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Janssen’s low dosage oral contraception regime patent valid

On September 11, 2012, The District Court for the District of New Jersey issued it opinion in an ANDA matter between Jansen and Lupin in respect of US patent 6,214,815 listed on the Orange Book against  Janssen’s oral contraceptive containing low dose ethinyl estradiol and norgestimate, ORTHO TRI-CYCLEN LO.  In the consolidated proceeding, Watson and Lupins had stipulated to infringing claims 1 and 4 of the ‘815 patent.  In February 2012, Watson settled with Janssen on the validity of claims 1 and 4 , allowing Watson to begin marketing and distributing a Jansen-supplied product no later than  December 31, 2015.   Lupin challenged the validity of the ‘815 patent on the following bases: anticipation, obviousness and double patenting.

The ’815 Patent

The ‘815 patent, entitled “triphasic oral contraceptive”,   generally relates to the present a triphasic contraceptive regimen containing a progestin and low doses of ethinyl estradiol (EE).  The ‘815 patent disclosed, in Background of the Invention section, that in the past years it has been recognized there are certain benefits of oral contraceptives having lower dosages of estrogen, including a lower incidence of nuisance side effects such side effects, such as, nausea, vomiting, and gastric upset, as well as a decreased incidence of serious side effects, such as, thromboembolism, stroke, and myocardial infarction.  The ‘815 patent further discloses that lowering estrogen dosages is associated with poorer cycle control – at estrogen doses below 30 µg per day, it has been observed that the incidence of breakthrough bleeding and/or spotting is increased to the point that many women can be expected to experience additional discomfort due to irregular bleeding.

Claims 1 and 4 of the ‘815 patent read:

 1. A method of contraception which comprises administering for 21 successive days to a female of childbearing age a combination of 17α-ethinylestradiol and norgestimate for the first 7 days in a daily dosage corresponding to 25 µg of 17α -ethinylestradiol and 0.180 mg of norgestimate, for the succeeding 7 days a daily dosage equal to 25 µg of 17α -ethinylestradiol and 0.215 mg of norgestimate; and for the next 7 days a daily dosage equal to 25 µg of 17α-ethinylestradiol and 0.250 mg of norgestimate; followed by 7 days without estrogen and progestogen administration.

4. A triphasic oral contraceptive unit having 21 separate dosage units, adapted for successive daily oral administration comprising: 7 dosage units containing in admixture with a pharmaceutically acceptable carrier, 25 µg of 17α-ethinylestradiol and 0.180 mg of norgestimate, 7 dosage units containing in admixture with a pharmaceutically acceptable carrier, 25 µg of 17α-ethinylestradiol and 0.215 mg of norgestimate; and 7 dosage units containing in admixture with a pharmaceutically acceptable carrier, 25 µg of 17α -ethinylestradiol and 0.250 mg of norgestimate; and optionally containing 7 additional dosage units free of estrogen and progestogen.

Novelty

Lupin alleged that the claims and 4 were anticipated by prior art (US 4616006 and 45445524 554) owned by Jansen disclosing triphasic oral contraception regimens.  The court concluded that the only material difference between the regimens in the ‘815 and the prior art is the amount of estrogen – the prior art patents disclose a range of 20 to 50 µg  (and all of the examples used an estrogen  concentration of  35 µg) whereas the ‘815 patent was limited to 25 µg.  The Court did not accept Lupin’s “narrowing”/”stand out” approach that a skilled person would understand that 20 – 50 ug range to mean only 7 possible estrogen with 5 µg steps ( ie 20, 25, 30, 35, 40, 45 and 50 µg). Rather, the Court concluded that the estrogen concentration in the ’006 patent is a genus, not a list, and the range contains an infinite set of rational numbers.  Further, Federal Circuit case law has not considered anticipation of a species by a genus where the species is within the genus, but not within the genus constrained by preferences.

The Court further conclude that Lupin’s narrowing approach improperly seeks to “rewrite the ‘006 patent and create hindsight anticipation”. Rather than 7 contraception regimes, the plaintiff’s submitted that the ‘006 patent discloses about 841 million potential contraception regimes.

Obviousness

The parties did not dispute that at the relevant time the skilled artisan was faced with the issue of estrogen-dependent side effects, and that these problems decreased at estrogen content in oral contraceptives decreased such that it was undisputed that skilled persons wanted to create oral contraception  regimens with lower estrogen concentrations.  The Plaintiff framed the obvious analysis as whether the skilled person would have believed that changing the ORTHO TRI-CYCLEN regimen by reducing the ethinyl estradiol dosage from 35 to 25 µg would have resulted in a deterioration in cycle control.   The District Court rejected Lupin’s argument that focusing on cycle control was improper (which is not mentioned in the claims) holding:

On this subject, this Court observes that the plain language of the ’815 patent does notsupport Defendants’ assertion that cycle control is irrelevant. First, the specification of the ’815patent makes very clear that the inventor believed that what was invented was an oral contraceptive regimen with unexpectedly good cycle control. …. In short, from the specification’s description of these five studies, it is unmistakable that the patentee understood the invention to be a contraceptive regimen that provided equivalent cycle control to prior art regimens.

The Court also rejected the Lupin’s position that teaching away and unexpected results are limited to the subject matter of the claims alone, as the authority relied upon by Lupin, Aventis Pharma S.A. v. Hospira, Inc.,  dealt with claim constriction and “[t]here is no claim construction dispute presently before this Court”

The Court characterized Lupin’s principal obviousness attack as follows:

Defendants’ principal obviousness argument could serve as a textbook example of an argument founded on hindsight. Defendants argue that the only difference between a regimen disclosed in the prior art ’006 patent and the regimen disclosed in claims 1 and 4 of the ’815 patent is a reduction in the EE dosage of 10 µg. The truth of this assertion is undisputed. From this starting point, though, Defendants argue that the skilled artisan would have found it obvious to make such a change. This appears persuasive only from the perspective of the rear-view mirror, and it perfectly exemplifies an obviousness argument which works backward from the invention. In hindsight, it is easy to compare the OTC regimen with the OTCLO regimen and see that, for sure, the only difference is 10 µg in the EE dosage. This key observation, however, pure hindsight: it is only apparent after the fact of the invention of the OTCLO regimen..

 

Following the obviousness analysis of the Court of Appeals  in In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., the District Court conclude that secondary oncsiderations were “highly relevant” and held:

In light of Cyclobenzaprine, then, the fact that the claimed invention falls within a range disclosed in the prior art has no special significance to the obviousness inquiry. It is but one fact to be weighed with the other evidence in performing the inquiry under 35 U.S.C. § 103(a)….”

The District Court also rejected the Plaintiff’s submission that Janssen had failed to provide any evidence of the unexpected results of the low estrogen dosage, In light of the presumption of validity, the plaintiffs do not bear any burden of proof on validity and the Court concluded:

In sum, Defendants have not persuaded this Court that a patentee faced with a validity challenge must provide evidence of unexpected results that passes muster under undefined high standards of scientific validity.

Obviousness-Type Double Patenting

While acknowledging that the double patenting analysis is not the same as  under obviousness, the Court concluded that Lupin had not established that it would have been obvious to the skilled person to reduce the dosage of etinyl estradiol disclosed in the prior art by 10 µg.

A copy of the District Court’s Opinion may be found here.

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