Friday, February 09, 2018

Merck loses to Amneal at CAFC in mometasone furoate monohydrate [Nasonex] case

This case, arising on appeal of a decision by Judge Robinson in D. Delaware, is strongly related to a case arising in D. New Jersey, and also appealed to the CAFC [2012 U.S. Dist. LEXIS 83414; Merck Sharp & Dohme Corp. v. Apotex Inc., 517 F. App’x 939 (Fed. Cir. 2013). ]

There is a lot to discuss.

For starters, there was an appeal of a discovery ruling.

This included the text

Following two discovery hearings on the issue, the
district court became aware of Amneal’s discovery violation
and acknowledged that ideally Amneal should have
produced samples of the Day 4 and A Batches. The
district court determined, however, that it did not have
enough information at the time to determine whether the
Day 4 and A Batch samples were materially different
from the Day 1 Batch samples. The district court concluded
that it was “not persuaded sitting right here that
mixing [] makes a substantive difference, and if it doesn’t,
then it doesn’t matter that Amneal didn’t give [Merck] a
sample of both [the Day 4 and A Batches] . . . [and] only
gave [Merck the Day 1 Batch].” J.A. 128 at 27:7–12. The
district court did not compel Amneal to produce the
additional samples. Nor did the court postpone trial.
Instead, the district court gave Merck the opportunity to
prove at trial that the Day 4 and A Batch samples were
substantively different than the Day 1 Batch samples and
warned Amneal that it was at risk of incurring costs if
Merck prevailed on the issue.


We start our analysis with the district court’s discovery
ruling. We review the district court’s denial of additional
discovery under regional circuit law. Digeo, Inc. v.
Audible, Inc., 505 F.3d 1362, 1370 (Fed. Cir. 2007). The
Third Circuit will not disturb a denial of additional discovery
absent an abuse of discretion and “a showing of
actual and substantial prejudice.” Anderson v. Wachovia
Mortg. Corp., 621 F.3d 261, 281 (3d Cir. 2010).

The district court’s standing discovery order required
Amneal to “immediately make available to Merck samples
of any further representative commercial batches sent to
the FDA.” J.A. 82 (emphasis added). Amneal, however,
did not produce samples of its Day 4 Batch that it submitted
to the FDA, in violation of the discovery order.

The earlier case in D.N.J. has some interesting text about
Dr. Matzger, who testified in the Amneal case:

Dr. Threlfall found Dr. Matzger's testimony troubling in four ways. Dr. Threlfall stated:

I think he went wrong at four levels: I don't think he applied proper scientific judgment to his testing; I think that the design of his experiments was wrong; the actual performance of experiments leads a lot to be desired; and I think that he analyzed the data incorrectly.
(T. 909, 15-19).
Dr. Threlfall opined that Dr. Matzger had "the mindset of an advocate rather than of a scientist. And in particular, Dr. Matzger [*13] went on the hunt for traces of material, without really applying scientific judgment, . . . ." (T. 910, 10-14). Although Dr. Matzger found that conversion begins to occur as soon as the Apotex ANDA Product is manufactured, Dr. Threlfall's calculation was far different. According to Dr. Threlfall, the "Apotex formulation would be stable against conversion to the monohydrate for around 800 years." (T. 922, 21-24).

Dr. Threlfall was very critical of the shaking or vortexing procedure of Dr. Matzger. Dr. Matzger indicates that the shaking was "gentle." Dr. Threlfall disagreed, he honed in on vortexing.

A. Vortexing is an even more energetic process. I mean it's like creating a mini tornado within the tube. And you can imagine that sort of — smashes all things to pieces, it grinds the nuclei together, it causes them to break and nascent surfaces to form, and nascent surfaces are much more susceptible to change than the intact one would be, because they lost their coatings basically for a moment, and therefore they can change when they wouldn't have otherwise been subjected to change.
(T. 925, 18 through T. 926, 1). Likewise, Threlfall was critical of the washing. He opined that Dr. Matzger [*14] "washed out some of the essential components," (T. 926, 8-10), and that the removal of Avicel by shaking and washing was deleting its "protective coating." (T. 926, 20). Threlfall likened the removal of Avicel to an explorer sent to the Arctic, and then his clothes are "pinched, and you leave him in his underwear." (T. 926, 19-23). Evidently, Threlfall believes that when Dr. Matzger washed and shaked the Apotex product, he was undermining the stability of the compound. (T. 926, 23-24).
In commenting on Dr. Matzger's procedures, Threlfall stated "I would describe this as making scrambled eggs and then claiming you still had the eggs with the shells in the carton." (T. 927, 17-19).

Also of interest are the following statements in the DNJ opinion:

XRPD is the standard method for looking at solid materials and polymorphs. (T. 228, 17-23). 7 XRPD looks at arrangement and characteristic spacings of molecules by measuring the intensity of refracted X-rays at different angles. (T. 230, 10-20). According to Dr. Matzger, XRPD is relatively sensitive and excellent at being able to differentiate between different forms of the same compounds. (T. 228, 17-23). Dr. Cockcroft found that Dr. Matzger did not find peaks due to the lack of intensity; and at best, he found "bumps." (T. 781, 13).


Dr. Cockcroft, 8 an expert for Apotex, noted that x-ray diffraction is covered by a very simple equation "developed by Nobel prize winner William Brack in 1913." The Brack formula relates "to the two-theta values in a diffraction powder" in terms of intensity. (T. 780, 13-21). Based on this formula, the XRPD testing device (diffractometer) was created, and it depicts material on a graph based on the intensity of its peaks. In Dr. Matzger's testing, he used an automatic diffractometer on which he set the scan through the two-theta angles. Once he filled a cell with the prepared sample, the diffractometer then automatically records any peaks based on the intensity on [*19] a graph. (T. 262, 21-25). A peak is produced by a clear signal or intensity. That is, the diffractometer "measures an intensity at each angle . . . so [there] is an intensity versus two-theta peak." (T. 261, 3-6). Often the prepared sample may have some different materials commingled in it during XRPD testing, and the peak may be surrounded by noise (non-peak sound). The signal to noise factor was critical in this case for several reasons.


According to Dr. Cockcroft, the history of the three peaks standard is derived from the work of Mr. Hanawalt. Evidently, in the 1940's, Hanawalt was researching numerous minerals which required him to perform XRPD tests on many minerals. Since there were so many samples, Hanawalt devised a database of XRPD patterns so he could identify each one. In developing a card system to identify each sample, he listed the three most intense peaks of the material on a separate card. This format became known as the Hanawalt Search Index. (T. 788, 4-12). Due to this practice, most scientists still use three peaks to identify a pattern. (T. 788, 4-12).

Lastly, the use of the Brack Formula recognizes [*22] that if a peak occurs at a specific level (say 7.8 degrees) and another peak occurs at a factor of 2 (say 15.6), the second peak is a duplication of the first; and hence it is not considered a unique peak (T. 780, 19-25). Hence, duplication must be considered in analyzing XRPD results.

All four samples were subject to XRPD analysis and recorded on a graph (PTX-451). In each of the samples, Dr. Matzger found "evidence of conversion" with peaks at 7.8 and 11.6 as recorded on figure 2 of the patent. (T. 272, 19-25). 9 On sample 012245, Dr. Matzger found that XRPD showed three peaks "consistent with conversion," namely 7.8, 15.6 and 11.6. (T. 277, 13-19). With regard to the 15.6 peak, it is a factor of 2 of the 7.8 peak. Dr. Matzger noted it "illustrates . . . the problems you can have with overlap because there is a shoulder here that is associated with the 15.6 degree peak as opposed to a "distinct peak as it did in the previous pattern." (T. 278, 11-18) (PTX-480). Despite the fact that it is a shoulder and not a peak, he opined that "its all consistent with conversion." (T. 278, 20). In sample 012245, Dr. Matzger fails to consider the limitation within Brack's formula (see above). Dr. [*23] Cockcroft had indicated that a peak at 7.8 and a peak at 15.6 were duplicative based on the application of the Brack formula. Hence, in sample 012245, there are not three peaks as Dr. Matzger finds, but only two in accordance with the Brack formula. Dr. Matzger never refuted the Brack formula, as such, the limitations within the Brack formula are credible.

For accuracy, the Nobel Prize in Physics 1915 was awarded jointly to Sir William Henry Bragg and William Lawrence Bragg "for their services in the analysis of crystal structure by means of X-rays" The experiment is x-ray diffraction, not refraction.

The Hanawalt method relates to identifying an unknown sample via powder x-ray diffraction. In the 1930's, Hanawalt decided to use the d-values of the three strongest strongest lines in the
diffraction pattern of the unknown (d1, d2, d3) along with their respective respective intensities intensities (I1,I2, I3) to search the powder diffraction diffraction file (PDF) database. There is no database search involved in the Nasonex matter.


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