UNITED STATES DISTRICT COURT
`DISTRICT OF NEW JERSEY
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`HELSINN HEALTHCARE S.A. and
`ROCHE PALO ALTO LLC,
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`)
`)
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`) Civil Action No. 11-3962 (MLC)(DEA)
`) Civil Action No. 11-5579 (MLC)(DEA)
`) (consolidated)
`)
`) Hon. Mruy L. Cooper, U.S.D.J.
`DR. REDDY'S LABORATORIES, LTD.,
`) Hon. Douglas E. Alpert, U.S.M.J.
`DR. REDDY'S LABORATORIES, INC.,
`SANDOZ, INC., TEVA PHARMACEUTICALS )
`USA, INC., and TEVA PHARMACEUTICAL
`)
`INDUSTRIES, LTD.,
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`)
`)
`)
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`Plaintiffs,
`V.
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`Defendants.
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`REPLY EXPERT REPORT OF PATRICK P. DELUCA, PH.D.
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`Helsinn Healthcare Exhibit 2029
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00008
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`Page 1 of 5
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`the rui cited by Dr. Amidon, taught that one should not study EDTA or a chelating agent lmtil it
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`was "proven" that metal ions catalyzed oxidation of palonoseu·on. Indeed, because it was well(cid:173)
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`known that a chelating agent binds metal ions to prevent metal-catalyzed oxidation, the effects of
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`metals and a chelating agent on degradation were often studied together. (See, e.g., DeLuca
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`Rep01i Ex. 11 , Connors, at 99-100.) The Syntex documents supp01i this. Specifically, "in the
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`study to detennine the effect of metals" during the pref01mulation studies on palonosetron,
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`Syntex reseru·chers tested "samples with metals or EDTA" " to dete1mine the catalytic effect of
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`metals and the stabilizing effect of EDT A." (Syntex Prefonnulation Book, ROCHE0010278,
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`0010282, underlining added.) Notably, Dr. Amidon omits data for pru·allel experiments on " 10
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`mg/ml with 0.1% EDTA" listed in the srune table in the Bonadeo Supplemental Declru·ation.
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`(Amidon Rebuttal Rep01i ~ 128.) Third, Dr. Amidon's alleged "teach[ing] away" (Amidon
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`Rebuttal Rep01i ~ 128) is also conu·my to the fact that Syntex reseru·chers concluded, as a POSA
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`would have done so, that "EDTA (0.1 %) improved the stability of [palonoseu·on] at 10 mg/ml in
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`aqueous solution" and proceeded to develop a fonnulation with EDTA as a stabilizing chelating
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`agent. (Syntex Pref01mulation Book, ROCHE0010275.)
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`210. Finally, Dr. Amidon does not disagree with my opinion that "the concenu·ation of
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`EDTA in the claimed f01mulation would have been obvious." (DeLuca Rep01i ~ 102.)
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`E.
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`Expectation of Success
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`211. As I explained in detail in my opening report (DeLuca Rep01i ~~ 105-1 09), a
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`POSA would have had more than a reasonable expectation of success in making a
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`phmm aceutically stable inu·avenous solution of palonoseu·on by using a low concenu·ation of
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`palonoseu·on, a slightly acidic pH and appropriate runounts of mannitol and EDTA in the
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`f01mulation. Dr. Amidon does not disagxee with the three specific reasons I provided in supp01i
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`of my opinion. (DeLuca Rep01i ~~ 106-108; see Amidon Rebuttal Rep01i ~~ 133-137.) Dr.
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`Amidon 's broad, general statements about the lmpredictability in the field of formulation
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`development do not refute my opinion.
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`212. Moreover, Dr. Amidon does not provide any factual supp01i for his general
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`criticism of my characterization of Syntex' s work on the palonosetron IV f01mulation as "routine
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`development work." (See Amidon Rebuttal Rep01i ~ 135.) Dr. Amidon does not explain why he
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`views the work as anything other than routine. Moreover, Dr. Amidon does not explain how the
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`"confidential infon nation, including clinical inf01mation" available to Syntex or Helsinn
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`researchers led to the claimed invention. Imp01i antly, I rely on the prior art and the skill of a
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`POSA to reach my opinion that a POSA would have made a palonoseu·on formulation as claimed
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`in the patents-in-suit, and would have reasonably expected the f01mulation to be
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`phmmaceutically stable. I do not rely on any other inf01mation, such as the "routine
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`development work" described in the patents-in-suit and recorded by Syntex, to come to my
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`opinion. However, as I made clem· (DeLuca Rep01i ~ 126), the Syntex documents confm n my
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`opinion that the claimed formulation would have been obvious over the prior mi.
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`213. Dr. Amidon appem·s to confuse the expectation of sufficient phmmaceutical
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`stability with the confnmation of such stability through actual long-te1m, real-time stability
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`testing. (See Amidon Rebuttal Rep01i ~ 136.) Stability is a property of a particulm· f01mulation.
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`Whether a fon nulation is stable (or unstable) has nothing to do with whether it was tested to be
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`so. Moreover, as taught in the prior a1i , those working in phmmaceutical development routinely
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`estimated f01mulation stability through experimentation lmder su·ess conditions. (Ex. 20,
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`Connors, Chapter 2.) Thus, a POSA ce1iainly could have had a reasonable expectation of
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`stability without actual stability testing data. Syntex's documents supp01i this. (See Syntex
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`Fon nulation Book, ROCHE0008768.) I also note that Helsinn even relied on the "predicted"
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`stability of the Example 13 formulation of the '333 patent to obtain the '724 patent (see Ex. 21,
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`p. 8), and Dr. Amidon relies on the same "predicted" stability to supp01i his (en oneous)
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`unexpected results argument. (See~ 222 below.)
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`214.
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`Finally, as discussed in my opening rep01i (DeLuca Rep01i ~~ 105-109), a POSA
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`would have had a reasonable expectation of stability based on the various prior rui references,
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`including Won. Conu·ruy to Dr. Amidon's asse1iion (Amidon Rebuttal Rep01i ~ 137), the
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`statements in Won regru·ding the negative effect of ce1iain impmities on the stability ofRG12915
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`would not by itself have established that a fon nulation of palonoseu·on would be unstable.
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`Instead, the statements would have caused a POSA to be mindful of the potential negative effects
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`of such impmities in a palonoseu·on f01mulation.
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`Vlll. SECONDARY CONSIDERATIONS
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`215.
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`I understand that ce1iain "objective" evidence of "secondruy considerations," such
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`as "unexpected results" and "commercial success" may be considered in evaluating the
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`obviousness of a claimed invention. In this case, Dr. Amidon asselis ce1iain "unexpected
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`prope1iies of the claimed invention and other objective indicia of nonobviousness" to supp01i his
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`opinions. (Amidon Rebuttal Rep01i ~ 138.) In my opinion, however, no such evidence of
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`secondruy considerations supports the alleged non-obviousness of the claimed palonoseu·on
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`f01mulation.
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`A.
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`The Alleged "Unexpected Efficacy"
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`216.
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`I understand that for a showing of "unexpected results" to be probative of non(cid:173)
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`obviousness, it must be established that the claimed invention exhibits an actual, superior
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`use a chelating agent or EDTA (AAmidon Rebbuttal Reportt ¶¶ 101-12
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`8), but Synteex researcherrs did
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`test ETDDA during their preformuulation studiees, even bef
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`ore formula
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`tion develop
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`ment. (Synttex
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`motivated to use ma
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`nnitol (Amiddon Rebuttall Report ¶¶ 1129-132), b
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`mannito
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`l as a tonicifying agent. (Syntex Forrmulation B
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`ook, ROCH
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`E0008766.)
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`Dr. Amidonn
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`Preformulation Book, ROCHE00010282.) Drr. Amidon assserts that a
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`been POSA woulld not have b
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`ut Syntex ressearchers didd test
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`asserts thhat a POSA would not haave reasonabbly expectedd a pharmaceeutically stabble formulatiion
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`(Amidon Rebuttal Report ¶¶ 133-137), but Syntex resea
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`rchers expe
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`cted that a foormulation
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`containi
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`ng a low palonosetron cooncentration,, EDTA andd mannitol a
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`t pH 5, “shouuld have an
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`life at room years shelf lat least two adequate stability of
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`temperatur
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`e.” (Syntex FFormulationn
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`Book, ROCHE0008768.) Dr. Ammidon asserts that “nu
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`merous exper
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`iments” or ““undue
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`experimentation” would have beeen required (Amidon R
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`mulation throlaimed formeached the cSyntex reesearchers r
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`ebuttal Rep
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`ort ¶¶ 119, 1224, 134), butt
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`ugh just a f
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`ew routine prreformulatioon
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`and formmulation screening and opptimization sstudies. (Thhe ‘724 pate
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`nt, Exampless 1-3; Syntexx
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`Formulation Book, ROCHE00088766-68.) AAll of these f
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`acts make c
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`lear that Dr.
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`Amidon’s
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`opinions are incorrect.
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`declare under penalty off perjury undder the laws
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`of the Unit
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`ed States of AAmerica thaat the
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` I
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`foregoin
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`g is true and correct to thhe best of myy knowledg
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`e, informati
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`on and belie
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`f.
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`Patrick
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`P. DeLuca, PPh.D.
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`November 22, 2013
`Dated:
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`959339 
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`37 
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`Page 5 of 5