UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`APOTEX INC., APOTEX CORR, APOTEX PHARMACEUTICALS
`HOLDINGS INC., and APOTEX HOLDINGS, INC.,
`Petitioners,
`V.
`
`081 PHARMACEUTICALS, INC.,
`Patent Owner.
`
`US. 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 CORR, APOTEX PHARMACEUTICALS
`HOLDINGS INC., and APOTEX HOLDINGS, INC.,
`Petitioners,
`V.
`
`081 PHARMACEUTICALS, INC.,
`Patent Owner.
`
`US. 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
`
`I. QUALIFICATIONS ........................................................................................ .. 2
`
`11. MATERIALS REVIEWED ............................................................................. .. 2
`
`III. OBJECTIVE INDICIA OF NONOBVIOUSNESS ........................................ .. 3
`
`A. A Person of Ordinary Skill in the Art Cannot Assess if Patent Owner’s
`
`Alleged Results are Unexpected .......................................................................... .. 3
`
`B. Patent Owner’s Alleged Unexpected Results Do Not Apply to All NSCLC
`
`Patients ................................................................................................................ .. 4
`
`C. The Method of Treatment Described in Claims 44-46 of the ’221 Patent Did
`
`Not Satisfy a Long-Felt Need .............................................................................. .. 5
`
`D. There were Many Successful Attempted Treatments in Mammals with
`
`NSCLC ................................................................................................................ .. 6
`
`IV. AVAILABILITY FOR CROSS EXAMINATION ...................................... .. 7
`
`V. RIGHT TO SUPPLEMENT ............................................................................ .. 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 conclusions I 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 US. Patent No. 6,900,221.
`
`(See “the ’221 patent, col. 14, 11. 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 (“081”) Response (Paper 20) and the materials cited in Appendix A
`
`attached thereto.
`
`I have further reviewed the documents referenced herein.
`
`[Hi
`
`APOTEX EX. 1053-003
`
`APOTEX EX. 1053-003
`
`
`
`US. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`IPR2016-01284
`
`III. OBJECTIVE INDICIA OF NONOBVIOUSNESS
`
`A.
`
`A Person of Ordinary Skill in the Art Cannot Assess if Patent
`Owner’s Alleged Results are Unexpected
`
`5.
`
`OSI and Dr. Bunn contend that 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 1] 109.) However, logic would
`
`dictate that a comparator is necessary to evaluate whether a result is unexpected.
`
`Indeed, in the context of patent claims, I understand that the correct comparator for
`
`evaluating whether a result is “unexpected” is to compare it with what is identified
`
`as being the closest prior art. In this case, the closest prior art is Schnur (US.
`
`Patent No. 5,747,498 (Ex. 1009)), which discloses the compound erlotinib as being
`
`effective to treat a range of conditions that involve inhibition of the EGF receptor,
`
`including lung cancer. (See Ex. 1009 at CO]. 14, ll, 1 — 16.) I understand that no
`
`such comparison was made. (See Paper 20 at 61; Ex. 2021 at 1111 108-109.) Dr.
`
`Bunn subsequently testified that he used chemotherapy as the closest prior art for
`
`his analysis. (Ex. 1048 at 111:9 — 113: 16.) However, Dr. Bunn’s declaration
`
`provides no analysis of why a survival benefit derived from the challenged claims
`
`of the ’221 patent would be unexpected in comparison with chemotherapy. (See
`
`Ex. 2021 at M 108-109.) Neither does Patent Owner’s Response.
`
`(See Paper 20 at
`
`61.) Thus, 081’s and Dr. Bunn’s statements that erlotinib’s therapeutic efficacy
`
`APOTEX EX. 1053-004
`
`APOTEX EX. 1053-004
`
`
`
`US. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., PhD.
`
`IPR2016-01284
`
`and potential survival benefits for NSCLC patients are unexpected is mere
`
`conjecture.
`
`6.
`
`051 refers to a “majority of compounds” failing at some point during
`
`preclinical and clinical development. (See Paper 20 at 61.) However, that is just a
`
`general statement about drug development. If FDA-approval is the benchmark and
`
`a failure to pass through various stages of preclinical and clinical development in
`
`general is the baseline comparator, this would mean that all FDA-approved drugs
`
`provide unexpected results. Moreover, because the compound erlotinib was
`
`already patented, I understand the issue here as being whether the use of erlotinib
`
`to treat NSCLC was unexpected 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 was not unexpected, particularly in view of Schnur, as well as the
`
`statements in 081’s 10-K and Gibbs.
`
`B.
`
`Patent Owner’s Alleged Unexpected Results Do Not Apply to All
`NSCLC Patients
`
`7.
`
`I further disagree with 081’s and Dr. Bunn’s contentions that
`
`erlotinib’s efficacy in treating NSCLC was unexpected because erlotinib plainly
`
`does not provide a survival to all, or even a majority, of NSCLC patients. Instead,
`
`in my experience, and as set forth in more recent articles, only a small subset of
`
`NSCLC patients actually respond to erlotinib. (See Ex. 1053 at 11 10; Ex. 1051 at
`
`APOTEX EX. 1053-005
`
`APOTEX EX. 1053-005
`
`
`
`U.S. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., PhD.
`
`IPR2016-01284
`
`3 — 4.) I believe Dr. Bunn agrees with this assessment that erlotinib treated only a
`
`small subset of NSCLC patients are actually treated with erlotinib. (Ex. 2021 at
`
`11 108; Ex. 1048 at 23:9 - 26:6.) Conversely, I understand that claims 44—46 and S3
`
`of the ’221 patent, as they relate to NSCLC, claim a treatment for all NSCLC
`
`patients. Because erlotinib’s actual efficacy in treating NSCLC is 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.
`
`C.
`
`The Method of Treatment Described in Claims 44-46 of the ’221
`Patent Did Not Satisfy a Long-Felt Need
`
`8.
`
`As I discussed above, erlotinib only treats a small subset of NSCLC
`
`patients who have certain EGFR mutations. Specifically, only NSCLC patients
`
`with an EGFR exon-19 deletion or an exon-21 L858R mutation respond to
`
`erlotinib. (Ex. 1048 at 99:22 — 101:13.) This accounts for about 10% of patients
`
`with NSCLC in the United States. (See Ex. 1051 at 3 — 4; Ex. 1048 at 23:9 — 26:6.)
`
`This leaves a vast number of patients that are still in need of a therapy. Dr. Bunn
`
`states that there was a need to replace cytotoxic chemotherapy. (See Ex. 2021 at
`
`1] 92.) However, for about 90% of patients with NSCLC, erlotinib did not replace
`
`cytotoxic chemotherapy. (See Ex. 1051 at 3
`
`4; Ex. 1048 at 23:9 — 26:6.) Thus,
`
`in my opinion erlotinib did not satisfy the treatment needs of the vast majority of
`
`NSCLC patients.
`
`APOTEX EX. 1053-006
`
`APOTEX EX. 1053-006
`
`
`
`US. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`IPR2016-01284
`
`9.
`
`Dr. Bunn states that “[W]hen Tarceva was first 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 need for a
`
`targeted NSCLC treatment.” (Ex. 2021 at 11 106.) I disagree with this statement
`
`because a FDA label indicating erlotinib as a treatment for all NSCLC does not
`
`change the 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 was still a significant void. Thus, in my
`
`opinion erlotinib cannot have satisfied the need described by 081 and Dr. Bunn
`
`because clearly the vast majority of NSCLC patients were not successfully treated
`
`by erlotinib.
`
`D.
`
`There Were Many Successful Attempted Treatments in Mammals
`with NSCLC
`
`10.
`
`Dr. Bunn states that other attempts to develop targeted, NSCLC drug
`
`products failed clinical trials. (Ex. 2021 at 47, Heading 2.) However, my
`
`understanding of claims 44-46 and 53 of the ’221 patent is that FDA approval is
`
`not required by any these claims.
`
`Instead, I understand that claims 44-46 and S3 of
`
`the ’221 patent are directed more broadly towards methods for the treatment of,
`
`among other conditions, NSCLC in a mammal.
`
`In my extensive experience
`
`APOTEX EX. 1053-007
`
`APOTEX EX. 1053-007
`
`
`
`US. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`IPR2016-01284
`
`conducting pre-clinical and clinical investigations of experimental medicines, FDA
`
`approval is not required to show anti—tumor activity in mammals with NSCLC.
`
`My experience coincides with Dr. Bunn’s testimony that news of 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.) I believe Dr. Bunn calls successful studies against NSCLC in animal
`
`models “promising activity.” (Ex. 2021 at 1137; Ex. 1048 at 38:12 - 39:12.) Thus,
`
`in my opinion if 1,631 new drugs were tested in Phase II clinical trials for NSCLC,
`
`this indicates that 1,631 new drugs successfully showed treatment of NSCLC in
`
`mammals during preclinical development. (Ex. 2021 at {[79; Ex. 1001 at col. 14, 11.
`
`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 appear for
`
`cross examination within the United States during the time allotted for cross
`
`examination.
`
`APOTEX EX. 1053-008
`
`APOTEX EX. 1053-008
`
`
`
`US. Patent No. 6,900,221
`Reply Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`IPR2016-01284
`
`V.
`
`RIGHT TO SUPPLEMENT
`
`12.
`
`I reserve the right to supplement my opinions in the future to respond
`
`to any arguments that Patent Owner raises and to take into account new
`
`information as it becomes available to me.
`
`I declare under penalty of perjury that, to the extent of my knowledge and
`
`belief, the foregoing is true and correct.
`
`I further declare that all statements made
`
`herein of my own knowledge are true 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 of title 18 of
`
`the United States Code.
`
`Date:
`
`3r 1‘? {'r LO! '1"
`
`1..., 11..“
`
`-'
`
`Giuseppe Giaccone, M.D., Ph.D
`
`APOTEX EX. 1053-009
`
`APOTEX EX. 1053-009
`
`
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