Opinion ID: 4445789
Heading Depth: 4
Heading Rank: 1

Heading: “Impurity A”

Text: Claim 4 of the ’913 patent recites a “topical formulation produc[ing] less than 0.1% [of] impurity A after 6 months at 25° C[] and 60% humidity.” ’913 patent col. 30 ll. 22–24. The district court concluded that “impurity A” is indefinite because a POSITA would not know, with reasonable certainty, the identity of the substance as claimed. We agree. The term “impurity A” only appears in claim 4 and Example 6 of the ’913 patent. Example 6 examines “the stability of the compositions of the present invention . . . at room temperature over a six month period.” ’913 patent col. 25 ll. 36–38. To do so, the example refers to a study where samples were placed into sealed plastic screw cap bottles and then stored at 25°C and 60% humidity for six months. Id. col. 25 ll. 47–49. After six months of storage, “the samples were tested for impurities by high performance liquid chromatography (HPLC).” Id. col. 25 ll. 49– 51. According to Example 6, this test revealed two unexpected findings: (1) that the composition of the invention contained a higher concentration of the active agent while resulting in a “lower concentration of a degradation impurity”; and (2) “that compositions using hydroxypropylcellulose (HPC) as the gelling agent had a significantly lower quantity of this impurity as compared to compositions made using carbomer gelling agents.” Id. col. 25 ll. 38–46. In discussing the results of the study, the example refers to “an impurity, termed ‘impurity A,’ [which] was seen to elute at about 6.6 minutes in varying amounts for the various [tested] compositions.” Id. col. 25 ll. 54–56. Table 13 HZNP MEDICINES LLC v. ACTAVIS LABORATORIES UT, INC. 15 shows the percentage of “impurity A” in relation to the tested compositions: Id. col. 25 ll. 57–66. The example goes on to remark that the appearance of “a lower percentage of ‘impurity A’” in the formulation “containing 3.5% HPC shows a higher degree of stability.” Id. col. 26 ll. 1–5. It also states that the “reduction in the level of impurity A” in the HPC gel formulation, as compared to the formulation containing 0.9% Carbopol, shows that the former “is more stable than” the latter. Id. col. 26 ll. 7–11. Because of that, it concludes that “the present invention provides improved stability,” which is evidenced by the “degrad[ation of] less than 0.034% or 0.09%” over the six-month period. Id. col. 26 ll. 11–16. Lastly, the example notes that “the amount of ‘impurity A’ found [was] . . . well below [the] limits that would require additional nonclinical testing of the impurity.” Id. col. 26 ll. 16–19. Although the specification does not define “impurity A,” Horizon argues that a POSITA would understand the term to mean “USP Related Diclofenac Compound A.” (“USP Compound A”). According to Horizon, a POSITA versed in the pertinent prior art would be able to ascertain the meaning of “impurity A” based on the intrinsic evidence. It is undisputed that the intrinsic evidence does not 16 HZNP MEDICINES LLC v. ACTAVIS LABORATORIES UT, INC. explicitly refer to USP Compound A, or its chemical formulation, in relation to “impurity A.” Still, Horizon maintains that, consulting the available pharmacopeias at the time, a POSITA would know “impurity A” refers to a specific impurity of diclofenac sodium. Horizon posits that because the specification refers to “impurity A” as a degradation of diclofenac sodium, which is the only component of the inventive formulation with a known impurity, a POSITA would know this term refers to “USP Related Diclofenac Compound A RS.” Actavis argues that the specification does not provide any clues as to the identity of “impurity A,” which implies that “impurity A” is an unknown impurity. According to Actavis’s expert, a POSITA reading the specification would read “impurity A” as referring to an unknown impurity because the specification: (a) does not disclose the chemical name of the impurity, which would be expected if such were known; (b) uses quotes to refer to “impurity A,” suggesting that it is not the formal name of a known impurity; and (c) justifies not conducting additional tests to identify the impurity merely because it occurs in low amounts. Actavis contends that the only relevant disclosure in the specification about “impurity A” is in relation to Example 6. But, citing to its expert’s declaration, Actavis maintains that the information in Example 6 is insufficient to allow a POSITA to determine the identity of “impurity A.” For instance, Actavis’s expert opined that the specification offers no information about the HPLC procedure used, including the column type, mobile solvent, and temperature used for the HPLC analysis reported. Moreover, Actavis contends that Example 6’s observation that the amount of “impurity A” is so low that no “additional nonclinical testing” is required implies further testing was necessary to ascertain the identity of “impurity A.” As to Horizon’s reliance on pharmacopeias, Actavis argues that the district court did not clearly err in rejecting Horizon’s view on what a POSITA would have surmised HZNP MEDICINES LLC v. ACTAVIS LABORATORIES UT, INC. 17 from those pharmacopeias. Actavis points out that the specification never mentions USP Diclofenac Related Compound A RS, which is a degradation of the active ingredient. Actavis also states that the claims refer to the degradation of the entire formulation—including other excipients (inactive ingredients)—as opposed to the degradation of the diclofenac sodium, the active ingredient. Actavis argues that even in light of the pharmacopeias, there is considerable doubt as to whether a POSITA would read “impurity A” to mean an impurity of the formulation as opposed to that of the active ingredient. We find no error in the district court’s conclusion that “impurity A” is indefinite. First, we look to the language of the claims to evaluate if the meaning of “impurity A” is reasonably clear. Berkheimer v. HP Inc., 881 F.3d 1360, 1363 (Fed. Cir. 2018) (“We look first to the language of the claim to determine whether the meaning of [the term] is reasonably clear.”). Claim 4 of the ’913 patent depends upon claim 1. Claim 1 recites: 1. A topical formulation comprising: diclofenac sodium present at 2% w/w; DMSO present at about 40 to about 50% w/w; ethanol present at 23–29% w/w; propylene glycol present at 10–12% w/w; hydroxypropyl cellulose; and water to make 100% w/w, wherein the formulation has a viscosity of 500–5000 centipoise. ’913 patent col. 30 ll. 9–17. Claim 4 then recites the topical formulation of claim 1, wherein such formulation “produces less than 0.1% impurity A after 6 months at 25° C[] and 18 HZNP MEDICINES LLC v. ACTAVIS LABORATORIES UT, INC. 60% humidity.” Id. col. 30 ll. 22–24. Although Horizon attempts to tie “impurity A” to diclofenac sodium, Actavis is correct to point out that the claims do not support such a result. Claim 4 refers to the entire topical formulation of claim 1, which includes several other excipients. The claims thus do not make clear that “impurity A” refers to an impurity of diclofenac sodium. Looking beyond the language of the claims, it is also undisputed that the written description contains no references to USP Compound A or its chemical name. Indeed, Horizon does not cite to any part of the specification, the claims, or the prosecution history that defines or directly connects “impurity A” to USP Compound A. The only part of the specification that uses the term “impurity A” is Example 6, which contains “[t]he only identity information provided for ‘impurity A.’” J.A. 9. That information consists of “retention times derived from a high performance liquid chromatography (‘HPLC’).” Id. The specification, however, is devoid of other information about the conditions of the HPLC experiment, such as the column, the mobile phase, and the flow rate. Thus, the written description provides no clue as to the identity of “impurity A.” Next, we turn to extrinsic evidence. Horizon attempted to connect “impurity A” to USP Compound A through pharmacopoeias and its expert’s opinion. The district court considered that evidence but found that Horizon’s expert did not explain why a POSITA would know that the HPLC test in Example 6 was undertaken using a pharmacopoeia chromatographic system. The district court understood this to mean that the basis upon which Horizon’s entire argument rests—that a POSITA familiar with pharmacopoeias would understand “impurity A,” as used in Example 6, to be USP Compound A—is incorrect. We agree. The district court emphasized that none of the “references relied upon by [Horizon’s expert] . . . that use [a] pharmacopoeia chromatographic system omit the details of HZNP MEDICINES LLC v. ACTAVIS LABORATORIES UT, INC. 19 the HPLC experiment . . . or identify USP Compound A by anything other than its actual chemical formula and/or structure.” J.A. 11. Put differently, because the specification omits the details of the HPLC experiment—such as the column, the mobile phase, and the flow rate—a POSITA faced with this specification would not reasonably presume that Example 6 was undertaken using a pharmacopoeia chromatographic system. This outcome undermines Horizon’s reliance on the pharmacopoeias to extrapolate meaning into “impurity A.” We see no clear error in the district court’s determination, based upon the extrinsic evidence, that “impurity A” is indefinite when used in the context of Example 6, which lacks sufficient information about the HPLC procedure to enable a POSITA to ascribe meaning to “impurity A” with reasonable certainty. See Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., 845 F.3d 1357, 1371–72 (Fed. Cir. 2017) (finding that the district court did not clearly err in determining, based on extrinsic evidence, what a POSITA would understand “vitamin B12” to mean in a medical context); Akzo Nobel Coatings, Inc. v. Dow Chem. Co., 811 F.3d 1334, 1343–44 (Fed. Cir. 2016) (finding that the district court did not clearly err in determining, based on extrinsic evidence, that a POSITA would measure viscosity at room temperature if no other temperature is specified); Berkheimer, 881 F.3d at 1363–64 (affirming district court’s conclusion that “minimal redundancy” limitation was indefinite because the subsidiary finding of fact that a POSITA would not have known what the term meant as used in claim was not clearly erroneous). To be clear, we do not hold that a reference to an impurity is indefinite in all contexts, only that on this record, the term “impurity A” is indefinite. 20 HZNP MEDICINES LLC v. ACTAVIS LABORATORIES UT, INC.