BUMB, District Judge.
I. INTRODUCTION .................................................................333 II. BACKGROUND ...................................................................334
A. The Asserted Claims of the '834 Patent ....................................334
B. Markman Hearing ...........................................................334
C. Federal Circuit Decision ..................................................334
D. Remand Proceedings ........................................................334
E. Defendants' Sterilization Processes .......................................335
III. LEGAL ANALYSIS ...............................................................335
A. Asserted Claims on Remand .................................................335
B. Infringement ..............................................................335
C. Invalidity Defenses .......................................................336
1. Reduction to Practice of the Invention .................................336
2. Obviousness ............................................................339
a. Motivation .....................................................340
b. Prior Art Sterilization Techniques .............................343
i. Sterile filtration/crystallization ...................344
a) 1994 FDA Inspection Guide .........................344
b) Lachman: The Theory and Practice of Industrial
Pharmacy (1986) .................................347
c) Ansel: Pharmaceutical Dosage Forms and Drug
Delivery Systems (1995) .........................348
d) Remington: The Science and Pharmacy (1995) ........349
e) Harris: U.S. Patent No. 6,187,765 (1997) ..........350
f) Conclusion ........................................361
ii. Moist Heat Sterilization .............................361
a) Sodium Chloride Saturation ........................363
b) Surfactant ........................................367
c) Sonication ........................................368
d) Milling ...........................................369
e) Rotary Sterilization ..............................370
f) Conclusion ........................................371
iii. Ethylene Oxide (EO) ..................................372
a) Toxic Residues ....................................372
b) Penetration of the Crystalline Structure ..........376
e) Conclusion ........................................377
iv. Irradiation ..........................................377
v. Dry Heat .............................................380
c. Secondary Considerations .......................................382
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 ...........................................................3974. Enablement .............................................................3985. Written Description ....................................................399 IV. CONCLUSION ...................................................................399
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 budesonide compositions. Plaintiffs AstraZeneca LP and AstraZeneca AB (collectively, "AstraZeneca") 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 ("ANDAs"). 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., 623 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.
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.
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:
`834 Patent col.11 ll.48-52 (emphasis added). Claim 50 recites:
`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.
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.
On appeal, the Federal Circuit reversed this Court's claim construction, construing the disputed term "micronized powder composition" to mean "finely divided dry particles"
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
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.
As the case now stands on remand, the following claim analysis applies to the independent claims:
`834 Patent col.11 ll.48-52; col.13 ll.54-60. Again, 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.
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) pharmaceutically acceptable, PFOF ¶¶ 103, 111, 118; (2) consisting of a micronized powder composition, PFOF ¶¶ 99, 104, 112, 119; (3) at least 98.5% of which is pure budesonide 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 AstraZeneca 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.
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:
2013 WL 1385224, at *10 (quoting 2012 Trial Tr. 3935:24-3936:13 (Chipps)).
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 (i.e., 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.
"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
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
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, AstraZeneca 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; AstraZeneca'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.
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.
As such, the Court finds that AstraZeneca 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
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).
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 obvious
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.
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 pharmaceutically acceptable, aqueous suspension consisting of a highly pure, micronized budesonide powder composition and thus encompasses all of the elements of asserted claims 50 and 51,
Defendants argue — and AstraZeneca agrees — that, by 1997, a POSA would have been motivated to prepare the sterile budesonide 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
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, AstraZeneca 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."
In any event, the comment letter is not necessarily inconsistent with Dr. Muhvich'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).
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);
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.
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.
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).
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:
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 (Zaccheo); see also PRFOF ¶ 16. For example, U.S. Patent No. 5,556,964, entitled
Regarding Step 2 of the FDA Inspection Guide process, Hofstraat further discloses that a POSA could recrystallize the budesonide out of the solution and obtain pure budesonide with an isomer ratio of 1:1. DTX 892 at col.2 ll.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 ll.45-51; Trial Tr. 373:6-12 (Zaccheo). 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.
AstraZeneca disputes that Steckel discloses pharmaceutically acceptable, micronized budesonide with purity greater than 99%. See PRFOF ¶ 40. This is unfounded. Indeed, Dr. Zhanel, AstraZeneca's witness, conceded his understanding of Steckel to be "using pharmaceutical grade budesonide of over 99 percent purity."
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.
The evidence also demonstrated that Step 3 of the FDA Inspection Guide, aseptic isolation of the sterile substance, and Step 4, aseptic drying, milling,
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.
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 Lachman. 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:
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:
DTX 960 at 025793-94 (emphasis added); see also Trial Tr. 350:1-4 (Zaccheo).
Motivated to produce a sterilized budesonide product — powder, solution or suspension — a POSA also understood from Lachman (and other "Bibles in sterility")
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, POSAs 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).
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:
DTX 2093 at 030995-96.
Ansel also discussed the use of aseptic processing in combination with sterile filtration and other sterilization methods:
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 Ansel (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,
DTX 2093 at 030999.
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
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 mometasone furoate monohydrate" (a glucocorticosteroid 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 mometasone of Example 1. Id. at col.6 1.65 to col.7 1.40. Harris thus discloses a nebulized aqueous suspension of a micronized corticosteroid for use in treating disorders of the lower airway (i.e., pharmaceutically acceptable). Id. at col.1 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 AstraZeneca's expert, Dr. Akers:
1994 FDA Inspection Guide Harris (1997) Example 1 Akers & Agalloco 22 (1993) ("typically") ("usually")Step 1: Conversion of the nonsterile (1) Dissolve mometasone furoateStep 1: Sterile filtration drug substance to the sterile in acetone (organic solvent), by dissolving in a solvent, mix to form a clear sterilization of the solution solution; by filtration and collection in a sterilized reactor (crystallizer). (2) Pump solution through a sterilizing filter into sterile precipitation vessel;Step 2: Aseptic precipitation or (3)-(4) add sterile purified water;Step 2: Crystallization (carried crystallization of the sterile drug maintain temperature (45-50°C); out under sterile conditions) substance in the sterile reactor. stir (5)-(6) maintain stirring and temperature, precipitate will begin to form; add sterile purified water (6)-(8) stir, cool to ambient temperatureStep 3: Aseptic isolation of the (9) filter the precipitate and washStep 3: Filtration (carried out sterile substance by with sterile purified water; under sterile conditions) centrifugation or filtrationStep 4: Aseptic drying, milling (10) dry in vacuum oven (30-35°CStep 4: Washing, drying, milling and blending of the sterile substance. 35C), 12-24 hours and blending (carried out under sterile conditions) Final product is dried mometasone furoate monohydrate; milling/micronization (Example 2)
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,
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
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 30 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 budesonide 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 micronized budesonide composition requires a POSA to conduct several steps subsequent to the sterile filtration of the budesonide 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 ("[O]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.
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). AstraZeneca also argues, the "very significant" likelihood of contamination eliminated any reasonable expectation of success with the process.
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:
Trial Tr. 2316:8-13; see also id. at 2315:14-21 (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
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:
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.
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.
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 AstraZeneca 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) ("[O]bviousness `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:
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,
DTX 0004 at 017536-37 (emphasis added). Thus, AstraZeneca argued that because it discovered a "
Yet, as the Federal Circuit has ruled, the patent is not limited to a process (a practical way), but rather it covers a product.
In response to AstraZeneca's arguments, the PTO reminded AstraZeneca that the claims at issue were product claims not drawn to any particular process.
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 micronizing, AstraZeneca amended the claim to specify that the composition was "micronized." See id. at 017619-20.
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 ll.36-40. This was a recognized potential disadvantage of the prior art, as Defendants' expert, Ms. Moldenhauer, 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.
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.
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®.
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
First, Defendants presented evidence that the use of moist heat to sterilize a pharmaceutical steroid composition was taught by O'Neill. DTX 848. Ms. Moldenhauer 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 autoclaving the steroid-sodium chloride mixture in Step A for 1 hour at 121°C.) DTX 848 at col. 4 ll.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,
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 (Moldenhauer). 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
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 budesonide 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 pharmaceutically 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 wellknown and routine methods that could be employed before or after steam sterilization to address these concerns, as discussed below. Id. at 161:8-11 (Moldenhauer).
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 ll.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 ll.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 re-crystallization 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 administration
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).
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
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.
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 ll.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 Loteprednol Etabonate for Ear, Eye, or Nose Treatment," filed on Oct. 25, 1993 by Yaacov 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 ll.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 ¶ 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.
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
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.
Third, defendants presented evidence that sonication, which is the use of ultrasonic energy to break up agglomerated particles, was "commonly known" to POSAs 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 he uses sonication routinely in his lab for several purposes including deagglomeration, 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?
The only reference in the art to sonication 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 (×50%) 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 there 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 an application." (citation omitted)).
In rebuttal, AstraZeneca agrees that sonication 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 sonicate 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.
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
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.
Lastly, Defendants introduced evidence that 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.
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. AstraZeneca 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.
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 budesonide compositions, would have had a reasonable expectation of successfully doing so using moist heat sterilization in combination with known and routine methods of
Defendants next argue that a POSA would have had a reasonable expectation of success in creating the claimed sterilized budesonide compositions using conventional ethylene oxide ("EO") sterilization as disclosed in Clark (discussed infra) in combination with a POSA's knowledge as of 1997. Defendants contend, that the asserted claims are invalid as obvious over Clark.
Prior to 1997, a POSA would have understood that EO was a common alternative sterilization method when the material to be sterilized was unable to withstand high temperatures. Trial Tr. 736:15-737:1 (Dalby); DTX 2278 at 0400321; DTX 2274 at 0400617. It was also the standard sterilization method of steroid suspensions in at least the 1950s and 1960s, and continues to be used today. See DRFOF ¶ 66; DFOF ¶ 144.
EO sterilization consists of placing the material to be sterilized in a chamber, which may be preconditioned to a particular temperature and humidity, introducing EO into the chamber until a certain concentration level is reached, and then maintaining that level for a period of time. PRFOF ¶ 136. A POSA understood that the exposure time could be decreased by increasing the relative humidity and temperature, but if the material being sterilized could not tolerate high humidity or temperature, a POSA could increase the exposure time. PRFOF ¶ 138. These were routine optimizations of the sterilization cycle. See Trial Tr. 594:21-595:11 (Miller); see also DTX 285 at 30000106. Although EO sterilization was a standard process as of 1997, a POSA was aware of two concerns with this sterilization technique, elimination of toxic residues and penetration of a product's crystal structure.
It is undisputed that a POSA knew how to determine the amount of EO residuals after sterilization of a steroid. This is confirmed by a 1965 article published by Norman Adler, entitled "Residual Ethylene Oxide and Ethylene Glycol in Ethylene Oxide Sterilized Pharmaceuticals," 54 J. PHARM. SCI. 735 ("Adler"), in which he describes and applies methods for determining EO residuals in steroids, vitamins, and antibiotics. DTX 2272 at 0400671. It is also undisputed that, as early as 1965, the prior art reflects concerns with the toxic residues left behind after EO sterilization. See id. In 1978, the FDA proposed a rule that would impose restrictions on the amount of EO residuals and byproducts permitted in drug products for human or veterinary use (the "1978 Proposed Rule") because these residues "may produce toxic reactions in patients, and because of the potential risk of mutagenicity from exposure to these residues" if they are not limited. PTX 2059 at 0400681. According to the proposal, EO residuals in parenteral, ophthalmic, and topical products would be limited to 10 ppm. See Trial Tr. 763:12-23 (Dalby). Notably, the 1978 Proposed Rule did not propose to eliminate this method of sterilization and, in fact the FDA explicitly stated its belief "that there is need for the continued use of ethylene oxide as a sterilant for certain drug products...." PTX 2059 at 0400684. In any event, this rule was never enacted. See DRFOF ¶¶ 68, 70.
Defendants presented evidence that a POSA as of 1997 would know how to remove the EO residuals using aeration or forced ventilation and vacuum purging. Indeed, a document entitled "Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products," published in 1994 by the
One such technique, aeration, can be accomplished by exposing the material to air at ambient temperature or subjecting the material to forced ventilation (i.e., forcing air over the material). See PRFOF ¶ 140. Dr. Zhanel, AstraZeneca's expert, agreed that a POSA would know to use aeration to remove EO residuals. Trial Tr. 1589:10-13. Clark, a 1995 reference, teaches a specific aeration cycle consisting of exposure for at least 72 hours at 50°C as a necessary method of reducing EO residuals following sterilization. PRFOF ¶ 142. Notably, Clark discloses EO sterilization of corticosteroids, tetrahydrocortexolone, and dexamethasone; the sterile powder can then be used to make sterile suspensions. See Trial Tr. 589:17-24 (Miller). In addition, Defendants' expert, Dr. Michael Miller, testified that the Portuguese Patent teaches a specific aeration or "degassification" process by which a substance is forcibly ventilated at 50°C for 48 hours, after which the residual EO can be determined. See Trial Tr. 596:24-597:15; DTX 2274. According to the Portuguese Patent and Dr. Miller, the EO content "can be substantially reduced in comparison with conventional methods in which degassification takes place by simply exposing the package to air (open packages) and those perform at ambient temperatures (14°C-18°C) with forced ventilation." DTX 2274 at 0400621; see also DFOF ¶ 140. In other words, the forced ventilation process set forth in the Portuguese Patent claims to be more effective than typical aeration cycles employed following EO sterilization.
In addition to aeration or forced ventilation, Defendants presented evidence that a POSA knew that EO residuals could be reduced through vacuum purging as taught by Adler. With vacuum purging, negative pressure is generated by sucking air out of the chamber containing the sterilized material to help remove the residuals. See DFOF ¶ 143. In Table V of his publication, Adler measures the EO residuals for several steroid, antibiotic, and vitamin substances, noting that certain samples underwent poststerilization vacuum treatment for 8 hours, while others underwent treatment for 2 hours. DTX 2272 at 0400673.
Dr. Miller also testified, without impeachment, that EO followed by aeration, as taught by Clark, was actually being used to sterilize ophthalmic glucocorticosteroids. See Trial Tr. 599:1-600:6. In a research article entitled "Sterile Ophthalmic Ointment and Suspension Manufacturing," published in 1986 by Robert Abshire et al. ("Abshire"), Abshire
In addition, as Dr. Zhanel conceded, these steroid suspensions sterilized by EO were pharmaceutically acceptable. Id. at 1580:4-11; PRFOF ¶ 67. This is further confirmed by Clark who utilized EO sterilization in connection with the preparation of ophthalmic suspensions to treat inflammation of the eye. DTX 160.
AstraZeneca's own Preferid® product demonstrates that budesonide can be successfully sterilized using EO to make a pharmaceutically acceptable product. Preferid® was a micronized budesonide suspension in the form of a topical cream that it marketed as sterile and which was 98-102% pure. See DTX 0004 017836-37, 017900-01; see also DTX 2277 at 0400588. From 1980 to 1983 — after the Adler and Portuguese Patent references —, Preferid® was manufactured in Sweden using a process that included exposing the budesonide particles to EO. Id. at 017836, 017908. Test results for three batches of Preferid® demonstrated that the EO residual of the budesonide powder amounted to 12 to 22 ppm, while the suspension would contain less than .006 ppm, which AstraZeneca considered a "low" content that did not "justify establishment of limits and routine analysis for [EO]." Id. at 017931.
According to a declaration of inventor Ann-Kristin Ekelund submitted in connection with the prosecution of the '834 Patent, "[a]round 1983, changes in the regulatory requirements for this product in the Scandinavian countries led to abandonment of the ethylene oxide exposure step and removal of the term `sterile' from the product description for Preferid® cream." Id. at 017836-37. Although AstraZeneca argues that it ceased marketing Preferid® as sterile because it determined that the residuals rendered the product pharmaceutically unacceptable, see PRFOF ¶ 135, there is no competent evidence in support of this assertion.
However, the European guidelines would not have applied in the United States. See id. 1854:7-9. The FDA's 1978 Proposed Rule would only have limited residuals to 10 ppm, but these were never enacted in the more than 30 years since, and EO sterilization continued — and still continues — to be used. Dr. Zhanel's testimony also appears to be based upon his opinion that the EO residual amounts in the Preferid product would be unacceptable in a product intended for injection or nebulization. See id. at 1575:16-1576:4. But these are not limitations of the claim and thus the Court accords less weight to Dr. Zhanel's opinion. Regardless, as the evidence amply demonstrated, a POSA concerned with achieving a specific level of EO residuals could employ known techniques for reducing residuals and optimize the parameters of any degasification process used in order to achieve the desired level. See infra.
Dr. Zhanel also testified that a POSA reviewing Table V in Adler would not only expect high residues of EO in steroid powders but also understand that the techniques for lessening residuals are ineffective. Trial Tr. 1343:6-12, 1344:7-21. Defendants' expert, Dr. Dalby, acknowledged that Adler reflects that even after 8 hours of vacuum treatment, hydrocortisone tert-butyl acetate (a steroid) still contained 0.51% EO residue as compared to 1.61% EO residue for a sample of the same steroid vacuum treated for only 2 hours. DTX 2272 at 0400673. Dr. Zhanel's conclusion, however, seems to be undermined by the significant reduction in residuals after only 6 hours of vacuum treatment. Id. The Court was persuaded by Dr. Dalby's perspective of the chart: "my characterization would be that more than half of the time it is possible to reduce the level to a reasonably low concentration, but sometimes that's difficult." Trial Tr. 774:21-23.
While recognizing the difficulty, Dr. Dalby testified that the parameters for vacuum purging provided in Adler could be adjusted to achieve the desired level of residuals. See id. at 740:5-741:1, 773:19-24. Notably, the vacuum treatment utilized by Adler consists of significantly less time than the "at least" 72 hour aeration cycle recommended by Clark, or the 48 hour forced ventilation cycle recommended by the Portuguese Patent; even so, the treatment demonstrates a considerable reduction in EO residuals when compared to
Defendants also introduced evidence demonstrating that a POSA would not be concerned with the ability of EO to penetrate water insoluble drug crystals like budesonide. Some prior art references suggest that EO is only a surface sterilant and may be unable to penetrate the crystal core of a sterile powder. See, e.g., PTX 2054 at 3. For example, the 1994 Inspection Guide provides
DTX 1000 at 029008.
Dr. Miller testified that he does not agree that EO is unable to penetrate the crystal core of a sterile powder. First, he is unaware of any scientific evidence demonstrating that spores are trapped within crystals and are not sterilized by EO. Trial Tr. 607:24-608:3. Ms. Moldenhauer similarly testified that she is unaware of any data as of 1997 demonstrating that EO fails to penetrate the crystal core of budesonide. Id. at 315:7-10. Second, Dr. Miller testified that a POSA would have known of Preferid®, a sterile micronized budesonide suspension that had undergone EO treatment but retained purity levels in excess of 98%. Id. at 608:3-9; accord DTX 0004 at 017893, 017901, 017927. Had EO been ineffective in penetrating the budesonide particle, Dr. Miller testified that it would not have been able to pass the sterility test requirements and could not have been marketed as sterile.
Contrary to Dr. Miller's testimony, Dr. Akers opined that EO sterilization would not be effective because of its inability to penetrate solid crystalline material. Id. at 2178:7-14. In support, he cited a 1968 article by Charles L. Mullican et al., entitled "Dry Heat or Gaseous Chemical Resistance of Bacillus subtilis var. niger
In sum, the Court finds that Defendants have clearly and convincingly demonstrated that a POSA, who is admittedly motivated to create sterile budesonide compositions, had a reasonable expectation of successfully creating the claimed compositions using EO sterilization. And, while a POSA was aware that such a sterilization technique may result in potentially toxic EO residuals, a POSA could employ known techniques for reducing those residuals to a pharmaceutically acceptable limit based upon the teachings of the prior art and the knowledge of a POSA. Indeed, a POSA would be aware of not only several sterile ophthalmic suspensions prepared using EO sterilization that continued to be marketed as of 1997 with no evidence of contamination or sterility issues, but also of AstraZeneca's Preferid® product. Thus, after consideration of all of the evidence, including the evidence of secondary considerations addressed below, the Court finds that the asserted claims are invalid as obvious.
Defendants next presented evidence that a POSA would have had a reasonable expectation of success in creating the claimed sterilized budesonide compositions using conventional irradiation sterilization as disclosed in Guy. Defendants contend that the asserted claims are invalid as obvious over Guy in view of Robertson (defined below).
Irradiation consists of using a type of ionizing radiation to kill microorganisms, including beta irradiation, which is an electron beam, or gamma irradiation, which is a radioisotope such as cobalt 60. PRFOF ¶ 155. Prior to 1997, irradiation sterilization processes were well known, a POSA would have understood how to optimize them, and it would be routine for one to do so. Specifically, a POSA would have considered the specific type of irradiation (i.e., beta, gamma), as well as the dose, energy level, and power output for irradiation sterilization. PRFOF ¶ 157.
Guy, filed in 1993 and issued in 1996, discloses pharmaceutically acceptable, sterile, aqueous, ophthalmic glucocorticosteroid suspensions, and teaches each element of the asserted claims except for budesonide. See DFOF ¶¶ 148-54. As a prior art patent, Guy is presumed to be enabled.
Moreover, Guy discloses that "[p]urity levels of all materials employed in the suspensions of the invention exceed 98%." DTX 853 at col.3 ll.61-63 (emphasis added); see also PRFOF ¶ 152. The asserted claims of the '834 Patent require that the budesonide be at least 98.5%, and thus it falls within the range disclosed by Guy. The Federal Circuit has held that "`when the difference between the claimed invention and the prior art is the range or value of a particular variable,' then a patent should not issue if `the difference in range or value is minor.'" Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1321-22 (Fed.Cir.2004) (quoting Haynes Int'l v. Jessop Steel Co., 8 F.3d 1573, 1577 n. 3 (Fed.Cir.1993); Titanium Metals Corp. of Am. v. Banner, 778 F.2d 775, 783 (Fed.Cir.1985)). If the claimed invention falls within the range disclosed by the prior art, the claims are presumed obvious. Id. That presumption may be rebutted if it can be shown: "(1) That the prior art taught away from the claimed invention, In re Geisler, 116 F.3d 1465, 1471 (Fed.Cir.1997); or (2) that there are new and unexpected results relative to the prior art, In re Woodruff, 919 F.2d 1575, 1578 (Fed.Cir.1990)." 392 F.3d at 1321-22. No such showing has been made here with respect to the purity levels.
Although Guy does not disclose the specific irradiation parameters such as type or dosage, Dr. Miller convincingly testified that these parameters were known to a POSA who would engage in routine optimization to determine the specific parameters required to irradiate budesonide. See Trial Tr. 627:13-17. As Dr. Miller explained, other well-known treatises discussed the successful use of irradiation for sterilization of steroids. Id. at 627:18-628:8. For instance, "Remington's Pharmaceutical Sciences" published in 1975, discloses that "[i]onizing radiation has been successfully used for the sterilization of ... steroids...." DTX 147 at 030060-61. It then describes the irradiation process in more detail, explaining that a POSA must consider the dose, the amount of radiation absorbed by the material, the energy level, and the material's density, inter alia. Trial Tr. 627:18-628:8 (Miller). Similarly, a 1974 publication entitled "Surface area stability of micronized steroids sterilized by irradiation," published by Lisbeth Ilium & Niels Moller ("Ilium"), also taught that irradiation could be successfully used on steroids. PTX 513 at 1332166. Ilium taught that "degradation of hydrocortisone acetate and prednisone was less than 1 per cent, while for hydrocortisone, prednisolone, and prednisolone hydrate it was about 2-4 per cent." Id. Despite this, Ilium concluded "that the steroid powders in question are physically stable when irradiated with doses realistic for irradiation sterilization." Id. Dr. Miller acknowledged that irradiation can but does not always result in undesirable degradation products that could render the product pharmaceutically unacceptable. Trial Tr. 647:8-13. However, the prior art clearly indicates that degradation for some steroids may be minimal. See, e.g., PTX 513 at 1332166. Notably, the inventors of the '834 Patent note that Ilium recommends the use of beta or gamma irradiation to sterilize glucocorticosteroids. See PTX 0004 at col.1 ll.62-65.
The only element of the asserted claims that is missing from Guy is budesonide. Dr. Miller persuasively testified that to arrive at a pharmaceutically acceptable, sterile budesonide suspension, a POSA would combine the teachings of Guy with those of U.S. Patent No. 5,589,184, filed March 16, 1995 by Stella M. Robertson et al. ("Robertson"), and entitled "Pharmaceutical Compositions and Methods of
AstraZeneca argues that a POSA as of 1997 would not have had a reasonable expectation of successfully using irradiation to sterilize budesonide as the prior art taught that irradiation would unacceptably degrade the drug substance and thus it would not meet the purity or pharmaceutical acceptability limitations of the asserted claims. Dr. Zhanel testified that Ilium discloses that irradiation of steroids causes degradation of 2% to 4% and a POSA would, therefore, expect reduced purity and degradation products with irradiation sterilization. Trial Tr. 1417:2-16. But, as noted above, Ilium concludes that steroid powders remain stable under irradiation and demonstrates certain of the tested steroids experience only minimal degradation, i.e., less than 1%. A POSA would not be dissuaded from using irradiation simply because some prior art references acknowledge that there may be associated degradation. This is because, as Dr. Miller testified, every sterilization method may cause some level of degradation. Id. at 658:23-25. Even the FDA recognized that irradiation of budesonide was a viable option. During the pre-NDA meeting with the FDA on November 20, 1996, AstraZeneca informed the FDA that gamma irradiation produced degradation, with substances exhibiting 95% potency. See DTX 760 at 1335703. In response, the FDA commended that "lower irradiation doses may be used to reduce bioburden with less degradation." Id. Thus, the evidence supports Dr. Miller's opinion that a POSA would have a reasonable expectation of successfully using this method to sterilize budesonide.
AstraZeneca also argues that other art, as well as the failures of AstraZeneca and the Defendants, demonstrate that irradiation of budesonide is not successful. In the '834 Patent, the inventors conclude "that micronized budesonide can not be satisfactorily sterilized with β- or γ- irradiation, due to significant chemical degradation." PTX 0004 at col.11 ll.43-45. In Comparative Example 8, however, the inventors provide the results of their attempts to irradiate budesonide. Table 8 reflects that when budesonide was exposed to beta irradiation at levels from 2.5 to 25 kGy, the budesonide content exceeded 98.8%. Id. at col.11 ll.10-35. Thus, as Dr. Miller persuasively testified, the inventors' data does not support the conclusion that irradiation unacceptably degrades budesonide. Trial Tr. 629:13-630:18.
AstraZeneca points to Defendants' purported failures to produce the claimed product through irradiation sterilization. Any such post-art failures are irrelevant to this Court's obviousness analysis. Even if relevant, the evidence does not demonstrate that either Apotex or [Redacted] failed to make the claimed products; nor does the evidence demonstrate a failure to use irradiation. [Redacted] See DTX 475; DRFOF ¶ 12. As such, AstraZeneca's conclusions are based solely upon speculation.
Finally, although the PTO Examiner considered Guy during patent prosecution, she focused on Guy's teaching that disodium edentate ("EDTA") could be added to a suspension to prevent microbial growth. See, e.g., DTX 0004 at 017496; see also id. at 017534.
Accordingly, 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 budesonide compositions, would have had a reasonable expectation of successfully doing so using the conventional sterilization technique of irradiation based upon the teachings of Guy in view of Robertson.
Finally, Defendants argue that a POSA would have had a reasonable expectation of success in creating the claimed sterilized budesonide compositions using conventional dry heat sterilization, as disclosed in Clark, in combination with the knowledge of a POSA. Defendants contend that the asserted claims are invalid as obvious over Clark.
In addition to disclosing the use of EO, Clark also discloses that dry heat may be used to sterilize the glucocorticosteroid used to make the sterile ophthalmic suspensions that are the subject of his patent. PRFOF ¶ 118. Dry heat sterilization consists of placing a material to be sterilized
As of 1997, a POSA understood that there is an inverse relationship between temperature and time, and that one can decrease the temperature and increase the time required for sterilization. See DFOF ¶ 121. The proper time and temperature would be based upon the characteristics of the drug product itself. PRFOF ¶ 122. However, the parties agree that a POSA would have understood that typical or conventional dry heat sterilization cycles as of 1997 run at temperatures from 140-180°C. See PRFOF ¶ 123.
Defendants contend that a POSA, understanding the inverse relationship between time and temperature, and knowing that some substances cannot withstand the typical temperatures, would have known to use temperatures lower than the typical temperatures and it would have been routine to do so. Dr. Miller testified that a POSA attempting to sterilize budesonide in 1997 would have tried lower temperatures. Trial Tr. 594:10-14. In support, he cites Remington, which provides that "[i]n dealing with pharmaceutical preparations, however, it must be emphasized that long experience has shown that many preparations cannot be subjected to such temperatures and other dry heat sterilization cycles have been established according to the nature of the various products." See id. at 593:18-23 (quoting DTX 147 at 0300155). According to Dr. Miller, Remington thus taught lower temperatures than 140°C for those pharmaceutical preparations that may not be able to withstand higher temperatures. Id. at 594:3-7.
Although Dr. Miller's testimony was credible, it is difficult to find that it was not influenced by what the inventors did here. None of the prior art references addressing dry heat provide a dry heat sterilization cycle with temperatures below 140°C. Dr. Zhanel testified that a POSA was aware that these unconventional temperatures were considered to be sublethal temperatures at which a product could not be sterilized. Id. at 1297:18-20. Moreover, by 1997, the trend was to use higher — not lower — temperatures. Ansel, published 20 years after the Remington reference on which Dr. Miller relies, teaches "Because dry heat is less effective in killing microorganisms than is moist heat, higher temperatures and longer periods of exposure are required." DTX 851 at 018243. While Ansel also recognizes that temperatures and times may be tailored to the particular substance sought to be sterilized, he provides only the typical temperature range. Id. ("For example, if a particular chemical agent melts or decomposes at 170°C, but is unaffected at 140°C, the lower temperature would be employed in its sterilization, and the exposure time would be increased over that required to sterilize another chemical that may be safely heated to 170°C.").
The Court questioned from time to time whether AstraZeneca's invention consisted of simply turning down the heat on the oven. It seemed to be common sense to do so, especially for a POSA taught to optimize a dry heat cycle by altering the time and temperature so as to achieve sterilization. The prior art, however, clearly taught that any such optimization should occur with a specific temperature range, 140 to 170°C, with a trend toward higher temperatures. AstraZeneca's heat sterilization process is directed to temperatures ranging from 100 to 130°C, preferably between 110 to 120°C. Thus, the Court finds that Defendants have failed to clearly and convincingly demonstrate that a POSA would have had a reasonable expectation
Turning to the final Graham factor, the Court considers the significance and relevance of any secondary considerations. "[S]econdary considerations [such] as commercial success, long felt but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances surrounding the origin of the subject matter sought to be patented" and "may have relevancy" as indicia of obviousness or nonobviousness. Graham, 383 U.S. at 17-18, 86 S.Ct. 684. "A nonmovant may rebut a prima facie showing of obviousness with objective indicia of nonobviousness." Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299, 1311 (Fed.Cir.2006) (citing WMS Gaming, Inc. v. Int'l Game Tech., 184 F.3d 1339, 1359 (Fed.Cir.1999); In re Kahn, 441 F.3d 977, 990 (Fed.Cir. 2006)). "Although secondary considerations must be taken into account, they do not necessarily control the obviousness conclusion." In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed.Cir.2011) (quoting Pfizer, 480 F.3d at 1372).
Secondary considerations must be "reasonably commensurate" with the scope of the claims. In re Huai-Hung Kao, 639 F.3d at 1068. "This does not mean that an applicant is required to test every embodiment within the scope of his or her claims. If an applicant demonstrates that an embodiment has an unexpected result and provides an adequate basis to support the conclusion that other embodiments falling within the claim will behave in the same manner, this will generally establish that the evidence is commensurate with scope of the claims." Id. (citations omitted).
In addition, the Federal Circuit requires the patentee to demonstrate a nexus "between the claimed features of the invention and the objective evidence offered to show non-obviousness." WMS Gaming, 184 F.3d at 1359 (citing Cable Elec. Prods., Inc. v. Genmark, Inc., 770 F.2d 1015, 1027 (Fed.Cir.1985)). "[I]f the feature that creates the commercial success was known in the prior art, the success is not pertinent." Ormco Corp., 463 F.3d at 1312; see also In re Woodruff, 919 F.2d 1575, 1578 (Fed.Cir.1990); Tokai Corp. v. Easton Enters., Inc., 632 F.3d 1358, 1369 (Fed.Cir.2011).
AstraZeneca urges this Court to evaluate seriously the objective indicia of nonobviousness, which AstraZeneca contends will prevent this Court from employing a hindsight bias in consideration of the prior art. Specifically, AstraZeneca points to (a) industry skepticism, (b) long-felt, unmet need, (c) the failure of AstraZeneca and others, and (d) commercial success. For the reasons discussed below, the Court rejects each of these considerations as insufficient to overcome the strong evidence of obviousness.
"[S]kepticism of skilled artisans before the invention" can demonstrate
As an initial matter, whether or not AstraZeneca's employees believed that a budesonide suspension could be sterilized using dry heat or any other known method is not the proper inquiry. The focus of this consideration is skepticism of others, not skepticism of the inventors. Santarus, 720 F.Supp.2d at 456. Nonetheless, the evidence did not demonstrate universal skepticism even within AstraZeneca. AstraZeneca relies upon slides that its scientists created in preparation for its November 1996 pre-NDA meeting, which provide "Sterilization of BNS [budesonide nebulizing suspension] is not required and not feasible." PTX 530 at 1337011. However, these slides reflect only "potential" disadvantages of each sterilization technique and were created prior to the FDA's instruction that AstraZeneca prepare a sterile product or prove that it could not be done.
Moreover, subsequent internal documents reflect opinions that the preliminary data collected in preparation for further meetings with the FDA do not support the conclusion that the drug substance cannot be sterilized. See, e.g., PTX 516 at 1334613 ("The documents do not provide conclusive evidence that the drug substance cannot be sterilized. In fact, in several instances the statements made are not supported by the data presented."); see also PTX 515 ("I don't think we can produce a sterile product!"); 2012 Trial Tr. 689:6-17. As mentioned earlier, even inventor Elkins admitted irradiation and EO were not unsuccessful at producing sterilized budesonide. 2012 Trial Tr. (Elkins) 655:11-18 ("I would not classify [attempts at irradiating the micronized budesonide] as unsuccessful. I think that they were feasible...."); id. at 657:2-9 ("[T]hese were feasibility experiments, they were not further pursued. The initial result of those experiments indicated that residuals from the ethylene oxide treatment would require further development to see whether or not a successful process could be developed."); see also id. at 655:22-656:2.
AstraZeneca also contends that as of 1997, it was generally believed in the industry that budesonide powder compositions and suspensions could not be sterilized in a way that preserved purity and pharmaceutical acceptability. See PFOF ¶ 24. In support, however, it cites only to itself. Id. For example, it cites a statement within Defendant Breath's McAffer Patent that "the sterilization of budesonide is generally considered by the market to be impossible," but that statement cites an AstraZeneca document that provides the basis for the '834 Patent. See PTX 507 at col.4 ll.45-49; accord DTX 0004 at 017807. Hence, as this Court has previously held, AstraZeneca's attempt to cast the statements in the McAffer Patent as Breath's independent description of the state of the art is rejected. See AstraZeneca LP v. Breath Ltd., No. 08-1512, 2014 WL 2526909, at *10 (D.N.J. June 4, 2014). The patentee, Ian McAffer, explained that this statement was also based upon communications from a few pharmaceutical companies that had failed to sterilize budesonide in which they expressed their belief that it was impossible.
As for AstraZeneca's contention that the FDA exhibited skepticism that budesonide could be sterilized, there is simply insufficient evidence to support this contention. In fact, the evidence is to the contrary. During the pre-NDA meeting with the FDA on November 20, 1996, the FDA acknowledged the technical difficulties associated with the sterilization of suspensions but in no way expressed its belief that it could not be done. DTX 760 at 1335702. Rather, the FDA commented that it "expects sterile products for both solutions and suspension for inhalation." Id. The agency further stated that "it would be precedent-setting to approve a nonsterile inhalation product" and thus "the first goal should be a sterile product." Id. at 1335703. These statements to AstraZeneca are consistent with statements the FDA had made to POSAs as early as the mid-'90s: any aqueous-based inhalation products must be sterile. See DFOF ¶¶ 234-35.
Most notably, during the pre-NDA meeting the FDA queried AstraZeneca as to what sterilization methods it had tried and actually offered suggestions for alternative methods of sterilization. See, e.g., DTX 760 at 1335703 ("G. Poochkian commented that lower irradiation does may be used to reduce bioburden with less degradation and this should be considered."). The FDA told AstraZeneca that it was "their [AstraZeneca's] burden to make the product sterile or justify why it can't be."
Trial Tr. 1167:12-19. In other words, the FDA was not skeptical as to whether budesonide could be sterilized; it simply did not know whether it could be done or not because it did not have sufficient data. Mr. Mathers confirms this finding:
See id. at 1166:16-1167:7 (emphasis added). Thus, the FDA instructed AstraZeneca to perform the tests and collect sufficient data.
AstraZeneca places great emphasis on the fact that the FDA did not impose a regulatory requirement on the industry that inhaled aqueous suspensions be made sterile until after AstraZeneca had demonstrated that this was possible with budesonide. See PFOF ¶ 11. Specifically, AstraZeneca argues that in the interim between the 1997 Proposed Rule (directed to inhalation solutions) and the 2000 Final Rule (covering all aqueous-based oral inhalation products), the FDA completed its microbiology review of AstraZeneca's Pulmicort Respules NDA. The review was signed on September 2 and September 15, 1998, thereby indicating as of those dates
As discussed above, the 1997 Proposed Rule explicitly required only that aqueous inhalation solutions be sterile. DTX 872. Mr. Mathers testified that the FDA is very deliberate in their choice of words and thus the 1997 Proposed Rule intentionally did not cover suspension products. Trial Tr. 1128:11-16. Dr. Muhvich persuasively testified, however, that the Proposed Rule was intended to apply to both solutions and suspensions. Id. at 1053:21-1054:2. Moreover, the parties agree that at the time of the 1997 Proposed Rule there was a motivation to make all aqueous-based products, solutions and suspensions, sterile. POSAs understood this. See supra.
As discussed supra, on December 1, 1997, Dr. Muhvich submitted a written comment to the FDA encouraging it to require inhalation suspensions, as well as solutions, be made sterile because of the similar contamination risks for both product types. PTX 3076. Dr. Muhvich's comment, submitted after he left the FDA, appears to have been intended to clarify the scope of the rule for the industry. The FDA stated that it had received a total of 61 comments on the 1997 Proposed Rule. "The majority of comments requested clarification of the scope of the rule and the drug products intended to be covered.... In response to these comments, the agency has revised the final rule to state [that all aqueous-based drug products must be sterile]." DTX 915 at 024786 (emphasis added). Hence, on May 11, 2000, the FDA published the Final Rule, which explicitly requires all "aqueous-based drug products for oral inhalation be manufactured sterile." Id. at 024785. The FDA's explanation that it clarified the Final Rule as a result of the comments submitted negates AstraZeneca's speculation that its own invention prompted an expansion of the scope. Indeed, when asked about the "impetus" for changing the language in the Final Rule to explicitly cover suspensions, Mr. Mathers, AstraZeneca's witness, opined that it was Dr. Muhvich's comment that motivated the change — and not AstraZeneca's successful sterilization of budesonide:
Trial Tr. 1177:23-1178:12. Finally, it is noteworthy that Mr. Muhvich's comment — dated December 1, 1997, only a few weeks
As such, the evidence does not demonstrate skepticism on the part of the industry, the FDA, or even AstraZeneca, and thus does not demonstrate the nonobviousness of the asserted claims.
"Evidence that an invention satisfied a long-felt and unmet need that existed on the patent's filing date is a secondary consideration of nonobviousness." Perfect Web Techs., Inc. v. InfoUSA, Inc., 587 F.3d 1324, 1332 (Fed.Cir. 2009). If prior art products were effective for the purpose of the claimed invention, there is no long-felt need. See, e.g., B.F. Goodrich Co. v. Aircraft Braking Sys. Corp., 72 F.3d 1577, 1583 (Fed.Cir.1996) (discounting long-felt need because invention "was similar to the teachings" of prior art).
Evidence of the long-felt need factor must squarely address the need satisfied by the asserted claims themselves. AstraZeneca proffered evidence of a long-felt, unmet need for an aqueous, sterile, nebulized, inhaled corticosteroid for the long-term maintenance treatment of asthma in young children. See PRFOF ¶ 220. The evidence here clearly demonstrated, however, that a nonsterile Pulmicort Respules® would have satisfied the long-felt, unmet need.
It is true, as AstraZeneca has claimed, that a sterile product may have been preferred based on health risks. Yet, the evidence conclusively established that, had the FDA determined that Pulmicort Respules® could be sold in the United States without being sterile, the unmet need would have been met. For example, several physicians testified that nonsterile Pulmicort Respules® would have addressed their patients' needs. Dr. Raul Wolf, a treating physician with a clinical practice who testified on behalf of Defendants, stated:
Trial Tr.1955:25-1956:3. He subsequently confirmed:
Id. at 2019:23-2020:5.
Dr. Peter Barnes, a treating physician, testified that the European Pulmicort Respules® satisfied the need to treat young children under the age of three who were unable to use effectively the other inhalation devices. See id. at 2549:4-18. That
Id. at 973:22-974:5. Dr. Zhanel, a microbiologist, also testified as to the long-felt need.
Id. at 1292:6-16 (emphasis added); see also id. at 1306:7-14. This testimony, however, contradicts Dr. Ververelli's testimony that the need was for nebulized budesonide and would have been satisfied by a nonsterile product. The Court affords more weight to the opinion of Dr. Ververelli, a treating physician, as it is consistent with the other evidence of record. Thus, while sterility may have been important, it was not the long-felt need. Rather, physicians wanted the nebulized corticosteroid that had demonstrated efficacy overseas.
Accordingly, AstraZeneca's attempt to equate the FDA's need
In addition, AstraZeneca's evidence as to the long-felt, unmet need is not reasonably commensurate with the scope of the claims as it goes to only a single embodiment of the claims — Pulmicort Respules®. See In re Huai-Hung Kao, 639 F.3d at 1068 ("Evidence of secondary considerations must be reasonably commensurate with the scope of the claims.... If an applicant demonstrates that an embodiment has an unexpected result and provides an adequate basis to support the conclusion that other embodiments falling within the claim will behave in the same manner, this will generally establish that the evidence is commensurate with scope of the claims."). None of the asserted claims are directed to a nebulized inhalation product that is used in the long-term treatment of asthma in young children. Rather, they are much broader in scope. See In re Greenfield, 571 F.2d 1185, 1189 (C.C.P.A.1978) (finding evidence of secondary considerations was not commensurate with the scope of the claims where evidence related to only one compound and there was no adequate basis to conclude that other compounds included within the scope of the claims would behave in the same manner); see also Dome Patent, L.P. v. Rea, No. 07-1695, 59 F.Supp.3d 52, 86, 2014 WL 2948927, at *27 (D.D.C. July 1, 2014) ("Evidence of secondary considerations `is not commensurate with the claims if the claims are broader than the scope' of such evidence.... `The claims are broader in scope than the objective evidence if a limitation or element recited in the claim is broader than the limitation or element in the objective evidence ... or if the objective evidence contains limitations or elements not recited in the claims.'" (citations omitted)). Because AstraZeneca's evidence of a long-felt, unmet need relates in large part to limitations or elements that do not form part of the asserted claims, there is no evidence to infer that other embodiments of the asserted claims would satisfy that long-felt, unmet need.
Evidence that others within the field have tried and failed to make the claimed invention can demonstrate that the invention was nonobvious. See, e.g., Advanced Display Sys., Inc. v. Kent State Univ., 212 F.3d 1272, 1285 (Fed.Cir.2000). "Failure of others `to find a solution to the problem which the patent[] in question purport[s] to solve' is evidence of non-obviousness." Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 923 F.Supp.2d 602, 680 (D.Del.2013), aff'd 752 F.3d 967 (Fed.Cir.2014), (quoting Symbol Techs., Inc. v. Opticon, Inc., 935 F.2d 1569, 1578 (Fed.Cir.1991)). The purpose of this evidence "is to show `indirectly the presence of a significant defect in the prior art, while serving as a simulated laboratory test of the obviousness of the solution to a skilled artisan.'" In re Cyclobenzaprine, 676 F.3d at 1082 (citation omitted). "In the pharmaceutical industry, the failure of others to develop a safe and effective drug often supports the nonobviousness of a drug that finally achieves success." Teva Pharma. USA, Inc. v. Sandoz, Inc., 876 F.Supp.2d 295, 417 (S.D.N.Y.2012).
AstraZeneca introduced evidence of its own failures to create the claimed budesonide compositions using conventional sterilization techniques other than dry heat. Defendants argue, however, that evidence of AstraZeneca's failures is legally irrelevant as it is only the failures of others that indicate nonobviousness. The Court agrees that the focus of this secondary consideration should be the failure of others and not the failure of the inventors, see, e.g., Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 348 F.Supp.2d 713, 759 (N.D.W.Va.2004) ("In the context of secondary considerations, the Federal Circuit has generally focused on the prior failures of others in the industry, not the inventors."), aff'd 161 Fed.Appx. 944 (4th Cir. 2005); In re Cyclobenzaprine, 676 F.3d at 1081 ("Evidence that others tried but failed to develop a claimed invention may carry significant weight in an obviousness inquiry."); Bristol-Myers Squibb Co. v. Teva Pharma. USA, Inc., 923 F.Supp.2d 602, 681-82 (D.Del.2013) (same); Advanced Display Sys., 212 F.3d at 1285 (citing cases), but nonetheless the Court has considered AstraZeneca's evidence of its own failures.
AstraZeneca has consistently contended that its own failures at sterilizing, other than low dry heat sterilization, are compelling evidence of nonobviousness. But the record is not as compelling as AstraZeneca makes it out to be. The record demonstrates that AstraZeneca created and marketed a pharmaceutically acceptable sterile product with Preferid® as early as the 1980s. There was no evidence that any EO residues rendered Preferid® pharmaceutically unacceptable or that AstraZeneca experienced problems with penetration of the crystal core of the budesonide molecule. Moreover, Dr. Elkins testified that AstraZeneca's irradiation experiments showed "feasibility" but that the amount of work required to create a commercial process was more than would be required of dry heat. 2012 Trial Tr. 655:11-21. She further stated that she "would not classify [the irradiation experiments] as unsuccessful." Id. And, importantly, like Defendants, AstraZeneca ultimately prepared sterilized budesonide compositions; AstraZeneca did so using its patented low
Although failures of others may demonstrate nonobviousness, there must be some understanding of the nature of those failures. See Advanced Display Sys., 212 F.3d at 1285; Orthopedic Equip. Co. v. All Orthopedic Appliances, Inc., 707 F.2d 1376, 1382 (Fed.Cir.1983) (finding while claimed invention made it possible to decrease inventories, there was "no evidence of any previous, unsuccessful attempts to reduce inventories"), abrogated on other grounds by Therasense, Inc. v. Becton, Dickinson & Co., 649 F.3d 1276 (Fed.Cir. 2011). Here, there is insufficient evidence of the extent or nature of any of Defendants' attempts to make a sterilized budesonide suspension from which this Court could make the finding AstraZeneca urges. AstraZeneca introduced an internal decision tree prepared by [Redacted] of sterile micronized budesonide, that purportedly shows [Redacted] chose filter sterilization after it determined the product could not be sterilized using conventional methods such as dry heat and ionizing radiation. See DTX 475 at 000148. However, there was no competent evidence that [Redacted] considered or even performed each of the listed steps.
As for [Redacted], the evidence shows that it attempted to use irradiation to terminally sterilize the final suspension. An [Redacted] progress report reflects that "Samples sent out for alternate way to sterilize FP. FP subjected to various dose 5, 10, 15, 20 and 25 Kgry) of Gamma and E-Beam for sterilization resulted in extensive degradation of the active. Sterilization post manufacturing is not possible so far." DTX 131 at 021099-100. Dr. Jiang testified that "FP" meant final product or budesonide suspension.
As such, there is no competent evidence demonstrating the nature and extent of Defendants' purported failures. The Court finds this lack of evidence to be particularly relevant here, where each of the Defendants (and Teva Pharmaceuticals USA, Inc. ("Teva"))
AstraZeneca also presented evidence, in the form of hearsay testimony from Mr. McAffer, that two or three other companies failed to sterilize budesonide. See PFOF ¶ 23. Here, again, because there was no evidence as to the nature of those purported failures, it is of little value. This is especially so in light of the evidence presented that there were several glucocorticosteroid ophthalmic suspensions on the market by 1997, thus demonstrating other companies' successful sterilization of glucocorticosteroids. See DFOF ¶ 246.
"Commercial success is relevant because the law presumes an idea would successfully have been brought to market sooner, in response to market forces, had the idea been obvious to persons skilled in the art. Thus, the law deems evidence of (1) commercial success, and (2) some causal relation or "nexus" between an invention and commercial success of a product embodying that invention, probative of whether an invention was non-obvious." Merck & Co., Inc. v. Teva Pharma. USA, Inc., 395 F.3d 1364, 1376 (Fed.Cir.2005). "Commercial success of an invention over the prior art also implies that the difference between an invention
AstraZeneca submitted evidence in support of the commercial success of Pulmicort Respules®. From 2000 to May 2014, AstraZeneca has sold more than 44 million packages of Pulmicort Respules®, and net sales in the United States have totaled $5.6 billion. DFOF ¶ 40. There is no question that Pulmicort Respules® has been very profitable for AstraZeneca in the United States.
However, AstraZeneca again attempts to create a nexus between its success and the '834 Patent by relying on FDA approval. It argues that its success is due to its ability to obtain FDA approval of its product, which could only be obtained because it was able to sterilize the budesonide suspension. Dr. Vellturo testified that, prior to AstraZeneca's invention, there was an opportunity to provide nebulized corticosteroids for use as an asthma treatment in small children, and only because of AstraZeneca's invention was AstraZeneca able to take advantage of that opportunity. Trial Tr. 2045:15-2046:13, 2052:16-23 (Vellturo). As AstraZeneca puts it, "If AstraZeneca had not been able to develop the claimed invention, it would either face significantly more competition (because the FDA would have permitted non-sterile products to enter the market), or would not be in the market at all (because FDA would have demanded sterility without AstraZeneca having achieved it)." PFOF ¶ 41.
As this Court has previously cautioned, AstraZeneca "cannot equate regulatory compliance with evidence of commercial success." In re OxyContin Antitrust Litig., 994 F.Supp.2d 367, 399-400 (S.D.N.Y. 2014) ("Purdue emphasizes that the low-ABUK process allowed the Rhodes facility to obtain FDA approval and that Rhodes could not have been successful without FDA approval. The Court cannot equate regulatory compliance with evidence of commercial success.").
Here, it cannot reasonably be concluded that sterility is the reason Pulmicort Respules® experiences substantial sales because nonsterile European Pulmicort Respules experienced significant sales overseas. In many senses, the Patent is creating its own isolation: AstraZeneca is using its Patent to enjoin other companies, like Defendants, from coming onto the market with their own budesonide inhalation suspension products. In an attempt
Id. at 1711:12-1712:5. In fact, it is certainly plausible that the potential sales of their products in the United States does not outweigh the expense of making them sterile. Cf. id. at 2229:1-14 (Akers).
In addition, the evidence does not demonstrate a connection between the sales of Pulmicort Respules® in the United States and sterility. Dr. Vellturo testified that the sterility of Pulmicort Respules® helped it to achieve commercial success by addressing doctors' concerns about safety. PFOF ¶ 42. Dr. Vellturo explained that FDA approval is connected to sterility because the FDA considered sterility an important requirement for a suspension. See Trial Tr. 1016:16-21. Dr. Vellturo testified in 2012, however, that he was "not aware of direct evidence that tie[d] the sterility of [Pulmicort Respules®] to specific demands of physicians." Id. at 2071:7-13. Rather, he relied solely on Dr. Ververelli's testimony that, after the difficulties with contaminated albuterol around 1992, sterility of nebulized suspensions became important to doctors because they treat small children. See id. at 895:21-896:23. But Dr. Ververelli repeatedly acknowledged that what was important was safety — not sterility. Indeed, she agreed that "if the FDA felt that even though the solutions had to be sterilized and the suspension did not have to be sterilized, then yes," nonsterile Pulmicort would satisfy the unmet need. See, e.g., id. at 973:22-974:5 (Ververelli).
The Court finds Dr. Vellturo's foregoing testimony regarding the commercial success of Pulmicort Respules® to be based upon a flawed analysis and, therefore, unhelpful and unpersuasive. Dr. Vellturo agreed that "there are multiple attributes that drive the commercial success of Pulmicort Respules®." Trial Tr. 2056:12-18. These include: (1) efficacy; (2) safety; (3) nebulized method of delivery; and (4) once-daily dosing. Id. at 2056:19-2057:7. However, he made no effort to compare the relative impact of each of these attributes on the success of Pulmicort Respules®, as he determined they were not "germane" to the inquiry. Id. at 2057:8-2060:20 (Vellturo).
Mr. Spadea, Defendants' expert, testified that while sterile Pulmicort Respules® has enjoyed significant sales in the United States, it is not due to a nexus between the commercial success and the patented invention. More specifically, Mr. Spadea opined that the commercial success of Pulmicort Respules® has been driven by factors unrelated to the '834 Patent: efficacy, safety of the budesonide molecule, and nebulized delivery. Id. at 2668:8-13. Sterility is not a marketed feature of the product, nor is it a driver for physicians' prescriptions. Id. at 2668:13-17.
Mr. Spadea persuasively explained that companies, especially pharmaceutical companies, promote features of their products that are important to consumers, and they test whether the features they are marketing are resonating with their audience. Id. at 2685:5-21. The evidence was firm that, while AstraZeneca promotes Pulmicort Respules®, the marketing materials do not extol the sterility of the product. Id. at 2067:25-2068:12 (Vellturo). Rather, AstraZeneca's marketing focuses on other features such as the safety and efficacy of the budesonide molecule. See DFOF ¶ 248. For instance, a 2001 marketing study of the reasons that physicians prescribed Pulmicort Respules® recommended that AstraZeneca promote its differentiating aspects, i.e., nebulizing delivery mechanism and efficacy. DTX 673 at 154898. Later, in a 2006 strategic plan for Pulmicort Respules®, which contains an internal analysis of strengths, weaknesses, opportunities, and threats, lists the historical safety of budesonide as a strength of the product. See Trial Tr. 2675:20-2677:1 (Spadea).
Mr. Spadea also examined physician surveys conducted by AstraZeneca that showed efficacy, nebulized delivery, and safety were the reasons why physicians prescribed Pulmicort Respules®. DFOF ¶ 247; see also DTX 673 at 0154887 ("Physicians choose to prescribe PR because it is efficacious and has a delivery system that is more compatible for young children."); PTX 174 at 0021513 (acknowledging "safety data associated with the budesonide molecule" was one reason for prescribing). In one third-party study, doctors connected safety with the safety of the budesonide molecule or pregnancy Category B labeling safety. See Trial Tr. 2670:1-3, 2673:5-2675:2 (Spadea). In another study, 91% of physicians chose efficacy over dosing as most influencing their choice of asthma controller. DTX 1210 at 0246188. Dr. Spadea found it telling that sterility was not raised in this questionnaire, which was consistent with his conclusion that AstraZeneca did not view sterility as a driver of the sales of Pulmicort Respules®. Trial Tr. 2681:9-17. In yet
AstraZeneca's attempt to connect "sterility" to physician's desire for "safety," and therefore create a nexus to the patented feature of the '834 Patent, fails. As the above discussion demonstrates, the "safety" factor prized by physicians related to long-term safety data on the budesonide molecule or pregnancy Category B elements.
In short, the evidence shows the lack of a nexus between the allegedly novel feature of the '834 Patent (i.e., sterility) and the commercial success of the product. Because the evidence shows that the commercial success of Pulmicort Respules® is attributable to aspects of the invention that were known in the art (i.e., the budesonide molecule), AstraZeneca has failed to satisfy its burden of establishing the requisite nexus. See, e.g., Ormco Corp., 463 F.3d at 1312 (finding patentee failed to demonstrate that the commercial success was "was due to the claimed and novel features"); see also Tokai Corp., 632 F.3d at 1370 (finding no nexus between commercial
For the reasons set forth above, the evidence clearly and convincingly demonstrates that a POSA would have had a reasonable expectation of successfully preparing the claimed sterile budesonide compositions (the powder set forth in claims 1 and 2, and the suspensions set forth in claims 50 and 51) using four of the five conventional sterilization techniques (i.e., sterile filtration/crystallization, moist heat, EO, and irradiation). Moreover, there is insufficient evidence of secondary considerations of nonobviousness. See Wyers v. Master Lock Co., 616 F.3d 1231, 1246 (Fed.Cir.2010) ("[S]econdary considerations of nonobviousness ... simply cannot overcome a strong prima facie case of obviousness."). As such, the asserted claims are invalid as obvious.
"[T]he dispositive question regarding anticipation is whether one skilled in the art would reasonably understand or infer from a prior art reference that every claim element is disclosed in that reference." AstraZeneca v. Apotex, 633 F.3d 1042, 1055 (Fed.Cir.2010) (quoting In re Baxter Travenol Labs., 952 F.2d 388, 390 (Fed.Cir.1991)) (internal quotations and brackets omitted). In other words,
Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1082 (Fed.Cir.2008), cert. den'd, 558 U.S. 990, 130 S.Ct. 493, 175 L.Ed.2d 346 (2009). Anticipation is a question of fact, and the party invoking this defense must establish it at trial by clear and convincing evidence. AstraZeneca, 633 F.3d at 1055 (citing Sanofi-Synthelabo, 550 F.3d at 1082; Purdue Pharma L.P. v. Boehringer Ingelheim GmbH, 237 F.3d 1359, 1365 (Fed.Cir.2001)).
Anticipation requires that "all limitations of the claimed invention are described in a single reference, rather than a single example in the reference." Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 n. 5 (Fed.Cir.2008). The court must look at the reference "as a whole" and determine whether it discloses all elements of the claimed invention as arranged in the claim. Id.; see also Cellectis S.A. v. Precision Bioscis., Inc., 937 F.Supp.2d 474, 487 (D.Del.2013) ("As noted above, a prior art reference must disclose all of the
Defendants argue that the asserted claims are anticipated by U.S. Patent No. 3,992,534, entitled "Compositions and Method of Treating with Component B of Stereoisomeric Mixtures of 2'-Unsymmetrical 16,17-Methylenedioxy Steriods [sic]," filed Nov. 6, 1975 by Ralph Lennart Brattsand et al. ("Brattsand"). DTX 849. Dr. Paul Myrdal, Defendants' expert, testified that Brattsand was looking at isomers of various glucocorticosteroids as well as certain compositions of them. Trial Tr. 450:15-17. The parties agree that Table 1 discloses budesonide. See id. at 451:9-11 (Myrdal); id. at 1700:9-19 (Zhanel). Brattsand notes "The present application also relates to pharmaceutical formulations or compositions containing new physiologically active steroids of the present invention." DTX 849 at col.12 ll.43-52. Dr. Myrdal testified that a POSA would understand this to disclose pharmaceutical formulations of different steroids. Trial Tr. 451:18-24. Brattsand discloses formulations intended for the treatment of asthma and other inflammatory conditions. PRFOF ¶ 257. In addition, Brattsand teaches that steroids "intended for oral or nasal inhalation" should contain "particles basically less than 5 m, which are suspended in the propellant mixture by the aid of a surfactant." PRFOF ¶ 259. Brattsand noted that due to the separation process set forth in the patent, "it is possible ... to prepare in a pure form new stereoisomeric components...." DTX 849 at col.2 ll.15-19. Brattsand further discloses a suspension for injection. PRFOF ¶ 260. According to Mr. Zaccheo, it was known in the art that a parenteral suspension must be sterile and of a reduced particle size. Trial Tr. 2567:13-16.
Dr. Zhanel testified that Brattsand reflects research studies looking at budesonide's therapeutic effectiveness, but it does not disclose sterility, purity, and pharmaceutical acceptability. Id. at 1329:19-1330:4. The Court agrees that Brattsand does not disclose any particular purity level, much less a purity level of 98.5%. See PRFOF ¶ 258; Trial Tr. 1786:22 (Zhanel). At best, Brattsand discloses that the process of his invention permits the preparation of stereoisomers in "pure form." See DTX 849 at col.2 ll.15-19. The testimony did not demonstrate a connection between this statement and the purity limitation of the asserted claims. As such, Defendants have failed to demonstrate by clear and convincing evidence that the asserted claims are anticipated by Brattsand.
Defendants also argue that the asserted claims are invalid under 35 U.S.C. § 112 for lack of enablement as the specification fails to provide information sufficient to enable a POSA to make the full scope of the claimed compositions without undue experimentation and, specifically, a suspension containing nonsterile budesonide powder. Defendant Sandoz previously asserted this argument in its opposition to AstraZeneca's motion for a preliminary injunction and the Court rejected it in its June 4, 2014 Opinion. See Docket No. 980 at 15-20. Accordingly, for the same reasons set forth therein, the Court finds that Defendants have failed to demonstrate by clear and convincing evidence that the asserted claims are invalid for lack of enablement.
Finally, Defendants argue that the asserted claims are invalid under 35 U.S.C. § 112 for lack of sufficient written description, in that it fails to convey to a POSA that the inventors possessed a suspension consisting of a nonsterile budesonide product. Here, again, the Court previously addressed this argument in its June 4, 2014 Opinion. See Docket No. 980 at 10-15. Accordingly, for the same reasons set forth therein, the Court finds that Defendants have failed to demonstrate by clear and convincing evidence that the asserted claims are invalid for lack of a sufficient written description.
Accordingly, for the foregoing reasons, the Court finds that the '834 Patent is invalid as obvious under 35 U.S.C. § 103 and, therefore, unenforceable. Judgment of non-infringement is hereby entered in favor of Defendants. See TypeRight Keyboard Corp. v. Microsoft Corp., 374 F.3d 1151, 1157 (Fed.Cir.2004) ("invalidity operates as a complete defense to infringement for any product, forever") (citation omitted). AstraZeneca's request for a permanent injunction against each Defendant is denied. Finally, AstraZeneca's request for judgment declaring this to be an exceptional case is dismissed as moot. A trial shall be held on the issue of damages.
Although the Court has found it difficult to pin down AstraZeneca on the date by which it purports to have reduced its invention to practice, see DRFOF 2013 ¶¶ 230-31 (March 26, 1997, or June 24, 1997); Pls.' Rep. to Defs.' Joint Proposed Findings of Fact ("PRFOF"), Docket No. 1128, ¶ 4 (March or July 1997); Docket No. 1155 (March or summer 1997), the evidence AstraZeneca relies upon was largely introduced in the prior trial with the exception of testimony from Dr. Zhanel that it would be routine to create a sterile suspension using sterile powder — a fact that Defendants do not dispute. See Defs.' Joint Proposed Findings of Fact ("DFOF"), Docket No. 1109, ¶ 25. As such, the Court does not find that AstraZeneca's findings of fact are violative of its Order and thus denies Defendants' motion.
Trial Tr. 2451:1-5.
DTX 0004 at 017619-20.
Id. at 1314:15-20; see also id. at 1317:20-23 ("And if all I had was this caption, this wouldn't advance my cause because I don't see the fulfillment of the triad, the purity, the acceptability, along with sterility."); id. at 1404:2-11 ("But what Abshire [DTX 163] really is doing here is he's simply stating that sterilization with antibiotics and steroids occurs with ethylene oxide, but it doesn't help the [POSA] because we have no data showing that we have our package that we're looking for, our package of three: Sterility, purity and pharmaceutical acceptability."); id. at 1407:1-8 ("But the [POSA] trying to solve their problem looks for the evidence and they see no data that they can see that Clark [DTX 160] is teaching showing our package: Sterility, purity and pharmaceutical acceptability."); id. at 1419:18-1420:4 ("Guy [DTX 853] teaches us about a steroid called loteprednol and what Guy does is he doesn't show us data that the product discussed was actually achieved, he does disclose purity.... [B]ut we just don't have all the information that we would like; sterility, purity and pharmaceutical acceptability.").
Dr. Zhanel appeared to discount those prior art references that did not explicitly teach the full "triad" or "package" of limitations. Yet, the law is clear that a patent may be obvious in light of a combination of prior art references. See, e.g., Medichem, 437 F.3d at 1165 ("Evidence of a motivation to combine prior art references `may flow from the prior art references themselves, the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved.'"); In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed.Cir.1986); see also KSR, 550 U.S. at 420, 127 S.Ct. 1727 (noting "in many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle"). But, for the reasons discussed herein, Defendants have clearly and convincingly shown combinability of the prior art, which Dr. Zhanel avoids.
In addition, Dr. Zhanel utilized a definition of a POSA that injected qualifiers. Although he testified on cross-examination that he did not insert "limited time and resources" limitations into his POSA definition, Trial Tr. 1595:22-1596:4, it is clear that he did. See, e.g., id. at 1477:23-25 ("And a [POSA] has limited time and resources. They are interested in bringing a product to market to help patients...."); id. at 1331:18-22 ("A person of ordinary skill is a very focused person. They know that in the drug discovery business, time is money. And their goal is to advance their discoveries as quickly as possible. So they're going to be very focused with their time."); id. at 1587:23-25. Dr. Zhanel appears to have mirrored AstraZeneca's approach, which, in effect, transforms a POSA into a drug manufacturing company, see discussion of large-scale manufacturing supra. For these reasons, Dr. Zhanel's testimony was not persuasive.
Dymnioski v. Crown Equip. Corp., No. 11-3696, 2013 WL 2297035, at *2 (D.N.J. May 24, 2013). The Court finds that Mr. Mathers, a regulatory lawyer who has practiced before the FDA for over 35 years, possesses specialized knowledge that can assist the Court in understanding the manner in which the FDA issues rules and regulations. Accordingly, his testimony is admissible under Rule 702.
Defendants also argue that Mr. Mathers' testimony is cumulative in violation of Rule 403 as it merely rebuts the same opinions that Mr. Muhvich proffered in the first trial and thus impermissibly provides Plaintiffs with a "redo". See Fed.R.Evid. 403 (permitting Court to exclude evidence where there is "a danger of ... undue delay, wasting time, or needlessly presenting cumulative evidence"). For similar reasons, Defendants argue that Mr. Mathers' report was untimely disclosed in violation of Federal Rule of Civil Procedure 27(a)(2)(B). In response, AstraZeneca argues that Mr. Mathers' opinions rebut a new issue first raised by Dr. Muhvich in his 2014 responsive expert report, i.e., whether the FDA's Final Rule in 2000 was affected by AstraZeneca's apparent successful sterilization of an inhaled suspension product. Because the Court ultimately finds Mr. Mathers' opinions to be unpersuasive, it need not address these objections.
