ROBINSON, District Judge.
This action arises out of the filing of an Abbreviated New Drug Application ("ANDA") by defendant Actavis Elizabeth LLC ("Actavis") seeking to market a generic sublingual tablet containing buprenorphine and naloxone. Plaintiffs Orexo AB and Orexo US. Inc. (collectively "Orexo") brought this action alleging infringement of U.S. Patent Nos. 8,454,996 ("the '996 patent") and 8,940,330 ("the '330 patent"). The court held a Markman hearing on August 31, 2015 and issued a claim construction order on October 6, 2015 construing certain disputed limitations. (D.I. 127) The court held a final pretrial conference on May 11, 2016 and a five-day bench trial from June 6-13, 2016 on the issues of infringement and validity, and the parties have since completed post-trial briefing. The 30-month stay of FDA final approval on Actavis's ANDA expires on November 16, 2016. The court has jurisdiction over this matter pursuant to 28 U.S.C. §§ 1331, 1338(a), and 1400(b). Having considered the documentary evidence and testimony, the court makes the following findings of fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52(a).
Buprenorphine is an opioid agonist used to treat patients for opioid dependence, such as heroin or other prescription pain medication. Buprenorphine may be solubilized and injected by patients seeking to abuse it. To address the abuse potential, naloxone (an opioid antagonist that reverses the effects of opioid analgesics) may be added to some buprenorphine formulations. Naloxone has poor transmucosal bioavailability, therefore, if used in a sublingual formulation, the small amount of
Suboxone® ("Suboxone") is a sublingual tablet containing buprenorphine and naloxone in a 4/1 ratio, which was on the market in the United States in 2004. ('330 patent, 2:5-8; JTX 69 at 2; D.I. 206 at 901:16-23) The 4/1 ratio is the preferred dose ratio of buprenorphine and naloxone to treat opioid addiction and deter abuse. ('330 patent, 10:27-29; D.I. 202 at 58:18-59:2)
Orexo developed Zubsolv® ("Zubsolv"), a sublingual tablet formulation containing buprenorphine and naloxone in a 4/1 ratio intended for the treatment of opioid dependence. (D.I. 202 at 53:9-14; D.I. 205 at 770:22-771:3) According to Thomas Lundqvist ("Lundqvist"), co-founder of Orexo, Orexo invested approximately $60 million to research and develop a more abuse-resistant buprenorphine product from 2009-2014. (D.I. 202 at 56:19-22; D.I. 196 at 6) Andreas Fischer ("Fischer"), the inventor of the '330 patent, testified that the "goal was to develop a product with at least 25% higher bioavailability compared to Suboxone." (D.I. 202 at 83:20-84:3; D.I. 196 at 9)
Fischer's first laboratory notebook entry set forth a formulation of an "interactive mixture (tablet)" for "sublingual administration." The ingredients included buprenorphine, naloxone, citric acid, and sodium citrate.
Lundqvist testified that the first clinical results showed that Zubsolv had a 66% improvement in bioavailability. (D.I. 202 at 58:9-15; D.I. 211 at 36) According to a bioequivalence study, Zubsolv increases the bioavailability of buprenorphine, such that patients require a 29% lower dose using Zubsolv as compared to Suboxone. (JTX 153; D.I. 202 at 63:11-17; D.I. 205 at 770:22-771:3; D.I. 196 at 12) Orexo's pharmaceutical development report stated that "[d]ue to the anticipated improved dissolution of buprenorphine the selected dose of 6 mg buprenorphine is expected to give approximately the same systemic buprenorphine exposure in humans as a Suboxone® tablet with 8 mg buprenorphine." (JTX 123 at 4; JTX 128 at 32; D.I. 203 at 352:11-22)
The '996 patent, titled "Pharmaceutical Composition for the Treatment of Acute Disorders," was filed on November 26, 2011 and issued on June 4, 2013, with a priority date of September 24, 1998.
('996 patent, 12:18-33) Claim 2 adds additional requirements, including that the composition be "essentially water free." ('996 patent, 12:34-43)
Orexo's expert, Dr. Sinko, and Actavis' expert, Dr. Dyar, agreed that the limitation "microparticles ... presented at the exterior surfaces of the carrier particles" describes an interactive mixture. An interactive mixture is made up particles of active ingredient adhered to the surface of carrier particles by interactive forces. (D.I. 205 at 676:4-18; D.I. 203 at 360:25-361:4, 365:13-366:9, 367:1-16; D.I. 127 at 3) The three "major elements" of the claims are a sublingual tablet; water soluble carrier particles and buprenorphine formulated as an interactive mixture; and a bioadhesive agent. (D.I. 203 at 387:2-14, 388:4-9; D.I. 205 at 734:6-22) Dr. Dyar explained that the "water free" requirement "relates to the bio-mucoadhesive, because if you have moisture in the tablet, then it could activate the mucoadhesive properties of that tablet and result in it sticking potentially to the package prior to being placed in the mouth." (D.I. 204 at 416:1-15)
The '330 patent, titled "Abuse-Resistant Pharmaceutical Composition for the Treatment of Opioid Dependence," was filed on September 18, 2012 and issued on January 27, 2015.
('330 patent, 24:17-32) The specification provides a pH timing diagram comparing the in vitro pH for the composition of the invention to that of Suboxone and certain other formulations in a small-volume funnel dissolution test. It also provides a graph of the release of buprenorphine and naloxone, respectively, from such formulations. ('330 patent, figures 5 and 6)
Claim 1 is directed to a sublingual tablet comprising buprenorphine, naloxone, one of three named disintegrants, and citric acid. The parties' experts, Dr. Sinko and Dr. Dyar, explained that the limitation "microparticles ... presented upon the surface of carrier particles" represents an interactive mixture. (D.I. 205 at 676:4-18; D.I. 203 at 360:25-361:4, 365:13-366:9; 367:1-16; D.I. 127 at 3) Orexo also asserted dependent claims 3-6. ('330 patent, 24:35-44)
"A patent may not be obtained... if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art." 35 U.S.C. § 103(a). Obviousness is a question of law, which depends on underlying factual inquiries.
KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 406, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) (quoting Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966)).
"[A] patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art." KSR, 550 U.S. at 418, 127 S.Ct. 1727. Likewise, a defendant asserting obviousness in view of a combination of references has the burden to show that a person of ordinary skill in the relevant field had a reason to combine the elements in the manner claimed. Id. at 418-19, 127 S.Ct. 1727. The Supreme Court has emphasized the need for courts to value "common sense" over "rigid preventative rules" in determining whether a motivation to combine existed. Id. at 419-20, 127 S.Ct. 1727. "[A]ny need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." Id. at 420, 127 S.Ct. 1727. In addition to showing that a person of ordinary skill in the art would have had reason to attempt to make the composition
A combination of prior art elements may have been "obvious to try" where there existed "a design need or market pressure to solve a problem and there [were] a finite number of identified, predictable solutions" to it, and the pursuit of the "known options within [a person of ordinary skill in the art's] technical grasp" leads to the anticipated success. Id. at 421, 127 S.Ct. 1727. In this circumstance, "the fact that a combination was obvious to try might show that it was obvious under § 103." Id.
A fact finder is required to consider secondary considerations, or objective indicia of nonobviousness, before reaching an obviousness determination, as a "check against hindsight bias." See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1079 (Fed. Cir. 2012). "Such secondary considerations 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." Graham, 383 U.S. at 17-18, 86 S.Ct. 684.
"Patents are presumed to be valid, and overcoming that presumption requires clear and convincing evidence." 35 U.S.C. § 282; Spectrum Pharm., Inc. v. Sandoz Inc., 802 F.3d 1326, 1333 (Fed. Cir. 2015) (citing Microsoft Corp. v. i4i Ltd. P'ship., 564 U.S. 91, 95, 131 S.Ct. 2238, 180 L.Ed.2d 131 (2011) (holding that an invalidity defense must be proved by clear and convincing evidence)). In conjunction with this burden, the Federal Circuit has explained that,
PowerOasis, Inc. v. T-Mobile USA, Inc., 522 F.3d 1299, 1304 (Fed. Cir. 2008) (citations omitted).
(Id. at 4:55-65) The formulation contains a pharmaceutical disintegrant, for example Ac-Di-Sol®, a modified cellulose gum, which is highly swellable in water. (Id. at 3:8-22)
The parties dispute whether the '725 application disclosed sublingual administration by discussing "enteral administration." The parties' experts offer a confusing and largely unhelpful explanation of the term "enteral," with Dr. Dyar concluding that sublingual administration would be understood by the disclosure of "oral" and Dr. Sinko reaching the opposite conclusion.
The
The Rote Liste 1997 publication
(Id. at 2:5-13)
The
Dr. Dyar identified each of the three major elements of asserted claim 1 in the prior art. He explained that "[i]f you're trying to relieve pain, you want something to work rapidly." Therefore, a person of ordinary skill would select an interactive mixture to do so. (D.I. 203 at 398:8-15) In other words, a person of ordinary skill would have started with Temgesic and understood that the bioavailability of buprenorphine needed to be enhanced. The person of ordinary skill would have tried an interactive mixture based upon the '725 application and added a mucoadhesive based upon the '686 patent to arrive at a product with enhanced bioavailability. Dr. Dyar also opined that a person of ordinary skill would have expected such combination to work based on the fact that Temgesic and interactive mixtures separately worked. (D.I. 203 at 396:10-397:10; 400:25-401:19, 408:10-22) The mucoadhesive element of the '996 patent is known from the '686 and '386 patents, as well as from Temgesic. The '996 patent only requires the presence of the bioadhesive, not any particular amount. (D.I. 203 at 406:18-25) As to claim 2, Dr. Dyar explained that the additional limitation of "being water free" was a well-known requirement of an interactive mixture as disclosed by the '725 application. (D.I. 203 at 387:15-20, 407:16-25)
According to Dr. Sinko, Dr. Dyar improperly combined references from three competing and incompatible groups to arrive at his obviousness conclusion: swallowed formulations using interactive mixtures; sublingual administration of buprenorphine without interactive mixtures; and bioadhesives. (D.I. 204 at 567:21-568:3, 578:11-24, 581:6-13, 583:11-19) There would be no motivation to combine the references as "you would not expect the interactive mixture to work sublingually; ... would expect that the bioadhesive formulations would not allow rapid dissolution of the drug; and
The first question addressed by the experts was whether the application of an interactive mixture to a sublingual formulation would be expected to increase dissolution in the sublingual space (as compared to a sublingual formulation without an interactive mixture). The '725 application generally provides that the use of an ordered mixture increases dissolution rate. Orexo argues that a person of ordinary skill would not have expected interactive mixtures to accelerate dissolution sublingually, because the sublingual volume is much smaller than the stomach volume. Dr. Sinko pointed to the explanation in the '996 patent that the volume of liquid sublingually is not conducive to dissolution. He explained that the small volume of liquid in the sublingual environment would affect both absorption and concentration, as compared to the stomach where the volumes are much larger. The absorption and concentration in the sublingual space would be "much different" than for the stomach. In the small volume of the sublingual space, drug concentration is increased and the elevated concentration can decrease dissolution rate. The decreased dissolution rate from the high concentration "competes" with the improved dissolution rate from the ordered mixture. Saliva flow may reduce the concentration by causing swallowing, but the flow is not fast enough to dilute it out to a low concentration. (D.I. 204 at 592:13-598:14) Dr. Dyar opined that, even though the sublingual volume is small, it is not a closed system. Instead, "the drug is actually moving in a continuous manner across the mucosal membrane and getting absorbed into the body. So once it's removed, then there's more space for drug to be absorbed." (D.I. 203 at 399:1-400:18) The parties' experts have each offered a plausible explanation for whether or not a person of ordinary skill would have expected interactive mixtures to increase dissolution sublingually.
The experts then addressed whether there would be a motivation to combine the various prior art references described above. "[W]hen the prior art teaches away from combining certain known elements, discovery of a successful means of combining them is more likely to be nonobvious." KSR, 550 U.S. at 416, 127 S.Ct. 1727. A reference teaches away from a claimed invention when a person of ordinary skill, "upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant." In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). The "mere disclosure of alternative designs does not teach away." In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). "[C]ourts must take an `expansive and flexible approach' to the question of obviousness." Dome Patent L.P. v. Lee, 799 F.3d 1372, 1380 (Fed. Cir. 2015) (citing KSR, 550 U.S. at 415, 127 S.Ct. 1727). "The degree of teaching away will of course depend on the particular facts." In re Gurley, 27 F.3d at 553. "[O]bviousness must be determined in light of all the facts, and there is no rule that a single reference that teaches away will mandate a finding of nonobviousness." Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006).
Dr. Sinko characterized interactive mixtures (the '725 application) and bioadhesives (the '686 and '386 patents, as well as the Gandhi reference) as "competing technologies" because "bioadhesives were associated with kind of slow release and interactive
Dr. Sinko referenced the '686 patent's statement — a dissolution period of more than one hour is desirable — as "not something" which would be associated with sublingual administration. He concluded that the '686 patent "in some ways ... expressly teaches away from formulations that dissolve rapidly in the mouth." (D.I. 204 at 604:24-605:5) Dr. Sinko pointed to the '386 patent's explanation — if disintegration occurs too quickly, the active ingredient is swallowed, resulting in less absorption and insufficient amount of medicament delivered to the body — to explain that increasing dissolution rate does not always increase absorption. (D.I. 204 at 574:14-577:1) Dr. Sinko concluded that both the '686 and '386 patents "taught that speeding up dissolution would decrease bioavailability and absorption." (D.I. 204 at 613:10-15) Dr. Sinko pointed to the Gandhi reference to argue that a person of ordinary skill in the art would understand that bioadhesives would not be promising for a fast releasing formulation. (D.I. 204 at 606:23-607:22)
According to Dr. Dyar, the '686 patent teaches a person of ordinary skill to "keep the tablet in place for the time that you need to keep it in place." (D.I. 203 at 404:22-405:1) The '386 patent teaches a person of ordinary skill that adjusting the amount of adhesive allows for different amounts of adhesion. The formulation includes sufficient adhesive for the formulation to remain in contact with the oral mucosa for a time sufficient for the absorption of the medicament. (D.I. 203 at 402:22-403:19) Dr. Dyar testified that the '725 application explained that when the active ingredient is dissolved more quickly, it can act more quickly. Dr. Dyar also relied on the Westerberg thesis to explain that the rate of dissolution "is very important for determining the evaluation of bioavailability of drugs with a low aqueous solubility." (D.I. 203 at 391:1-392:3)
A motivation to combine can be found implicitly or explicitly in the prior art, or can be demonstrated by proving "by clear and convincing evidence that a person of ordinary skill in the [drug formulation arts] at the time of the invention" would have recognized the problem identified by the inventors and found it obvious to solve such problem in the manner claimed in the invention. Mintz v. Dietz & Watson, Inc., 679 F.3d 1372, 1378 (Fed. Cir. 2012). The court has determined that the '725 application does not disclose sublingual administration. The record also supports Dr. Sinko's observation that interactive mixtures and sublingual tablets were known in the art for over twenty years, but not combined before September 24, 1998, the priority date for the '996 patent. (D.I. 204 at 572:21-24; D.I. 205 at 737:21-740:10) The question is whether Actavis has proven, by clear and convincing evidence, that a person of ordinary skill
The prior art commercial formulations contain citric acid. Citric acid is a common excipient, used as a buffer system. (D.I. 204 at 420:20-421:5) For example, a
(Id. at 1:53-64) In describing preferred embodiments, the specification provides that "it has been surprisingly discovered that the absorption of one particular agonist, buprenorphine, can provide an optimum absorption at a pH of about 2-4 as well as about 5.5-6.5. Thus, one may `optimize' the absorption of buprenorphine by providing a pH of about 2-4 or about 5.5-6.5." (Id. at 3:27-32) The buffer used "to control the local pH of the film composition... may include sodium citrate, citric acid, and combinations thereof." (Id. at 12:62-13:10)
(JTX 61 at 715-16)
('832 patent, 11:44-57) "The term `local pH' refers to the pH of the region of the carrier matrix immediately surrounding the active agent as the matrix hydrates and/or dissolves, for example, in the mouth of the user." (Id. at 3:35-38) The buffer is used to provide a "local pH of the composition within a range that provides the desired level of absorption of the buprenorphine." (Id. at 11:65-67) In example 8,
(Id. at 21:35-23:7)
The court starts with the observation that the scope of the prior art for the '330 patent had expanded greatly from that just discussed for the '996 patent. The most significant change was the introduction in 2004 of a commercial product, Suboxone, which was a tablet administered sublingually containing buprenorphine, naloxone, and citric acid. The art, of course, developed even further after Suboxone tablets came to the market, to include prior art references which disclosed the use of an interactive mixture to improve
The court concludes that the expert opinions offered by Dr. Dyar were more credible than those offered by Dr. Sinko in this regard. Dr. Dyar opined that claim 1 was obvious in light of the combination of Suboxone with the interactive mixture disclosures (the '443 application and '725 application). Dr. Dyar testified that a person of ordinary skill would have started with the Suboxone sublingual tablet (which contains buprenorphine, naloxone, and citric acid) and then would have used an interactive mixture in order to enhance bioavailability. The person of ordinary skill would have looked to an interactive mixture to enable the active ingredient to dissolve more rapidly (as disclosed in the '443 and '725 applications) and, consequently, to act more quickly. The use of disintegrants was disclosed in the art, for example, the '725 application discloses disintegrants, including Ac-di-sol, which swells in water. He further explained that citric acid is present in many pharmaceutical products and is used as a pH buffering system. The citric acid also fits the definition of a carrier particle — "a pharmaceutically acceptable substance that is water soluble." As citric acid is of appropriate size, "it would act as a carrier if you made an interactive mixture." According to Dr. Dyar, "mannitol was also in Suboxone and would form a[n] ... active carrier." The combination would have been expected to work as Suboxone was a commercial product and interactive mixtures had been shown to enhance bioavailability. As to claim 6, Dr. Dyar opined that "citric acid is pharmaceutically acceptable, water soluble, and of the right size, so therefore it would act as a carrier particle, because it is in the Suboxone tablet." (D.I. 204 at 417-427, 433)
Orexo offers several different arguments in opposition, notwithstanding the undisputed fact that, as of 2012, every other sublingual buprenorphine formulation that was sold commercially contained citric acid and Dr. Sinko's admissions that, by the time of the '330 patent, the prior art taught a person of ordinary skill that "sublingual formulations with interactive mixtures could be used with formulations of buprenorphine and naloxone together." (D.I. 205 at 674:3-12) In the first instance, Orexo argues that Suboxone taught away from using an interactive mixture; i.e., it does not teach one of skill in the art how to formulate an interactive mixture. The record demonstrates, however, that the prior art was replete with instructions on how to make interactive mixtures, the appropriate particle sizes to use, and the mixing that is required to achieve adhesion to a variety of carrier particles. (See, e.g., D.I. 203 at 391:4-11; D.I. 204 at 423:20-24, 426:3-11, 433:8-15; D.I. 205 at 674:8-12, 682:5-15; JTX 50 at ¶¶ 1, 20, 22, 23, 31, 33, 51; JTX 54 at 4-5, 56-57) Given the teachings of
Orexo also argues that a person of ordinary skill would not have been motivated to combine the prior art references at issue because buprenorphine would have been expected to follow the pH partition theory, which stands for the proposition that the lower the pH (an ionized state), the lower the transmucosal absorption of a drug such as buprenorphine. (D.I. 205 at 650-654; JTX 61 at 716) To put the point another way, "[f]aster disintegration/dissolution would be expected to release citric acid faster, lowering the pH and putting buprenorphine in the wrong state for absorption." (D.I. 200 at 29-30) According to Orexo, the '330 patent discloses a new theory of how the transmucosal absorption of buprenorphine occurs:
(Id. at 33) This argument persuaded the examiner to issue the '330 patent. (JTX 4 at 945)
Orexo presented exhaustive explanations with citations to technical references in connection with its arguments that the unclaimed pH timing effect disclosed in the '330 patent is relevant to a finding that one of skill in the art would not be motivated to combine the prior art references at issue. See Intelligent Bio-Systems, 821 F.3d at 1368.
Contrary to Orexo's position, the court finds that the '832 patent
As to claims 8-10, Orexo argues that Actavis "fails to refer to citric acid, a required element." Orexo offers the same criticisms of the prior art (addressed above) and concludes that "there is no teaching that particles of buprenorphine and citric acid should be dry mixed together." (D.I. 200 at 51) For the reasons articulated above, a person of ordinary skill in the art would not have excluded citric acid. Interactive mixtures were known in the art and the '725 application described how to make such a mixture using dry mixing.
Orexo argues that the '330 patent is nonobvious in light of unexpectedly increased bioavailability; teaching away arguments;
"To be particularly probative, evidence of unexpected results must establish that there is a difference between the results obtained and those of the closest prior art, and that the difference would not have been expected by one of ordinary skill in the art at the time of the invention." Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014) (citations omitted). A new compound is not necessarily rendered nonobvious by unexpected properties. "While a `marked superiority' in an expected property may be enough in some circumstances to render a compound patentable, a `mere difference in degree' is insufficient." Id. (citations omitted). [D]ifferences in degree' of a known and expected property are not as persuasive in rebutting obviousness as differences in `kind' — i.e., a new property dissimilar to the known property." Id. (citations omitted).
Orexo points to the patent's disclosure of 66% improved bioavailability for the claimed structure compared to Suboxone, and to Zubsolv having 29% less opioid than Suboxone. ('330 patent, 19:47-52; JTX 153; D.I. 202 at 63:11-17; D.I. 205 at 770:22-771:3) The prior art sought to improve the bioavailability of the opioid. Generally, interactive mixtures were known to improve bioavailability. Although the court rejected Orexo's arguments that the use of citric acid was expected to decrease bioavailability,
Orexo identifies a long-felt need for an abuse-resistant formulation of Suboxone, based on diversion
Orexo's global chief medical officer, Dr. Michael Sumner ("Dr. Sumner"), opined that Zubsolv is less susceptible to diversion based on "Study 006;" a decrease in utilization of buprenorphine when Zubsolv is the preferred product for an insurance plan; and his interactions with healthcare professionals. Study 006 revealed that certain patients with a preference for Zubsolv still selected the Suboxone film when offered a choice of drug. Moreover, certain patients requested higher doses of Suboxone
Dr. William Santoro ("Dr. Santoro"), Actavis' expert, testified that he has treated between 4,000 and 5,000 patients for opioid dependence since 1988. He explained that he prescribes Suboxone tablets, Suboxone film, and Zubsolv tablets to his patients. A physician treating opioid dependence is limited to 100 patients (the "patient cap"). Dr. Santoro described an instance of finding out that one of his patients was diverting her medication to her father ("therapy sharing"), who later became a patient. He cited the Smith article,
On cross-examination, Dr. Santoro testified that he has treated approximately 40 patients with Zubsolv and only a few patients with both Zubsolv and Suboxone. He has not participated in clinical trials regarding opioid dependence. He spent four to five hours reviewing the documentation provided to him (approximately 5,000 pages). (D.I. 206 at 910:7-913:16) Dr. Santoro stated that the Suboxone film is beneficial in that it cannot be crushed and snorted, as opposed to Suboxone (and Zubsolv) tablets. (D.I. 206 at 923:17-924:12) He agreed that the
Orexo's contention that Actavis copied the ratios and proportion of key ingredients
Orexo alleges Dr. Dyar used improper hindsight, by mixing and matching between the Suboxone reference, the Suboxone tablet, and the '443 application. Orexo argues that Dr. Dyar saw citric acid and then searched the art for references to citric acid included in buprenorphine formulations. (D.I. 204 at 507:4-508:25) In light of the secondary considerations analyzed above, the court concludes that Actavis' obviousness combination should not be discounted because of hindsight.
The court determined that Actavis demonstrated, by clear and convincing evidence, a motivation to combine and a reasonable expectation of success. Having reviewed the secondary considerations, the court concludes that the unexpected result of increased bioavailability provides some support for nonobviousness, while Orexo's long-felt need and copying arguments are not persuasive evidence of such. The court finds that Actavis has met its burden to prove, by clear and convincing evidence, that claims 1, 3-6, and 8-10 are obvious.
A patent is infringed when a person "without authority makes, uses or sells any patented invention, within the United States ... during the term of the patent." 35 U.S.C. § 271(a). To prove direct infringement, the patentee must establish that one or more claims of the patent read on the accused device literally or under the doctrine of equivalents. See Advanced Cardiovascular Sys., Inc. v. Scimed Life Sys., Inc., 261 F.3d 1329, 1336 (Fed. Cir. 2001). A two-step analysis is employed in making an infringement determination. See Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed.
The parties dispute whether Actavis' products are interactive mixtures, i.e., whether the products meet the "presented at,"
Orexo's expert, Dr. Martyn Davies ("Dr. Davies"), testified that his laboratory scientist, Dr. Shen Luk ("Dr. Luk"), drafted instructions to manufacture the precompression blend pursuant to Dr. Davies' instructions based on Actavis' ANDA. A laboratory technician made the precompression blends ("the 1.4 mg blend" and "the 5.7 mg blend"). (D.I. 202 at 190-196; PTX 316) Dr. Davies was not present for the manufacturing. Actavis criticizes the manufacturing process and the documentation for the blends.
Actavis next argues that it is unclear whether the proper procedure was followed as to "the retains." (D.I. 203 at 370-372) Certain materials are passed through a 40 mesh stainless steel screen and collected in an appropriate vessel ("the screened ingredients"). Dr. Davies testified that screening is a common practice in the pharmaceutical industry and retains are usually added back into the screened ingredients.
There can be no real question that the documentation was not up to usual laboratory or commercial standards. Dr. Davies agreed that looking at just the documentation leads to the conclusion that the ANDA procedure was not followed, and Dr. Dyar testified that if such errors were detected in the manufacturing documentation, the product would need to be remade. Dr. Dyar, however, also testified that if an investigation revealed that the proper process was followed after errors like these were detected, he would accept the manufactured product.
Actavis also criticizes Dr. Davies' use of a lab-scale bin blender as opposed to the commercial scale V-blender used by Actavis, and points out that Dr. Davies did not conduct a validation test of the two blenders to assess any differences. The
The
The Lemieux article provides support for Dr. Davies' conclusion that the use of a lab-scale bin-blender instead of a lab-scale V-blender does not render the precompression blend unrepresentative of Actavis' precompression blend. The issue at bar is one of scale, i.e., the substitution of a lab-scale blender for the industrial scale V-blender used by Actavis. Dr. Davies relied on the Malmqvist article to opine that because scaling up increases interactive forces, the lab-scale mixing process would have underestimated the interactive forces. (D.I. 202 at 151-156) Actavis' insistence that Orexo should have performed industrial size testing by either making the precompression blends in an industrial blender or validating the use of the lab-scale blender is unreasonable. Such experiments would entail considerable expense and logistical challenges.
Dr. Davies used scanning electron microscopy ("SEM") to demonstrate that the precompression blends were interactive mixtures.
Dr. Sinko analyzed Actavis' documents and concluded that Actavis' blend uniformity tests over time show the existence of interactive forces. He opined that the different particle sizes and free flowing blend would need interactive forces to remain uniform over time, otherwise segregation of the particles would occur. (D.I. 203 at 287-88; JTX 28, JTX 106; D.I. 212 at 26-28) On cross-examination, Dr. Sinko conceded that mixtures with "large particles like carrier particles and smaller particles" do not "necessarily" exhibit interactive forces. (D.I. 203 at 322:14-17) Dr. Davies explained that mixing particles of very different particle sizes (like those present in Actavis' blend) can cause problems with content uniformity. He concluded that the content uniformity of Actavis' mixtures is due to the presence of an interactive mixture. (D.I. 203 at 258-59) On cross-examination, Dr. Davies maintained his position regarding mixtures with different sized particles, but agreed that "for particles which are ... the same particle size," it was "possible to have a random mixture, not an interactive mixture, but still have good content uniformity." (D.I. 203 at 246-247) Dr. Davies also maintained that the Malmqvist article used blend uniformity to indicate the presence of ordered mixing. (D.I. 203 at 249:2-251:16) Dr. Dyar opined briefly that blend uniformity "measur[ed] the uniformity of the blend prior to it being compressed" and "tells you if you have a well-mixed material." He stated that "[w]hether it's interactive mixture or a random mixture, you cannot determine from content uniformity or blend uniformity alone." (D.I. 203 at 379:25-380:15)
Actavis argues that the above testimony
Dr. Davies performed Raman imaging on Actavis' tablets and concluded that the consistent special positioning of the particles was due to interactive forces.
Actavis represents that it "argued [during discovery] that the only samples it should have to produce are samples of the final product" because it "did not have any of the precompressed blend to produce." However, Actavis represented to the court that it did not have intermediates to produce and the intermediates (which would include the precompression blend) were "irrelevant" as "it is Actavis' ANDA product that is accused of infringement in this case, not its `intermediates.'" (D.I. 119 at 3) The court did not compel the production of the intermediates as they were not available. (D.I. 126; D.I. 148) Such non-production shaped Orexo's case, making it incongruous for Actavis to now argue that analysis of the final tablets cannot provide any evidence of the presence of an interactive mixture.
Dr. Sinko offered a brief opinion that the characteristics of Actavis' manufacturing process would result in an interactive mixture. He compared Actavis' process, key ingredients, particle sizes, and resulting products to the examples of the '330 patent. (D.I. 203 at 292-295) On cross-examination, Dr. Sinko conceded that "large particles like carrier particles and smaller particles" do not "necessarily" exhibit interactive forces. (D.I. 203 at 322:14-17) Dr. Sinko acknowledged that the mixing times in the examples of the '330 patent were much longer (7 hours and 40 hours). (D.I. 203 at 318-319)
Actavis argues that this testimony has no value and points to a statement by Dr. Dyar made while discussing blend uniformity.
Dr. Davies manufactured a representative precompression blend on a lab-scale following Actavis' ANDA protocol, which was determined to be an interactive mixture. Orexo's experts attributed the blend uniformity of Actavis' precompression blend documented in its records and the consistent special positioning of particles in Actavis' tablets to interactive forces. Dr. Sinko testified that Actavis' manufacturing process would yield an interactive mixture. Despite Actavis' criticisms of such opinions, for the reasons articulated above, the court finds that Orexo has proven, by a preponderance of the evidence, that Actavis' tablets infringe the asserted claims.
For the foregoing reasons, the court finds that the asserted claims of the '996 patent are not invalid as obvious; the asserted claims of the '330 patent are invalid as obvious; and Actavis infringes the asserted claims of the '996 patent. An appropriate order shall issue.
At Wilmington this 15th day of November 2016, consistent with the opinion issued this same date;
IT IS ORDERED that:
1. The asserted claims of the '996 patent are valid.
3. Defendant infringes the asserted claims of the '996 patent.
4. The clerk of court is directed to enter judgment in favor of plaintiff and against defendant as to the '996 patent, and in favor of defendant and against plaintiff as to the '330 patent.
(D.I. 203 at 265:21-266:3; D.I. 203 at 287:2-6)
