After filing of an ANDA by Teva for a generic
version of Nasonex (mometasone furoate), Merck responded by filing a patent
infringement suit based on U.S. Patent No. 6,127,353 (‘353 Patent).[1] The ‘353 Patent claims a monohydrate
crystalline form of the active ingredient in Nasonex. Teva’s formulation was made with another
crystalline form, but Merck argued that Teva’s crystalline form converted to the
patented crystalline form over the two year shelf life of Teva’s
product.
On November 16, 2016, Judge Robinson of the U.S. District Court of Delaware found the '353 Patent to be valid, but not infringed by Teva.
The court first addressed the validity of the ‘353
Patent. Teva asserted that the ‘353
Patent was invalid for double patenting based on the Federal Circuit’s holding
in “Gilead,” which held that a
later-issued but earlier-expiring patent can serve as a double-patenting
reference against an earlier issued but later-expiring patent. Gilead
Sciences, Inc. v. Natco Pharma Ltd., 753 F.3d 1208, 1212 (Fed. Cir.
2014). Recently, the holding in “Gilead”
was relied on to invalidate a patent covering the drug Remicade.[2] In this case, a terminal disclaimer was
required to revive another related application during prosecution (relating to
the amount of time during which the application was abandoned, not to the
subject matter of the claims). The parties disputed whether the patent that
issued from the revived application qualified as a double patenting reference
because it expired before the '353 patent.
The court held that the '353 patent was not invalid for double patenting
since the patents-at-issue were from the same family, were examined by the same
examiner at the PTO, and that “[t]his is not an instance of a patentee seeking
to extend the patent term with ‘sequential’ applications.”
After finding the patent to be valid,[3]
the court found that Teva’s product did not infringe the ‘353 Patent. The question for infringement was whether
Teva's ANDA product (an aqueous suspension made with prior art anhydrous form) contained
any patented monohydrate during the product's shelf life.
Merck’s expert tested several of Teva’s batches
after their expiration dates (2.5 years and 4 years after expiration). Merck’s expert testified that Teva’s crystals
changed to the patented crystals but did not know when these crystals formed,
and "the testing did not tell us anything about whether [the patented
monohydrate] was present before expiry." Instead, the testing of the expired
samples only revealed that the patented crystals appeared at some point between
when it was manufactured and when it was tested. The court concluded that the expired samples were
not representative of the ANDA product and that without testimony (or evidence)
of when the monohydrate crystals formed in the expired products, the conclusory
statements provided by Merck’s expert did not establish infringement.
Regarding Teva’s commercial
batches, Merck’s expert allowed the crystals from Teva’s product to dry before
performing single crystal X-ray diffraction (SCXRD) analysis. Merck’s expert explained that he was not able
to harvest the monohydrate crystals from a wet slide like he had from the
samples of the expired batches. (For the
expired batches, Merck’s expert gave the bottle containing the product a small
shake in order to disperse the suspension inside the spray bottle and sprayed a
sample on a clean glass slide. He selected a particular crystal using optical
microscopy; withdrew the crystal; mounted it onto a MiTeGen loop; and performed
SCXRD on the crystal). The parties
disputed whether the drying of the slides promoted crystal growth. Merck’s expert testified that he "viewed
lots of slides where they were drying and ...noticed no formation of new
crystals of any sort, including [the monohydrate]." He testified that "[d]rying
itself doesn't provide a crystal. It's not part of our standard
crystallographic practice. It doesn't happen." Teva’s expert disagreed, testifying that when
Merck’ expert allowed the wet slides to dry over extended period of time, he
provided an uncontrolled experiment, which was actually conducive to formation of
the monohydrate.
Merck’s expert testified that
following a "learning period," he was confident in his ability to
visually distinguish (with optical microscopy) between the monohydrate and
anhydrous crystals. In summarizing his findings, he testified that he had
identified "dozens and dozens" of monohydrate crystals in Teva’s
products. Teva’s expert disagreed with
the reliance on visual observation alone, testifying that such observation
"has to be coupled with X-ray crystallography of that same crystal in
order to have any confidence of the chemical identity in the solid form of that
crystal."
Merck also presented the
testimony of Teva's 30(b)(6) deposition witness who testified that he could see
a peak at 1710 cm-1 in Raman spectroscopy (corresponding to a peak
characteristic of the monohydrate). The court,
relying on case law,[4]
concluded that at least three peaks on a spectra must be used to identify
material based on accepted practices, and that Teva’s internal testing did not
establish the presence of the monohydrate in Teva's product.
The court found that Teva did not
infringe the ‘353 Patent since “the literature and the experts consistently
pair optical microscopy with another measurement method before conclusively
distinguishing polymorphs. . . the court finds that Merck has not established,
by a preponderance of the evidence, the presence of [monohydrate] in Teva's
ANDA product during its two-year shelf life.” At no point during his testing of
Teva’s commercial batch did Merck’s expert harvest a monohydrate crystal from a
wet slide, and only relied on crystals from slides which he had dried.
The court’s Order can be found at
< https://www.docdroid.net/OqaCSNc/merck-opinion-nov-16-2016.pdf.html>.
[1] Merck Sharpe & Dohme Corp. v. Teva
Pharmaceuticals USA Inc., case number 1:14-cv-00874, U.S. District Court for
the District of Delaware.
[2]
<https://www.pharmapatentsblog.com/2016/10/05/judge-grants-gilead-motion-to-invalidate-remicade-patent/>
[3] The District Court also
dismissed Teva’s position that the ‘353 Patent lacked written description
support
[4] Schering Corp. v. Apotex Inc.,
2012 WL 2263292 (D.N.J. June 15,2012).
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