Replies to post #128834 on Biotech Values

[mouton29]

This affidavit was filed in support of the sur reply. It was not filed as a text file so I had to run my own OCR, so the errors may be mine (or Adobe's):

Case 1:11-cv-11681-NMG Document 77-2 Filed 10/19/11 Page 1 of 6
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF MASSACHUSETTS
)
MOMENTA PHARMACEUTICALS, INC., et aI., )
)
Plaintiffs, )
)
v. )
)
AMPHASTAR PHARMACEUTICALS, INC., et al. )
)
Defendants. )
-----------------------------------)
C.A. No.1 :11-cv-11681-NMG
SUPPLEMENTAL DECLARATION OF PARASTOO AZADI IN SUPPORT OF
DEFENDANTS' OPPOSITION TO PLAINTIFFS' MOTION FOR A TEMPORARY
RESTRAINING ORDER AND PRELIMINARY INJUNCTION
Steven M. Bauer (BBO No. 542531)
[e-mail]
Isaac A. Hubner (BBO No. 677719)
[e-mail]
PROSKAUER ROSE LLP
One International Place
Boston, MA 02110
Telephone: [phone]
Facsimile: 617.526.9899
Anthony T. Pierce (admitted pro hac vice)
[e-mail]
Mark Mansour (admitted pro hac vice)
[e-mail]
Jonathan P. Robell (admitted pro hac vice)
[e-mail]
AKIN GUMP STRAUSS HAUER & FELD LLP
1333 New Hampshire Avenue NW
Washington, DC 20036
Telephone: [phone]
Facsimile: 202.887.4288
Jan P. Weir (admitted pro hac vice)
[e-mail]
STRADLING YOCCA CARLSON & RAUTH
660 Newport Center Drive, Suite 1600
Newport Beach, CA 92660
Telephone: [phone]
Facsimile: 949.725.4100
Counsel for Defendants Amphastar Pharmaceuticals, Inc., International Medication Systems,
Ltd., and Watson Pharmaceuticals, Inc.
DOCSOC/1521746vl/014312-00l3
Case 1:11-cv-11681-NMG Document 77-2 Filed 10/19/11 Page 2 of 6
1. I, Dr. Parastoo Azadi, make this declaration based upon my personal knowledge unless
indicated otherwise.
2. I have reviewed the October 16, 2011 Declaration of Dr. Zachary Shriver, including the
publication authored by Andrew J. Rhombert et al. attached for Dr. Shriver's declaration. I have
also reviewed the CE procedures disclosed in the' 886 patent including its priority applications.
3. I have reviewed the '886 patent and conducted a computerized word search through the
patent's specification and there is no mention of aI, 6-anhydro ring structure any where in the
patent.
4. At paragraph 18 of his declaration, Dr. Shriver states that one skilled in the art would
understand that the claim term "separation method" encompasses the use of HPLC, CE and other
separation methods. I disagree based upon the context of the claimed separation step. Although
they are both separation technique but the mode of separation is different and the information
obtained are different from the two different techniques. Just like, for example the information
one can obtain by running "Mass Spectrometry" can be totally different depending on the type of
mass spectrometer one uses i.e. MALDI-MS, ESI-MS, GC-MS. They are all mass spectrometry
techniques but each will give totally different results and information that is not obtained by the
other method if used to analyze any mixture. The separation step is used to identify and separate
out what is described as a "non-naturally occurring sugar associated with peak 9 of FIG. 1" of
the patent. FIG. 1 is generated by CEo One using HPLC would not be able to obtain a
electropherogram of FIG. 1. As the "non-naturally occurring sugar associated with peak 9 of
FIG. 1" is not described anywhere else in the patent, one skilled in the art would have to use the
CE method that generated FIG. 1 to separate and identify the sugar. A person of skill in the art
could not use a separation method different than CE as there is no identification of the sugar at
peak 9, other than the CE method. The SAX-HPLC will not produce one peak for 1,6-anhydro
sugars so it cannot be compared to CEo Due to the lack of any other identification one would
have no way of knowing whether the sugar they obtained in a different peak ofa different
separation method (SAX-HPLC) was the same sugar that occurred at peak 9 of FIG. 1 of the
'886 patent.
DOCSOCI1521746vl/014312-0013
Case 1:11-cv-11681-NMG Document 77-2 Filed 10/19/11 Page 3 of 6
5. The '886 patent claims that peak 9 is the non-naturally occurring sugar generated by the
analysis of enoxaparin sample with CEo However, The SAX-HPLC method which is a different
separation technique based on different separation criteria actually gives four peaks for the 1,6
anhydro sugars present in an enoxaparin sample. There are more than one 1,6-anhydro sugars
present in an enoxaparin sample and that is why the SAX-HPLC gives several peaks for the 1,6-
anhydro sugars.
6. At paragraph 31, Dr. Shriver states that a person of ordinary skill in the art could
reproduce the CE separation method that generated FIG. 1 of the patent. I disagree. The
methodology that resulted in FIG. 1 is disclosed in Example 1 of the patent. Example 1 states
only: "The CE sample was prepared by diluting the digest with H20 to give a final heparin
concentration of 1.0 ng/nL. 57nL of this CE sample was injected into the CE." No other
relevant information is provided. No information is provided regarding the buffer, the pH, any
additives to the buffer, the type of capillary, the length and diameter of the capillary, the voltage
applied, or the temperature of the column used during analysis. All of these conditions can
impact the results of the CE and will impact whether or not there is an identifiable peak 9.
7. In addition in ' 886 patent information is given on the heparinase I, II, III digestion of
UFH and identification of 1-8 peaks in the CE generated after the UFH digestion. However, no
such detailed peak assignments are given for the enoxaparin sample which is claimed to produce
additional peaks compared to the UFH using the CE separation technique. The Heparinase I, II,
III digestion of UFH and CE separation and of the disaccharides and the assignments of
disaccharides has already been reported in the Ampofo, S. et aI., "Disaccharide Compositional
Analysis of Heparin and Heparan Sulfate Using Capillary Zone Electrophoresis,"Analytical
Biochem., 199:249-255 (1991). However, the '886 patent makes no attempt to give any
additional information of the CE analysis of enoxaparin sample and the identification of Peak 9
that is not present in CE of UFH.
8. Dr. Shriver cites to Col. 27, lines 26-:31 of the '886 as evidence that the CE process
relating to FIG. 1 is disclosed in the '886 patent. The portion of the '886 patent he cites contains
only a summary description of the Figures. No information is provided about the CE conditions.
Dr. Shriver also cites Col. 47:54-65. There is no statement relating to the CE conditions of
Example 1 in that portion of the patent either. Dr. Shriver cites Col. 48:56-49:20 which relates to
2
DOCSOC/1521746vIl014312-0013
Case 1:11-cv-11681-NMG Document 77-2 Filed 10/19/11 Page 4 of 6
Example 1, but the cited text merely describes the use of CE and not the CE conditions that
generated FIG. 1. Dr. Shriver also cites Cols. 48:56-49:20 which as stated above provides some
information regarding digestion with heparinase step, but insufficient information regarding the
conditions for the CEo Lastly, Col. 62:47-60 relates to a different example and FIG 10, not FIG
1. Thus, Dr. Shriver has not pointed to any disclosure in the' 886 patent of the CE conditions
that generated FIG. 1.
9. Dr. Shriver references the Rhomberg (1998) publication in paragraphs 31 and 32 of his
declaration. Rhomberg does provide a statement of the CE conditions he used for his
experiments in his article. Dr. Shriver does not say that Example 1 of the '886 patent used these
exact conditions and there is no support in the' 886 patent for concluding that it did.
10. I am informed that Plaintiffs are contending that the language in claim 54 of the '886
patent means that the separation step in claim 6 covers the use of HPLC. I disagree. Claim 54
relates to a method for determining the structural signature of the non-naturally sugar that resides
at peak 9 of FIG. 1, not separating the sugar from other sugars. The language of the claim states
"structural signature is determined" not "the non-naturally occurring sugar is separated using".
11. I note that claims 5 5, 57, 58 and 60 use the same "structural signature is determined"
language as claim 54. Claims 55, 57, 58, and 60 claim the use ofNMR, MALDI-MS, ESI-MS,
and ELISA respectively. None of these methods are separation methods.
12. If one were to put a mixture of heparinase digested enoxaparin oligosaccharides into any
one of these systems, one would not obtain any data comparable to CEo
13. I have reviewed claims 6, 15 and 53 of the '886 patent. I understand that the PTa
rejected the steps of providing a digested enoxaparin sample, using a separation method, and
making a determination about the sample base upon a comparison to a reference standard as
disclosed in Desai et al. The additional step of making a determination regarding the quality of
the sample as based upon the comparison of the sample to a reference standard is standard and
obvious to anyone of skill in the art and less. Any comparison of a test sample to a control,
results in a determination of whether the sample satisfies the control conditions and thus is an
assessment of the samples "quality."
3
DOCSOC/1521746vl1014312-0013
Case 1:11-cv-11681-NMG Document 77-2 Filed 10/19/11 Page 5 of 6
14. Further, inherent in standard CE processes is a determination of the amount of whatever
substance is found under a given peak. This is a standard and well known process. The amount
is readily available from the CE electropherogram as the area under the peak. Even if one not
even calculate the area under the peak, the relative heights of the peaks shows the relative
amounts of the substances under the peaks in the test sample.
15. Selecting a batch as claimed in the last element of claim 53 is also inherent and obvious
in any quality control testing where a test sample is compared to a reference standard. The very
purpose of such testing is to determine if the test sample meets the control so that it can be
further used. This is standard well known laboratory procedures well within the knowledge of
anyone of skill in the art and I would say within the skill of any undergraduate chemistry or
biochemistry student with at least one semester of a laboratory class.
16. Dr. Shriver also contends that claims 1 and 8 of the' 466 patent were allowed because
claim included the limitation that the tetrasaccharides had to be first isolated prior to sequencing
and claim 8 required determining the amount of one of the tetrasaccharides in the table in the
claim. These are not novel features and were know in the art. United States Patent No.
4,847,338 to Linhardt et aI., attached as Exhibit A, discloses both limitations. At Col. 4:10-30,
Linhardt discloses the isolation of heparinase digested heparin fragments, including the isolation
oftetrasaccharides, before further processing the tetrasaccharides with SAX-HPLC. This is also
described in Example 1, Col. 5:50-59: "Six distinct peaks were observed representing, from last
to first eluted, disaccharide, mixed tetrasaccharide fragments, missed hexasaccharide fragments,
mixed octasaccharide fragments, mixed decasaccharide fragments." Thus, Lindhardt teaches the
step of first isolating tetrasaccharides prior to further sequencing.
17. Linhardt also teaches sequencing the previously isolated tetrasaccharides in Example II.
(Col. 6:29-41.) The Figure 2A represents the results of the further separation of the
tetrrasaccharides. One of ordinary skill in the art would know that the area under the curve
represents the amount of the tetrasaccharide represented by the peaks in Figure 2A.
4
DOCSOC11521746v1l014312-00l3
Case 1:11-cv-11681-NMG Document 77-2 Filed 10/19/11 Page 6 of 6
I declare under penalty of perjury that the foregoing is true and correct. Executed on this
19 day of October, 2011 at Athens, Georgia.
Parastoo Azadi
5
DOCSOC/1521746vl/014312-0013

[iwfal]

MNTA - Translation double check:

The good news is that it looks like Ampha is, in fact, violating patent 866 - probably using the HPLC method (which is claim 50 something).

The bad news is that without some really good lawyering by Momenta they won't win:

a) It appears like Momenta, in the original patent filing, mentioned that HPLC wasn't good enough as a measurement technique to measure the un-natural sugars.

b) The entire patent being claimed is explicitly about making manufacturing decisions based upon the signature of certain un-natural sugars. But generally Momenta's only description of those sugars is a description of them as whatever causes Peak 9 in a CE plot. Is this specific enough... or not? Note that they are also somewhat unspecific about exactly what the signature is.

As Mouton noted - it really is impossible to figure out where this is likely to go without seeing the Momenta filings too. I can certainly envision strong counters to each of the above two Amphastar assertions - but what matters is what Momenta does.

[iwfal]

MNTA - 466 Patent Comments:

Amphastar appears to be making two arguments:

1) Patent is invalid because it is an obvious combination of Linhardt et al., United States Patent No. 4,847,338 (’338 patent) and Sasisekharan ’642.

I have no comments on this at this time. Hopefully somebody smarter about chemistry (like winchem) will make some interesting comments

2) Use is covered under Safe Harbor. Amphastar's primary claim here is that ANY use of ANY patent that is used solely to make the FDA happy is protected. More specifically they appear to be implicitly acknowledging routine use subsequent to regulatory filing - but claiming Safe Harbor because the language of the law is not specific to filings to get approvals. (this is consistent with what I noted in a post at the very start of these hearings - Amphastar is attempting to extend Safe Harbor not just to use of patents of branded drugs about to expire, but to ANY use of ANY patent for ANY testing required by the FDA at ANY time.)

Comment: I think Amphastar will have a hard time on this one. For instance, Momenta appears to be asserting portions of Classen v Biogen for which the CAFC ruled very crisply

"§271(e)(1) provides an exception to the law of infringement in order to expedite development of information for regulatory approval of generic counterparts of patented products. The statute does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained."

And, interestingly, as others have noted on this board, even if Amphastar were only using the patent for submission for approval of the generic I think the Classen case is still reasonably clear since they cite some of the congressional notes which are completely unambiguous:

The House Report explains that the Act “provides that it is not an act of patent infringement for a generic drug maker to import or to test a patented drug in preparation for seeking FDA approval if marketing of the drug would occur after expiration of the patent[emphasis added]."

This purpose was emphasized throughout the legislative process: “The purpose of sections 271(e)(1) and (2) is to establish that experimentation with a patented drug product, when the purpose is to prepare for commercial activity which will begin after a valid patent expires, is not a patent infringement.” Id. Again in Part 2 of H.R. Rep. No. 98-857, at 8 (1984), the Report is explicit that “the only activity which will be permitted by the bill is a limited amount of testing so that generic manufacturers can establish the bioequivalency of a generic substitute.” The Report states that “the generic manufacturer is not permitted to market the patented drug during the life of the patent; all that the generic can do is test the drug for purposes of submitting data to the FDA for approval.” Id. at 30.

See Patent Barista Classen v Biogen

Amphastar's primary defense for their very broad interpretation of Safe Harbor is a SC ruling on Merck KGaA vs Integra. This ruling was about the use of patented items used in pre-clinical studies of new drugs even though, in the end, the data was not submitted as part of the IND for the drug found. The SC ruled that because the experimenter could not know in advance what, precisely, would end up being needed for FDA submission it was therefore protected by Safe Harbor.

Interesting notes:

1) Merck pointed out in their brief to the USCA that they would not market their drug until after the patent had expired in any case. And that they had not done so in the past.

2) The USCA clearly violated one of the expressed intents of congress when they broadened Safe Harbor - i.e. the house notes I quoted above said "the only activity which will be permitted by the bill is a limited amount of testing so that generic manufacturers can establish the bioequivalency of a generic substitute" and yet the USCA broadened the statute to cover non-generics. The point here being that although the congress is crystal clear that Safe Harbor should not apply in Amphastar's case the USCA does not always live within the congressional intent.

Comparing the two cases referenced by the two parties I think it is very clear that Classen is very very much more on-point than the Merck. Of course Merck is a USCA ruling and Classen is only a CAFC case, but it toto I think Amphastar is likely to lose on this.