Court Opinion

ID: 8411986
Source: CourtListenerOpinion
Date Created: 2022-11-02 19:17:24.380258+00
Date Added: 2024-06-11T16:47:08.534179
License: Public Domain

DYK, Circuit Judge,
coneurring-in-part and dissenting-in-part.
I join Parts IIA and III of the majority’s opinion. However, I respectfully dissent from Parts IIB, IIC, and IID. In my view, the asserted claims of U.S. Patent Nos. 6,562,873; 6,627,210; 6,641,834; and 6,673,337 (collectively, the “related patents”) are invalid as obvious over the combination of Alphagan® and Refresh Tears® in view of the related prior art.
A finding of obviousness under the “obvious to try” standard “does not require absolute predictability of success ... all that is required is a reasonable expectation of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed.Cir.2009) (quoting In re O’Farrell, 853 F.2d 894, 903-04 (Fed.Cir.1988)) (emphasis altered). I think that standard was satisfied here. It is undisputed that all asserted claims of the related patents read on a combination of Alphagan® and Refresh Tears®. The undisputed evidence further establishes that, at the time of the invention, a person having ordinary *1379skill in the art (“PHOSITA”) would have known that: (1) Alphagan® had common side effects, two of which included eye irritation and dry eye (known to be exacerbated by its benzalkonium chloride (“BAK”) preservative); (2) the higher pH of Refresh Tears®, nearer to that of the human eye, would likely reduce irritation; (3) the “gentle” stabilized chlorine dioxide (“Purite®”) preservative in Refresh Tears® would likely be less harmful than Alphagan’s® “toxic” BAK preservative; (4) inclusion of Refresh Tears’® earboxymethylcellulose (“CMC”) viscosity agent would likely further reduce eye irritation; and (5) physicians were routinely prescribing Refresh Tears® to glaucoma patients on Alphagan® to help alleviate irritation and dry eye, two of Alphagan’s® known side effects.
Under these circumstances, I think a PHOSITA would have found a combination of these two commercially successful products “obvious to try.” KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 421, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007).
Despite the extensive evidence of the motivations for a PHOSITA to combine Alphagan® and Refresh Tears®, the district court held that the combination was not obvious to try because a PHOSITA would have had concerns regarding the solubility and oxidation of brimonidine in Refresh Tears®, thereby preventing a PHOSITA from having any anticipated success in combining the products. However, I think the district court made clearly erroneous findings of fact regarding these purported concerns.
The district court first found that “a [PHOSITA] would not have expected effective concentrations of brimonidine to be soluble in [the elevated] pH range” of Refresh Tears®. In re Brimonidine Patent Litigation, 666 F.Supp.2d 429, 442 (D.Del. 2009). The court viewed brimonidine concentrations of 0.2% to 0.5% as necessary for therapeutic effect, and it concluded that a PHOSITA would not have expected these concentrations to be soluble at the 7.2-7.9 pH range of Refresh Tears®. This was based on Dr. Stella’s testimony that a PHOSITA would have expected “0.2 percent and 0.5 percent” brimonidine to have solubility problems at higher pHs. J.A. 7922-23. The difficulty with this finding is that the district court improperly assumed that the 0.2% brimonidine in Alphagan® was the lowest dosage concentration that could achieve efficacy. The Derick reference (entitled “Brimonidine Tartrate: A One-Month Dose Response Study”) confirms brimonidine’s effectiveness at lower dosages. The authors of the Derick reference conducted “a multi-centered, double-masked, randomized, placebo-controlled, parallel, 1-month dose response evaluation of brimonidine 0.5%, 0.2%, and 0.08% in patients with open-angle glaucoma or ocular hypertension.” J.A. 25670. The study concluded that “[a]ll concentrations of brimonidine significantly reduced IOP, compared to baseline and placebo, at all followup visits.” J.A. 25669. A PHOSITA would have understood Derick as disclosing that brimonidine can be therapeutically effective at concentrations as low as 0.08%. There is also no basis for finding that 0.08% brimonidine would be insoluble at the higher pH range of Refresh Tears®.
The majority dismisses the Derick reference by citing Dr. Robert Noecker’s testimony that Derick’s findings were “not compelling” evidence of 0.08% brimonidine’s efficacy and that he would not prescribe 0.08% brimonidine to his patients based on the Derick study. J.A. 7507; see Maj. Op. at 1373 n. 1. But notably, Dr. Noecker said nothing as to whether a PHOSITA would have considered it obvious to try concentrations lower than 0.2% in light of Derick’s findings regarding the *13800.08% concentration. Dr. Noecker himself acknowledged that the efficacy of a particular drug concentration can never be known for certain “without having ... the actual concentration tested.” J.A. 7508. Derick’s plain findings that “23 (51%) of 45 patients in the 0.08% group ... showed a reduction of 20% or more from baseline at one or more scheduled visits over the course of the study” clearly suggested trying concentrations lower than 0.2%. J.A. 25671.
The majority further dismisses the Derick reference because “the therapeutic efficacy of brimonidine varies with pH,” and the study “did not indicate the pH of the carrier.” Maj. Op. at 1373 n. 1. But if the carrier in Derick had a higher pH than Alphagan®, then it demonstrated the likely success of combining Alphagan® and Refresh Tears® using some brimonidine concentration lower than 0.2%. Conversely, if the carrier had a pH lower than Alphagan®, a PHOSITA would have known that the 0.08% concentration would be even more effective at the higher pH range of Refresh Tears® due to the pH Partition Theory discussed below. Either way, a PHOSITA concerned with the solubility of 0.2% brimonidine at the higher pH of Refresh Tears® would have been prompted by Derick to simply try using a lower dosage.
Quite apart from Derick, there was no reason for a PHOSITA to be deterred from combining Alphagan® and Refresh Tears® because of solubility problems with brimonidine concentrations in the 0. 2% to 0.5% range. As the majority recognizes, the pH Partition Theory establishes that an ocular drug’s bioavailability (the percentage of the drug that reaches the targeted tissue) increases in correlation with pH, which means that increasing pH lowers the minimum dosage concentration required for efficacy. See Maj. Op. at 1368-69. The district court failed to recognize that a PHOSITA with knowledge of the pH Partition Theory would have known that some concentration of brimonidine less than 0.2% could still achieve efficacy at the higher pH range of Refresh Tears®, and that the lower brimonidine concentration would in turn help offset the expected decrease in the maximum soluble concentration. A PHOSITA thus would have been motivated to lower the dosage concentration below 0.2%.1
In short, solubility problems with brimonidine concentrations in the 0.2% to 0.5% range, as found by the district court, would not have deterred a PHOSITA from trying a lower concentration of brimonidine at the higher pH range of Refresh Tears®.
The district court next found that a PHOSITA would have had “concerns that the Purite® preservative in Refresh Tears® would preservative in Refresh Tears® would oxidize the brimonidine in Alphagan[ ]®.” In re Brimonidine Patent Litigation, 666 F.Supp.2d at 444. However, the court based this holding on two clearly erroneous fact findings.
The court’s first error regarding oxidation concerns was its dismissal of the Thompson reference. Thompson discloses *1381a study in which the oxidative effect of hydrogen peroxide on brimonidine and other drugs was tested using electrochemical oxidation. This included placing an electrode in a formulation of hydrogen peroxide and a drug, pouring electrons into the system, and observing how long it took to oxidize the drug. The test lasted for 120 minutes before it was terminated “due to the destruction of the [hydrogen peroxide] under the experimental conditions.” J.A. 27315. The least oxidatively stable drug tested was amodiaquine, which oxidized in under one minute; the most oxidatively stable drugs were clonidine and brimonidine, which did not oxidize during the 120 minute test. Id. Thompson ultimately concluded that “[c]lonidine and brimonidine proved to be oxidatively stable in sharp contrast to [the other drugs tested].” J.A. 27312. There was no testimony that the Thompson test was in any way inaccurate.
The sole reason the district court gave for dismissing the Thompson reference was that it “teaches nothing about the oxidative stability of brimonidine in a Purite®-containing formulation that needs to be shelf-stable for two years. ” In re Brimonidine Patent Litigation, 666 F.Supp.2d at 444 (emphasis added). But as the majority appears to acknowledge, it was improper for the district court to distinguish Thompson based on the fact that its oxidation test lasted for only 120 minutes, rather than two years, because “the claims [of the related patents] do not require a particular period of shelf stability.” Maj. Op. at 1375.
Having accepted the fact that no shelf stability time limit is mandated by the asserted claims of the related patents, the majority must agree that, in view of the teachings of Thompson, a PHOSITA would have known that brimonidine would not oxidize in hydrogen peroxide for a period of at least 120 minutes. The undisputed evidence — including Dr. Stella’s testimony and Alergan’s own promotional documents — establishes that a PHOSITA would have known that hydrogen peroxide was a stronger oxidant than Purite®. Because hydrogen peroxide was known to be a stronger oxidant than Purite®, and Thompson disclosed that brimonidine is “oxidatively stable” in hydrogen peroxide for at least 120 minutes, a PHOSITA must have known that brimonidine would be oxidatively stable in Purite® for at least 120 minutes. Even if the claims had included a two year stability limitation, the knowledge that brimonidine would be oxidatively stable in Purite® for some time exceeding 120 minutes should have still been enough for a PHOSITA to consider the combination of Aphagan® and Refresh Tears® at least obvious to try.
While the district court’s dismissal of the Thompson reference itself provides a sufficient ground for reversal on the oxidation issue, the court made a second clearly erroneous fact finding regarding oxidation. As an affirmative basis for finding that a PHOSITA would have had concerns that brimonidine would oxidize in Purite®, the court credited Dr. Stella as having “testified that at the time of these inventions, it was well-known in the art that ... the structural features of brimonidine made it particularly susceptible to oxidation.” In re Brimonidine Patent Litigation, 666 F.Supp.2d at 444 (emphasis added). Alergan agreed at oral argument that the testimony the district court attributed to Dr. Stella regarding brimonidine being “particularly susceptible” to oxidation was “important” to the court’s finding of non-obviousness. See Oral Ag. at 14:47-19:57, available at http://www.cafc.uscourts.gov/ oral-argument-recordings/2010-1102/all. However, Dr. Stella did not testify that brimonidine was “particularly susceptible” *1382to oxidation. The relevant portion of Dr. Stella’s testimony reads:
[I]f you look at the structure of brimonidine, ... there are elements in the structure, for example, there are nitrogens in a ring structure....
That section of the molecules lends itself to, in fact, what we call chlorination as well as N-oxide formation.
J.A. 7918 (emphasis added). While Dr. Stella stated that the structure of brimonidine “lends itself’ to N-oxide formation, he said nothing as to whether brimonidine was “particularly susceptible” to oxidation in comparison to other drugs. This is significant because the Thompson reference disclosed that “brimonidine proved to be oxidatively stable in sharp contrast to [the other drugs tested],” J.A. 27312 (emphasis added), which Dr. Stella’s actual testimony does not refute. The district court’s finding that oxidation concerns would teach away from the combination of Alphagan® and Refresh Tears® was simply not supported by the record.
Because the undisputed evidence establishes that a PHOSITA would have been motivated to try a combination of Alphagan® and Refresh Tears® to arrive at the claimed formulation, and because the district court made clearly erroneous fact findings in determining that solubility and oxidation concerns would have deterred a PHOSITA from trying this combination, I think that the “obvious to try” standard has been satisfied. I respectfully dissent from the majority’s contrary conclusion.

. A PHOSITA also would have found a lower dosage preferable because Alphagan's® high 0.2% brimonidine concentration commonly caused allergic conjunctivitis (inflammation of the inner eyelid tissue), and it was known at the time of the invention that reducing the brimonidine concentration would help alleviate this side effect. See J.A. 7486-87, 7493-96, 7512 (Dr. Noecker); J.A. 6737-38 (Dr. Tanna); J.A. 6416 (Dr. Whitcup); J.A. 7580 (Dr. Banker). The pH Partition Theory thus provided an additional affirmative motivation for a PHOSITA to exploit the higher pH range of Refresh Tears® to make a dosage reduction possible.