# AstraZeneca LP v. Breath Ltd.

> District Court, D. New Jersey · February 13, 2015 · 88 F. Supp. 3d 326

URL: https://www.frixlaw.com/law-library/cases/7230016

## Case

- **Full name:** ASTRAZENECA LP and AstraZeneca AB v. BREATH LIMITED, AstraZeneca LP and AstraZeneca AB v. Apotex, Inc. and Apotex Corp., AstraZeneca LP and AstraZeneca AB v. Sandoz, Inc., AstraZeneca LP and AstraZeneca AB v. Watson Laboratories, Inc.
- **Court:** District Court, D. New Jersey
- **Decided:** February 13, 2015
- **Citations:** 88 F. Supp. 3d 326; 2015 WL 777460
- **Precedential status:** Published
- **Opinion:** Opinion of the court by Bumb
- **Judges:** Bumb
- **Cited by:** 6 later opinions in the Frix Law Library

## Citator (automated)

- No negative treatment found by the automated citator. That is not the same as a confirmation that the case is good law; read the citing cases.
- Full citator and citing cases: https://www.frixlaw.com/law-library/cases/7230016

## How later opinions describe it (automated extraction)

- describing secondary consideration as “prior failures of others” and rejecting argument that failures of patent holder should be taken into account

## Opinion text

REDACTED OPINION (PUBLIC)
BUMB, District Judge.
Table of Contents
I. INTRODUCTION.333
II. BACKGROUND. CO CO
A. The Asserted Claims of the '834 Patent. CO CO
B. Markman Hearing. CO CO ^
C. Federal Circuit Decision. CO CO
D. Remand Proceedings. CO CO
E. Defendants’ Sterilization Processes. CO CO OI
III. LEGAL ANALYSIS . to 00
LEGAL ANALYSIS . A. Asserted Claims on Remand. to w 00 00
B. Infringement. w 00
C. Defenses. co 00
1. Reduction to Practice of the Invention . ío 00
2. Obviousness. oí 00
a. Motivation. o CO
b. Prior Art Sterilization Techniques . co CO
i. Sterile filtration/crystallization ^ 00
1994 FDA Guide ^ CO
b) Lachman: The Theory and Practice of Industrial . 00
c) Ansel: Pharmaceutical Dosage Forms and Drug Delivery Systems (1995).
d) Remington: The Science and Pharmacy (1995) .
e) Harris: U.S. Patent No. 6,187,765 (1997).
f) Conclusion.
ii. Moist Heat Sterilization.
Sodium Chloride Saturation.
b) Surfactant.
c) Sonication.
d) Milling.
e) Rotary Sterilization.
f) Conclusion.
iii. Oxide (EO).
a) Toxic Residues.
b) Penetration of the Crystalline Structure.
c) Conclusion.
iv. Irradiation .
v. Heat.
c. Secondary Considerations.
*333 i. Industry Skepticism.382
ii. Long-felt, Unmet Need.387
iii. Failures of AstraZeneca and Others .390
iv. Commercial Success.392
v. Conclusion.397
3. Anticipation .397
4. Enablement.398
5. Written Description .399
IV. CONCLUSION.399
I. INTRODUCTION
This matter comes before the Court upon remand from the Federal Circuit for further proceedings consistent with the Circuit’s new claim construction related to U.S. Patent No. 7,524,834 (the “ '834 Patent”). The '834 Patent is entitled “STERILE POWDERS AND METHODS FOR PRODUCING THE SAME,” and is addressed in relevant part to sterile budeso-nide compositions. Plaintiffs AstraZeneca LP and AstraZeneca AB (collectively, “As-traZeneca”) bring this consolidated action for patent infringement against the defendants, Breath Limited, Watson Laboratories, Inc. (collectively, “Breath/Watson”), Sandoz, Inc. (“Sandoz”), Apotex Corp., and Apotex, Inc. (collectively, “Apotex,” and together with Breath/Watson and Sandoz, “Defendants”), based upon their filings of Abbreviated New Drug Applications (“AN-DAs”). See ANDA Nos. 78-404, 202558 (Breath/Watson), 78-202 (Apotex), 20-1966 (Sandoz).
AstraZeneca originally alleged infringement of U.S. Patent Nos. 6,899,099 and 6,598,603. See AstraZeneca LP v. Apotex, Inc., 628 F.Supp.2d 579 (D.N.J.2009), aff'd, 633 F.3d 1042 (Fed.Cir.2010). The Court found no likelihood of success on the merits of claims for infringement of U.S. Patent No. 6,899,099, and claims 29 and 30 of the '603 Patent because the patented claims were likely invalid as a matter of law as they did not functionally alter a known product so as to create a new patentable product. Id. The Federal Circuit agreed. 1 633 F.3d at 1065 . As to the other asserted claims of the '603 Patent, the Court found — and was affirmed on appeal — that those claims were invalid as obvious under the prior art. AstraZeneca, 542 Fed.Appx. at 978-81. The Court further found the claims invalid as anticipated by prior art. 2013 WL 1385224 , at *28-32. As such, only the '834 Patent remains at issue in this protracted litigation.
The '834 Patent is also invalid as obvious. Given the Federal Circuit’s broad claim construction, the Court finds that Defendants have clearly and convincingly demonstrated that the '834 Patent is invalid as obvious because a POSA, whom the parties agree was motivated to prepare a sterile budesonide composition, would have had a reasonable expectation of successfully doing so using the well-known techniques of sterile filtration/aseptic recrystallization, moist heat sterilization, ethylene oxide sterilization, or irradiation. 2 Accordingly, the Court enters judgment against Plaintiffs and in favor of Defendants. This Opinion constitutes the Court’s findings of *334 fact and conclusions of law pursuant to Rule 52(a).
II. BACKGROUND
A. The Asserted Claims of the '834 Patent
Claims 1 and 50 of the '834 Patent, the independent claims at issue, teach a powder and suspension, respectively, comprising a “micronized powder composition.” Specifically, claim 1 recites:
A pharmaceutically acceptable, micron-ized powder composition at least 98.5% by weight of which is pure budesonide or an ester, acetal or salt thereof, wherein the composition meets the criteria of sterility according to the U.S. Pharmacopoeia [sic ] 23/NF18, 1995, pages 1686-1690 and 1963-1975.
'834 Patent col.11 ll.48-52 (emphasis added). Claim 50 recites:
A pharmaceutically acceptable suspension consisting of a micronized powder composition at least 98.5% by weight of which is pure budesonide or an ester, acetal or salt thereof, suspended- in an aqueous solution, wherein the suspension meets the criteria of sterility according to the U.S. Pharmacopoeia [sic ] 23/NF18, 1995, pages 1686-1690 and 1963-1975.
'834 Patent col.13 ll.54-60 (emphasis added). The dependent claims — claims 2 and 51 — include the additional limitation that 98.5% of the “micronized powder composition” is pure budesonide. '834 Patent col.11 ll.53-54 & col.13 ll.61-63.
B. Markman Hearing
After the Markman hearing, this Court construed “micronized powder composition” as a product-by-process claim, to mean “heat-sterilized finely divided dry particles.” See AstraZeneca, 2013 WL 1385224 , at *43. The trial thus focused on AstraZeneca’s heat sterilization process, for which AstraZeneca has another patent that is not at issue in this case. 3 See U.S. Patent No. 6,392,036 .
C. Federal Circuit Decision
On appeal, the Federal Circuit reversed this Court’s claim construction, construing the disputed term “micronized powder composition” to mean “finely divided dry particles” without requiring any particular process for sterilizing the particles. AstraZeneca, 542 Fed.Appx. at 976-78. In light of the broadened claim construction, much of the remand proceedings centered on what was known in the art regarding the five conventional sterilization techniques. Defendants contend that now that AstraZeneca successfully obtained a broader claim construction not limited to a particular process, the so-construed patent is vulnerable to invalidity challenges based upon a significantly greater selection of prior art. See Sandoz Br., Docket No. 908, at 1, 8 (“AstraZeneca paid a steep price for its victory in the Federal Circuit.”).
D. Remand Proceedings
On remand, the parties argued that additional claim terms required construction. As to these terms, the Court concluded that “pharmaceutically acceptable” means what the parties have always agreed— “acceptable for administration as a pharmaceutical.” Docket No. 980 at 22 (citing Joint Claim Construction Chart, Docket No. 93; AstraZeneca’s Preliminary Claim Constructions to Breath for the '834 Patent, Declaration of Heinz J. Salmen, Docket No. 975, Ex. 1 at 2 (“ ‘Pharmaceutically *335 acceptable’ requires no construction and should be accorded its plain meaning.”)). The Court also concluded that, in accordance with the Federal Circuit’s decision, “meetsAhe criteria of sterility according to the U.S. Pharmacopoeia [sic] 23/NF18, 1995, pages 1686-1690 and 1963-1975” means “sterile.” See Sept. 24, 2014 Tr. 32:12-24 (citing 542 Fed.Appx. at 973, 977).
In addition, Plaintiffs moved for a preliminary injunction on remand. In the interest of judicial efficiency and expediency, the Court consolidated the preliminary injunction hearing with the trial on the merits pursuant to Federal Rule of Civil Procedure 65(a)(2). Docket No. 980 at 43. Subsequently, the Court conducted a 13-day bench trial from October 6 through October 29, and November 17 through November 18, 2014. Upon the conclusion of the trial, the parties submitted voluminous post-trial briefing materials after which the Court held closing arguments.
E. Defendants’ Sterilization Processes
[Redacted]
[Redacted]
[Redacted]
III. LEGAL ANALYSIS
A. Asserted Claims on Remand
As the case now stands on remand, the following claim analysis applies to the independent claims:
1. “A pharmaceutically acceptable, [finely divided dry particles] at least 98.5% by weight ... wherein the composition [is sterile].... ”
50. “A pharmaceutically acceptable suspension consisting of [finely divided dry particles] at least 98.5% by weight ... suspended in an aqueous solution, wherein the suspension [is sterile].... ”
'834 Patent col.11 ll.48-52; col.13 11.54-60. Again, the dependent claims — claims 2 and 51 — include the additional limitation that 98.5% of the “mieronized powder composition” is pure budesonide. '834 Patent col.11 ll.53-54 & col.13 11.61-63.
B. Infringement
AstraZeneca contends Defendants’ submissions of their ANDAs for generic versions of Pulmicort Respules® budesonide inhalation suspension were acts of infringement of the '834 Patent. To establish infringement, AstraZeneca bears the burden of proving by a preponderance of the evidence that each element of a claim is found in the accused product. See Allen Eng’g Corp. v. Bartell Indus., Inc., 299 F.3d 1336, 1345 (Fed.Cir.2002).
Defendants have not contested that each of the accused products meets each of the elements of the asserted claims: (1) phar-maceutically acceptable, PFOF ¶¶ 103, 111, 118; (2) consisting of a mieronized powder composition, PFOF ¶¶ 99, 104, 112, 119; (3) at least 98.5% of which is pure budeso-nide or an ester, acetal or salt thereof, PFOF ¶¶ 100, 105, 113, 120; and (4) suspended in an aqueous solution, PFOF ¶¶ 106, 114, 121. Prior to this Court’s construction of the term “meets the criteria of sterility” as “sterile,” Defendants had contested infringement because As-traZeneca had not submitted test results establishing that the accused products meet the criteria of sterility set forth in the 1995 USP. However, as each of the Defendants conceded that its accused products were “sterile,” this argument is rejected. See Sept. 14, 2014 Tr. 31:02-10, 34:05-07, 34:15-20.
Accordingly, the Court finds that AstraZeneca has demonstrated infringement by a preponderance of the evidence.
*336 C. Invalidity Defenses
As a defense to infringement, Defendants assert the following grounds for invalidity: obviousness, anticipation, lack of written description, and lack of enablement.
In addressing these arguments, the Court adopts the definition of a person of ordinary skill in the art (“POSA”) that was set forth in the prior trial and agreed to by the parties:
A person of ordinary skill in the art ... would have had a medical degree with three years of experience in treating patients, particularly children with asthma, or either a doctorate or degree in pharmaceutics, chemical engineering, or a related field and three to five years of practical experience in one or more aspects of the pertinent arts, or a master’s degree in pharmaceutics, chemical engineering, or a related field, and five to seven years of practical experience in one or more aspects of the pertinent arts.
2013 WL 1385224 , at *10 (quoting 2012 Trial Tr. 3935:24-3936:13 (Chipps)).
1. Reduction to Practice of the Invention
The parties agree that the “critical date” of the '834 patent is November 11, 1997, one year prior to the earliest U.S. filing date to which the '834 patent can claim priority. Velander v. Garner, 348 F.3d 1359, 1363 (Fed.Cir.2003). In an attempt to circumvent several prior art references (ie., Leuschner and Harris), AstraZeneca has put forth evidence that it reduced its invention to practice by at least March 1997, and certainly by July 1997. 4 Heretofore, the Court has not decided this issue and thus it remains ripe for consideration.
“To antedate (or establish priority) of an invention, a party must show either an earlier reduction to practice, or an earlier conception followed by a diligent reduction to practice.” See Purdue Pharma L.P. v. Boehringer Ingelheim GmbH, 237 F.3d 1359, 1365 (Fed.Cir.2001) (citation omitted). “In order to establish an actual reduction to practice, the inventor must prove that: (1) he constructed an embodiment or performed a process that met all the limitations of the interference count; and (2) he determined that the invention would work for its intended purpose.... The inventor must also ‘contemporaneously appreciate that the embodiment worked and that it met all the limitations of the interference count.’ ” Henkel Corp. v. Procter & Gamble Co., 560 F.3d 1286, 1289 (Fed.Cir.2009) (citation omitted); see also Purdue Pharma, 237 F.3d at 1365-66 . The patentee bears the burden of producing evidence supporting an earlier invention date but the burden of proof remains on the defendant “to establish by clear and convincing evidence that the patentee’s invention date does not precede the date of *337 the ostensible prior art reference.” Power Integrations, Inc. v. Fairchild Semiconductor Int’l, Inc., 585 F.Supp.2d 568, 575-76 (D.Del.2008) (citing Spectralytics, 576 F.Supp.2d at 1045). 5 AstraZeneca points to laboratory reports, dated March 1997, demonstrating inter alia that heating the substance for 60 minutes at 110°C would result in more than a 7 log reduction in Bacillus subtilis spores. See PTX 1034 at 1335867; PTX 1527. Redacted versions of these laboratory reports were submitted with AstraZeneca’s Rule 131 Declaration. PTX 5A. Dr. George Zha-nel, an expert for AstraZeneca, and Dr. Cheryl Larrivee-Elkins, one of the named inventors on the '834 Patent, testified that a six or seven log reduction was the “standard” used to define the goal of a sterilizing process because it indicates a 1/1 million sterility assurance level. See 2012 Trial Tr. 615:2-11; id. at 4213:9-16. Dr. Zhanel further testified that a POSA would understand from the laboratory data that this experiment would result in a sterile product as it demonstrates rapid spore reduction. Id. at 4276:9-4277:16. Although Defendants’ expert, Dr. Scott Sutton, testified that this data only demonstrates spore reduction and not a sterilized product, he acknowledged that he was the “wrong person to ask” how the spore reduction translated into sterility. Id. at 2463:14-18, 2465:20-23. However, while the conclusion expressed in the documents was that heating for 60 minutes at 110°C “will give” more than a 7 log reduction, PTX 1034 clearly demonstrates that the samples were not actually heated at that time and temperature. PTX 1034 at 1335866-67; cf. Purdue Pharma, 237 F.3d at 1365 (“To prove actual reduction to practice, ‘an inventor must establish that he actually prepared the composition-’” (citing Estee Lauder Inc. v. L’Oreal, S.A., 129 F.3d 588, 592 (Fed.Cir.1997))). Similarly, PTX 1527 provides no information regarding sterility of the heat-treated samples, and the testing conducted was not intended to even address sterility. See PTX 1527 at 1339829.
In fact, Dr. Elkins testified that the March data indicated “we were honing in on something that would be acceptable to the [FDA],” but that they had to “confirm this is real.” 2012 Trial Tr. 615:19-616:1. However, their first attempts at doing so *338 proved “unsuccessful and concerning.” See id. at 617:1-4 . Even as of April 23, 1997, Dr. Elkins informed others that the “microbiological validation of the cycle is not going well” and that they had been unable to replicate the earlier results. See PTX 1533 at 1350873.
The evidence suggested that by May 1997 AstraZeneca felt confident that it could produce a sterile product through dry heat sterilization in combination with aseptic processing, and had begun preparing data to update the FDA on its findings. See PTX 523 at 1336448-49; 2012 Trial Tr. 620:3-622:5 (Elkins). Soon thereafter, As-traZeneca contends that batch records show it prepared a batch of Pulmicort Respules® on May 10, 1997 that was sterile, pure, micronized, and pharmaceutically acceptable. See PTX 401 at 0321477; As-traZeneca’s Proposed Findings of Fact (“PFOF”), Docket No. 1111, ¶ 83. Defendants argue that AstraZeneca presented no testimonial evidence corroborating this internal documentation, which in any event shows no analysis of the suspension was performed until the end of June. 6 See Defs.’ Joint Responses to AstraZeneca’s Proposed Findings of Fact (“DRFOF”), Docket No. 1127, ¶ 83. Defendants’ reliance on Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1171-72 (Fed.Cir.2006), is misplaced. There the Federal Circuit simply held that an inventor’s claim to an earlier reduction in practice date must be sufficiently corroborated, not that every piece of evidence must be corroborated, as Defendants suggest here. However, the Court is inclined to agree with Defendants that, while the batch records show a bude-sonide suspension was manufactured on May 10, 1997, the test results demonstrating the claim limitations of sterility were not recorded until June 24, 1997, at the earliest. 7 PTX 401 at 0321473, 0321477. The analysis of the impurities and degradation products did not occur until July 9, 1997. Id. Thus, the evidence suggests that, until those tests were performed, As-traZeneca was unaware of whether it possessed a budesonide suspension that met all of the limitations of the asserted claims.
Defendants also argue that, even if sufficient to demonstrate reduction in practice of the suspension, the evidence presented fails to demonstrate reduction in practice of the powder composition prior to the '834 Patent’s critical date. Although the Court acknowledges the limited evidence directly-confirming AstraZeneca’s possession of the powder, the Court finds that Defendants have failed to demonstrate by clear and convincing evidence that AstraZeneca had not reduced its invention to practice (powder and suspension) prior to the challenged prior art references. 8
As such, the Court finds that AstraZene-ca has submitted sufficient evidence demonstrating that it reduced its invention to practice at least by July 9, 1997. See, e.g., Streck, Inc. v. Research & Diagnostic Systems, Inc., 659 F.3d 1186, 1193 (Fed.Cir.2011) (“When testing is needed to establish *339 that an invention worked for its intended purpose, the inventor must have recognized that the tests were successful.” (citing Estee Lauder, 129 F.3d at 594-95 )), cert. den’d by — U.S. -, 132 S.Ct. 2442 , 182 L.Ed.2d 1064 (2012).
2. Obviousness
Although patents are presumed valid, an accused infringer can rebut this presumption with clear and convincing evidence of invalidity. Sciele Pharma Inc. v. Lupin Ltd., 684 F.3d 1253, 1260 (Fed.Cir.2012) (citing 35 U.S.C. § 282 ; Microsoft Corp. v. i4i Ltd. P’ship, — U.S. -, 131 S.Ct. 2238, 2245 , 180 L.Ed.2d 131 (2011)). To be clear, the burden of establishing invalidity by clear and convincing evidence remains on the party asserting invalidity. In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1078 (Fed.Cir.2012). A patent is invalid as obvious if the differences between the claimed invention and prior art are such that the invention as a whole would have been obvious to a person of ordinary skill in the art at the time the invention was made. Sciele Pharma, 684 F.3d at 1259 (quoting 35 U.S.C. § 103 (a)). Whether a patent claim is obvious is a question of law based on four underlying facts: (1) the scope and content of the prior art; (2) the level of ordinary skill in the pertinent art; (3) the differences between the prior art and the claims at issue; and (4) such secondary considerations as commercial success, long-felt but unsolved need, and the failure of others. Id. (quoting Graham v. John Deere Co., 383 U.S. 1, 17-18 , 86 S.Ct. 684 , 15 L.Ed.2d 545 (1966)); see also KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 406 , 127 S.Ct. 1727 , 167 L.Ed.2d 705 (2007).
Generally, this inquiry considers whether a person skilled in the art would have had (1) a reason to combine the teachings of the prior art references to achieve the claimed invention, and (2) a reasonable expectation of success in doing so. In re Cyclobenzaprine, 676 F.3d at 1068-69 (internal citations omitted). “[O]bviousness does not require absolute predictability of success.... For obviousness under § 103, all that is required is a reasonable expectation of success.” In re O’Farrell, 853 F.2d 894, 903-04 (Fed.Cir.1988); see also Bayer Schering Pharma AG v. Barr Labs., Inc., 575 F.3d 1341, 1350 (Fed.Cir.2009); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed.Cir.2007). 9
In KSR, the Supreme Court cautioned that this inquiry must be “expansive and flexible” and must account for the fact that a person of ordinary skill in the art is also “a person of ordinary creativity, not an automaton.” Id. at 415, 421, 127 S.Ct. 1727 . There need not be “precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 418 , 127 S.Ct. 1727 .
Importantly, “if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.” Id. at 417 , 127 S.Ct. 1727 . Relevant to this analysis is whether there was a reason or motivation to combine the known elements in the manner claimed by the patent. Id. at 418 , 127 S.Ct. 1727 . Indeed, “[o]ne of the ways in which a patent’s subject matter can be proved ob *340 vious is by noting that there existed at the time of invention a known problem for which there was an obvious solution encompassed by the patent’s claims.” Id. at 419-20 , 127 S.Ct. 1727 . “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. at 420 , 127 S.Ct. 1727 .
Finally, an invention is “obvious-to-try” and therefore invalid under 35 U.S.C. § 103 if it results from a skilled artisan merely pursuing “known options” from “a finite number of identified, predictable solutions.” In re Cyclobenzaprine, 676 F.3d at 1070 (quoting KSR, 550 U.S. at 421 , 127 S.Ct. 1727 ) (internal quotations omitted).
Defendants contend that the asserted claims are obvious in light of prior art setting forth five conventional sterilization techniques, each of which Defendants assert could have been used by a POSA with a reasonable expectation of successfully obtaining the claimed products. The Court will address the prior art concerning each technique in turn. First, however, it will address whether a POSA in 1997 would have been motivated to prepare the sterilized budesonide compositions that are the subject of the asserted claims.
a. Motivation
By 1997, AstraZeneca was marketing and selling a pharmaceutically acceptable, aqueous suspension consisting of highly pure, micronized budesonide powder in Europe under the name PULMICORT®. See PULMICORT RESPULES- adver., 49 Thorax: J. of British Thoracic Soc’y (April 1994), DTX 1026. It is undisputed that European Pulmicort discloses a pharma-ceutically acceptable, aqueous suspension consisting of a highly pure, micronized bu-desonide powder composition and thus encompasses all of the elements of asserted claims 50 and 51, except for sterility. See Trial Tr. 421:11-13 (Plaintiffs stipulating that European Pulmicort meets all claim limitations of claims 50 and 51 except sterility); DFOF St 31. In addition, by 1997, AstraZeneca was marketing and selling Pulmicort® Turbuhaler®, a dry powder inhaler dispensing budesonide inhalation powder. DTX 694 at 0299768. Pulmi-cort® Turbuhaler® discloses a pharma-ceutically acceptable, micronized powder composition of highly pure budesonide. PRFOF ¶ 62. Thus, the Pulmicort® Tur-buhaler® discloses every element of asserted claims 1 and 2, except for sterility. Because these prior arts disclosed all limitations of the asserted claims except for sterility, the question before the Court is whether it would have been obvious to a POSA to create a sterilized budesonide composition. 10
Defendants argue — and AstraZeneca agrees — that, by 1997, a POSA would have been motivated to prepare the sterile bu-desonide powder and suspension that are the subject of the asserted claims because of FDA and industry expectations, as well as sterility requirements applicable to other pharmaceutical products on the market. See Trial Tr. 795:12-19.
This is true even though the FDA proposed rule at the time dealt only with solutions. Specifically, around the time of the '834 Patent, in September 1997, the FDA had issued a proposed rule (the “Proposed Rule”) requiring “that all [aqueous-based] inhalation solutions for nebulization be manufactured as sterile.” DTX 872 at *341 018500. 11 AstraZeneca hones in on the fact that the Proposed Rule explicitly refers only to “solutions” — and not suspensions, which are the focus of the '834 Patent. However, several experts testified that POSAs understood the Proposed Rule to apply to all aqueous-based inhalation products, whether solutions or suspensions. See Trial Tr. 194:13-195:9 (Moldenhauer); 2012 Trial Tr. 2935:22-2937:25 (Miller). Moreover, Defendants introduced the testimony of Dr. Kenneth H. Muhvich, who assisted with drafting the Proposed Rule beginning in 1994. Trial Tr. 1044:1-8; 2012 Trial Tr. 2742:12-2743:14. According to Dr. Muhvich, the FDA began drafting the Proposed Rule in Spring 1994 in response to a recent case of contaminated inhalation solution products involving Copley Pharmaceuticals. 2012 Trial Tr. 2743:7-14. Dr. Muhvich testified, however, that while he used the term “solutions” in the Proposed Rule, he intended for the term to broadly cover “all aqueous-based products for nebulization, including suspensions.” Trial Tr. 1044:5-15. The reason for this is that the health risks from contaminated aqueous-based inhalation products are virtually the same, regardless of whether they are solutions or suspensions. See id. at 1045:18-23, 1046:10-17.
In the FDA’s Final Rule, published on May 26, 2000, the FDA required “all ... aqueous-based drug products for oral inhalation be manufactured sterile” (the “Final Rule”). DTX 915 at 024785. Thus, the Final Rule clearly covered solutions and suspensions. During the original trial, the Court questioned Dr. Muhvich about a statement in the Final Rule in which the FDA noted “[o]ne comment [to the Proposed Rules] suggested that the rule cover inhalation suspension products, stating that they contain more nutrients that contaminating microorganisms can metabolize than do inhalation solutions, and suggested that the title of the rule be modified to reflect this change.” DTX 915 at 024786. Dr. Muhvich agreed that whoever was the commentator was not well-versed, was not paying attention, or was generally confused about whether or not the rule covered suspensions. See 2012 Trial Tr. 2772:15-24. Subsequently, during this trial, AstraZeneca submitted adequate evidence that the comment referenced in the Final Rules and discussed during Dr. Muhvich’s testimony was, in fact, a letter signed by Dr. Muhvich. Accordingly, As-traZeneca contends that, in light of this discovery, Dr. Muhvich’s prior testimony regarding the broad scope of the Proposed Rule has been “call[ed] into serious question” and AstraZeneca urges the Court to accord less weight to that testimony when it considers industry skepticism, see infra. The Court declines to do so.
AstraZeneca admittedly possessed the comment letter as of July 2014, but made the calculated decision not to question Dr. Muhvich about it during Dr. Muhvich’s deposition in September 2014, shortly before the remand trial. When questioned as to why, AstraZeneca’s counsel stated they “didn’t trust the answers we would get.” 12 See Trial Tr. 2845:2-4, 2851:5-10. Instead, AstraZeneca asks this Court to conclude, based upon a single line of inquiry from Dr. Muhvich’s 2012 testimony, that he is not a credible witness. AstraZ- *342 eneca’s failure to seek an explanation from Dr. Muhvich when it had an opportunity to do so precludes this Court from making such conclusion. It is clear to this Court that in 2012 when the Court questioned him, Dr. Muhvich forgot that he had authored the comment. Indeed, when questioned, he did not have before him the comment letter purportedly reflecting his signature.
In any event, the comment letter is not necessarily inconsistent with Dr. Muh-vich’s testimony. Dr. Muhvich has steadfastly maintained that when he drafted the FDA Proposed Rule he intended for it to cover all aqueous-based products, both solutions and suspensions, because of the contamination risks associated with such products. See 2012 Trial Tr. 2749:23-2750:9. The comment does not contradict this testimony, but instead could be viewed as an attempt merely to make this intention absolutely clear to the industry. This interpretation is borne out by the statement in the Final Rule that the agency “agrees that further clarification of products covered by the rule is warranted.” DTX 915 at 024786 (emphasis added). 13 See further discussion infra.
Regardless, both parties’ experts agree that a POSA would understand at the time of the invention that the trend in the industry was moving toward the requirement that' all aqueous-based inhalation . products be manufactured as sterile. See, e.g., Trial Tr. 2492:20-2495:6 (Akers); 14 id. at 432:3-10 (Myrdal); 2012 Trial Tr. 2443:21-2444:5 (Sutton); id. at 2935:4-2936:16, 2937:8-25 (Miller). This understanding is consistent with Dr. Muhvich’s testimony that the FDA was publicly advising the industry by Fall 1994 that it expected all aqueous-based inhalation products, suspensions or solutions, to be sterile. 2012 Trial Tr. 2750:21-2752:13. In fact, Dr. Poochikian of the FDA instructed AstraZeneca during a pre-NDA meeting held on November 20, 1996 that “the Division expects sterile products for both solutions and suspension for inhalation. ...”. DTX 760 at 1335702. AstraZ-eneca’s witness, Dr. Zhanel, does not contradict this testimony. See Trial Tr. 1752:11-23 (“Q. And you heard from Ms. Moldenhauer, Doctor Miller and Mr. Zac-cheo that people of ordinary skill in the art in 1997 were being told by FDA, you’re going to make a suspension, you better make it sterile, you were here for that, right? A. I heard them use those words. Q. And you have no basis to disagree with that testimony, do you? A. That’s what they said. My understanding is that the FDA was telling AstraZeneca, try to make this sterile. Q. Just like they were telling everybody else of ordinary skill in the art, right, about suspensions? A. I don’t know what FDA was telling everybody about — I don’t know what the FDA was telling everybody.”).
*343 Moreover, the testimony at trial demonstrates that there were sterile parenteral and ophthalmic products already on the market. The FDA required these products to be sterile because the manner in which they are administered, like inhaled products, permits them to “bypass the body’s natural defense mechanisms” and thus contaminated versions of these products carry increased risks. See, e.g., Trial Tr. 339:4-16 (Zaccheo). As Kenneth Avis explained in “Sterile Products,” a chapter contained within The Theory of Practice and Industrial Pharmacy (Lachman et al. eds., 3d ed.1986),
[P]arenteral products are unique among dosage forms of drugs because they are injected through the skin or mucous membranes into internal body compartments. Thus, because they have circumvented the highly efficient first line of body defense, the skin and mucous membranes, they must be free from microbial contamination and from toxic components as well as possess an exceptionally high level of purity. All components and processes involved in the preparation of these products must be selected and designed to eliminate, as much as possible, contamination of all types, whether of physical, chemical, or microbiologic origin.
Preparations for the eye, though not introduced into internal body cavities are placed in contact with tissues that are very sensitive to contamination. Therefore, similar standards are required for ophthalmic preparations.
DTX 960 at 025799. Mr. Mike Zaccheo, Defendants’ expert, credibly testified that because a POSA would appreciate that suspensions and solutions inhaled directly into the lungs similarly bypass the body’s defenses, a POSA would understand the benefits of making these products sterile. Trial Tr. 341:12-342:2. Thus, the Court concludes that the Proposed Rule, as well as the FDA’s contemporaneous communications to AstraZeneca and other industry participants, provided POSAs with a strong motivation to prepare a sterilized budesonide composition.
b. Prior Art Sterilization Techniques
Under the current claim construction, the asserted claims are not limited to any particular sterilization method and, thus, as long as it was obvious to make the claimed product using any sterilization process, the claims are invalid as obvious. The parties agree that at the time of the '834 Patent, there were five well-known, conventional sterilization techniques for sterilizing steroids such as budesonide: (1) sterile filtration followed by aseptic crystallization; (2) moist heat; (3) dry heat; (4) ethylene oxide (“EO”); and (5) irradiation. PRFOF ¶ 8. In other words, faced with the motivation to prepare a sterilized suspension or solution, a POSA had five “tools” in her “toolbox.” Trial Tr. 3407:2-4. As set forth below, each of these sterilization methods had well-known disadvantages. Yet, a POSA had within her toolbox several methods to address them.
The Court now turns to each of these known sterilization techniques. In doing so, the Court recognizes that before it can make a determination that the asserted claims are invalid as obvious, the Court must consider all of the evidence, including evidence of secondary considerations. See, e.g., In re Cyclobenzaprine, 676 F.3d at 1078 . Thus, while the Court has chosen to include its discussion of the secondary considerations after its discussion of each sterilization process for organizational purposes only, the Court has in fact considered the secondary considerations along with its consideration of the prior art as to each process.
*344
i. Sterile filtration!crystallization
Defendants first argue that a POSA would have had a reasonable expectation of success in creating the claimed sterilized budesonide compositions using conventional sterile filtration/crystallization in combination with standard aseptic processing. Defendants contend that the asserted claims are invalid as obvious over any one of (a) the IPPL, European Pulmicort®, or Pulmicort® Turbuhaler® and (b) the 1994 FDA Inspection Guide, Lachman, Ansel, or Remington 1995 (and optionally Steckel or Harris).
a) 1994 FDA Inspection Guide
In July 1994, the FDA issued guidelines for use by its inspectors when examining manufacturers of bulk drug substances. DTX 1000. Entitled “Guides to Inspections of Sterile Drug Substance Manufacturers”, the guide set forth:
In the preparation for a sterile bulk drug substance inspection, a flow chart with the major processing steps should be obtained. Generally, the manufacture of a sterile bulk substance usually includes the following steps:
1. Conversion of the non-sterile drug substance to the sterile form by dissolving in a solvent, sterilization of the solution by filtration and collection in a sterilized reactor (crystallizer).
2. Aseptic precipitation or crystallization of the sterile drug substance in the sterile reactor.
3. Aseptic isolation of the sterile substance by centrifugation or filtration.
4. Aseptic drying, milling and blending of the sterile substance.
5. Aseptic sampling and packaging the drug substance.
These operations should be performed in closed systems, with minimal operator handling. Any aseptic operations performed by an operators[] [sic] other than in a closed system should be identified and carefully reviewed.
DTX 1000 at 029003. As written, the FDA Inspection Guide described the “usual” steps for sterile filtration/crystallization: (1) dissolving a nonsterile substance in an appropriate solvent to create a solution and filter-sterilizing the solution; (2) aseptic precipitation or crystallization; (3) aseptic isolation of the sterile substance by centrifugation or filtration; (4) aseptic drying, milling and blending; and (5) aseptic sampling and packing. DFOF ¶ 11. Moreover, the FDA Guide explicitly recognized that sterile filtration in combination with aseptic processing was routinely used to produce sterile products by 1997.
Defendants introduced evidence that a POSA would have had a reasonable expectation ' of successfully preparing the claimed sterilized budesonide compositions in the asserted claims by following each of the “usual” steps set forth in the 1994 FDA Inspection Guide (and other prior arts discussed herein). Defendants presented considerable and convincing testimony that, by 1997, a POSA who wanted to make sterile budesonide would know to start with highly pure, pharmaceutically acceptable budesonide. DFOF ¶ 19. In fact, highly pure budesonide of pharmaceutical grade — and therefore acceptable for administration as a pharmaceutical — was commercially available by 1997. DFOF ¶ 20.
As to Step 1 of the FDA Inspection Guide, both parties’ experts agreed that a POSA would know that budesonide was “readily soluble in a variety of organic solvents” under conditions that were well-known to a POSA by 1997. Trial Tr. 1678:3-11 (Zhanel); id. at 371:12-22 (Zac-cheo); see also PRFOF ¶ 16. For example, U.S. Patent No. 5,556,964, entitled *345 “Process for the Manufacture of Budeso-nide,” was issued September 17, 1996 to Robert G. Hofstraat et al. (“Hofstraat”), and describes a process in which crude budesonide is dissolved in methanol at about 60°C and then filtered through a closed filter. DTX 892 at col.2 11.28-30. The experts also agreed that a POSA would know to pass the nonsterile budeso-nide solution through a 0.2 micron sterilizing filter, which would exclude all microorganisms, dead or alive, as well as any matter larger than the 0.2 pore size. See, e.g., Trial Tr. 334:13-335:3 (Zaccheo); id. at 1680:5-16, 1673:22-1674:15 (Zhanel); see also PRFOF ¶ 17. Indeed, as Dr. Zhanel testified, a POSA in 1997 would have known that solutions could be readily filter-sterilized. Trial Tr. 1673:14-21.
Regarding Step 2 of the FDA Inspection Guide process, Hofstraat further discloses that a POSA could recrystallize the bude-sonide out of the solution and obtain pure budesonide with an isomer ratio of 1:1. DTX 892 at col.2 11.45-51; see also Trial Tr. 1679:19-1680:16 (Zhanel). Hofstraat explained this could be done by adding an antisolvent, water, for injection through the same sterilization filter. See DTX 892 at col.2 11.45-51; Trial Tr. 373:6-12 (Zac-cheo). These reactions could take place as part of a closed system in a sterile reactor, which provides aseptic conditions, as suggested by the FDA Guide. 15 DTX 1000 at 029003; see also Trial Tr. 375:4-10 (Zac-cheo) (testifying that a POSA would know to carry out steps under aseptic conditions). In addition, a June 13, 1997 article, entitled “Micronizing of steroids for pulmonary delivery by supercritical carbon dioxide,” written by H. Steckel 16 et al. (“Steckel”), and published in the International Journal of Pharmaceutics, taught that budesonide could be dissolved in an organic solvent and crystallized into finely-divided dry particles without affecting the purity and morphology of the budesonide. DTX 871 at 018486, 018496; PRFOF ¶ 68.
AstraZeneca disputes that Steckel discloses pharmaceutically acceptable, mi-cronized budesonide with purity greater than 99%. See PRFOF ¶ 40. This is unfounded. Indeed, Dr. Zhanel, AstraZene-ca’s witness, conceded his understanding of Steckel to be “using pharmaceutical grade budesonide of over 99 percent purity.”
Q. So what Steckel found or what Steckel informed the skilled person is that when he took his steroids of Bude-sonide, dissolved them in organic solvent like methanol, treated them with super-critical carbon dioxide and mieronized them and then recrystallized them back out, he found no decomposition in purity, correct?
And I’m referring to the conclusions on page 11 of 14 of DTX 871.
A. Correct.
Trial Tr. 1667:2-10. Other AstraZeneca witnesses agreed with Dr. Zhanel. See Trial Tr. 2319:10-23 (Akers) (“Q. And the budesonide they were working with was pharmaceutical grade 99 percent pure, correct? A. Correct.”); 2012 Trial Tr. *346 3792:6-15 (Williams) (“Q. Now look at Page BREATH(Bud) 18492 [of DTX 871], the right column, under materials. What does this portion of Steckel say with respect to the purity of the corticosteroids? A. So here, this is Steckel describing what they used, and it says the steroids listed in Table 2 were used for the experiments. All of them were of pharmaceutical grade with a content of active ingredient greater than 99 percent. So that [] would be understood by a skilled person to mean that the materials that Steckel started with, that they ordered and got in, had a 99 percent or greater purity.”). Moreover, Dr. Robert 0. Williams, III, agreed that Steckel teaches methods for micronization, or reducing particle size, of steroids. See Trial Tr. 2819:23-2820:10 (Williams) (“Q. Can we refer to this as the Steckel reference? A. I’ll understand that. Q. The methods for reducing particle size by su-percritical carbon dioxide that are described in Steckel, are those consistent with the methods that you’re familiar with? A. I’m familiar with this method. Q. Okay. Any reason to believe that the authors of Steckel were unable to achieve the particle size, the micronized particle size that they claimed to achieve in this publication? A. No, I accept what — I know Bern Muller who’s the senior — he’s the professor in Germany. I accept these results.”); see also 2012 Trial Tr. 3791:16-19 (Williams). 17
The evidence also demonstrated that Step 3 of the FDA Inspection Guide, aseptic isolation of the sterile substance, and Step Jp, aseptic drying, milling, 18 and blending, were “routine” processes used by PO-SAs at the time of the '834 Patent. See, e.g., Trial Tr. 378:2-9 (Zaccheo); DFOF ¶¶ 170-71. Even AstraZeneca’s expert, Dr. James Akers, acknowledged that a POSA would know how to dry, mill, and blend budesonide to form a finely-divided, dry budesonide powder. See Trial Tr. 22 62:17-21. And, other prior art references explained how this could be done aseptically. See DFOF ¶ 171. For example, Dr. Michael J. Akers 19 et al. disclosed in a 1997 publication that the dried sterile drug substance is aseptically discharged into suitable bulk containers or to the milling unit. DTX 986 at 028822. Dr. Michael Akers further disclosed the necessity of designing the overall sterilization process to account for aseptic filling to minimize product exposure and thus contamination risks.. See id.; see also DTX 988 at col.22 11.38-39 (describing sterile micronization of sterile drug crystals); Trial Tr. 380:15-18.
As for sterile suspensions, the parties agree that as of 1997, “it was a matter of routine for a POSA to create a sterile, pharmaceutically acceptable, suspension of micronized budesonide when starting with sterile, micronized budesonide powder.” PFOF ¶ 84; see also DFOF ¶ 25. 20
*347 Based upon the above evidence, Mr. Zaccheo credibly opined that, by following the typical sterilization steps laid out in the 1994 FDA Inspection Guide, a POSA would have a reasonable expectation of successfully preparing a sterile budesonide composition (powder and suspension). Trial Tr. 381:3-6.
b) Lachman: The Theory and Practice of Industrial Pharmacy (1986)
Mr. Zaccheo also opined that it would have been obvious to a POSA in 1997 how to prepare the sterile compositions in the asserted claims (both powder and suspension) based upon the teachings of Lach-man. Published in 1986, Lachman taught that sterile filtration was the “method of choice” for heat-labile, or heat sensitive, substances and is often “an ideal technique.” Specifically, Lachman stated:
Filtration is frequently the method of choice for sterilization of solutions that are chemically or physically unstable under heating conditions. In many applications, sterile filtration is an ideal technique. Sterile filtration of liquids and gases is commonly used in the pharmaceutical industry. Final product solutions or vehicles for suspensions are sterile-filtered prior to an aseptic filling process. Sterile filtration of bulk drug solution prior to an aseptic crystallization process eliminates the possibility of organisms being occluded within crystals.
DTX 960 at 025756.
Lachman went on to explain that aseptic processing was routine after sterile filtration.
In 1997, there were two methods of manufacturing sterile products: terminal sterilization or aseptic processing from sterilized components. Trial Tr. 336:20-337:5 (Zaccheo). Terminal sterilization refers to a process by which a pharmaceutical product is prepared under clean conditions and sealed in its final container, which is then subjected to a sterilization process. Trial Tr. 335:4-14 (Zaccheo); DTX 2105 at 5000006. It is “terminal” because there are no further steps that need to be undertaken. Trial Tr. 335:4-14 (Zaccheo). Aseptic processing, on the other hand, “involves the filling or assembly of presterilized 'drug products under aseptic conditions into presterilized containers.” DTX 2105 at 500005. Aseptic conditions refers to “the absence of living organisms.” Trial Tr. 336:5 (Zaccheo). Because sterile filtration can only be conducted on solutions, it cannot be a terminal sterilization process for a suspension; in other words, .there are subsequent . steps that must be conducted under aseptic conditions to achieve a sterile suspension. Id. at 335:4-14 (Zaccheo). As Lachman explained:
Aseptic Processing. Sterilization of a solution by filtration provides an extremely clean solution, removing dirt particles as well as microorganisms in the micron size range. After sterilization,. however, the filtrate must be transferred from the receiver and subdivided into the individual final containers. The objective of this process, known as aseptic processing, is to exclude every microorganism from- all ' steps of the process subsequent to filtration. Accomplishing this requires a rigidly controlled aseptic environment and technique. The difficulty of maintaining such an aseptic condition is the greatest problem associated with sterilization by filtration; however, for solu *348 tions that are adversely affected by heat, this may be the only way in which sterilization can be accomplished.
Aseptic processing is technically .not a sterilization process, but is mentioned here because of its close involvement with sterilization by filtration. It is used for products that cannot be terminally sterilized, that is, sterilized after they have been sealed in the final container.
DTX 960 at 025793-94 (emphasis added); see also Trial Tr. 350:1-4 (Zaccheo).
Motivated to produce a sterilized bude-sonide product — powder, solution or suspension — a POSA also understood from Lachman (and other “Bibles in sterility”) 21 that routine optimization of a sterilization process would be necessary-depending upon the specific characteristics of the substance or product to be sterilized. Lach-man (and others) taught “to arrive at a safe process for any particular material it becomes a compromise between the ideal process and the practical process” and that within each process there would be a range of operating parameters that can be used.... ” Trial Tr. 345:19-25 (Zaccheo). As Mr. Zaccheo testified, the process of determining what constitutes “an optimized process” is just “simple routine process optimization with the characteristics of the product in view.” Id. at 346:2-3 .
Mr. Zaccheo credibly testified that, while Lachman recognized the difficulty of maintaining a completely aseptic environment, a POSA would not have been discouraged from using sterile filtration as a sterilization technique for budesonide. This is so, Mr. Zaccheo explained, because POSAs were aware of the availability at that time of facilities and equipment that could be used to create an aseptic environment. See id. at 350:16-351:5 . Indeed, the 1994 FDA Guide discussed above illustrates Mr. Zaccheo’s point. The Guide described such facilities and equipment and advised its inspectors how to identify problem areas during an inspection to eliminate risks associated with contamination. See, e.g., DTX 1000 at 029004-06. For example, the FDA Guide advised that if any processes occurred outside of a “closed system” then they must be identified and carefully reviewed. Id. at 029003 . Therefore, as Mr. Zaccheo testified, PO-SAs would have realized that closed systems for use in aseptic processing were available at least as of the time when the FDA was advocating their use in sterilization processes in 1994. See Trial Tr. 377:11-15.
Moreover, Lachman recognized that the use of aseptic processing in conjunction with other sterilization techniques may be the only viable means of producing certain pharmaceutical products. DTX 960 at 025794. If it was well-known that certain pharmaceutical products could only be sterilized in this fashion, then the equipment and facilities necessary to accomplish it must have been available at that time. See also Trial Tr. 375:16-25 (Zaccheo).
c) Ansel: Pharmaceutical Dosage Forms and Drug Delivery Systems (1995)
Defendants also rely upon Ansel, a 1995 publication that reinforced the advantages of sterile filtration for heat-sensitive compounds like budesonide. See Trial Tr. 353:20-354:14. Ansel stated:
Sterilization by filtration, which depends upon the physical removal of microorganisms by absorption on the filter medium or by a sieving mechanism, is used *349 for the sterilization of heat-sensitive solutions ....
Commercially available filters are produced with a variety of pore-size specifications ....
The major advantages of bacterial filtration include its speed in the filtration of small quantities of solution, its ability to sterilize effectively thermobile materials, the relatively inexpensive equipment required, and the complete removal of living and dead microorganisms as well as other particulate matter from the solution. One serious disadvantage to the use of bacterial filters is the possibility of a flaw in the construction of the filter and thus some uncertainty of sterility, a circumstance not true of methods involving dry- or moist-heat sterilization in which the procedures are just about guaranteed to give effective sterilization. Also, filtration of large volumes of liquids would require more time, particularly if the liquid were viscous, than would, say, steam sterilization. In essence, the bacterial filters are useful when heat cannot be used and also for small volumes of liquids.
DTX 2093 at 030995-96.
Ansel also discussed the use of aseptic processing in combination with sterile filtration and other sterilization methods:
In the preparation of parenteral solutions, the required ingredients are dissolved according to good pharmaceutical practice either in water for injections, in one of the alternate solvents, or in a combination of solvents. The solutions are then usually filtered until sparkling cleár through a membrane-type filter. After filtration, the solution is transferred as rapidly as possible and with the least possible exposure into the final containers. The product is then sterilized, preferably by autoclaving, and samples of the finished product are tested for sterility and pyrogens. In instances in which sterilization by auto-claving is impractical due to the nature of the ingredients, the individual components of the preparation that are heat or moisture labile may be sterilized by other appropriate means and added aseptically to the sterilized solvent or to a sterile solution of all of the other components sterilizable by autoclaving.
DTX 2093 at 030999. Armed with the ' knowledge that budesonide is a heat-sensitive compound, a POSA would have been persuaded to try sterile filtration followed by aseptic processing as suggested by An-sel (and Lachman).
Ansel also confirms that it would have been a matter of routine for a POSA to create a sterile suspension from a sterile micronized budesonide powder. Ansel specifically disclosed the preparation of sterile suspensions for parenteral use and the necessity of utilizing aseptic processing techniques in these preparations. According to Ansel,
Suspensions of drugs intended for parenteral use may be prepared by reducing the drug to a very fine powder with a ball mill, micronizer, colloid mill, or other appropriate equipment and then suspending the material in a liquid in which it is insoluble. It is frequently necessary to sterilize separately the individual components of a suspension before combining them, as frequently the integrity of a suspension is destroyed by autoclaving.
DTX 2093 at 030999.
d) Remington: The Science and Pharmacy (1995)
The Science and Pharmacy was published by Remington in 1995 (“Remington”) and, as with Lachman and Ansel, addressed the five conventional sterilization techniques. DTX 2351 at 028980. Like *350 Lachman, Remington also taught that sterile filtration is “one of the oldest methods” and also “the method of choice for solutions that are unstable to other types of sterilizing processes.” Id. at 028994 (“Over the past 30 years, membrane filters have become the method of choice for the sterilization of heat-labile sterile products.”). Significantly, Remington discusses the use of sterile filtration to remove bacteria from steroids in organic vehicles followed by aseptic crystallization. Id. Remington recognizes that “aseptic processing is a technique frequently used in the compounding of prescriptions or commercial products that will not withstand sterilization but in which all of the ingredients are sterile.” Id. at 028998 . He further suggests the use of laminar-airflow devices or barrier technology to ensure aseptic conditions. Id.
e) Hams: U.S. Patent No. 6,187,765 (1997)
Although U.S. Patent No. 6,187,765, entitled “Mometasone Furoate Suspensions for Nebulization,” provisional app. dated Oct. 9, 1997, issued to David Harris et al. (“Harris”), is not deemed prior art under this Court’s holding that AstraZeneca reduced its invention to practice prior to Harris’ publication date, Defendants contend that Harris may still be considered by the Court as contemporaneous art that confirms a POSA’s reasonable expectation of success. The Court agrees with Defendants that, while Harris is not deemed prior art, it is still relevant to the Court’s analysis of a POSA’s understanding at the time of the invention. See, e.g., Netscape Comm’ns Corp. v. ValueClick, Inc., 707 F.Supp.2d 640, 655 (E.D.Va.2010) (“Although the Levergood patents and the Kristol, Holtman, and Behlendorf proposals are excluded from the content of the prior art, these references may yet be relevant to a different factual predicate under Graham, namely the characteristics and understanding of an individual of ordinary skill in the art at the time of invention. In this regard, the Federal Circuit has long held that ‘evidence adduced in support of the § 102 defenses ... can be probative on the issue of the level of skill in the pertinent art [under § 103] even if it be considered inadequate to establish the existence of a § 102 defense.’ ”); see also Ecolochem, Inc. v. Southern Cal. Edison Co., 227 F.3d 1361, 1379 (Fed.Cir.2000) (“The fact of near-simultaneous invention, though not determinative of statutory obviousness, is strong evidence of what constitutes the level of ordinary skill in the art.”).
Example 1 of Harris is directed to a method of preparing a “[s]terile mometa-sone furoate monohydrate” (a glueocorti-costeroid like budesonide) using a sterile filtration process.. DTX 971 at col.6 11.26-62. Example 2 teaches how to create a sterile suspension using the sterile mome-tasone of Example 1. Id. at col.6 1.65 to col.7 1.40. Harris thus discloses a nebu-lized aqueous suspension of a micronized corticosteroid for use in treating disorders of the lower airway (i.e., pharmaceutically acceptable). Id. at col.l 11.10-30, 37-42.
In its June 4, 2014 Opinion, the Court held that the '834 Patent appeared vulnerable to a validity challenge in light of the teachings of Harris. Docket No. 980 at 35-39. In a nutshell, the Court viewed Harris to be a step-by-step procedure on how to prepare a pharmaceutically acceptable, sterile corticosteroid suspension, similar to the process contained in the FDA’s 1994 Inspection Guide but with more detailed steps-. Indeed, a chart prepared by Defendants demonstrates the similarities among the 1994 FDA Inspection Guide, Harris, and a prior art publication by As-traZeneca’s expert, Dr. Akers:
*351 1994 FDA Inspection Guide (“usually”)
Step 1: Conversion of the nonst-erile drug substance to the sterile form by dissolving in a solvent, sterilization of the solution by filtration and collection in a sterilized reactor (crystallizer).
Step 2: Aseptic precipitation or crystallization of the sterile drug substance in the sterile reactor.
Step 3: Aseptic isolation of the sterile substance by centrifugation or filtration
Step 4: Aseptic drying, milling and blending of the sterile substance.
Harris (1997) Example 1
(1)Dissolve mometasone fu-roate in acetone (organic solvent), mix to form a clear solution;
(2)Pump solution through a sterilizing filter into sterile precipitation vessel;
(3)-(4) add sterile purified water; maintain temperature (45-50°C); stir
(5)-(6) maintain stirring and temperature, precipitate will begin to form; add sterile purified water
(6)-(8) stir, cool to ambient temperature
(9) filter the precipitate and wash with sterile purified water;
(10) dry in vacuum oven (30-35°C), 12-24 hours
Final product is dried mometa-sone furoate monohydrate; milling/micronization (Example 2)
Akers & Agalloco 22 (1993) (“typically”)
Step 1: Sterile filtration
Step 2: Crystallization (carried out under sterile conditions)
Step 3: Filtration (carried out under sterile conditions)
Step 4: Washing, drying, milling and blending (carried out under sterile conditions)
See Watson Closing Slide 42. Harris thus confirms that a POSA would have had a reasonable expectation of successfully creating the claimed sterile budesonide compositions using sterile filtration/aseptic crystallization in combination with aseptic processing.
AstraZeneca argues, however, that if Harris is not deemed prior art, 23 then “the message from Harris must be it is considered inventive,” Trial Tr. 3496:12-13 (counsel), and “stands for ... the belief in the industry that achieving a sterile corticosteroid suspension ... is novel and non-obviousness-” Id. at 3501:15-18. The record contains no evidence to support As-traZeneca’s argument, however, as nowhere in the patent does Harris assert that sterile filtration followed by aseptic crystallization is a novel and nonobvious process.
Nor does Harris claim a sterile product. Although Harris discloses the preparation of a sterile product, made by following the steps of the FDA’s 1994 Inspection Guide, Harris does not claim, a sterile product but a “nebulizer suspension” without mention *352 of sterility. 24 Thus, the “message” to be deduced from Harris can only be that it was obvious that a sterile corticosteroid product could be produced from a well-known sterile filtration/aseptic crystallization process. AstraZeneca’s contention that Harris confirms that achieving such a sterile corticosteroid suspension in 1997 was novel is belied by the simple fact that Harris does not claim a sterile product.
The above evidence clearly and convincingly demonstrated that in 1997 sterile filtration was considered the “method of choice” for sterilizing heat-labile or heat sensitive pharmaceutical products such as budesonide, see DFOF ¶ 14, and it had been in use for more than 3 0 years at the time of the '834 Patent. For this reason, a POSA would have been motivated to use this method to sterilize budesonide. See Trial Tr. 333:12-17 (Zaccheo).
Moreover, the Court is persuaded by Mr. Zaccheo’s testimony that a POSA in 1997 would have been able to routinely optimize the usual steps set forth in the 1994 FDA Inspection Guide to create a sterile form of the pharmaceutically acceptable, highly pure, micronized budeso-nide compositions available as European Pulmicort® or Pulmicort® Turbuhaler® with a reasonable expectation of success. This is so because a POSA knew the appropriate solvent conditions for budesonide and routinely employed sterile filtration, crystallization, and micronization techniques as set forth in the 1994 Guide. Once a sterile powder had been obtained, it would have been a routine process to create the suspension. PFOF ¶ 84; see also DFOF ¶ 25.
Although preparation of a sterile mi-cronized budesonide composition requires a POSA to conduct several steps subsequent to the sterile filtration of the bude-sonide solution {e.g., micronization/milling, combination with solvent to create suspension), the evidence conclusively demonstrates that a POSA would understand that those steps should and could be conducted in an aseptic environment. See, e.g., Trial Tr. 2563:1-8 (Zaccheo) (“Q. Would a person of ordinary skill in the art be able to conduct the crystallization step described in Hofstraat under aseptic conditions in 1997? A. Yes, they would. Especially as part of a closed system. THE COURT: I’m sorry, especially — THE WITNESS: As part of a closed system. Q. Without undue experimentation? A. Yes.”); id. at 2561:22-25 (Zaccheo) (“Q. Mr. Zaccheo, would this type of closed system crystallization technology be available to a person of ordinary skill in the art in 1997? A. Yes, it would.”). Indeed, as of 1997, aseptic processing techniques were widely-used in the preparation of pharmaceutical products, as even AstraZeneca recognized in 1997, though it has now retreated from such concession. See PTX 523 (“[0]ur efforts were directed to the possibility of sterilizing all components of the drug product prior to final mixing of the suspension and proceeding with the manufacturing method under aseptic conditions.”). Although some of the prior art (such as Lachman) acknowledged contamination risks associated with aseptic processing, the Court is persuaded by the testimony that a POSA in 1997 could routinely optimize the usual processing steps and all of the relevant materials, equipment, and procedures necessary to do so were known and available in 1997.
*353 AstraZeneca’s response to Defendants’ evidence actually serves to confirm this Court’s obviousness finding. Importantly, AstraZeneca does not dispute that sterile filtration was a known sterilization process. Nor does it dispute that a POSA had a reasonable expectation of successfully performing a sterile filtration of a budesonide solution. Trial Tr. 2284:16-20 (Akers) (“Q. And I think we agreed the sterilization step, you have no problem with that, the skilled person could reasonably expect success in performing a sterile filtration of the budesonide solution, correct? A. They could reasonably expect success....”). And their own witness, Dr. Akers, agreed that the steps in the 1994 FDA Inspection Guide were typical in 1997. See PTX 2110 at 54 (“The preparation of sterile solids typically includes a sterile filtration, followed by crystallization, filtration, washing, drying, milling, and blending, all of which are carried out under sterile conditions.”); see also chart supra. As he testified:
Q. Now, you called these steps typical in PTX-2110 because skilled persons were in fact performing them in the field, correct?
A. There’s no dispute from me that people were making sterile drug substances aseptically and that they needed to be validated at the time that Mr. Agalloco and I wrote this chapter, that’s the purpose of writing it.
Q. And skilled persons were in fact performing filtration and aseptic crystallization steps, correct?
A. Yes. And some of them no doubt were skilled.
Trial Tr. 2299:12-21.
Rather, AstraZeneca attempts to salvage the '834 Patent by claiming that the use of sterile filtration in combination with aseptic processing involved technical capabilities and equipment that were not available to a POSA in 1997. Specifically, it avers, the necessary sophisticated equipment, such as isolators, was not available. See Trial Tr. 2242:4-16 (Akers). AstraZ-eneca also argues, the “very significant” likelihood of contamination eliminated any reasonable expectation of success with the process. 25 In support, AstraZeneca cites to the FDA’s 1991 proposed rule entitled “Use of Aseptic Processing and Terminal Sterilization in the Preparation of Sterile Pharmaceuticals for Human and Veterinary Use” (the “1991 Proposed Rule”). DTX 2105 (“there is a substantial likelihood that at least some drug products will be microbiologically contaminated”). In essence, AstraZeneca argues that a POSA had no reasonable expectation of successfully preparing a sterilized micronized bu-desonide product using known and routine processes (i.e., sterile filtration and aseptic processing) because this particular drug substance (ie., budesonide) required a POSA to employ several known and routine processes after the sterile filtration step and a POSA would understand that when these processes were conducted aseptically it could yield a contaminated drug product 1 out of every 1000 times the POSA followed the routine and well-known steps.
*354 The FDA’s 1991 Proposed Rule, which was never implemented and dealt with'terminal sterilization, is of limited value. Although there is a risk of contamination, Dr. Akers acknowledged that aseptic processing could be done:
Q. Just a couple questions about this. Now, does the patent-at-issue here, the '834 patent, speak only to, using the words here, large scale manufacturing?
A. No.
Q. So it could be — it could be producing the materials in a laboratory?
A. It could be.
Q. But why do you find this of relevance to the opinions you are offering about sterile filtration and recrystallization and aseptic processing?
A. Well, I think that whether you were doing this at the laboratory scale or a larger scale, these are complex manufacturing steps that would have required some form of human intervention, and human intervention and aseptic processing is directly associated with risk.
Trial Tr. 2218:12-2219:1. But, Dr. Akers went on to explain that a POSA could create a sterile product in a closed system as long as there was no equipment malfunction:
Q. Assuming no minor equipment malfunctions, and that the skilled person performs the steps properly, in a closed system, the result of an aseptic crystallization, drying, milling, will be a sterile product, correct?
A. I’m going to stipulate that a closed system means that there’s no opportunity or requirement for human intervention.
Trial Tr. 2316:8-13; see also id. at 2315:14r-21 (Akers) (“Q. So the skilled person, following the proper procedure in 1997, using a closed system, could adequately perform an aseptic crystallization, aseptic isolation, aseptic milling, correct? A. Even then, there would be — there would be risk, because any time we do aseptic processing, it only requires a minor mistake, a minor miscue, a minor equipment malfunction, in order to lose the integrity required to retain asepsis.”).
Dr. James Akers further explained the challenges presented by aseptic processing set forth in a 1987 article by Dr. Michael Akers entitled, “Formulation Design and Development of Parenteral suspensions.” DTX 862. There, Dr. Michael Akers notes that
Recrystallization and size reduction techniques are common in large-scale manufacturing, but if these must be done under aseptic conditions, a significant challenge must be confronted. Sterilization of drug and vehicle may not be unusually difficult, but aseptically combining, dispersing, and mixing drug and vehicle again cause great potential difficulties on a large scale.
DTX 862 at 018397. Yet, the following testimony of Dr. Akers, which this Court found to be credible and neutral, demonstrates that the real issue at the time of the '834 Patent of which AstraZeneca complains was not whether there was a technological impossibility, but whether an inventor was willing to invest in the necessary infrastructure to manufacture the claimed product on a large-scale basis. See Trial Tr. 2244:1-9 (Akers) (“[The process] requires a very substantial physical plant to accomplish.”). As the cross-examination testimony of Dr. Akers demonstrates:
Q. I’d like to start out by seeing where we can agree and maybe narrow the focus a little bit on the state-of-the-art. As an initial matter, you agree that the skilled person in 1997 would know about the availability of non-sterile European budesonide nebulizing suspension that was pharmaceutically acceptable and *355 contained highly pure budesonide, correct?
A. Yes.
Q. Now, the skilled person in 1997 also would have known of the availability of highly pure, 99 percent pure pharmaceutical grade budesonide... ?
A. Yes.
Q. Now, the skilled person in 1997 that wants to make a sterile budesonide product is going to want to start with the highest purity budesonide possible, correct?
A. You certainly want to start with sufficiently pure budesonide, yes.
Q. Now, the skilled person in 1997 would be trained in and familiar with conventional sterilization techniques for sterile products, including sterile filtration, correct?
A. They would.
Q. And the skilled person in 1997 would know that a conventional sterile filtration employs a 0.22 micron pore size filter that excludes all microorganisms, dead or alive, as well as any other particulate matter larger than the filter pore size?
A. They would have understood that such a filter had a mean pore size rating of .2 micrometers, which implies that some pores may have been larger, some may have been smaller.
Q. And the skilled person would have understood that a filter of that size, .22 microns, would be a sterilizing filter, correct?
A. It’s commonly called a sterilizing grade filter.
Q. And the skilled person in 1997 would know that in order to sterile filter a dry steroid powder like budesonide, they would first have to put that powder into solution, correct?
A. Correct.
Q. And the skilled person in 1997 would also know how to dissolve budeso-nide and make a solution using organic solvents like methanol, correct?
A. They would.
Q. And the skilled person in 1997 would know how to then take and sterile filter a budesonide solution with a 0.22 micron pore size sterilizing filter which would result in a sterile filtrate or sterile budesonide solution, correct?
A. They would.
Q. Now, I want to put aside aseptic conditions. So, my next question, just exclude or ignore aseptic conditions. Putting those aside, the skilled person in 1997 would know how to crystallize highly pure budesonide from solution without losing purity, correct?
A. They would.
Q. Now, again, putting aside aseptic conditions for the moment, the skilled person in 1997 would know how to dry and mill recrystallized budesonide to form a finely dry divided budesonide powder, correct?
A. Correct.
Q. Now, assuming the skilled person already had in hand sterile budesonide that was 98.5 percent pure finely divided dry powder that was pharmaceutically acceptable, the skilled person would know how to aseptically combine that sterile budesonide powder with other pre-sterilized aqueous components to form a sterile budesonide suspension, correct?
A. If we stipulate — if we stipulate that claim of sterility through the manufacturing process that would be required to get to that endpoint, could achieve sterility, and they did indeed have a sterile *356 product, then I agree with you, that could be combined into a suspension.
Q. And that would be a routine aseptic filling process to the skilled person in 1997, correct?
A. The aspects of it downstream of the mixing of the powder with the vehicle would be considered relatively routine.
Q. Okay. Now, the skilled person in 1997 would have known that most sterile pharmaceutical products were made using some form of aseptic processing, correct?
A. Yes.
Q. And, in fact, the skilled person in 1997 would have known that if you cannot terminally sterilize a pharmaceutical product, you would likely have to use some type of aseptic processing, correct?
A. Correct.
Q. Now, all that said, I want to narrow the issue. You’ve already told me that it’s routine to take the sterile powder and make the suspension. So, your primary opinions are that it would be complex and the skilled person would not reasonably expect success to do the aseptic crystallization, isolating, drying and milling processes, correct?
A. I believe that would be a far more risk intensive activity than terminally sterilizing it, and that one would not have been assured of absolute success. 26
Q. So, you take no issue with the filtration step, correct?
A. Products for which terminal sterilization is inapplicable, generally because they lack the chemical stability to withstand terminal sterilization, are made by aseptic processing. In my view, the preferred process is to terminally sterilize the bulk drug substance.
Q. But the skilled person would know if you can’t do that, you can’t terminally sterilize, you would have to use aseptic procfessing?
A. With the condition that you can’t do it, you would have to use 'aseptic processing.
Trial Tr. 2259:22-2264:20 (emphasis added).
AstraZeneca contends that filter sterilization and aseptic processing required “sophisticated equipment” that was “capable of running complex aseptic processes” was not available in 1997. See Pls.’ Br. 30-31. AstraZeneca places undue emphasis on large-scale technical capabilities, however. Under the asserted claims, a POSA — who •is not defined as a pharmaceutical manufacturing company — does not have to have a reasonable expectation of successfully preparing the claimed product in a scaled-up process. 27 Defendants presented clear and convincing evidence before this Court that sterile powder or suspension could have been produced in 1997 in a laboratory., 28 See, e.g., DTX 1000 at 029003-06; *357 Trial Tr. 377:11-15 (Zaccheo) (POSAs “would have understood that not only was aseptic crystallization well known and used by 1997, but they would have realized that closed systems were available to conduct this even as early as 1995 when the FDA was saying that that’s where they should be performed.”); see also DTX 960 (Lach-man) at 025794. Indeed, AstraZeneca’s own witness, Dr. Akers, agreed. See, e.g., Trial Tr. 2315:12-14 (“Could it be done? Under ideal conditions? Yes.”). Specifically, Dr. Akers stated, “I’m saying [PO-SAs would] have a reasonable doubt that they could follow that approach [sterile filtration in combination with aseptic processing] and make a product that was consistently sterile.” Id. at 2318:12-14. A “reasonable doubt” as to a “consistently sterile” product, does not equate to no “reasonable expectation of success of making a sterile product.” See also id. at 2336:4-10 (Akers) (“Q. And once we have that sterile steroid powder, I believe you told me earlier that a skilled person could easily take that powder and aseptically fill and combine it with the presterilized aqueous components to form a suspension, correct? A. That’s — that certainly was a very well developed form of the art in 1997.”). Another AstraZeneca witness, Dr. Zhanel, concurred. Id. at 1672:2-6. (“Q. While you call it complex, most products in 1997 were made with some form of aseptic processing, correct? A. My understanding is that many products in 1997 were made using some aseptic processing. Yes.”).
In short, the record does not support that the equipment was not available at the time. As discussed above, the FDA’s own Inspections Guide discussed equipment use. Moreover, Dr. Akers testified that isolators began being installed and verified for use in the mid-1980s. He explained, “the purpose of isolators could be to provide, I would prefer to say rather than to provide sterility, they were to provide a human free aseptic processing environment superior to a man clean room....” Id. at 2428:15-18. Dr. Akers also acknowledged that the use of an isolator to conduct the last steps of the sterilization and aseptic filling process would “mitigate the risks associated” with those steps and that, while isolators were available long before 1997, “it was not a common technology in sterile bulk drug manufacturing.” Id. at 2242:4-16 (emphasis added), 2265:24-2267:8 (citing DTX 2351).
Notably, AstraZeneca concedes that “[a]septic processing of 40 million units of budesonide nebulizing suspension could potentially result in 40,000 contaminated units as opposed to 40 units with terminal sterilization.” PFOF ¶ 77. In other words, the use of aseptic processing, even in AstraZeneca’s view, would result in a sterilized budesonide product 999 times in 1,000. 29 Dr. Akers candidly admitted that *358 aseptic processing, while difficult, could be done in 1997. See Trial Tr. 2317:13-20 (“THE COURT: I just want to make sure I understand your testimony, Doctor. It sounds like you’re saying that if these risks were removed and if there were a closed system and there weren’t malfunctions in the equipment or human error, that a [POSA] would be able to aseptically process, assuming all of those facts. THE WITNESS: Assuming they got it absolutely right, Judge Bumb.”).
There is no doubt that a terminal sterilization process, such as the heat sterilization process for which AstraZeneca obtained a separate patent, reduces the chances of contamination through human error of the kind to which Dr. Akers testified. But that does not permit AstraZene-ca to patent a product that could have been successfully created through implementation of other well-known and routine sterilization processes. See, e.g., Cubist Pharm., Inc. v. Hospira, Inc., No. 12-367, 75 F.Supp.3d 641, 663 , 2014 WL 6968046, at *15 (D.Del. Dec. 8, 2014) (“[Ojbviousness ‘cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.’ ” (quoting Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed.Cir.2007))). It is interesting to note that AstraZeneca also pressed similar, and equally-flawed, arguments before the PTO, which largely rejected them as irrelevant to a product claim. The following summary of the file is instructive.
On February 18, 2005, the Patent Examiner rejected the asserted claims (prior to their amendment) as obvious under Jakupovic:
It would have been obvious to one having ordinary skill in the art at the time the invention was made to sterilize the respirable, dry powders disclosed by JA-KUPOVIC .by either treatment with ethylene oxide or filtration of the product in solution before precipitation as described in the JAKUPOVIC process. The artisan would have been motivated to sterilize the respirable particles, to prevent microbial growth in the packaged material meant for administration to patients, with a reasonable expectation of success. It is noted that the filter size recommended by JAKUPO-VIC would not be adequate for sterilization. However, the reference does not disclose filter size as a variable that controls particle size. See page 4, lines 14-19. Therefore it would be obvious to ' use a smaller filter and conduct the balance of the process under sterile conditions to obtain a sterile product.
DTX 0004 at 017492-93.
AstraZeneca acknowledged before the Examiner that sterile filtration and aseptic processing were well-known in the art. But, according to AstraZeneca, such technique was not “practicable” for “manufacture of powder pharmaceutical in bulk.” Id. at 017536.
Applicants point out that, in general,
sterilization by filtration may not have been cpnsidered a practicable technique for a pharmaceutical powder such as presently claimed — particularly years ago, at the priority date of the present application. One significant reason for this is because the filtration step would have to be carried out while the compound was in solution, a number of process steps upstream from packaging the final sterile powder product. This means that every reagent (e.g., the anti-solvent) and every piece of equipment and packaging material used subsequent to the filtration step would have to be sterilized and then maintained aseptically during use. This would be complicated and difficult to ensure. Further evidence that this technique may not be a *359 method of choice is found in Ansel, for example at page 297, col.1:
One serious disadvantage to the use of bacterial filters is the possibility of a flaw in the construction of the filter and thus somh uncertainty of sterility, a circumstance not true of methods involving dry- or moist-heat sterilization in which the procedures are just about guaranteed to give effective sterilization.
Ansel also says that “[mjedicinal preparations sterilized by this method are required to undergo severe validation and monitoring since the effectiveness of the filtered product can be greatly influenced by the microbial load in the solution being filtered” (page 296, col.1), and appears to endorse the technique primarily where only small quantities of solution are involved, e.g., in a pharmacy (see page 296, col.2), last sentence (“filtration of small quantities”); and page 296, col.1-2, carryover paragraph). This suggests that filtration would not be the sterilization technique of choice for manufacture of a powder pharmaceutical in bulk, where speed and convenience in handling large quantities of materials and assurance of sterility of the final product are important criteria. Thus, for a number of reasons outlined above, Applicants submit that one of ordinary skill in the art who understands the complications of maintaining sterility throughout multiple processing and packaging steps, and who has read An-sel’s comments, would be dissuaded from trying filtration as a means to sterilize a pharmaceutical powder. Neither Rubinfeld nor any of the other cited references does anything to counter Ansel’s teaching-away. If sterilization of .a pharmaceutical powder were considered desirable, one of ordinary skill would be more likely to try a straightforward, easily verifiable method such as irradiation, despite the possible loss of purity that Would entail. Applicants were the first to discover a practical way to produce a pharmaceuti-cally acceptable, sterile (or sterilized) powder composition at least 98.5% by weight of which is pure budesonide or an ester, acetal or salt thereof. As such, Applicants are entitled to claim that composition.
DTX 0004 at 017536-37 (emphasis added). Thus, AstraZeneca argued that because it discovered a “practical way” to produce a budesonide composition, it should receive patent protection.
Yet, as the Federal Circuit has ruled, the patent is not limited to a process (a practical way), but rather it covers a product. The fact that AstraZeneca admitted to the PTO that there existed a (arguably) less practical way to make the product in and of itself, it seems, should end the obviousness analysis. Notably, in Orthopedic Equipment Co. v. United States, 702 F.2d 1005 (Fed.Cir.1983), the Federal Circuit recognized that while a POSA may not combine two prior art apparatuses for “economic feasibility” reasons, that decision is not relevant to non-obviousness. 702 F.2d at 1013 (“In other words, the fact that the two disclosed apparatus would not be combined by businessmen for economic reasons is not the same as saying that it could not be done because skilled persons in the art felt that there was some technological incompatibility that prevented their combination. Only the latter fact is telling on the issue of nonobviousness.”). Similarly, while a drug manufacturing company may not have ultimately utilized sterile filtration in combination with aseptic processing to manufacture sterilized budesonide in bulk due to the associated high costs of maintaining an aseptic environment at that scale, that is not to say that a POSA would not be motivated to employ these well- *360 known sterilization processes in a laboratory with a reasonable expectation of successfully preparing the claimed sterilized budesonide compositions.
In response to AstraZeneca’s arguments, the PTO reminded AstraZeneca that the claims at issue were product claims not drawn to any particular process.
Applicant further discusses at length possible problems with filtration sterilization. The fact that one process may be more cumbersome than another may be persuasive in prosecuting a process claim but the claims are not drawn to a process. Applicant has merely speculated that the recited product could not be produced by this process. Again, argument is not evidence.
DTX 0004 at 017587 (emphasis added).
AstraZeneca did not agree with the Examiner but, nonetheless, in an effort to address the concerns raised by the Patent Examiner, and to sidestep the Jakupovic reference, which taught away from micron-izing, AstraZeneca amended the claim to specify that the composition was “micron-ized.” See id. at 017619-20. 30 Ultimately, the Patent Examiner determined the above arguments were “moot” in light of Harris. Id. at 017745. The Patent Examiner found that it would have been obvious to prepare a sterile suspension comprising micronized budesonide using the method of Harris, pumping a solution of mometa-sone furoate through a sterilizing filter, precipitating with water, and micronizing to a preferred particle size of less than 2.0<fm. Thus, in light of Jakupovic’s teaching, which drew “equivalence between mometasone and budesonide,” one would expect a similar sterile suspension comprising micronized budesonide. DTX 0004 at 017747. However, once AstraZeneca submitted the Rule 1.131 Declaration in support of a reduction in practice predating the Harris reference, the Examiner accepted the asserted claims. There is no further discussion of filter sterilization or these references. 31
*361 The Court is well aware that it must give great deference to the Examiner’s ultimate decision to allow the asserted claims notwithstanding the Jakupovic/An-sel references. However, it is evident that what was not considered by the Examiner is the evidence Defendants have persuasively put forth in this proceeding. In 1997, a POSA would have known how to dry and mill crystallized budesonide to form a finely-divided (micronized) powder. Indeed, AstraZeneca concedes this point. PRFOF ¶ 23. Moreover, a POSA would have known how to routinely conduct aseptic processing to preserve the sterility of the micronized budesonide composition, for the reasons set forth above. See, e.g., Sciele Pharma, 684 F.3d at 1260 (recognizing Court may afford less weight to references that were before the PTO).
Finally, AstraZeneca argues that both parties’ “experts agree” that U.S. Patent No. 3,962,430, filed on July 14, 1975 by Joseph L. O’Neill (“O’Neill”), entitled “Sterilization of Solid Non-Electrolyte Medicinal Agents Employing Sodium Chloride,” teaches that aseptic recrystallization is problematic due to the formation of needle-shaped crystals. DTX 848. The Court finds that AstraZeneca has taken-the deposition testimony of Ms. Jeanne Moldenhauer, Defendants’ expert, out of context as counsel for Sandoz aptly pointed out. See Trial Tr. 2221:19-2222:5, 2439:6-2442:3. In demonstrating the value of his invention, O’Neill addresses problems in the prior art, including the fact that aseptic recrystallization resulted in the formation of needle-shaped crystals unsuitable for parenteral suspensions. DTX 848 at col.3 11.36-40. This was a recognized potential disadvantage of the prior art, as Defendants’ expert, Ms. Molden-hauer, indicated. However, O’Neill then provided his salt saturation method, which as explained below, resulted in no change in crystal form. Ms. Moldenhauer thus concluded that a POSA would be motivated to try the O’Neill process and would have a reasonable expectation of success that the O’Neill process would result in a sterile budesonide product that would satisfy the asserted claims. Dr. Akers, who read Ms. Moldenhauer’s deposition testimony, expressed no opinions disagreeing with her conclusion. See Trial Tr. 2441:17-2442:3.
f) Conclusion
Accordingly, for the reasons set forth above along with the Court’s findings below regarding secondary considerations, the Court finds that Defendants have demonstrated by clear and convincing evidence that a POSA, admittedly motivated to create the claimed sterilized budesonide compositions, could have done so utilizing sterile filtration in combination with aseptic processing and would have had a reasonable expectation of success.
ii. Moist Heat Sterilization
Defendants next argue that a POSA would have had a reasonable expectation of success in creating the claimed sterilized budesonide compositions using conventional moist heat sterilization. Defendants contend, that the asserted claims are invalid as obvious over (a) O’Neill and (b) either the IPPL or European Pulmicort®. 32
Conventional steam sterilization, also known as autoclaving or moist heat sterilization, employs steam under pressure and is the “method of choice ... where the product is capable of withstanding such *362 treatment.” 33 DTX 851 at 018242; PRFOF ¶ 73. According to Ansel, moist heat sterilization destroys bacteria by de-naturation and coagulation of essential proteins in the microbial cell. DTX 851 at 018242. While the presence of moisture allows the destruction of bacteria at lower temperatures than when moisture is absent, pressure is used to obtain higher temperatures within the autoclave. Autoclaves are routinely operated at 121°C at 15 pounds pressure for 15 minutes. Id. at 018243 . Although AstraZeneca argues that moist heat sterilization was a well-known sterilization technique as of 1997 that would be expected to yield a sterile product, it contends that budesonide could not withstand the temperatures typically used in moist heat sterilization cycles. PRFOF ¶ 76. There are several recognized concerns with the use of moist heat sterilization, including the potential degradation or decomposition of the active ingredient, as well as particle size or agglomeration issues. However, Defendants presented evidence that a POSA would have a reasonable expectation of successfully using moist heat sterilization to create the claimed compositions in spite of these concerns.
First, Defendants presented evidence that the use of moist heat to sterilize a pharmaceutical steroid composition was taught by O’Neill. DTX 848. Ms. Mol-denhauer convincingly testified that O’Neill taught a POSA that a corticosteroid suspension could be saturated with an excess of sodium chloride, sterilized by moist heat, and aseptically processed to create a pharmaceutically acceptable product without any degradation or decomposition of the steroid. Trial Tr. 156:3-12. Degradation or decomposition of the steroid would impact the purity of the steroid — in this case, budesonide. See Trial Tr. 461:6-8 (Zaccheo). However, O’Neill experienced no decomposition. (“Analytical studies, including infra-red analysis, indicated intact dexamethasone acetate with no decomposition even after autoclav-ing the steroid-sodium chloride mixture in Step A for 1 hour at 121°C.) DTX 848 at col. 4 11.60-64. Thus, while some prior art references recognized that moist heat “can be considered unsuitable” for sterilizing heat sensitive materials such as steroids, see PTX 513 at 1332160; DTX 2274 at 0400617, 34 a POSA would also know from O’Neill that the application of moist heat to a steroid can result in a pharmaceutically acceptable, sterilized steroid composition that did not degrade or result in a loss of purity. In addition, a POSA would know based upon the teachings of Lach-man that the time, temperature, and pressure could be routinely altered to create the optimal steam sterilization cycle. See Trial Tr. 148:3-8 (Moldenhauer); DFOF ¶ 77.
Agglomeration and particle size changes •were “well understood” and “well known” consequences of moist heat sterilization of suspensions, which could render the sterilized product pharmaceutically un acceptable. See Trial Tr. 747:24-25 (Dalby); DFOF ¶¶ 78, 80; Trial Tr. 150:8-11 (Mol-denhauer). As Dr. Richard Dalby, Defendants’ expert, explained, molecules that comprise the drug product particles dissolve in a solution and break away from larger particles. During the cooling phase after moist heat sterilization, these free molecules (1) may associate with other *363 molecules to form new particles that could have a different shape, (2) may associate with other particles that did not completely dissolve to form larger particles, or (3) partially undissolved particles could stick to one another (bridging). See Trial Tr. 746:13-747:28. The potential for particle growth after moist heat sterilization was not a concern unique to budesonide. Id. at 756:18-25 (Dalby). O’Neill acknowledged this problem in describing the value of his invention: when dexamethasone acetate suspended in water or sodium chloride solutions “having a concentration below that of saturated solutions” were then auto-claved, the suspensions resulted in crystal growth of 300 to 400 microns. DTX 848 at col.3 11.51-61.
The evidence persuasively demonstrated that particle size growth and agglomeration would not have been concerns for a POSA attempting to create the claimed pharmaceutically acceptable, sterilized bu-desonide compositions, however, because those compositions do not require any particular particle size or pharmaceutical use that would limit the particle size. It is the route of administration that necessitates specific particle size ranges; thus, even large budesonide particles may be pharma-ceutically acceptable in a topical application or in a capsule for oral administration. See Trial Tr. 308:3-20 (Moldenhauer); id. at 2826:20-2827:1 (Williams). Although the asserted claims are not limited to a specific particle size or pharmaceutical use, the Federal Circuit’s claim construction does require “finely-divided dry. particles.” Regardless, the evidence demonstrated that a POSA, admittedly motivated to prepare a pharmaceutically acceptable, sterilized budesonide composition, would not have been dissuaded from using steam sterilization due to the known agglomeration and particle growth issues because POSAs were aware of a number of well-known and routine methods that could be employed before or after steam sterilization to address these concerns, as discussed below. Id. at 161:8-11 (Molden-hauer).
a) Sodium Chloride Saturation
First, a POSA could reduce the amount of solvent available to dissolve the drug particles by using a saturated sodium chloride solution prior to sterilization by moist heat, as described by O’Neill. This is set forth in O’Neill. One object of O’Neill’s invention was the elimination of particle size changes during sterilization in the preparation of sterile suspensions. DTX 848 at col.2 11.6-11; Trial Tr. 148:23-149:2, 150:3-7 (Moldenhauer); id. at 745:3-7 (Dalby). O’Neill taught that adding an excess amount of sodium chloride to a solution, such that the solution was saturated, prevented caking and agglomeration during the steam sterilization process. Id. at 152:3-15 (Moldenhauer); see also DTX 848 at col.3 11.6-11 (“The addition of sodium chloride in a concentration sufficient to form saturated solutions at both room and elevated temperatures, plus a 10% excess, prevents the solution of the drugs at elevated temperatures, thus eliminating changes in crystal size and form upon recrystallization during subsequent cooling.”). O’Neill’s invention theorizes that if one .makes the water unavailable to dissolve the glucocorticosteroid during the heating phase, then the drug particles cannot reassociate with one another during the cooling phase, thereby preventing particle size issues. He accomplishes this through the addition of large quantities of sodium chloride, which requires water to dissolve; because the water is dissolving the sodium chloride, it is not available to dissolve the glucocorticosteroid. Trial Tr. 748:9-23 (Dalby).
Example 1 of O’Neill teaches a sterile aqueous suspension suitable for adminis *364 tration as a parenteral pharmaceutical containing the corticosteroid dexamethasone acetate. DFOF ¶ 95. A suspension of finely divided dexamethasone acetate particles is formed in a solution saturated with sodium chloride and containing a wetting agent. This suspension is autoclaved at 121°C for 20-30 minutes. Other ingredients are separately autoclaved and then aseptically combined. Id. O’Neill explains that tests indicated no crystal size growth or change in form, or degradation. See Trial Tr. 156:5-12 (Moldenhauer); DTX 848 at col.4 11.56-64. Indeed, AstraZeneca’s own witness, whose testimony was introduced by Defendants, Dr. Williams, testified that a POSA would expect the O’Neill method in Example 1 to work on budeso-nide without resulting in agglomeration. Trial Tr. 2759:12-19.
Dr. Dalby similarly testified that a POSA would have reason to believe the O’Neill method would work on budesonide because it is also a glucocorticosteroid, like the dexamethasone used in O’Neill. Id. at 749:523 ; see also id. at 149:20-21 (Moldenhauer). 35 Dr. Dalby convincingly explained that a POSA would know that both dexamethasone and budesonide are soluble in organic solvents and have low solubility in water; thus, a POSA would recognize their similar solubility properties and conclude that what works for one may work for the other. See id. at 55:7-756:8 . This testimony was unrebutted. Dr. Zhanel even agreed that because steroids have similar chemical structures, a POSA would expect similar outcomes. See id. at 1443:12-20 ; DFOF ¶ 105. 36
*365 In rebuttal to the foregoing, AstraZene-ca cites a number of references that postdate the priority date applicable here, arguing that these references “confirm” what was known in the art as of 1997 and show that a POSA would not have had a reasonable expectation of successfully preparing a sterilized budesonide composition that meets the purity requirement of the asserted claims. 37 See, e.g., PRFOF St 77. Specifically, U.S. Patent No. 6,464,958, filed Oct. 28, 1999 (“Bernini”), notes that beclomethasone dipropionate “suspensions subjected to. a wet steam process under conditions similar to those reported in [O’Neill] (121 x C. for 15 minutes) undergo a remarkable decrease in the content in active ingredient (about 8-9%), with a corresponding significant increase in degradation products (about 10-11%).” PTX 1764 at col.6 11.24-32. In addition, U.S. Patent No. 6,863,865, filed Sept. 30, 2002 (the “McAffer Patent”), reports that “the application of a standard autoclaving technique to budesonide suspension has also resulted in a significant increase in the levels of impurities present.” PTX 507 at col.8 11.49-51. These two references suggest that moist heat sterilization causes unacceptable degradation of a steroid and of budeso-nide in particular.
The Court reserved on Defendants’ objections at trial to these later references. The Court overrules the objection, but finds that they have no persuasive value as the question is what was known prior to 1997. These references do not shed credible light on that question. The conclusion that AstraZeneca wants the Court to draw from these references is not only unsupported but it is also contradicted by O’Neill and other more contemporaneous art. See infra note 39; cf. Plant Genetic Sys., N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1344 (Fed.Cir.2003). As described above, O’Neill conducted the experiment as set forth in the patent and provided the results of the experiment, i.e., no crystal size growth or change in form, or degradation. The bare statement in *366 Bernini fails to provide any description of which “conditions” of O’Neill’s process that Bernini attempted to replicate; the parenthetical reference suggests only the time and temperature conditions of the wet steam process but does not indicate that Bernini attempted to use the salt saturation technique disclosed by O’Neill. As such, the Court accords little weight to this ambiguous critique of O’Neill dated more than two years after the relevant time period or to Dr. Zhanel’s related testimony. 38
There is no evidence prior to 1997, however, warning a POSA that budesonide will unacceptably degrade under thermal sterilization conditions. To the contrary, O’Neill discloses a pharmaceutically acceptable glucocorticosteroid product sterilized using a conventional moist heat cycle (121°C for 20 minutes). Thus, while a POSA was aware that degradation can be a potential disadvantage with moist heat sterilization of any substance, which Ms. Moldenhauer acknowledged, Trial Tr. 289:4-13, 22-25, O’Neill demonstrates that it was not a deterrent to a POSA seeking to sterilize a steroid substance and, in fact, degradation did not occur when O’Neill did so. 39 Indeed, Defendants introduced the deposition testimony of Dr. Williams, who stated that “based on O’Neill, [POSAs] would expect substituting in Budesonide in example one ... then undergoing the autoclave process and the mixing, ... should produce a suspension of finely divided particles that does not agglomerate.” Trial Tr. 2766:6-12. Moreover, a POSA would expect sterility:
Q. ... So just following what O’Neill says it says, if you swapped in Budeso-nide for dexamethasone, follow the procedure, you would — a [POSA] at the time would reasonably expect to have the resulting product be finely divided *367 Budesonide suspension that is sterile and doesn’t agglomerate, is that right?
A. I mean O’Neill uses the word sterile.
Q. Right.
A. So I think a person of ordinary skill in the art would — probably would believe that what’s produced here would be sterile.
Trial Tr. 2766:23-2767:8 (Williams).
AstraZeneca contends further that even though O’Neill asserts that dexamethasone avoids decomposition, O’Neill presents no data showing the purity of the final product despite the degradation that would be expected at such temperatures. However, O’Neill plainly states that the analytical studies indicated no decomposition. See DTX 848 at col.4 11.59-63. AstraZeneca offered the testimony of Dr. Zhanel who opined that O’Neill did not address the degradation problem. Dr. Zhanel opined that if degradation occurred at Step A of O’Neill’s example, a POSA would not expect a pharmaceutically acceptable product after Steps B and C. Trial Tr. 1778:2-14. This testimony, however, ignores the fact that O’Neill taught that a POSA could achieve no degradation after autoclaving the steroid-sodium chloride mixture in Step A for even 1 hour at 121°C. See DTX 848 at col.4 ll.59-63.
Plaintiffs also point to U.S. Patent No. 5,540,930, entitled “Suspension of Lotep-rednol Etabonate for Ear, Eye, or Nose Treatment,” filed on Oct. 25, 1993 by Yaa-cov J. Guy et al. (“Guy”). DTX 853. This patent notes that suspensions of corticosteroids are “frequently hampered by the subsequent formation of cakes resulting from aggregation of the suspended material.” Id. at col.1 ll.14-17. The caking occurs while the suspension is stored— after sterilization and filling. Guy explains that the presence of ions causes caking. Id. at col.3 11.41-45. Plaintiffs contend that Guy teaches a POSA that the use of sodium chloride in a budesonide aqueous Suspension would promote caking and thus teaches away from the O’Neill method. However, Ms. Moldenhauer persuasively explained that, in viewing Guy as a whole, a POSA would understand Guy to be discussing low levels of sodium chloride, e.g. 0.9% sodium chloride (isotonic), in contrast to the saturation or excess of saturation levels discussed in O’Neill. See Trial Tr. 295:22-296:23. AstraZeneca’s characterization of Ms. Moldenhauer’s testimony as a blanket statement that a POSA reading Guy would be taught away from using sodium chloride in an aqueous budesonide suspension is erroneous.
Notably, the PTO relied upon O’Neill to reject AstraZeneca’s claims directed to sterile, dry solids (not suspensions as in claims 50 and 51). DFOF ¶ 107. For its part, AstraZeneca argued that O’Neill discloses a sterile aqueous suspension for parenteral administration which “is not a heat sterilized inhalation powder.” DTX 0004 at 017308. There was no reference to O’Neill after the addition of what are now claims 50 and 51. See DFOF St 107. Although the PTO Examiner was technically aware of O’Neill at the time that she addressed the asserted claims and discussed moist heat sterilization, it is worth noting that the examiner did not discuss O’Neill after claims 50 and 51 were added. Cf. Sciele Pharma, 684 F.3d at 1260 .
b) Surfactant
Second, the evidence demonstrated that a POSA concerned with preventing agglomeration and caking could add a surfactant or wetting agent to the product, and this was known and routine as of 1997. Lachman recognized the importance of stabilization of a suspension between manufacture and use to prevent settling and caking, which may prevent redispersion of *368 particles prior to use. DTX 960 at 025814. Lachman suggests the inclusion of a surfactant: “Surface active agents may aid in the preparation and stabilization of a suspension by reducing the interfacial tension between the particles and the vehicle.” Id. Ms. Moldenhauer explained that a surfactant covers the particles, making it less likely that they could agglomerate or cake. Trial Tr. 162:10-14. In addition to providing several surfactants used in parenteral suspensions, Lachman provides an example of a specific formulation. DTX 960 at 025814-15. AstraZeneca’s expert, Dr. Ak-ers, agreed that Lachman teaches the use of surfactants to prevent agglomeration and that this was known in the art prior to 1997. Trial Tr. 2448:16-23, 2449:2-6. Dr. Williams, AstraZeneca’s expert, also agreed that surfactants or wetting agents can be used by a POSA to prevent agglomeration and caking. See id. at 2770:1-7. (Even O’Neill teaches several steroidal formulations that contain wetting agents. See DFOF SI 84.) Moreover, Dr. Williams testified that a POSA could “routinely” calculate the amount of surfactant necessary to prevent agglomeration. See id. at 2770:16-2772:11. And, a POSA would know that the use of surfactants does not render a product pharmaceutically unacceptable. See DFOF ¶ 84.
AstraZeneca’s only response to Defendants’ evidence is that the use of surfactants may not entirely eliminate agglomeration or caking. AstraZeneca points to. Dr. Akers’ testimony that the use of surfactants addressed by Lachman was intended only to prevent agglomeration that occurs after the manufacturing process, see PRFOF ¶ 85, thereby suggesting that surfactants could not be used to prevent agglomeration that occurs in the moist heat sterilization process. However, the experts agreed that surfactants can be utilized to prevent agglomeration regardless of the point in the process at which the agglomerates form. Moreover, O’Neill utilizes surfactants prior to steam sterilization in an attempt to address changes in particle size that occur in the steam sterilization process. AstraZeneca further argues that O’Neill discloses that a wetting agent is not sufficient to prevent agglomeration or particle size change as he discloses that “further steps are necessary in order to overcome the issues that it identifies with moist heat sterilization,” such as the use of sodium chloride. PRFOF ¶ 84. This argument is confusing. Even if the addition of a surfactant did not prevent all forms of particle size growth or agglomeration, then a POSA could follow the remaining steps of O’Neill to obtain the claimed products.
c) Sonication
Third, defendants presented evidence that sonication, which is the use of ultrasonic energy to break up agglomerated particles, was “commonly known” to PO-SAs since the 1970s and “very easy to do.” Trial Tr. 162:23-163:5, 166:11-14, 313:10-16 (Moldenhauer). Ms. Moldenhauer testified that it would be known to POSAs to use aseptic sonication if attempting to create a sterilized product. Id. at 166:11-14, 165:4-8 (Moldenhauer). Indeed, as discussed above, in 1997, a POSA routinely conducted several post-sterilization steps aseptically. See also DFOF ¶ 87. Dr. Williams, AstraZeneca’s expert, agreed that sonication was commonly known. Trial Tr. 2768:8-25. Dr. Williams testified that hé uses sonication routinely in his lab for several purposes including deagglomer-ation, but that it has been in use since at least the 1980s. Id. Dr. Akers agreed as well. Id. at 2451:6-16 (“Q. Okay. Now, sonication, not only were you familiar with it, but it was well known by those of skill in the art in 1997, right? A. As a technology, yes. Q. Okay. And indeed, you ran into it in 1960s, if I recall; is that right? *369 A. Maybe not quite that long ago. Q. Needless to say, long before 1997? A. Before 1997. Q. Okay. It’s not a new technology, right? A. No, it’s not a new technology.”).
The only reference in the art to sonieation was Steckel. DTX 871. Steckel describes the suspension of particles in an aqueous solution, which was then subjected to ultrasonic treatment. Steckel writes: “The particle size distribution was measured before and after 90 s of ultrasonication treatment. Previous test series have shown that the deagglomeration process was completed after 90 s. This is in agreement with results from (Bleich et al., 1994). The ratio of median particle size (x50%) before ultrasonication to median particle size after ultrasonication was calculated and then termed ‘index of agglomeration’.” DTX 871 at 018489-90. Ms. Moldenhauer testified that Steckel teaches that “before and after the're was no change in particle size when they sonicated.” Trial Tr. 163:15-18. However, it also demonstrates, consistent with the testimony of Ms. Moldenhauer and Dr. Williams, that sonication was known in the art as a means of addressing agglomeration as of 1997. See DTX 871 at 018489-90 (citing 1994 reference); Plant Genetic Sys., 315 F.3d at 1344 (“This court has approved use of later publications as evidence of the state of art existing on the filing date of án application.” (citation omitted)). 40
In rebuttal, AstraZeneca agrees that so-nication was widely known but contends that aseptic sonication was not routine. Dr. Akers testified that aseptic sonication would have been “difficult” in 1997 because of the need to sterilize the sonication equipment. Trial Tr. 2183:5-21. However, as discussed at length above, the equipment and technology necessary to prepare the claimed compounds on a laboratory (as opposed to manufacturing) scale existed as of 1997. Indeed, Dr. Akers agreed that sterile isolator technology was available at the time, and an isolator would mitigate the risks associated with micronization of the drug substance. See DFOF ¶ 87; accord Trial Tr. 2242:1-7. Moreover, as noted, Ms. Moldenhauer persuasively testified that it would be known to POSAs to soni-cate the drug product aseptically in order to prevent contamination of the sterilized suspension. Trial Tr. 166:11-14, 165:4-8. And, in 1997, POSAs routinely conducted several post-sterilization steps aseptically. See supra; see also DFOF ¶ 87.
d) Milling
Fourth, Defendants presented evidence that milling, a mechanical process for reducing particle size, was well-known to a POSA as of 1997. See Trial Tr. 166:17-20 (Moldenhauer); PRFOF ¶ 89. In fact, several prior art references teach aseptic or sterile milling as a method of particle size reduction. In addressing the preparation of parenteral suspensions, Dr. Michael Akers notes that after drying a sterile powder, “it will usually require some method of particle size reduction. Because of the small quantity of powder usually available for development work, fluid energy mills such as the Jet-O-Mizer or Gem Mill are more practical. They are available for sterile milling....” DTX 862 at 018395-96. The 1994 FDA Inspections Guide also recognizes that one of the usual steps in the manufacture of sterile bulk drug substances is aseptic milling. DTX 1000 at 029003. Entitled “Ophthalmic Composition,” U.S. Patent No. 5,407,926 issued on *370 Apr. 18, 1995 by Abbot F. Clark (“Clark”) discloses in an Example the preparation of a micronized drug suspension consisting of a glucocorticosteroid, like budesonide, that includes the use of sterilized balls to aseptically .mill the steroid drug substance. See DTX 160 at eol.7 11.19-26. Specifically, sterilized glass balls are added to a vessel containing the drug substance in sterilized aqueous solution form, “and the contents of the container are milled aseptieally at 225 rpm for 16 hours, or until all particles are in the range of approximately 5 microns.” DTX 160 at eol.7 11.19-23; see also Trial Tr. 166:21-167:9 (Moldenhauer). Based upon these teachings, Ms. Molden-hauer testified that a POSA who moist heat sterilized a drug product and wanted to affect the particle size of the resulting sterilized product would have no reason not to utilize the routine process of aseptic milling. See Trial Tr. 167:18-23. Further, she testified that aseptic milling could be employed on either a sterile powder or suspension. Id. at 167:24-168:3 . This testimony was convincing.
AstraZeneca does not dispute that milling techniques were well known by 1997 but asserts that they could not be used to create a finely-divided powder. Dr. Akers testified to the distinction between milling and micronization, stating that milling “would not achieve micronization levels of particle size reduction.” Id. at 2185:14-20 . However, the claims require only “finely-divided” dry particles and do not require that the particles undergo a micronization step. See id. at 2278:12-22 (Akers). In addition, Dr. Akers was asked about Ansel on cross-examination; Ansel discloses that parenteral suspensions “may be prepared by reducing the drug to a very fine powder with a ball mill, micronizer, colloid mill, or other appropriate equipment and then suspending the material in a liquid in which it is insoluble.” DTX 2093 at 030999 (emphasis added). Dr. Akers acknowledged that the equipment and processes set forth in Ansel “could arrive at a powder with a defined particle size to one degree or another” as milling does affect particle size. See Trial Tr. 2305:5-7, 2306:22-23. Dr. Akers does not dispute that milling can be utilized to effect a change in particle size; nor does he dispute that the resultant particle size could fall within a low micron range that would be deemed finely-divided. Id. at 2309:2-25, 2305:5-7, 2306:22-23 . Rather, his concern is that the resultant particle size may not be finely-divided enough for certain routes of administration and intended uses. 41 However, the asserted claims are not so limited. Moreover, O’Neill discloses that milling inter alia could be utilized to reduce particle size to 10 microns for use in suspensions. DTX 848 at col.2 11.37-42. AstraZeneca points out that this step was done prior to moist heat sterilization, but this is a distinction without a difference. The point is that milling could be utilized to achieve a finely-divided powder.
e) Rotary Sterilization
Lastly, Defendants introduced evidence thgt a POSA would be aware of rotary sterilization, which involves a steam sterilizer equipped with an inner chamber that rotates like a dryer to ensure the contents are constantly agitated throughout the sterilization process. Trial Tr. 168:4-169:1. According to Ms. Moldenhauer, this prevents particles from sticking together and forming agglomerates or cakes. *371 Id. Ms. Moldenhauer credibly testified that rotary sterilization has been known in the pharmaceutical industry since the 1970s and 1980s, and that she was aware of several other pharmaceutical companies that utilized rotary sterilization. Id. at 169:13-22 . In support, she cites Dr. Michael Akers, who discloses the characteristics of a well-formulated suspension, which include easy resuspension of drug particles after “mild shaking” and dispersed particles do not settle rapidly after shaking. DTX 862 at 018391. As Ms. Moldenhauer explains, Dr. Michael Akers discusses that agitation or shaking, which is exactly what rotary sterilization is, causes the particles not to settle out of suspension. Trial Tr. 170:1-11.
In rebuttal, Dr. Akers testified that he is not aware of the use of rotary sterilization after a moist heat process to deal with particle size change, agglomeration, or caking; nor would a POSA expect shaking to address these issues. See id. at 2186:2-.19. Dr. Akers opines that Dr. Michael Akers’ discussion was intended to address shaking as a method of resuspending a suspension after manufacture but does not teach a solution to the problems associated with moist heat sterilization. While Dr. Akers may not have personally been aware of this use, however, Ms. Moldenhauer convincingly testified that other divisions of her employer used rotary sterilization as early as the '70s and '80s. See supra. Moreover, while AstraZeneca contends that rotary sterilization would not be viewed as a “full solution” to the problems associated with moist heat sterilization, a POSA encountering any particle size or agglomeration issues would be able to employ rotary sterilization in conjunction with the other known methods discussed herein to resolve any problems. As such, Defendants have demonstrated that a POSA could use rotary sterilization to address particle growth or agglomeration issues.
AstraZeneca’s primary argument in rebuttal is that each of the techniques described above only addresses one or two of the potential problems with moist heat sterilization, but not all of’them. However, Defendants need not prove, that each individual technique would adequately address all known problems where, as here, all of these methods were available and widely-used to address the known limitations of moist heat sterilization. AstraZ-eneca also argued that a POSA in 1997 did not have the ability to conduct many of these techniques aseptically due to the limited technology. However, as addressed in depth in connection with sterile filtration, Dr. Akers candidly acknowledged the availability of the required equipment and knowledge but recognized the impact of human error, especially in the manufacture of large quantities of pharmaceutical drugs. Under ideal aseptic conditions, following the known and routine processes a POSA would have had a reasonable expectation of successfully preparing the claimed compositions using moist heat sterilization and would have been able to routinely optimize the sterilization process to address any particle size, agglomeration, or caking issues by employing the teachings of O’Neill alone or in combination with any of the other known and routine processes discussed above.
f) Conclusion
After considering the evidence set forth above, as well as the evidence of secondary considerations set forth infra, Defendants have presented clear and convincing evidence that a POSA, admittedly motivated to prepare the claimed sterilized budeso-nide. compositions, would have had a reasonable expectation of successfully doing so using moist heat sterilization in combination with known and routine methods of *372 addressing any particle growth, agglomeration, or caking issues.
iii. Ethylene Oxide (EO)
Defendants next argue that a POSA would have had a reasonable expectation of s

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Source: Frix Law Library, https://www.frixlaw.com/law-library/cases/7230016. Public record. Not legal advice.