics of the product. This optimization involves balancing ideal and practical processes, with recognized operating parameters for effective outcomes. Although maintaining a completely aseptic environment is challenging, POSAs were not deterred from using sterile filtration for budesonide, as they were aware of available facilities and equipment designed to create aseptic environments.

Supporting this, a 1994 FDA Guide emphasized the importance of closed systems in aseptic processing and provided inspectors with criteria to identify contamination risks. The guide indicates that POSAs would have recognized the feasibility of closed systems for aseptic processing as early as 1994. Furthermore, Lachman acknowledged that combining aseptic processing with other sterilization methods might be necessary for certain pharmaceuticals.

Well-established knowledge indicates that certain pharmaceutical products require specific sterilization methods, necessitating the availability of appropriate equipment and facilities at that time. A 1995 publication by Ansel emphasizes the benefits of sterile filtration for heat-sensitive compounds, such as budesonide, highlighting that this method relies on the physical removal of microorganisms through filters with varying pore sizes. Advantages of bacterial filtration include rapid processing of small volumes, effectiveness for thermolabile materials, low equipment costs, and thorough removal of microorganisms and particulates. However, it also presents risks, such as potential filter flaws leading to sterility uncertainties, unlike more reliable heat sterilization methods. Additionally, filtering larger volumes can be more time-consuming, especially with viscous liquids.

Ansel also outlines aseptic processing in conjunction with sterile filtration for preparing parenteral solutions, which involves dissolving ingredients in suitable solvents, filtering, and rapidly transferring the solution into final containers for sterilization. When autoclaving is impractical, heat-sensitive components can be sterilized separately and combined aseptically. Recognizing budesonide's heat sensitivity, a person of ordinary skill in the art (POSA) would likely consider sterile filtration and aseptic processing as viable methods, as Ansel confirms that creating sterile suspensions from micronized budesonide powder would be routine. Ansel details the preparation of these suspensions, emphasizing the need for prior sterilization of individual components to maintain suspension integrity, as autoclaving could compromise it.

Additionally, a 1995 publication by Remington reiterates the conventional sterilization techniques, noting that sterile filtration is one of the oldest and preferred methods for solutions that are unstable to other sterilization processes.

Membrane filters have become the preferred method for sterilizing heat-labile products over the past 30 years. Remington emphasizes the importance of sterile filtration for removing bacteria from steroids in organic solvents, followed by aseptic crystallization, and notes that aseptic processing is commonly used for ingredients that cannot undergo traditional sterilization but are themselves sterile. He recommends utilizing laminar-airflow devices or barrier technologies to maintain aseptic conditions.

Regarding U.S. Patent No. 6,187,765, which pertains to “Mometasone Furoate Suspensions for Nebulization,” the court determined that this patent is not considered prior art due to AstraZeneca's earlier reduction to practice. However, it may be relevant for assessing the understanding of a person of ordinary skill in the art (POSA) at the time of the invention. The court referenced previous rulings, noting that evidence supporting a Section 102 defense can inform the level of skill under Section 103, even if not sufficient for a 102 defense.

The court also observed that simultaneous inventions can indicate the level of ordinary skill in the art. Example 1 of Harris outlines a method for preparing sterile mometasone furoate monohydrate using a sterile filtration process, while Example 2 describes creating a sterile suspension from this compound, intended for treating lower airway disorders. The court's June 4, 2014 Opinion indicated that the '834 Patent might face validity challenges based on Harris’ disclosures, which include detailed steps for preparing a sterile corticosteroid suspension. The court noted that Harris’ procedure is akin to the FDA’s 1994 Inspection Guide, which outlines similar steps for converting non-sterile drug substances to sterile forms through filtration and aseptic crystallization.

Aseptic isolation of sterile substances involves centrifugation or filtration, followed by aseptic drying, milling, and blending. The process for preparing mometasone furoate includes dissolving it in acetone, sterile filtration, and then maintaining specific temperature conditions while stirring to form a precipitate, which is later filtered, washed, and dried in a vacuum oven. Harris (1997) indicates that a person of ordinary skill in the art (POSA) would have reasonably expected to create sterile budesonide compositions using sterile filtration in combination with aseptic crystallization. AstraZeneca contends that if Harris is not prior art, then the process must be considered inventive, asserting that the industry viewed the achievement of a sterile corticosteroid suspension as novel. However, the record reveals no assertion from Harris that sterile filtration and aseptic crystallization are novel or nonobvious. Harris mentions the preparation of a nebulizer suspension but does not claim sterility. The evidence indicates that in 1997, sterile filtration was the preferred method for sterilizing heat-sensitive pharmaceuticals, and a POSA would have been motivated to use this method for budesonide. Testimony supports that a POSA could routinely optimize the sterilization steps outlined in the FDA’s 1994 Inspection Guide, ensuring a reasonable expectation of success in creating a sterile form of budesonide. Although multiple steps are necessary following sterile filtration, it is clear that a POSA would be capable of performing these in an aseptic environment, especially within a closed system.

In 1997, the closed system crystallization technology was accessible to a person of ordinary skill in the art (POSA), supported by the widespread use of aseptic processing techniques in pharmaceutical manufacturing at that time. The court noted AstraZeneca's prior acknowledgment of these techniques, despite its later retraction. The testimony indicated that a POSA could routinely optimize processing steps and had access to all necessary materials and equipment. AstraZeneca did not dispute the known sterilization method of sterile filtration or the reasonable expectation of success in performing this on a budesonide solution. Furthermore, the steps for preparing sterile solids, including sterile filtration followed by crystallization and other processes, were recognized as typical for that period. AstraZeneca's defense argued that the sophisticated equipment required for sterile filtration and aseptic processing wasn't available in 1997, and highlighted contamination risks as a significant barrier to success. They referenced a 1991 FDA proposed rule indicating a substantial likelihood of microbiological contamination in drug products, to support their claims regarding the challenges of the process.

AstraZeneca contends that a person of ordinary skill in the art (POSA) would not reasonably expect to successfully create a sterilized micronized budesonide product using conventional methods such as sterile filtration and aseptic processing. This uncertainty stems from the necessity of employing multiple known processes following sterile filtration, where aseptic conditions could lead to contamination in approximately 1 out of 1,000 attempts. The FDA's 1991 Proposed Rule, which addressed terminal sterilization but was never enacted, is deemed of limited relevance. Despite acknowledging contamination risks, Dr. Akers indicated that aseptic processing can be effective in a closed system, provided there are no equipment malfunctions and human intervention is minimized. He clarified that executing aseptic crystallization, isolation, and milling in a closed system could yield a sterile product, although any minor error could jeopardize aseptic integrity. Dr. Akers also referenced a 1987 article by Dr. Michael Akers, which highlights that while sterilizing the drug and vehicle may not be overly challenging, achieving aseptic combination, dispersion, and mixing at scale poses significant difficulties. Ultimately, Dr. Akers' testimony suggests that the issue was not one of technological impossibility but rather the willingness of an inventor to invest in the necessary large-scale manufacturing infrastructure.

In 1997, a skilled individual in the pharmaceutical field would have been aware of the non-sterile European budesonide nebulizing suspension containing highly pure budesonide and the availability of 99 percent pure pharmaceutical grade budesonide. Such a person would recognize the importance of starting with the highest purity budesonide for creating a sterile product. They would be familiar with conventional sterilization methods, including sterile filtration using a 0.22 micron pore size filter that eliminates all microorganisms and larger particulate matter. The individual would understand that this filter is classified as a sterilizing grade filter and would know that to sterile filter dry budesonide powder, it must first be dissolved in a solution, typically using organic solvents like methanol. 

The skilled person would be capable of sterile filtering the budesonide solution to obtain a sterile filtrate. Without considering aseptic conditions, they would also know how to crystallize highly pure budesonide from solution while maintaining its purity, and how to dry and mill the recrystallized budesonide into a finely divided powder. If they possessed sterile budesonide powder at 98.5 percent purity, they would understand how to aseptically combine it with other pre-sterilized aqueous components to create a sterile budesonide suspension, assuming that the manufacturing process could ensure sterility. This combination would be regarded as a routine aseptic filling process by the skilled person in 1997, who would also recognize that most sterile pharmaceutical products are produced using some form of aseptic processing.

In 1997, a skilled person would recognize that if terminal sterilization of a pharmaceutical product is not feasible, aseptic processing would be necessary. The witness acknowledged that creating a sterile suspension from sterile powder is routine but opined that the processes involved in aseptic crystallization, isolation, drying, and milling are complex and carry significant risks, with no guarantee of success. While AstraZeneca argued that sophisticated equipment for aseptic processing was unavailable in 1997 and emphasized large-scale technical capabilities, the court found that such a perspective was overstated. Evidence was presented showing that sterile powders or suspensions could be produced in laboratory settings at that time. It was established that aseptic crystallization was well-known and that closed systems for such processes were already available by 1995, contrary to AstraZeneca's claims. Although the AstraZeneca witness expressed doubt about consistently achieving sterility using the proposed methods, this did not preclude a reasonable expectation of success. Other witnesses confirmed that aseptic processing was commonly used in the production of pharmaceutical products in 1997.

The record indicates that the equipment necessary for aseptic processing was available prior to 1997, supported by the FDA’s Inspections Guide and Dr. Akers’ testimony regarding the installation and verification of isolators since the mid-1980s. Isolators are designed to create a human-free aseptic environment, which Dr. Akers noted could reduce risks associated with sterilization and aseptic filling processes. Although isolators were not commonly used in sterile bulk drug manufacturing at that time, the potential for contamination using traditional aseptic methods was significantly higher, with AstraZeneca acknowledging that 40 million units processed aseptically could lead to approximately 40,000 contaminated units.

Dr. Akers confirmed that aseptic processing was feasible in 1997 if risks were minimized and proper systems were in place. He contrasted this with terminal sterilization methods, like heat sterilization, which AstraZeneca patented, highlighting that such methods lower contamination risks associated with human error. However, the court pointed out that AstraZeneca could not patent a product that could have been successfully produced using established sterilization techniques.

In a related patent examination on February 18, 2005, the Patent Examiner rejected AstraZeneca's claims as obvious, noting that it would have been evident to a skilled artisan at the time to sterilize the powders using either ethylene oxide or filtration processes, despite some limitations in filter size mentioned in the prior art. The examiner concluded that there was a reasonable expectation of success in sterilizing the particles to prevent microbial growth, reinforcing the argument that the claimed invention lacked the requisite novelty and non-obviousness for patentability.

AstraZeneca claimed that sterile filtration and aseptic processing were well-known techniques but argued they were impractical for bulk pharmaceutical powder manufacturing. The company noted that sterilization by filtration typically required the compound to be in solution, necessitating the sterilization of all reagents and equipment used afterward, which complicates the process. Ansel's references emphasized that bacterial filters pose risks of sterility flaws and suggested that such methods are not preferred for bulk powder production due to the challenges of maintaining sterility across multiple steps. Instead, Ansel recommended more reliable methods like heat sterilization or irradiation, despite potential purity loss. AstraZeneca asserted that they were the first to develop a practical method for producing a sterile budesonide composition, allowing them to claim patent rights. However, the Federal Circuit clarified that patent protection applies to the product itself, not just the process used to create it.

AstraZeneca's acknowledgment to the PTO of a potentially less practical method for producing its product raises critical questions about the obviousness of the claims. The Federal Circuit's decision in Orthopedic Equipment Co. v. United States clarifies that economic feasibility does not negate non-obviousness; rather, technological incompatibility is the relevant consideration. Although AstraZeneca did not utilize a combination of sterile filtration and aseptic processing due to high costs, a person of ordinary skill in the art (POSA) would still be motivated to apply these known sterilization methods in a laboratory setting with reasonable expectations of success.

The PTO emphasized that the claims in question pertained to the product rather than any specific process. AstraZeneca's arguments about the impracticality of certain sterilization processes lacked supporting evidence, as mere speculation does not constitute proof. To address the Patent Examiner's concerns and avoid the Jakupovic reference, AstraZeneca amended its claims to specify "micronized" compositions. The Patent Examiner ultimately found that it would have been obvious to create a sterile suspension of micronized budesonide using a method derived from Harris, which included techniques for filter sterilization.

Despite the Patent Examiner's decision to allow the claims, there is concern that the evidence presented by the Defendants, particularly regarding the knowledge available to a POSA in 1997 about drying and milling budesonide into a micronized powder and conducting aseptic processing, was not fully considered. AstraZeneca conceded that a POSA would have had the necessary knowledge to carry out these processes.

The Court acknowledges that the weight of references previously presented to the PTO may be diminished, as noted in Sciele Pharma, 684 F.3d at 1260. AstraZeneca asserts that both parties' experts concur that U.S. Patent No. 3,962,430, filed by Joseph L. O’Neill, identifies issues with aseptic recrystallization, specifically the formation of problematic needle-shaped crystals. The Court finds AstraZeneca's interpretation of Ms. Jeanne Moldenhauer's deposition testimony to be taken out of context, as highlighted by Sandoz. O’Neill's patent addresses prior art issues, noting that aseptic recrystallization yields unsuitable crystals for parenteral suspensions. O’Neill proposed a salt saturation method that did not alter crystal form, leading Ms. Moldenhauer to conclude that a person of skill in the art (POSA) would be motivated to apply O’Neill's method with a reasonable expectation of achieving a sterile budesonide product. Dr. Akers did not dispute this conclusion.

The Court ultimately determines that Defendants have proven by clear and convincing evidence that a motivated POSA could create the claimed sterilized budesonide compositions using sterile filtration and aseptic processing, with a reasonable expectation of success. Furthermore, Defendants argue that a POSA would also reasonably expect to achieve the claimed sterilized budesonide compositions through conventional moist heat sterilization (autoclaving). This method, recognized for its effectiveness in sterilizing products capable of withstanding high temperatures, operates at 121°C and 15 pounds of pressure for 15 minutes. Although AstraZeneca claims that moist heat sterilization was a known technique capable of producing sterile products by 1997, it contends that budesonide might not endure the temperatures typically used in such sterilization cycles.

Concerns regarding moist heat sterilization include the potential degradation of active ingredients and issues with particle size and agglomeration. Despite these concerns, evidence was presented showing that a person of skill in the art (POSA) would reasonably expect successful use of moist heat sterilization for creating the claimed compositions. Notably, O’Neill's work indicated that corticosteroid suspensions could be effectively sterilized with moist heat without degradation. Analytical studies confirmed that dexamethasone acetate remained intact after sterilization at 121°C for one hour, countering any prior art assertions that moist heat was unsuitable for heat-sensitive materials. Additionally, Lachman's teachings allowed for adjustments in the sterilization parameters to optimize the process. 

While agglomeration and changes in particle size are recognized outcomes of moist heat sterilization, they were not deemed problematic for creating pharmaceutically acceptable budesonide compositions, as these do not necessitate specific particle sizes. The route of administration dictates particle size requirements, allowing for larger budesonide particles to be acceptable for topical or oral use.

The claims in question are not restricted to a specific particle size or pharmaceutical application; however, Federal Circuit claim construction mandates the use of "finely-divided dry particles." Evidence shows that a person of ordinary skill in the art (POSA), motivated to create a sterile budesonide composition, would not be deterred from employing steam sterilization despite known issues of agglomeration and particle growth. Various established methods could mitigate these concerns before or after sterilization.

One effective approach involves using a saturated sodium chloride solution prior to moist heat sterilization, as outlined in O’Neill's invention. O’Neill sought to prevent changes in particle size during the sterilization of sterile suspensions. By saturating the solution with sodium chloride, it is theorized that caking and agglomeration can be avoided during steam sterilization. This saturation reduces the solvent available for dissolving drug particles, preventing reassociation during cooling, which would otherwise lead to size changes.

O’Neill’s Example 1 illustrates a sterile aqueous suspension of dexamethasone acetate in a sodium chloride saturated solution, which is autoclaved without crystal size growth or degradation. Testimony from AstraZeneca's witness, Dr. Williams, affirmed that a POSA would expect the O’Neill method to be effective for budesonide without causing agglomeration. Dr. Dalby corroborated this by noting the similarities in solubility between dexamethasone and budesonide, suggesting that techniques effective for one would likely apply to the other.

Testimony regarding the expectations of a person of ordinary skill in the art (POSA) concerning the sterilization of budesonide was not contradicted. Dr. Zhanel acknowledged that similar chemical structures among steroids would lead a POSA to anticipate similar outcomes. AstraZeneca referenced several post-priority date documents to argue that a POSA would not have reasonably expected to create a sterilized budesonide composition meeting purity standards as of 1997. Notably, U.S. Patent No. 6,464,958 indicated that certain steroid suspensions subjected to wet steam processes experienced significant degradation, while U.S. Patent No. 6,863,865 suggested that standard autoclaving increased impurity levels in budesonide. The Court found AstraZeneca's cited references unpersuasive, as they did not clarify what was known before 1997, contradicting more contemporaneous evidence, particularly O’Neill's findings. O’Neill’s experiments showed no growth or degradation of crystals under specified sterilization conditions, which was not addressed adequately in the critiques from AstraZeneca. The Court concluded that there was no prior evidence indicating that thermal sterilization would unacceptably degrade budesonide, and O’Neill's work demonstrated that degradation was not a concern for a POSA during the sterilization of steroid substances. Testimony from Dr. Williams further supported that a POSA would expect successful results when applying the autoclave process to budesonide, confirming expectations of sterility.

A person of ordinary skill in the art (POSA) would expect that substituting budesonide for dexamethasone, following O’Neill's procedure, would yield a sterile, finely divided budesonide suspension that does not agglomerate. AstraZeneca challenges O’Neill's findings, noting that while O’Neill claims no decomposition occurs, he provides no data on the final product's purity, particularly given expected degradation at high temperatures. Dr. Zhanel testified that if degradation happened in the initial step of O’Neill’s method, the final product would not meet pharmaceutical standards. However, O’Neill asserts that degradation can be avoided through proper autoclaving, which he states can be effective even at 121°C for an hour.

Plaintiffs reference U.S. Patent No. 5,540,930, which mentions that corticosteroid suspensions often face issues with caking due to aggregation during storage, especially when sodium chloride is present. They argue that this teaches against using sodium chloride in budesonide suspensions. However, Ms. Moldenhauer clarified that the patent discusses low sodium chloride concentrations, contrasting with the excess levels mentioned by O’Neill. AstraZeneca misinterpreted her testimony as a general teaching against sodium chloride use. The Patent and Trademark Office (PTO) previously relied on O’Neill to reject AstraZeneca’s claims related to sterile dry solids, while AstraZeneca claimed O’Neill disclosed sterile aqueous suspensions, not heat-sterilized inhalation powders.

Additionally, evidence indicates that a POSA could routinely incorporate a surfactant or wetting agent to prevent agglomeration and caking, a practice recognized as important for maintaining suspension stability from manufacture to use, as noted by Lachman.

Lachman advocates for the use of surfactants to enhance the preparation and stabilization of suspensions by decreasing interfacial tension between particles and the vehicle, thereby reducing the likelihood of agglomeration or caking. Ms. Moldenhauer corroborated this by explaining that surfactants coat particles to prevent clumping. Lachman lists several surfactants suitable for parenteral suspensions and provides a specific formulation example. AstraZeneca's expert, Dr. Akers, confirmed that Lachman teaches the preventative use of surfactants against agglomeration, a concept recognized in the field prior to 1997. Dr. Williams, another expert for AstraZeneca, similarly acknowledged that surfactants or wetting agents are effective in preventing agglomeration and caking.

O’Neill’s work also includes steroidal formulations with wetting agents, and Dr. Williams clarified that a person of ordinary skill in the art (POSA) could routinely determine the appropriate surfactant quantity needed to prevent agglomeration. AstraZeneca, however, contended that surfactants may not completely eliminate agglomeration or caking and suggested that their effectiveness was limited to agglomeration occurring post-manufacturing. Despite this, experts uniformly agreed that surfactants can mitigate agglomeration regardless of when it occurs in the process. O’Neill’s methodologies involve using surfactants prior to steam sterilization to counteract particle size changes during that process.

Additionally, evidence presented indicated that sonication, a technique using ultrasonic energy to break up agglomerated particles, has been well-known since the 1970s and is straightforward to implement. Ms. Moldenhauer noted that POSAs would employ aseptic sonication when developing sterilized products. Dr. Williams and Dr. Akers both recognized sonication as a familiar technique in the field prior to 1997.

Sonication, as referenced in Steckel (DTX 871), involves the suspension of particles in an aqueous solution followed by ultrasonic treatment to measure particle size distribution. Steckel indicates that deagglomeration is completed after 90 seconds of sonication, consistent with earlier findings by Bleich et al. (1994). Ms. Moldenhauer testified that there was no change in particle size before and after sonication, yet the evidence supports that sonication was recognized as a method for addressing agglomeration by 1997. AstraZeneca acknowledged that sonication was known but argued that aseptic sonication was not commonplace due to the sterilization challenges of equipment, a claim contested by Dr. Akers. He acknowledged the availability of sterile isolator technology in 1997, which could mitigate micronization risks. Ms. Moldenhauer further testified that it would have been understood by a person of ordinary skill in the art (POSA) to perform aseptic sonication to avoid contamination. By 1997, POSAs routinely executed post-sterilization steps aseptically. 

Additionally, milling, a mechanical technique for particle size reduction, was well-established in 1997. Evidence presented by the defendants showed that aseptic or sterile milling methods were documented in prior art. Dr. Akers highlighted that sterile powder typically requires particle size reduction, and fluid energy mills were practical for this purpose. The 1994 FDA Inspections Guide acknowledged aseptic milling as a standard step in manufacturing sterile bulk drug substances. U.S. Patent No. 5,407,926 (Abbot F. Clark) describes a micronized drug suspension preparation using sterilized balls for aseptic milling of glucocorticosteroids, reinforcing the known techniques of that period.

The container's contents undergo aseptic milling at 225 rpm for 16 hours to achieve particle sizes around 5 microns. Ms. Moldenhauer testified that a person of ordinary skill in the art (POSA) would routinely use aseptic milling after moist heat sterilization to modify particle size, applicable to both sterile powders and suspensions. AstraZeneca contests the efficacy of milling for creating finely-divided powders, with Dr. Akers distinguishing milling from micronization, asserting milling does not achieve micronization levels. However, the claims merely require "finely-divided" particles, not specifically micronized ones. Dr. Akers acknowledged that milling can alter particle size and that this size can fall within a finely-divided range, but he expressed concerns regarding adequacy for certain administration routes, a limitation not present in the claims. O’Neill's disclosure supports that milling can reduce particle size to 10 microns for suspensions. AstraZeneca noted that milling occurs before moist heat sterilization, but this distinction is deemed irrelevant as milling can produce finely-divided powders. Additionally, evidence was presented on rotary sterilization, which involves a rotating steam sterilizer that keeps contents agitated to prevent agglomeration. Ms. Moldenhauer confirmed rotary sterilization's pharmaceutical use since the 1970s and cited Dr. Akers, who stated that agitation prevents drug particles from settling in suspensions.

Dr. Akers testified that he lacks knowledge of rotary sterilization being used post-moist heat sterilization to address issues like particle size change, agglomeration, or caking, and that a person of skill in the art (POSA) would not expect shaking to resolve these concerns. He asserted that Dr. Michael Akers’ discussion focused on resuspending a suspension after manufacturing, rather than solving problems linked to moist heat sterilization. However, Ms. Moldenhauer provided credible evidence that her employer's other divisions utilized rotary sterilization as early as the 1970s and 1980s. While AstraZeneca claimed that rotary sterilization is not a comprehensive solution to moist heat sterilization challenges, Defendants argued that a POSA could effectively combine it with other known methods to tackle particle size and agglomeration issues. AstraZeneca contended that the techniques mentioned only address select problems, but Defendants countered that it is not necessary to demonstrate that each technique resolves every issue, given that all methods are widely recognized for mitigating the limitations of moist heat sterilization. AstraZeneca also noted that a POSA in 1997 lacked the capability to conduct many techniques aseptically due to technological limitations. Dr. Akers acknowledged the availability of necessary equipment and knowledge while noting the potential for human error in large-scale pharmaceutical manufacturing. He concluded that under optimal aseptic conditions, a POSA could reasonably expect to successfully prepare the claimed compositions using moist heat sterilization alongside known methods to manage particle size, agglomeration, or caking issues. Ultimately, Defendants provided clear evidence that a motivated POSA would have a reasonable expectation of preparing the claimed sterilized budesonide compositions using moist heat sterilization in conjunction with conventional methods. Additionally, Defendants argued that a POSA would have reasonably expected success in creating the claimed compositions using ethylene oxide sterilization, as disclosed in Clark, which supports their claim of invalidity due to obviousness.

Prior to 1997, ethylene oxide (EO) was recognized by a person of ordinary skill in the art (POSA) as a common sterilization method for materials that could not withstand high temperatures. EO sterilization was the standard process for steroid suspensions since at least the 1950s and is still in use today. The process involves placing the material in a chamber, conditioning it to a specific temperature and humidity, introducing EO until a target concentration is reached, and maintaining that concentration for a designated time. POSAs understood that increasing humidity and temperature could reduce exposure time, but could extend exposure time if the material could not tolerate these conditions, which were standard optimizations.

Despite its commonality, concerns existed regarding EO sterilization, specifically related to toxic residues and product penetration. A POSA was aware of methods for determining EO residuals, as evidenced by a 1965 publication by Norman Adler outlining these methods for various pharmaceuticals. By 1965, the issue of toxic residues was recognized in the prior art, and in 1978, the FDA proposed a regulation to limit EO residuals due to potential patient toxicity and mutagenicity risks, suggesting a maximum of 10 ppm in certain drug products. However, the FDA acknowledged the need for continued use of EO sterilization for certain products, and this rule was never enacted.

Defendants argued that by 1997, a POSA would know how to effectively remove EO residuals through aeration, forced ventilation, and vacuum purging. A 1994 FDA guidance document confirmed the ongoing use of EO sterilization and outlined cycle parameters, including degassing and aeration. The ophthalmic sector notably continued to use EO for sterilizing formulations in the mid-1990s.

Defendants provided evidence that ethylene oxide (EO) sterilization was actively utilized up until the invention date of the '834 Patent, with those skilled in the art (POSAs) employing methods to mitigate EO residuals. One such method is aeration, which involves exposing materials to air at ambient temperature or using forced ventilation. Dr. Zhanel, an expert for AstraZeneca, acknowledged that POSAs would use aeration to reduce EO residuals. A 1995 reference, Clark, specifies an aeration cycle of at least 72 hours at 50°C for effective reduction of EO residuals in corticosteroids and other compounds. Additionally, the Portuguese Patent outlines a forced ventilation process at 50°C for 48 hours, achieving a greater reduction of EO residuals compared to conventional aeration. Evidence from Dr. Michael Miller supports that vacuum purging, another technique known to POSAs, can also decrease EO residuals by generating negative pressure. Adler’s research indicates that different vacuum treatments can effectively reduce EO levels in various substances. Both Dr. Miller and Dr. Dalby confirm that EO sterilization followed by aeration was in use for ophthalmic glucocorticoids by the 1980s and 1990s. The 1995 USP noted that gas sterilization is often preferred for heat-sensitive materials, and AstraZeneca's expert confirmed that EO sterilization remains in practice today. The FDA has not mandated the removal of EO-sterilized products from the market, despite concerns about residuals, and Dr. Zhanel conceded that steroid suspensions sterilized by EO are considered pharmaceutically acceptable.

Clark utilized ethylene oxide (EO) sterilization for preparing ophthalmic suspensions aimed at treating eye inflammation. AstraZeneca's Preferid® product, a micronized budesonide suspension marketed as sterile and 98-102% pure, also underwent EO sterilization. Manufacturing from 1980 to 1983 involved exposing budesonide particles to EO, resulting in residual levels of 12 to 22 ppm in the powder and less than 0.006 ppm in the suspension. AstraZeneca later abandoned the EO exposure step due to new regulatory requirements in Scandinavian countries, removing the term ‘sterile’ from the product description. While AstraZeneca claims the residuals rendered the product pharmaceutically unacceptable, there is insufficient evidence supporting this assertion. Inventor Ekelund's declaration fails to detail the regulatory changes or connect them to the acceptability of the EO-sterilized product. Evidence suggests the discontinuation of EO sterilization was related to regulations on exposure limits for manufacturing personnel, not the product's pharmaceutical acceptability. Dr. Zhanel testified that, as of 1997, a person of ordinary skill in the art (POSA) would expect zero tolerance for EO residuals, with European Union recommendations limiting steroid powder residuals to 1 ppm. He argued that residuals of 12 to 22 ppm from Preferid would be considered unacceptable. However, these European guidelines did not apply in the U.S., where a 1978 FDA proposed rule suggested a 10 ppm limit that was never enacted, allowing continued use of EO sterilization. Dr. Zhanel's opinion on the acceptability of residuals was based on products intended for injection or nebulization, which are not limitations of the claim and thus carry less weight in court.

A person of skill in the art (POSA) can effectively reduce ethylene oxide (EO) residuals in steroid powders by utilizing established techniques and optimizing degasification processes. Dr. Zhanel noted that a POSA would expect high EO residues in steroid powders, recognizing that existing methods to reduce these residues are often ineffective. Defendants’ expert, Dr. Dalby, highlighted that even after 8 hours of vacuum treatment, a steroid sample still contained 0.51% EO residue, significantly less than the 1.61% found after only 2 hours. However, Dr. Dalby also pointed out that substantial reductions in EO residuals could be achieved after 6 hours of vacuum treatment, suggesting that longer treatment cycles, as indicated in other prior art, would likely yield even lower residual levels. Both experts agreed that diluting EO residuals occurs when a sterilized powder is added to a suspension.

Additionally, evidence was presented indicating that a POSA would not be overly concerned about EO's ability to penetrate the crystalline structure of water-insoluble drugs, like budesonide. Some prior art suggests EO primarily acts as a surface sterilant, with doubts about its penetration into the core of sterile powders. However, Dr. Miller and Ms. Moldenhauer both testified against this notion, indicating a lack of scientific evidence that spores are trapped within crystals and not sterilized by EO, thus affirming a POSA would be aware of EO's penetrative capabilities.

A sterile micronized budesonide suspension treated with ethylene oxide (EO) maintained purity levels over 98%. Dr. Miller testified that if EO failed to penetrate the budesonide particles, the product would not have passed sterility tests and could not be marketed as sterile. He referenced several sterile ophthalmic corticosteroid suspensions that would not meet sterility standards without EO inactivation of spores, noting that he was unaware of any recalls or contamination issues related to these products, which the Court found credible and consistent with prior art.

In contrast, Dr. Akers argued that EO sterilization was ineffective due to its inability to penetrate solid crystalline materials, citing a 1968 study on bacterial spores in water-soluble crystals. However, this study did not address the sterilization of glucocorticosteroids, and Dr. Akers admitted he knew of no prior art suggesting EO could not penetrate budesonide or similar corticosteroids. The Court deemed his opinion unhelpful.

Ultimately, the Court concluded that defendants demonstrated a person of ordinary skill in the art (POSA), motivated to create sterile budesonide compositions, would reasonably expect success with EO sterilization, despite potential toxic residuals. The POSA could employ known methods to reduce these residuals to acceptable levels. The existence of marketed sterile ophthalmic suspensions using EO without contamination issues further supported this conclusion. Therefore, the Court found the asserted claims invalid due to obviousness.

Additionally, the defendants provided evidence that a POSA would have a reasonable expectation of success in using conventional irradiation sterilization for budesonide compositions, as described in the Guy reference, which involved killing microorganisms through ionizing radiation methods like beta and gamma irradiation.

Prior to 1997, irradiation sterilization processes were already established, and a person of ordinary skill in the art (POSA) could routinely optimize these processes, considering factors such as the type of irradiation (beta or gamma), dose, energy level, and power output. The patent filed by Guy in 1993 and issued in 1996 discloses sterile, aqueous ophthalmic glucocorticosteroid suspensions, teaching all elements of the asserted claims except for budesonide. Guy is assumed to be enabled as a prior art patent. He specifies that irradiation can sterilize the glucocorticosteroid used in these suspensions and mentions the potential use of other steroids, including beclomethasone and betamethasone.

Guy's disclosures indicate that the purity levels of the materials used in the suspensions exceed 98%, while the asserted claims of the '834 Patent require a minimum purity of 98.5%, thus falling within Guy's disclosed range. The Federal Circuit has established that if the difference between a claimed invention and prior art is merely a range or value, a patent should not be granted if that difference is minor. Claims that fall within a prior art range are presumed obvious unless it can be demonstrated that prior art taught away from the claimed invention or that new and unexpected results were achieved.

No evidence was presented to rebut the presumption of obviousness regarding purity levels. Although Guy does not specify the irradiation parameters, expert testimony indicated these parameters were well-known to a POSA capable of routine optimization. Additionally, established literature from 1975 and 1974 supports the successful use of irradiation for the sterilization of steroids, detailing necessary considerations such as dose and material density.

Ilium's findings indicate that degradation rates for hydro-cortisone acetate and prednisone are below 1%, while hydrocortisone, prednisolone, and prednisolone hydrate have degradation rates of about 2-4%. Despite these degradation rates, Ilium concludes that the steroid powders are physically stable when subjected to realistic irradiation doses for sterilization. Dr. Miller acknowledges that irradiation can lead to undesirable degradation products, potentially affecting pharmaceutical acceptability, but prior art suggests minimal degradation for certain steroids. The inventors of the '834 Patent reference Ilium's recommendation for beta or gamma irradiation to sterilize glucocorticosteroids.

The only absent element from Guy’s disclosures in the asserted claims is budesonide. Dr. Miller argues that a person of ordinary skill in the art (POSA) would integrate Guy's teachings with U.S. Patent No. 5,589,184 by Robertson, which also covers ophthalmic pharmaceutical compositions and includes budesonide as a viable option. AstraZeneca contends that a POSA in 1997 would doubt the efficacy of irradiation for budesonide due to concerns about degradation impacting purity and acceptability. Dr. Zhanel supports this by citing Ilium's degradation data.

However, Ilium's overall conclusion is that steroid powders maintain stability under irradiation, and minimal degradation is observed, which would not deter a POSA from considering irradiation as a sterilization method. Furthermore, the FDA acknowledged the potential for successful gamma irradiation of budesonide, stating that lower doses could mitigate degradation while reducing bioburden. This evidence aligns with Dr. Miller's assertion that a POSA would reasonably expect successful sterilization of budesonide via irradiation. AstraZeneca also cites other references and its own experiences to argue against the success of this method for budesonide.

The '834 Patent indicates that micronized budesonide cannot be satisfactorily sterilized using beta irradiation due to significant chemical degradation, as stated by the inventors. However, in Comparative Example 8, the inventors' data shows that budesonide exposed to beta irradiation at doses between 2.5 to 25 kGy maintained over 98.8% of its content. Dr. Miller testified that this evidence contradicts the inventors’ conclusion regarding degradation from irradiation. Additionally, although there was an increase in unknown foreign steroids after irradiation, Dr. Miller argued that a person of ordinary skill in the art (POSA) would recognize that impurities are acceptable in pharmaceutical powders, noting that the tested budesonide already contained unknown foreign steroids prior to irradiation. The levels of these steroids post-irradiation were similar to those in data from AstraZeneca’s heat treatment process, yet no credible evidence was presented to deem these levels pharmaceutically unacceptable. Dr. Elkins testified that AstraZeneca's irradiation experiments demonstrated feasibility but required more effort to develop a commercial process than dry heat methods. AstraZeneca's claims about the Defendants’ inability to produce the claimed product via irradiation sterilization were deemed irrelevant to the Court's analysis of obviousness, and evidence did not support any failure in making the claimed products or using irradiation. The PTO Examiner considered the prior art, specifically Guy's teaching about using EDTA to inhibit microbial growth, but did not address it in the context of the current arguments. The Defendants provided compelling evidence that a POSA, motivated to create sterilized budesonide compositions, would reasonably expect to succeed with conventional irradiation techniques based on the teachings of Guy and Robertson. They also argued that a POSA would have similarly expected success using dry heat sterilization methods disclosed in Clark, leading to the assertion that the claims are invalid due to obviousness.

Clark disclosed the use of ethylene oxide (EO) and dry heat for sterilizing glucocorticosteroids in sterile ophthalmic suspensions. Dry heat sterilization involves placing materials in an oven-like chamber, introducing filtered air, and raising the temperature for a sufficient period to achieve sterilization. As of 1997, a person of ordinary skill in the art (POSA) recognized the inverse relationship between temperature and time for sterilization, allowing for lower temperatures with extended exposure times, tailored to the drug's characteristics. Conventional dry heat cycles typically ran between 140-180°C. Defendants argued that a POSA would routinely opt for lower temperatures due to the sensitivity of some substances. Dr. Miller testified that a POSA would have likely attempted lower temperatures for sterilizing budesonide, citing Remington, which indicates that some pharmaceutical preparations cannot withstand conventional temperatures. However, it was noted that prior art did not provide dry heat sterilization cycles below 140°C, and Dr. Zhanel stated that unconventional lower temperatures were viewed as sub-lethal. By 1997, the trend favored higher temperatures for dry heat sterilization, as indicated by Ansel, which emphasized the need for higher temperatures and longer exposure due to the lower effectiveness of dry heat compared to moist heat. Ansel acknowledged that sterilization parameters could be adjusted based on the specific substance but mainly referenced the typical temperature range. The Court raised questions about whether AstraZeneca's innovation merely involved reducing sterilization temperatures, noting that prior art recommended maintaining a specific temperature range (140-170°C) with a trend towards higher temperatures, whereas AstraZeneca's process operated between 100-130°C, ideally 110-120°C.

Defendants did not convincingly establish that a person of ordinary skill in the art (POSA) would have reasonably expected to create the claimed budesonide compositions using dry heat at lower temperatures than conventional methods. The Court evaluated secondary considerations of nonobviousness, including commercial success, unmet needs, and failures by others, which can inform the patentability of the subject matter. Although these factors are relevant, they do not solely determine the obviousness conclusion. Secondary considerations must align with the scope of the claims, and demonstrating unexpected results in one embodiment can support the broader claim scope. A nexus is required between the claimed features and the evidence presented for nonobviousness, and prior knowledge of features that contributed to commercial success negates their relevance. AstraZeneca presented several arguments against obviousness, such as industry skepticism, unmet needs, failures by AstraZeneca and others, and commercial success. However, the Court found these arguments insufficient to counteract the strong evidence of obviousness. Specifically, while skepticism from skilled artisans can indicate nonobviousness, the inquiry should focus on the ability to sterilize budesonide rather than AstraZeneca's internal beliefs about the process.

Skepticism regarding the sterilization of budesonide is primarily directed at external parties rather than the inventors. Evidence presented by AstraZeneca, including slides from a November 1996 pre-NDA meeting, indicated that sterilization was deemed "not required and not feasible." However, these slides highlighted only potential disadvantages of sterilization techniques and were created before the FDA mandated a sterile product or proof of infeasibility. Subsequent documents suggested that preliminary data did not support the assertion that the drug substance could not be sterilized. Statements made in these documents often lacked adequate data support. Notably, inventor Elkins acknowledged that irradiation and ethylene oxide (EO) methods were feasible, although not pursued further due to the need for additional development to address residuals from EO treatment.

AstraZeneca claimed that, as of 1997, the industry widely believed that budesonide could not be sterilized while maintaining purity, but this claim was primarily self-referential. For instance, a statement in the McAffer Patent about the impossibility of budesonide sterilization was based on AstraZeneca's own documentation. Additionally, communications from other pharmaceutical companies indicated a desire for sterile budesonide, contradicting the claim of impossibility. McAffer testified that the scientific community did not share the market's skepticism about the sterilization of budesonide, suggesting a divergence between industry beliefs and scientific opinion. Therefore, the evidence does not substantiate AstraZeneca's assertion of widespread industry skepticism.

AstraZeneca's claim that the FDA was skeptical about the sterilization of budesonide lacks sufficient evidence; instead, the FDA acknowledged the challenges associated with sterilizing suspensions but did not dismiss the possibility. During a pre-NDA meeting on November 20, 1996, the FDA stated that it expects sterile products for inhalation and indicated that approving a non-sterile inhalation product would set a negative precedent. The FDA emphasized the necessity for AstraZeneca to produce a sterile product or justify its inability to do so, as the responsibility for generating data lies with the manufacturer. AstraZeneca's own witness, Mr. Peter Mathers, noted that the FDA does not conduct its own testing and that it was uncertain whether sterilization was possible due to a lack of data. The FDA's instructions to AstraZeneca focused on performing tests to gather sufficient data, highlighting that the agency did not express skepticism about the sterilization of budesonide but rather sought confirmation of its feasibility. Additionally, the FDA did not enforce a regulatory requirement for the sterility of inhaled aqueous suspensions until after AstraZeneca demonstrated the possibility.

AstraZeneca contends that the FDA's microbiology review of its Pulmicort Respules NDA, completed in 1998, demonstrated satisfaction with the sterility assurance for inhalation solutions prior to the 2000 Final Rule, which mandated sterilization for all aqueous-based oral inhalation products. AstraZeneca argues this indicates that the FDA believed sterilization of suspensions was not feasible and only imposed the 2000 Final Rule due to AstraZeneca’s unexpected success. However, the 1997 Proposed Rule explicitly required sterility for aqueous inhalation solutions, intentionally excluding suspensions, as testified by Mr. Mathers. Dr. Muhvich asserted that the Proposed Rule was meant to apply to both solutions and suspensions, reflecting a shared understanding of contamination risks. His subsequent comment to the FDA advocated for the requirement of sterility in inhalation suspensions, which led to requests for clarification on the rule’s scope. The FDA ultimately revised the Final Rule to specify that all aqueous-based drug products must be sterile, effective May 11, 2000, contradicting AstraZeneca's speculation about the impetus for the rule change. Mr. Mathers indicated that the change was motivated by safety concerns regarding contamination in both solutions and suspensions, rather than AstraZeneca’s successful sterilization innovation. The FDA acknowledged receiving numerous comments that influenced the clarification of the Final Rule's language.

POSAs understood that the FDA expected inhalation products, including suspensions, to be sterile, indicating that other entities besides AstraZeneca were producing sterile suspensions, weakening AstraZeneca's position. AstraZeneca's claim that the FDA altered its Final Rule due to the '834 Patent is characterized as unfounded speculation. The evidence presented does not show skepticism from the industry, FDA, or AstraZeneca, which undermines the nonobviousness of the patent claims. 

Regarding the long-felt, unmet need, evidence must directly relate to the asserted claims. AstraZeneca argued that there was a long-felt need for an aqueous, sterile, nebulized corticosteroid for young children with asthma. However, it was established that a nonsterile version of Pulmicort Respules® would have satisfied this need. While a sterile product was preferable for health safety, had the FDA allowed nonsterile Pulmicort Respules® in the U.S., the unmet need would have been addressed. Testimony from physicians indicated that nonsterile products would have met the treatment needs of young children, confirming that European and Canadian versions could have sufficed even in nonsterile form. AstraZeneca's own witness acknowledged that the essential need was for nebulized budesonide, which the nonsterile Pulmicort Respules could fulfill pending FDA approval.

Dr. Ververelli acknowledged that FDA approval of a nonsterile Pulmicort Respules would have addressed the unmet need he testified about, suggesting that although sterility was important, the primary need was for a nebulized corticosteroid with proven efficacy, particularly for treating young children with asthma. Dr. Zhanel corroborated the existence of a long-felt need for a sterile steroid suspension suitable for nebulization, indicating that while sterile formulations were desired in some contexts, the pressing requirement was a nebulized suspension for pediatric use. This contrast with Dr. Ververelli's assertion that the unmet need was specific to nebulized budesonide suggests a more nuanced understanding of the community's needs.

The Court favored Dr. Ververelli's testimony, aligning with other evidence, and concluded that AstraZeneca's argument linking the FDA's requirements for sterile products with the community's needs was flawed. AstraZeneca's reference to Knoll Pharm. Co. v. Teva Pharm. USA was deemed inapplicable because, unlike that case, there was no evidence of failed attempts to gain FDA approval for their products; rather, the defendants had successfully obtained FDA approval for their ANDA products. Consequently, AstraZeneca failed to establish a nexus between the sterility feature of the '834 Patent and the long-felt unmet need, as their evidence was limited to a specific embodiment (Pulmicort Respules) and did not sufficiently support the broader claims made. The Court noted that secondary considerations must align with the claims' scope, and the asserted claims did not pertain specifically to long-term asthma treatment in children, being broader in nature.

Evidence of secondary considerations in patent claims must align with the scope of the claims; if the evidence pertains only to one compound and does not adequately address other compounds within the claim, it may not be sufficient. Secondary considerations are deemed not commensurate with claims if the claims are broader than the evidence, either due to differences in limitations or elements. AstraZeneca's evidence of long-felt unmet needs largely relates to elements not included in its asserted claims, failing to support the notion that other embodiments would satisfy such needs.

The failures of others in developing similar inventions can demonstrate nonobviousness, as established in several case law precedents, indicating that these failures reflect significant defects in prior art. AstraZeneca’s own failures in creating claimed budesonide compositions using conventional sterilization methods have been presented but are considered less relevant compared to the failures of others in the field. The focus of secondary considerations typically rests on evidence of others' failures, and while AstraZeneca argues that its own failures indicate nonobviousness, the court finds this evidence less compelling than AstraZeneca suggests.

AstraZeneca developed and marketed a sterile product, Preferid®, in the 1980s, with no evidence indicating that ethylene oxide (EO) residues made it pharmaceutically unacceptable or that there were issues with the penetration of the budesonide molecule’s crystal core. Dr. Elkins testified that while AstraZeneca's irradiation experiments indicated feasibility, the effort needed to commercialize this process exceeded that of dry heat sterilization. She did not classify the irradiation experiments as unsuccessful. Importantly, AstraZeneca successfully created sterilized budesonide compositions using a patented low dry heat process shortly after receiving FDA guidance. 

The document highlights that while failures by others can indicate nonobviousness, a clear understanding of these failures is necessary. The evidence presented was insufficient to ascertain the nature of the defendants’ attempts to produce a sterilized budesonide suspension, which AstraZeneca contended was crucial. AstraZeneca introduced a decision tree from [Redacted] that showed a preference for filter sterilization after deeming conventional methods ineffective. However, there was a lack of competent evidence to confirm that [Redacted] had actually considered or undertaken all the listed sterilization steps.

Dr. Akers noted uncertainty about whether [Redacted] explored methods beyond sterile crystallization, and he did not expect the Drug Master File to include feasibility studies for other methods, confirming their absence. He also acknowledged that the decision tree was derived directly from a European Medicines Agency publication aimed at selecting optimal sterilization methods, not created by [Redacted]. Additionally, evidence indicated that [Redacted] tried using irradiation for terminal sterilization but faced degradation of the active ingredient with various doses, concluding that post-manufacturing sterilization was not achievable at that time.

Dr. Jiang clarified that "FP" refers to final product or budesonide suspension. Evidence indicates that [Redacted] did not attempt to sterilize budesonide powder, nor is there proof of any efforts to do so. AstraZeneca argues that [Redacted] failed to produce a pharmaceutically acceptable sterile budesonide due to particle size changes, with Mr. Madsen confirming that [Redacted] used a process that was not acceptable, leading to the decision to use a conventional method known since 1997 to achieve a compliant product. The Court noted a lack of competent evidence regarding Defendants' failures, particularly as AstraZeneca and Teva successfully prepared sterile budesonide through established sterilization techniques. The failure of others to solve the problem supports a finding of non-obviousness, although the significance diminishes when recognizing that failures were limited to treating one type of infection. AstraZeneca also presented hearsay evidence of other companies' sterilization failures, but the lack of details regarding those failures weakens their relevance, especially considering the existence of multiple successful gluco-corticosteroid ophthalmic suspensions by 1997.

Commercial success is a critical factor in determining non-obviousness, as it implies that a product would have reached the market sooner if it were obvious. AstraZeneca demonstrated significant commercial success with Pulmicort Respules, having sold over 44 million packages and generating $5.6 billion in net sales from 2000 to May 2014. This success suggests a substantial difference between the invention and prior art, although it must be distinguished from success due to marketing efforts.

AstraZeneca asserts a connection between its commercial success and the '834 Patent based on FDA approval, claiming that its ability to sterilize budesonide suspension enabled this approval. Dr. Yellturo testified that AstraZeneca's invention allowed the company to capitalize on the market for nebulized corticosteroids for children, suggesting that without this invention, AstraZeneca would face increased competition or potentially be excluded from the market due to FDA demands for sterility. The court, however, cautions that regulatory compliance cannot be equated with commercial success. It notes that while FDA approval is necessary for market access, it does not inherently drive demand for Pulmicort Respules, as demonstrated by the success of nonsterile versions of the product in Europe. AstraZeneca's argument conflates sterility as a regulatory requirement with factors influencing sales. The court emphasizes that the evaluation of any nexus between the patented product's features and commercial success must focus on sales drivers rather than mere compliance. Additionally, AstraZeneca attempts to justify its claims by citing hearsay regarding competitors' decisions not to pursue sterility, but this evidence lacks clarity on the reasons behind those decisions. Overall, the court remains skeptical of AstraZeneca's assertions about the relationship between sterility and its market success.

The decision by the manufacturers of fluticasone and beclomethasone not to pursue U.S. market approval remains unclear, with no definitive insight into their reasoning. It is suggested that the potential revenue from these products may not justify the costs associated with ensuring sterility. Evidence does not establish a direct correlation between the sales of Pulmicort Respules® and its sterility. Dr. Vellturo indicated that sterility contributed to the product's commercial success by alleviating safety concerns among physicians, as the FDA considers sterility essential for suspensions. However, he admitted a lack of concrete evidence linking sterility to physicians' specific demands. Dr. Ververelli corroborated that safety, not sterility, is paramount, asserting that a nonsterile product could still fulfill market needs if FDA approved it, as physicians would trust its safety. The court found Dr. Vellturo's analysis of Pulmicort Respules®' commercial success flawed and unconvincing, noting he failed to assess the relative impacts of multiple factors driving success, including efficacy, safety, delivery method, and dosing frequency. Mr. Spadea, the defendants’ expert, argued that the product's success stemmed from factors unrelated to the '834 Patent, emphasizing that sterility is not a marketed feature or a primary reason for physician prescriptions. He highlighted that pharmaceutical companies focus on promoting consumer-relevant product attributes, indicating that sterility does not significantly influence marketing or sales strategies.

AstraZeneca's marketing materials for Pulmicort Respules® do not emphasize the product's sterility but rather highlight the safety and efficacy of the budesonide molecule. A 2001 marketing study recommended promoting the product's unique nebulizing delivery mechanism and efficacy. An internal 2006 strategic plan identified the historical safety of budesonide as a strength. Physician surveys indicated that efficacy, delivery compatibility for young children, and safety were the primary reasons for prescribing Pulmicort Respules, with sterility not mentioned as a significant factor. A third-party study linked safety to the budesonide molecule and its pregnancy Category B labeling. Notably, 91% of physicians prioritized efficacy over dosing when choosing asthma controllers, and sterility was absent from the considerations. Additionally, nonsterile versions of Pulmicort sold successfully in Europe and Canada, leading American physicians to request availability in the U.S. Dr. Ververelli provided nonsterile Canadian Pulmicort to some patients, considering it safe and effective. The evidence indicates no connection between the patented feature of sterility and the product's commercial success, which is attributed to known aspects such as the budesonide molecule. AstraZeneca has not demonstrated a requisite nexus between the commercial success and the claimed novel features of the '834 Patent, as established in relevant case law.

The patentee did not demonstrate a sufficient connection between secondary considerations and the patented invention, leading to the conclusion that the claimed sterile budesonide compositions (as set forth in claims 1, 2, 50, and 51) were obvious. Evidence indicated that a person of ordinary skill in the art (POSA) would reasonably expect to create these compositions using four conventional sterilization methods: sterile filtration/crystallization, moist heat, ethylene oxide (EO), and irradiation. Furthermore, secondary considerations of nonobviousness were deemed insufficient to counter a strong prima facie case of obviousness, resulting in the asserted claims being invalidated on this ground.

Regarding anticipation, the critical issue is whether a POSA could find every claim element disclosed in a prior art reference. Anticipation is established when the claimed subject matter is not novel and was previously known. To invalidate a claim on this basis, every element must be described in a single prior art reference, either explicitly or inherently. The party asserting anticipation must provide clear and convincing evidence at trial. The court evaluates the prior art as a whole to determine if it discloses all elements of the claim in the claimed arrangement.

Defendants contended that the asserted claims were anticipated by U.S. Patent No. 3,992,534, which discusses compositions and methods involving glucocorticosteroids. Expert testimony indicated that this patent included budesonide and disclosed pharmaceutical formulations containing various steroids, which supports the anticipation argument.

Brattsand presents formulations for treating asthma and inflammatory conditions, emphasizing that steroids for oral or nasal inhalation must contain particles smaller than 5 micrometers, aided by a surfactant in the propellant mixture. The patent allows for the preparation of new stereoisomeric components in pure form, but does not specify sterility, purity, or pharmaceutical acceptability levels, particularly not achieving the purity level of 98.5%. Testimony indicated that while Brattsand discusses budesonide’s therapeutic effectiveness, it lacks disclosure on the requisite purity standards. The Court finds that Defendants did not provide clear and convincing evidence that Brattsand anticipates the asserted claims.

Defendants also claimed that the asserted claims lack enablement under 35 U.S.C. § 112, arguing that the specification does not provide enough information for a person of skill in the art (POSA) to produce the claimed compositions without undue experimentation, particularly a nonsterile budesonide suspension. The Court previously rejected this argument and reiterated that Defendants failed to prove a lack of enablement.

Additionally, Defendants argued that the claims lacked a sufficient written description under 35 U.S.C. § 112, asserting that the inventors did not possess a suspension with a nonsterile budesonide product. The Court found that this argument was addressed in a prior opinion and also failed to demonstrate a lack of a sufficient written description.

In conclusion, the Court declared the '834 Patent invalid due to obviousness under 35 U.S.C. § 103, leading to a judgment of non-infringement in favor of Defendants. AstraZeneca’s requests for a permanent injunction and for the case to be declared exceptional were dismissed as moot, and a trial on damages will be held, with the related claims dismissed without prejudice.

The Court has rejected the Defendants' arguments regarding the invalidity of AstraZeneca's patent based on anticipation, enablement, and written description. AstraZeneca sought to establish an invention date before October 9, 1997, through a Rule 131 Declaration submitted to the Patent and Trademark Office (PTO), which allows patent applicants to demonstrate that their invention occurred prior to the relevant prior art date. The PTO examines such declarations for compliance but does not investigate the claims made therein.

Defendants moved to strike new arguments and evidence from AstraZeneca concerning its reduction to practice of the invention, asserting that these were in violation of a prior Court order prohibiting additional evidence on this issue. The Court noted that AstraZeneca had previously chosen not to brief the alternative invention dates proposed by Dr. Elkins and found that the evidence presented was largely from the prior trial, with the exception of unchallenged testimony regarding standard sterile suspension practices.

The Court determined that AstraZeneca's findings of fact did not violate its prior order and denied Defendants' motion to strike. While Defendants highlighted that documentation was not certified by a supervisor until October 21, 1997, the Court deemed this irrelevant since batch records contained relevant analysis dates. AstraZeneca's argument regarding a specific method code indicating a sterility test lacked supporting evidence; however, the batch records showing satisfactory sterility results were considered sufficient. This context may clarify AstraZeneca's agreement that the Steckel reference qualifies as prior art.

AstraZeneca's assertion that a guarantee of success is required for its experts is incorrect; the relevant standard is a reasonable expectation of success. AstraZeneca disputes the defendants' claim that the International Patient Package Leaflet (IPPL) satisfies all claim limitations due to its failure to disclose the purity of budesonide. The 1997 Proposed Rule, established as prior art, was published on September 23, 1997, and AstraZeneca did not provide comments to the defendants until after the remand trial began. There is no evidence indicating that the defendants knew Muhvich authored the comment prior to that time. It is noted that public understanding of the rule may have been limited, but significant investments in drug product development necessitate a clear understanding of regulatory requirements. Industry perceptions indicated a need for sterile aqueous inhalant products. Various prior art references recognize the need for aseptic processing systems, particularly for crystallization. The parties agreed that Steckel qualifies as prior art under 35 U.S.C. § 102(b), with stipulations being binding. AstraZeneca contests the testimonies regarding Steckel's disclosure of suitable budesonide solvent conditions for sterile filtration. However, AstraZeneca's own witness acknowledged that a person of ordinary skill in the art (POSA) would know how to design studies for the compatibility of budesonide and dichloromethane. Additionally, milling is defined as the mechanical reduction of particle size to achieve a desired range. Dr. Michael Akers, who authored prior art references, is not related to AstraZeneca's expert, Dr. James Akers, and describes two methods for preparing parenteral suspensions: combining sterile powder with a vehicle aseptically or combining sterile solutions to form crystals in situ.

Ansel disclosed the preparation of sterile suspensions through the combination of a fine powder drug with an insoluble liquid, emphasizing the necessity of pre-sterilizing components and aseptic filling. Dr. Zhanel referred to key texts on sterility, including Remingtons and Lachmans, as essential references. AstraZeneca contends that if a certain patent, Harris, is considered prior art, a person of ordinary skill in the art (POSA) would not expect success due to the absence of process simulation data supporting Harris' sterility claim. Conversely, if Harris is deemed non-prior art, AstraZeneca claims it is novel. The existing record regarding the invented product is limited, with testimony suggesting that the nebulizer suspension of mometasone furoate monohydrate had potential as an innovative product.

AstraZeneca argues that sterile filtration combined with aseptic processing is positioned unfavorably in certain decision-making frameworks, suggesting that this evidence indicates a POSA would be discouraged from utilizing sterile filtration. However, Dr. Akers countered that these frameworks simply guide organizations in selecting appropriate manufacturing technologies for sterile processes without demanding absolute success. Both Dr. Akers and AstraZeneca’s testimony indicated that the claims do not impose restrictions concerning commercial scale production. Evidence presented by the plaintiffs regarding equipment availability is inconclusive for 1997, primarily showing that a certain company chose to invest in infrastructure that may or may not have been necessary for large-scale sterilized product manufacturing. Importantly, the trial evidence confirmed that knowledge and equipment for small-scale production were available to a POSA in 1997. Additionally, the claims do not stipulate a specific sterility assurance level (SAL), and AstraZeneca's experts acknowledged that the SAL for aseptic processes has been considered to be 10^-3, suggesting that this figure underrepresents the capabilities of current aseptic processes in healthcare.

The 1-0 value is noted as arbitrary and unsupported by technical literature. Experts Drs. Akers and Agalloco assert that the capability of aseptic processing cannot be derived as accurately as that of destructive physical processes, though this does not undermine aseptic processes' suitability for sterile product manufacturing. AstraZeneca previously argued that the cumbersome nature of the filtration process would deter a person of ordinary skill in the art (POSA) from attempting it, thus rendering the product nonobvious. The connection between a product's obviousness and the feasibility of its production process is emphasized, indicating that if a process is deemed too cumbersome, it would likely not be pursued, preventing product development. Applicants challenge the Examiner's proposed significant modifications to the Jakupovic process, which aimed to produce crystalline budesonide without micronization, arguing that the modifications might not achieve the intended results. The Applicants have amended claim 65 to clarify that the powder composition is "micronized," a method typically used for reducing particle size, while Jakupovic sought to avoid micronization due to potential adverse effects on crystalline structure and properties. Nearly ten years elapsed between the U.S. application filing and the issuance of the '834 Patent. Defendants introduced Leuschner as a prior art reference that could render the claims obvious; however, the Court does not accept this due to AstraZeneca's demonstration of a reduction in practice date before September 30, 1997. Moist heat sterilization's classification as a terminal process is discussed, highlighting that its effectiveness can vary with different glucocorticosteroids, though a POSA would have reasonable expectations of success in creating a sterile budesonide suspension. Dr. Zhanel's testimony regarding sterilization methods was critiqued as overly narrow and restrictive in relation to prior art.

Dr. Zhanel testified that a person of ordinary skill in the art (POSA) seeks a product that meets three criteria: sterility, purity, and pharmaceutical acceptability. He expressed skepticism towards evidence that does not demonstrate all three aspects, stating that simply showing sterilization does not suffice without proof of purity and acceptability. He noted that previous references, like Abshire and Guy, failed to provide data on this complete triad, thus undermining their relevance. Despite this, the law allows for a patent to be considered obvious based on a combination of prior art, as established in cases like Medichem and KSR. Dr. Zhanel's approach was criticized for introducing qualifiers into his definition of a POSA, suggesting limitations on time and resources that are not typically part of that definition. He acknowledged the urgency and focus of a POSA in drug development, but his testimony was deemed unpersuasive, especially when he appeared to align with AstraZeneca's approach, which overemphasized manufacturing concerns. Relevant references also indicated that certain sterilization processes may not apply to drug substances due to degradation risks.

Steroids in powder form are unstable at temperatures above 60°C, with existing references emphasizing the advantages of specific sterilization techniques while providing little evidence regarding the state of the art. AstraZeneca criticizes the Patent Examiner's reliance on the McAffer Patent, which indicated that moist heat sterilization degraded budesonide, referencing Table 4 that did not meet purity requirements. The Court finds this evidence insufficient due to its context and the absence of specific claims at that time. However, two subsequent references suggest that a person skilled in the art (POSA) would likely achieve successful moist heat sterilization of budesonide without degradation. The first, U.S. Patent No. 5,858,998 (Leuschner), describes a budesonide solution prepared for parenteral administration that undergoes moist heat sterilization without noted degradation. The second, U.S. Patent No. 6,066,292 (Purwar), acknowledges the O’Neill patent and employs steam sterilization for hydrocortisone, contradicting AstraZeneca's claims about the art. These later patents serve as evidence of the state of the art at the time of AstraZeneca’s invention. Additionally, while Dr. Akers argues that prior art does not support aseptic sonication for particle size issues, he concedes that the technology was well-known before 1997. He acknowledges that while milling can resize particles, achieving the necessary small sizes for certain products may be unlikely. Abshire, associated with Alcon, notes their use of various sterilization techniques including dry heat and UV radiation.

Dr. Zhanel's testimony regarding AstraZeneca's decision to stop marketing Prefer-id® as sterile is characterized as speculative. AstraZeneca claims this decision was due to issues with toxicity and the ethylene oxide (EO) process, but concerns about residuals were documented over a decade before Prefer-id® was manufactured. Although Prefer-id® ceased to be marketed as sterile after 1983, no evidence establishes that this was due to AstraZeneca discovering failures in the EO process. AstraZeneca's assertion that Ms. Moldenhauer confirmed the presence of unacceptable foreign steroids in Table 8 lacks supporting testimony. While Dr. Miller confirmed the amounts of these steroids, it does not substantiate AstraZeneca's conclusions. In a 1996 meeting with the FDA, AstraZeneca provided specifications for its budesonide product, allowing for total impurities and individual unknown degradants within specified limits, indicating that mere presence of unknown degradants does not imply failure of irradiation. The Examiner had previously rejected sterile powder claims as obvious, and AstraZeneca's arguments against these rejections were based on the presence of irradiation byproducts, which are not relevant here. During closing arguments, Plaintiffs acknowledged their secondary consideration argument regarding unexpected results pertains only to dry heat sterilization. The court determined that Defendants did not provide enough evidence for a reasonable expectation of success with dry heat, rendering the secondary consideration arguments unnecessary. Furthermore, there is no evidence detailing the efforts of other companies to sterilize budesonide. J. Jenkins emphasized the importance of achieving a sterile product, advising discussions with the FDA if it proves unfeasible, as the FDA does not support nonsterile products. Defendants objected to Mr. Mathers' testimony during the trial, citing Federal Rules of Evidence 702 and 403, claiming it was untimely and intended to rebut opinions from the prior trial.

The Court has overruled the Defendants’ objections regarding Mr. Mathers' testimony, which they argued was based solely on his experience as an attorney, questioning his competency under Federal Rule of Evidence 702. The Court found that Mr. Mathers, with over 35 years of experience practicing before the FDA, possesses the specialized knowledge necessary to assist the Court in understanding FDA regulations. His testimony is deemed admissible under Rule 702 criteria, which requires expert testimony to help the trier of fact, be based on sufficient data, utilize reliable methods, and apply those methods to the case facts.

Defendants also claimed Mr. Mathers' testimony was cumulative and violated Rule 403, as it merely repeated opinions from the first trial, and argued that his report was disclosed too late under Federal Rule of Civil Procedure 27(a)(2)(B). AstraZeneca countered that Mr. Mathers’ opinions address a new issue raised by Dr. Muhvich in 2014 regarding the impact of AstraZeneca's sterilization of a product on the FDA's Final Rule in 2000. Ultimately, the Court finds Mr. Mathers' opinions unpersuasive and does not need to consider the objections further.

Additionally, testimony from Dr. Ververelli indicated that doctors sought Pulmicort Respules® in the U.S. due to its success in Europe, despite FDA requirements for sterility. The Court noted that the FDA had not ruled out the approval of a nonsterile product if AstraZeneca could convincingly demonstrate its necessity. AstraZeneca’s reference to a case involving FDA approval as an indicator of nonobviousness was found unhelpful, as prior formulations failed to demonstrate the same stability achieved by the FDA-approved formulation.

Several sterile pharmaceutically acceptable corticosteroids are available on the market, rendering AstraZeneca's reliance on certain case law regarding inventor failures inapposite, particularly in the context of secondary considerations. Evidence from cases like Sanofi-Synthelabo v. Apotex and Gusmer v. Parker illustrates different interpretations of inventor efforts related to nonobviousness. AstraZeneca did not depose a key representative, and Dr. Zhanel acknowledged uncertainty regarding a document's intent related to sterilization efforts. Single failed experiments provide limited evidence of nonobviousness, aligning with Dr. Zhanel's assertion that multiple attempts often lead to success. AstraZeneca's argument that the delayed sterilization of budesonide by Defendants indicates the novelty of its invention lacks substantial evidence, as it would require speculative reasoning about the Defendants' project delays. Furthermore, the absence of FDA approval does not establish a long-felt need, despite Dr. Zhanel's claims that sterility enhances the safety of nebulized steroid delivery, which contrasts with Dr. Ververelli's testimony that sterility does not guarantee safety. Lastly, AstraZeneca's claim of having no competitors for Pulmicort Respules® contradicts its internal documents, which acknowledge threats from competing products like Flovent.

The excerpt discusses the lack of evidence regarding the sterility of Budesonide powders and suspensions, which is critical in evaluating its commercial success. A review indicated that sterility was not mentioned among 46 features assessed, implying that if sterility were a significant selling point, it would likely have been noted. In a physician survey regarding Pulmicort Respules, key reasons for prescription included nebulized delivery (77.9%), effective anti-inflammatory properties (73.7%), and proven safety (52.1%), with sterility again not highlighted. Dr. Barnes emphasized the nebulized delivery system as particularly beneficial for treating young children. AstraZeneca's evidence was found insufficient to demonstrate nonobviousness relative to the patent claims, as commercially desirable properties did not align with the patent scope. The court noted that if desirable properties are limited to specific embodiments, evidence of commercial success cannot be generalized to the entire patent. Furthermore, defendants' late argument regarding the difficulty of preparing a sterile micronized budesonide composition was deemed waived since it was not included in the pretrial order, adhering to the principle that unraised issues are forfeited.