Federal Circuit Uses Dependent Claims to Construe "Therapeutically Effective Amount"

13 August 2012 PharmaPatents Blog

In Alcon Research, Ltd. v. Apotex Inc., the Federal Circuit held that most claims of Alcon’s patent were obvious in view of prior art that suggested the use of the recited active agent to treat the recited condition, but not by the recited mechanism of action, because the prior art used a concentration of active agent that overlapped with the concentration recited in several dependent claims. Two claims that recited a specific concentration outside the range disclosed in the prior art and used in Alcon’s commercial product were upheld, due in part to the evidence of commercial success.

The Patent at Issue

The patent at issue was Alcon’s U.S. Patent No. 5,641,805, which is listed in the Orange Book for Alcon’s Patanol® (olopatadine) product, which is used to treat the allergic conjunctivitis. The following claims are relevant to the court’s decision:

1. A method for treating allergic eye diseases in humans comprising stabilizing conjuctival mast cells by topically administering to the eye a composition comprising a therapeutically effective amount of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz(b,e)oxepin-2-acetic acid or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the . . . amount . . . is from about 0.0001 w/v. % to about 5% (w/v).

4. The method of claim 3 wherein the amount . . . is about 0.1% (w/v).

The State of the Art

As explained in the Federal Circuit decision:

Anti-allergy drugs can treat allergic symptoms by interfering at one of several points in this process. Antihistamines, for example, prevent the histamine that is released from mast cells from binding to receptors in surrounding tissues and also displace the histamine that is already bound to receptors. By contrast, drugs known as mast cell stabilizers prevent mast cells from releasing mediators, and thus counteract the effects of histamine and other mediators that cause allergic symptoms.

The ’805 patent acknowledges that olopatadine was known to be an effective antihistamine, and characterizes the invention as relating to the discovery that olopatadine has mast cell stabilizing activity. As a result, olopatadine “may be applied as infrequently as once or twice a day,” while antihistamines usually must be used every few hours.

The Prior Art

The prior art at issue was a publication by Kamei et al., which reported the testing of “an ophthalmic formulation of olopatadine in guinea pig eyes at concentrations that overlap with those recited in most of the ’805 patent claims.” In particular, Kamei “discloses treating eye allergies in guinea pigs using eye drops with olopatadine concentrations ranging from 0.0001% w/v to 0.01%.” Kamei also reported that “although olopatadine is a good antihistamine, it is not an effective mast cell stabilizer.”

Claim Construction

The Federal Circuit’s claim construction analysis focused on the “therapeutically effect amount” language in claim 1. The district court had construed that language in conjunction with the “stabilizing conjunctival mast cells” language, and interpreted the claims as reciting “concentrations of olopatadine that stabilize conjunctival mast cells ‘to an extent clinically relevant in the treatment of allergic eye disease.’”

The Federal Circuit expressed some dissatisfaction with that claim construction, but noted that because it was not appealed, it would “not decide whether this construction is correct.” Nevertheless, the Federal Circuit stated that it “must determine what olopatadine concentrations constitute a ‘therapeutically effective amount’” in order to address the validity issues that were on appeal.

I found it interesting that the Federal Circuit used the dependent claims as “a starting point” for this analysis, even though Alcon’s expert testified that olopatadine at 0.001% w/v “would not stabilize human conjunctival mast cells to a clinically relevant extent,” and even though the district court found that “[n]ot every concentration of olopatadine applied to the human eye will stabilize the mast cells in the human eye.”

Instead of considering factual evidence as to what may or may not be a “therapeutically effect amount,” the court applied principles embodied in 35 USC 112, ¶4: 

[A] claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.

In particular, noting that claim 2 recites concentrations of olopatadine “from about 0.0001 w/v. % to about 5% (w/v),” and citing the principles that “a dependent claim cannot be broader than the claim from which it depends,” and “must incorporate . . . all the limitations of the claim to which it refers,” the Federal Circuit reasoned that the “effective amount” of claim 1 must cover at least the range recited in claim 2.

The Federal Circuit also found support for this claim construction in the specification of the ‘805 patent, which states:

The concentration of [olopatadine] is 0.0001 to 5 w/v %, preferably 0.001 to 0.2 w/v %, and most preferably about 0.1 w/v %, based on the sterilized purified water.

The Federal Circuit was not impressed by Alcon’s arguments to the contrary:

Alcon’s counsel argued [at oral hearing] that, “to the extent that the dependent claims cover a broader range than the range that would be operative to stabilize mast cells,” the inoperative portion of the range “wouldn’t be covered by the claim by virtue of the limitation in claim 1” that mast cell stabilization must occur to a clinically relevant extent.

The Federal Circuit soundly rejected this position:

This is not how patent law works. When you claim a concentration range of 0.0001-5% w/v (as claim 2), you can’t simply disavow the invalid portion and keep the valid portion of the claim. If everything up to 0.001% w/v is admittedly not enabled, then the entire claim is invalid. Similarly, if prior art discloses a portion of the claimed range, the entire claim is invalid. Courts do not rewrite the claims to narrow them for the patentee to cover only the valid portion. Alcon cannot have it both ways. Because claim 2 sets forth a concentration range, that range at a minimum must be included in claim 1, whatever its limitations.

Thus, the court summarized its claim construction as follows:

When analyzing the validity of claim 1 or claim 2, by the express claim language, the clinically relevant therapeutic amount must include 0.0001-5% w/v olopatadine. That is the claimed concentration range which should be compared to the disclosure of the prior art.

Obviousness of Claims 1-3 and 5-7

The Federal Circuit noted that Kamei “discloses treating eye allergies in guinea pigs using eye drops with olopatadine concentrations . . . [of a range that] overlaps with the concentrations covered by claims 1-3 and 5-7” of the ’805 patent. Thus, according to the court, “[t]he only remaining dispute is whether there was a motivation to adapt the formulation disclosed in Kamei, which was tested in guinea pigs, for use in treating allergic eye disease in humans.”

The Federal Circuit noted the district court’s finding that “animal tests, including guinea pig models, are predictive of a compound’s antihistaminic activity and its topical ocular availability in humans.” The Federal Circuit found that “the district court clearly erred when it concluded that a person of skill in the art would not have been motivated to use the olopatadine concentration disclosed in Kamei in human eyes, based on its finding that “the prior art did not teach that olopatadine would stabilize human conjunctival mast cells, and indeed taught away from using olopatadine for this purpose.” According to the Federal Circuit, “[a] person of ordinary skill in the art at the time of invention would have been motivated to use olopatadine to treat human eye allergies as claimed for its established antihistaminic efficacy.”

Given that the patent defines, and expressly claims, olopatadine concentrations that are “therapeutically effective” to stabilize conjunctival mast cells, Kamei’s disclosure of overlapping concentrations, even if for a different purpose, meets these claim limitations.

With regard to the recited mechanism of action, the Federal Circuit noted:

The district court’s construction of “stabilizing conjunctival mast cells” restricts the claims to certain olopatadine concentrations. As in In re Kubin, this claim language does not impose any additional requirement because the ’805 patent itself defines mast cell stabilization as a property that is necessarily present at those concentrations.

Non-Obviousness of Claims 4 and 8

The Federal Circuit reached a different conclusion on claims 4 and 8, which recite a concentration of olopatadine outside the range disclosed in Kamei:

These claims are limited to using formulations with an olopatadine concentration of about 0.1% w/v. Kamei, however, only tested formulations with olopatadine concentrations up to 0.01% w/v and thus does not disclose this limitation. . . .

As the [district] court noted, the concentrations tested in Kamei were substantially lower than 0.1%. The [district] court relied on expert testimony that a person of ordinary skill in the art would not have a reasonable expectation of success for increasing the highest dosage used in Kamei by an order of magnitude. . . .

Objective evidence further supports the district court’s holding that claims 4 and 8 would not have been obvious. . . . The court found that Patanol® was “an outstanding commercial success,” achieving nearly 70% market share within two years of its launch, accounting for nearly $2 billion in sales within ten years, and garnering wide-spread praise within the industry. . . .  The 0.1% w/v olopatadine concentration recited in claims 4 and 8 is the same as is used in Patanol®. As a result, with respect to claims 4 and 8, Alcon’s objective evidence demonstrates that “the commercial success was caused by the merits of the invention as distinct from the prior art.”

 The Federal Circuit therefore reversed the district court’s holding on the non-obviousness of claims 1-3 and 5-7, and affirmed its holding on the non-obviousness of claims 4 and 8.

The Danger of Dependent Claims

This case illustrates the risk that dependent claim language will be used to interpret independent claims in an unintended manner that may jeopardize their validity. Here, the Federal Circuit relied on the principle that dependent claims necessarily must meet the limitations of their referenced independent claim, and construed the independent claim as necessarily being broad enough to encompass the dependent claims. The doctrine of claim differentiation, while not always invoked by the court, can have an even greater impact on the scope of an independent claim. For example, the court may use the doctrine of claim differentiation to construe the referenced independent claim as being not only broad enough to encompass the dependent clam, but also broad enough to encompass other embodiments, in order to differentiate the scope of the dependent clam from that of the independent claim. Applicants and practitioners may want to keep these principles in mind whether they are drafting and prosecuting their claims, and consider the potential impact of any dependent claims on the scope of the independent claims.

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