UNITED STATES PATENT AND TRADEMARKOFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`APOTEX INC., APOTEX CORP., APOTEX PHARMACEUTICALS
`HOLDINGSINC., and APOTEX HOLDINGS,INC.,
`Petitioners,
`Vv.
`
`OSI PHARMACEUTICALS, INC.,
`Patent Owner.
`
`U.S. Patent No. 6,900,221
`Issue Date: May 31, 2005
`
`Case No. IPR2016-01284
`
`REPLY DECLARATION OF GIUSEPPE GIACCONE, M.D., PH.D.
`
`APOTEX EX. 1053-001
`
`APOTEX EX. 1053-001
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`APOTEX INC., APOTEX CORP., APOTEX PHARMACEUTICALS
`HOLDINGSINC., and APOTEX HOLDINGS,INC.,
`Petitioners,
`Vv.
`
`OSI PHARMACEUTICALS, INC.,
`Patent Owner.
`
`U.S. Patent No. 6,900,221
`Issue Date: May 31, 2005
`
`Case No. IPR2016-01284
`
`REPLY DECLARATION OF GIUSEPPE GIACCONE, M.D., PH.D.
`
`APOTEX EX. 1053-001
`
`APOTEX EX. 1053-001
`
`
`
`TABLE OF CONTENTS
`
`T. QUALIFICATIONS0.0ee eecceeeceseeeseenenseaneeeneesssesecssasensaeasaneesneessenanensaaes 2
`
`Il. MATERIALS REVIEWED... cece cess eeceeesncereereseneesenaeeseaseeeseneessseeesnnees 2
`
`III. OBJECTIVE INDICIA OF NONOBVIOUSNESS 0.0... eecsccesecetersseneeeeenneees 3
`
`A. A Person of Ordinary Skill in the Art Cannot Assess if Patent Owner’s
`
`Alleged Results are Unexpected... ceceeceeeeesseseessesnessacsseesnseeareessaseseeserenensnes 3
`
`B. Patent Owner’s Alleged Unexpected Results Do Not Apply to All NSCLC
`
`PAti@Nts .......ccccesceccsccsssceseecsceceseecseecceeseseececeseseeaeseasonegesaesesesesnesseseseesaeseuseeeseaustoeaeens 4
`
`C. The Method of Treatment Described in Claims 44-46 of the ’221 Patent Did
`
`Not Satisfy a Long-Felt Need... eeeeeesceseeeerereseeeseaeceasseseasessseteessseseeenerenes 5
`
`D. There were Many Successful Attempted Treatments in Mammals with
`
`NSCLC ooo eeecccccssecsecceeneccsnnecesneseeneesssneeeeeeeeeeeeeeseessesenseneesearsdcsuseeeeanneeesnaessaaaeecaneas 6
`
`IV. AVAILABILITY FOR CROSS EXAMINATION |... ececsersersserenteerseees 7
`
`V. RIGHT TO SUPPLEMENT....... eee cee eee eeceseeeescannnrecsnaeessseessaeeesseeeesnesessanees 8
`
`i
`
`APOTEX EX. 1053-002
`
`APOTEX EX. 1053-002
`
`
`
`I, Giuseppe Giaccone M.D., Ph.D, declare and state as follows:
`
`1.
`
`The opinions and conclusionsI express in this declaration are based
`
`on my education, my extensive experience in the diagnosis and treatment of
`
`various lung cancers, and my review of materials related to this matter.
`
`2.
`
`For the purposes of my opinions and conclusions, I apply the
`
`definition of “treating” and “treatment” as provided by U.S. Patent No. 6,900,221.
`
`(See “the °221 patent, col. 14, Il. 9-15.)
`
`I.
`
`QUALIFICATIONS
`
`3,
`
`For a discussion of my qualifications and credentials, I refer to my
`
`June 17, 2016 declaration (Ex. 1002) and my curriculum vitae, which is
`
`Appendix A to Ex. 1002.
`
`II. MATERIALS REVIEWED
`
`4.
`
`In forming my opinions, I have relied upon my accumulated
`
`knowledge and experience.
`
`I have reviewed Patent Owner OSI Pharmaceuticals,
`
`LLC’s (“OSI”) Response (Paper 20) and the materials cited in Appendix A
`
`attached thereto.
`
`I have further reviewed the documents referenced herein.
`
`bo
`
`APOTEX EX. 1053-003
`
`APOTEX EX. 1053-003
`
`
`
`IPR2016-01284
`U.S. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`Ill. OBJECTIVE INDICIA OF NONOBVIOUSNESS
`
`A.
`
`A Person of Ordinary Skill in the Art CannotAssessif Patent
`Owner’s Alleged Results are Unexpected
`
`5.
`
`OSI and Dr. Bunn contendthat erlotinib’s therapeutic efficacy and
`
`ability to provide survival benefits to non-small cell lung cancer (NSCLC)patients
`
`was unexpected, (Paper 20 at 61; Ex. 2021 at § 109.) However, logic would
`
`dictate that a comparator is necessary to evaluate whethera result is unexpected.
`
`Indeed,in the context of patent claims, I understand that the correct comparator for
`
`evaluating whethera result is “unexpected” is to compare it with whatis identified
`
`as being the closest prior art. In this case, the closest prior art is Schnur(U.S.
`
`Patent No. 5,747,498 (Ex. 1009)), which discloses the compounderlotinib as being
`
`effective to treat a range of conditions that involve inhibition of the EGF receptor,
`
`including lung cancer. (See Ex. 1009 at col. 14, Il,
`
`1 - 16.) I understand that no
`
`such comparison was made. (See Paper 20 at 61; Ex. 2021 at {J 108-109.) Dr.
`
`Bunn subsequently testified that he used chemotherapy asthe closestprior art for
`
`his analysis. (Ex. 1048 at 111:9 — 113:16.) However, Dr. Bunn’s declaration
`
`provides no analysis of whyasurvival benefit derived from the challenged claims
`
`of the ’221 patent would be unexpected in comparison with chemotherapy. (See
`
`Ex. 2021 at ff 108-109.) Neither does Patent Owner’s Response.
`
`(See Paper 20at
`
`61.) Thus, OSI’s and Dr. Bunn’s statementsthat erlotinib’s therapeutic efficacy
`
`APOTEX EX. 1053-004
`
`APOTEX EX. 1053-004
`
`
`
`IPR2016-01284
`U.S. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`and potential survival benefits for NSCLC patients are unexpected is mere
`
`conjecture.
`
`6.
`
`OSIrefers to a “majority of compounds”failing at some point during
`
`preclinical and clinical development. (See Paper 20 at 61.) However, thatis just a
`
`general statement about drug development. [f FDA-approvalis the benchmark and
`
`a failure to pass through various stages of preclinical and clinical developmentin
`
`general is the baseline comparator, this would meanthat all FDA-approved drugs
`
`provide unexpected results. Moreover, because the compounderlotinib was
`
`already patented, I understand the issue here as being whetherthe use oferlotinib
`
`to treat NSCLC wasunexpected in view of Schnur, which discloses its use to treat
`
`lung cancer generally. As set forth in my earlier Declaration, the use of erlotinib to
`
`treat NSCLC wasnot unexpected,particularly in view of Schnur, as well as the
`
`statements in OSI’s 10-K and Gibbs.
`
`B.
`
`7.
`
`Patent Owner’s Alleged Unexpected Results Do Not Apply to All
`NSCLCPatients
`
`I further disagree with OSI’s and Dr. Bunn’s contentions that
`
`erlotinib’s efficacy in treating NSCLC was unexpected because erlotinib plainly
`
`does not provide a survivalto all, or even a majority, of NSCLC patients. Instead,
`
`in my experience,and asset forth in more recent articles, only a small subset of
`
`NSCLCpatients actually respond to erlotinib. (See Ex. 1053 at 7 10; Ex. 1051 at
`
`APOTEX EX. 1053-005
`
`APOTEX EX. 1053-005
`
`
`
`IPR2016-01284
`U.S. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`3-4.) I believe Dr. Bunn agrees with this assessmentthaterlotinib treated only a
`
`small subset of NSCLCpatients are actually treated with erlotinib. (Ex. 2021 at
`
`q 108; Ex. 1048 at 23:9 - 26:6.) Conversely, I understand that claims 44-46 and 53
`
`of the ’221 patent, as they relate to NSCLC, claim a treatmentfor all NSCLC
`
`patients. Because erlotinib’s actual efficacy in treating NSCLCis much more
`
`narrow than the claims 44-46 and 53 of the ’221 patent, in my opinion there are no
`
`unexpected results provided by erlotinib that overlap with these claims.
`
`OF
`
`The Method of Treatment Described in Claims 44-46 of the ’221
`Patent Did Not Satisfy a Long-Felt Need
`
`8.
`
`AsI discussed above,erlotinib only treats a smal! subset of NSCLC
`
`patients who have certain EGFR mutations. Specifically, only NSCLCpatients
`
`with an EGFR exon-19 deletion or an exon-2!] L858R mutation respond to
`
`erlotinib. (Ex. 1048 at 99:22 — 101:13.) This accounts for about 10% ofpatients
`
`with NSCLCin the United States. (See Ex. 1051 at 3 — 4; Ex. 1048 at 23:9 — 26:6.)
`
`This leaves a vast numberofpatients that are still in need of a therapy. Dr. Bunn
`
`states that there was a need to replace cytotoxic chemotherapy. (See Ex. 2021 at
`
`492.) However, for about 90% ofpatients with NSCLC,erlotinib did not replace
`
`cytotoxic chemotherapy. (See Ex. 1051 at 3—4; Ex. 1048 at 23:9 — 26:6.) Thus,
`
`in my opinionerlotinib did not satisfy the treatment needs of the vast majority of
`
`NSCLC patients.
`
`APOTEX EX. 1053-006
`
`APOTEX EX. 1053-006
`
`
`
`IPR2016-01284
`U.S. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`9.
`
`Dr. Bunnstates that “[w]hen Tarceva wasfirst approved by the FDA
`
`in November 2004, it was indicated for the treatment of NSCLC and,as the only
`
`alternative to chemotherapy,it filled a significant long-felt unmet needfor a
`
`targeted NSCLCtreatment.” (Ex. 2021 at § 106.) I disagree with this statement
`
`because a FDAlabel indicating erlotinib as a treatment for all NSCLC does not
`
`changethe scientific fact that erlotinib did not treat about 90% of NSCLC patients
`
`in the United States. (See Ex. 1051 at 3 — 4; Ex. 1048 at 23:9 — 26:6.) Regardless
`
`if erlotinib was the only alternative to chemotherapy, 90% of NSCLC patients still
`
`required chemotherapy. Thus, there wasstill a significant void. Thus,in my
`
`opinion erlotinib cannot have satisfied the need described by OSI and Dr. Bunn
`
`because clearly the vast majority of NSCLCpatients were not successfully treated
`
`by erlotinib.
`
`D.
`
`There Were Many Successful Attempted Treatments in Mammals
`with NSCLC
`
`10.
`
`Dr, Bunn statesthat other attempts to develop targeted, NSCLC drug
`
`products failed clinicaltrials. (Ex. 2021 at 47, Heading 2.) However, my
`
`understanding of claims 44-46 and 53 ofthe ’221 patent is that FDA approvalis
`
`not required by any these claims.
`
`Instead, I understand that claims 44-46 and 53 of
`
`the 221 patent are directed more broadly towards methods for the treatment of,
`
`among other conditions, NSCLC in a mammal.
`
`In myextensive experience
`
`APOTEX EX. 1053-007
`
`APOTEX EX. 1053-007
`
`
`
`IPR2016-01284
`U.S. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`conducting pre-clinical andclinical investigations of experimental medicines, FDA
`
`approvalis not required to show anti-tumoractivity in mammals with NSCLC.
`
`My experience coincides with Dr. Bunn’s testimony that newsof a drug reaching
`
`Phase II clinical studies for targeting NSCLC indicates successful preclinical
`
`studies showing bioactivity towards treating NSCLC in animal models. (Ex. 1048
`
`at 95:3 —8.) J believe Dr. Bunncalls successful studies against NSCLC in animal
`
`models “promising activity.” (Ex. 2021 at 937; Ex. 1048 at 38:12 — 39:12.) Thus,
`
`in my opinion if 1,631 new drugs weretested in PhaseII clinical trials for NSCLC,
`
`this indicates that 1,631 new drugs successfully showed treatment of NSCLC in
`
`mammals during preclinical development. (Ex. 2021 at 979; Ex. 1001 at col. 14,Il.
`
`9-15.) I believe Dr. Bunn agrees with this conclusion. (Ex. 1048 at 95:3 — 8.)
`
`IV. AVAILABILITY FOR CROSS EXAMINATION
`
`11.
`
`In signing this declaration, I recognize that the declaration will be
`
`filed as evidence in a contested case before the Patent Trial and Appeal Board of
`
`the United States Patent and Trademark Office. I also recognize that I may be
`
`subject to cross examination in the case and that cross examination will take place
`
`within the United States. If cross examination is required of me, I] will appearfor
`
`cross examination within the United States during the timeallotted for cross
`
`examination.
`
`APOTEX EX. 1053-008
`
`APOTEX EX. 1053-008
`
`
`
`IPR2016-01284
`U.S. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`Vv.
`
`RIGHT TO SUPPLEMENT
`
`12.
`
`[reserve the right to supplement my opinionsin the future to respond
`
`to any arguments that Patent Ownerraises and to take into account new
`
`information as it becomesavailable to me.
`
`I declare underpenalty of perjury that, to the extent of my knowledge and
`
`belief, the foregoingis true and correct.
`
`I further declare thatall statements made
`
`herein of my own knowledgearetrue and that all statements made on information
`
`and belief are believed to be true; and further that these statements were made with
`
`the understanding that knowing and willful false statements and the like so made
`
`are punishable by fine or imprisonment, or both, under section 1001 oftitle 18 of
`
`the United States Code.
`
`Date:
`
` -+ | 24 { 201 +
`
`fe
`
`Giuseppe Giaccone, M.D., Ph.D
`
`APOTEX EX. 1053-009
`
`APOTEX EX. 1053-009
`
`
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