APOTEX INC., APOTEX CORP.,
`APOTEX PHARMACEUTICALS HOLDINGS INC.,
`and APOTEX HOLDINGS, INC.,
`Petitioners,
`v.
`OSI PHARMACEUTICALS, INC.,
`Patent Owner.
`
`IPR2016-01284
`
`APOTEX’S DEMONSTRATIVES
`
`FOR ORAL HEARING
`
`United States Patent & Trademark Office
`Before the Patent Trial & Appeal Board
`
`W. Blake Coblentz, Aaron S. Lukas
`
`Cozen O’Connor PC
`Counsel for Petitioners
`
`APOTEX EX. 1066
`
`1
`
`
`APOTEX PHARMACEUTICALS HOLDINGS INC.,
`and APOTEX HOLDINGS, INC.,
`Petitioners,
`v.
`OSI PHARMACEUTICALS, INC.,
`Patent Owner.
`
`IPR2016-01284
`
`APOTEX’S DEMONSTRATIVES
`
`FOR ORAL HEARING
`
`United States Patent & Trademark Office
`Before the Patent Trial & Appeal Board
`
`W. Blake Coblentz, Aaron S. Lukas
`
`Cozen O’Connor PC
`Counsel for Petitioners
`
`APOTEX EX. 1066
`
`1
`
`
`
`OVERVIEW
`
`• Petitioners’ Case that Claims 44-46 and 53
`of the ’221 Patent are Prima Facie Obvious
`
`• Motivation to Combine
`
`• Reasonable Expectation of Success
`
`• Opposition to Patent Owner’s Response
`
`• Secondary Considerations
`
`2
`
`
`
`The Challenged Claims of the ’221 Patent
`
`Erlotinib
`
`Petition at p. 4, Appendix A
`
`3
`
`Ex. 1001, ’221 Patent at Col. 35:26-42
`
`Ex. 1001, ’221 Patent at Col. 35:64-65
`
`
`
`The Prior Art References
`
`Schnur
`
`OSI’s 10-K
`
`Gibbs
`
`’221 Patent
`
`May ’98
`
`Dec ’98
`
`Jan ’00
`
`March ’00
`
`1998
`
`1999
`
`2000
`
`Petition at pp. 9-10, 14, 17, 18
`
`4
`
`
`
`The Level of Skill in the Art
`
`Petition at p. 13; Petitioners’ Reply at pp. 4-5
`
`5
`
`Ex. 1002, Dr. Giaccone Declaration at ¶52
`
`
`
`Schnur Teaches Erlotinib
`to Treat Lung Cancer in a Mammal
`
`Ex. 1009, ’498 Patent at Col. 5:49-52
`
`Ex. 1009, ’498 Patent at Col. 4:8-9
`
`Petition at pp. 14-15, 24-25, Appendix A
`
`6
`
`Ex. 1009, ’498 Patent at Col. 14:6-10
`
`
`
`The ’221 Patent Admits that
`Schnur Teaches Erlotinib
`
`Ex. 1001, ’221 Patent at Col. 8:43-45
`
`Ex. 1001, ’221 Patent at Col. 13:13-15
`
`Petition at p. 15
`
`7
`
`
`
`Schnur Teaches a
`“therapeutically effective amount” of Erlotinib
`
`Ex. 1009, ’498 Patent at Col. 15:55-62
`
`Petition at pp. 16, 25, Appendix A
`
`8
`
`
`
`Schnur Teaches
`Pharmaceutical Compositions and Carriers
`
`Ex. 1009, ’498 Patent at Col. 16:21-22
`
`Ex. 1009, ’498 Patent at Col. 16:41-45
`
`Petition at pp. 14-15, 25-26, Appendix A
`
`9
`
`
`
`Schnur Teaches that
`Erlotinib Functions by EGFR Inhibition
`
`Ex. 1009, ’498 Patent at Col. 14:1-6
`
`Petition at pp. 14, 26, 32, Appendix A
`
`10
`
`
`
`Schnur Teaches Neo-Adjuvant/Adjuvant Monotherapy
`
`Ex. 1009, ’498 Patent at Col. 16:46-51
`
`Petition at pp. 17, 30, Appendix A
`
`11
`
`
`
`The PTO Rejected the Challenged Claims as Anticipated
`by Schnur During Prosecution of the ’221 Patent
`
`Petition at p. 7
`
`12
`
`Ex. 1004, Office Action at 10-11
`
`
`
`The Patent Owner Overcame
`the Anticipation Rejection over Schnur
`
`Ex. 1005, Office Action Amendment at 23
`
`Petition at p. 8
`
`13
`
`
`
`Reasons for Allowance of the ’221 Patent
`
`Ex. 1006, Notice of Allowance at 6
`
`Petition at p. 8
`
`14
`
`
`
`Gibbs Teaches Anticancer Activity
`in Patients with NSCLC
`
`Petition at pp. 18, 27-28, Appendix A; Petitioners’ Reply at p. 16
`
`15
`
`Ex. 1010, Gibbs Paper at 2
`
`
`
`OSI Admits that a POSA
`Would Review Moyer to Understand Gibbs
`
`Patent Owner’s Response at p. 48
`
`16
`
`Paper 20, Patent Owner’s Response at p. 48
`
`
`
`CP-358,774 Is Erlotinib
`
`Ex. 1016, Moyer Paper at 4839
`
`Schnur
`
`Petition at Exhibit List; Petitioners’ Reply at p. 13
`
`17
`
`Ex. 1009, ’498 Patent at Col. 4:8-9
`
`
`
`Dr. Paul Bunn. Jr Testimony:
`CP-358,774 Is the Same Compound Disclosed in Schnur
`
`Q.
`
`I would like you to stay on page 4839 of Moyer under the
`materials and methods that we just reviewed.
`A. Okay.
`
`Q. And so if we look at the Schnur patent, which is Exhibit 1009, I
`want you to go to column 40, lines 1 through 2.
`A. Yes.
`
`Q. And if we look at column 40, lines 1 through 2, this chemical
`name is identical to the chemical name that is listed in Moyer
`identifying CP-358,774, correct?
`A. Yes, sir.
`
`Q. And the chemical structure for the CP-358,774 that is listed in
`Moyer has been the same since the publication of Moyer; is that
`correct? What I mean is the structure hasn’t changed for CP-
`358,774; is that correct?
`A. Not my knowledge.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 92:2-92:20
`
`Petitioners’ Reply at p. 13
`
`18
`
`
`
`Hidalgo Confirms that NSCLC was Treated in Humans
`During a Phase I Clinical Trial
`
`Ex. 1031, J Clin Oncology, Vol 19, 13:3267-3279 at 3267
`
`Petitioners’ Reply at pp. 14-15
`
`19
`
`Ex. 1031, J Clin Oncology, Vol 19, 13:3267-3279 at 3274
`
`
`
`OSI’s 10-K Disclosure: Erlotinib Completes Phase I
`Studies, and Begins Phase II Studies for NSCLC
`
`Ex. 1011, OSI’s Form 10-K at 6
`
`Petition at pp. 19, 28, 32, Appendix A
`
`20
`
`
`
`A POSA Would Have Been
`
`Motivated to Combine
`
`Schnur with Gibbs or OSI’s 10-K
`
`21
`
`
`
`Motivation to Combine
`
`Ex. 1002, Dr. Giaccone Declaration at ¶¶104, 105
`
`Petition at pp. 33-34
`
`22
`
`
`
`Motivation to Combine
`
`Ex. 1002, Dr. Giaccone Declaration at ¶106
`
`Petition at pp. 33-34
`
`23
`
`
`
`Motivation to Combine
`
`Ex. 1002, Dr. Giaccone Declaration at ¶107
`
`Petition at pp. 33-34
`
`24
`
`
`
`Motivation to Combine
`
`Ex. 1002, Dr. Giaccone Declaration at ¶109
`
`Petition at p. 34
`
`25
`
`
`
`Motivation to Combine
`
`Petition at pp. 33-34
`
`26
`
`Ex. 1002, Dr. Giaccone Declaration at ¶110
`
`
`
`Motivation to Combine
`
`Petition at pp. 33-34
`
`27
`
`Ex. 1002, Dr. Giaccone Declaration at ¶118
`
`
`
`Motivation to Combine
`
`Petition at p. 34
`
`28
`
`Ex. 1002, Dr. Giaccone Declaration at ¶129
`
`
`
`A POSA Would Have Had a
`
`Reasonable Expectation
`
`of Success
`
`29
`
`
`
`Reasonable Expectation of Success
`
`Petition at p. 35
`
`30
`
`Ex. 1002, Dr. Giaccone Declaration at ¶67
`
`
`
`Reasonable Expectation of Success
`
`Ex. 1002, Dr. Giaccone Declaration at ¶130
`
`Petition at p. 35
`
`31
`
`
`
`Reasonable Expectation of Success
`
`Q. What are other examples of promising activities in preclinical models?
`
`A. Well, there are many other models, okay? So you may have a mouse tumor
`in a mouse, you may have a human tumor in a mouse, you may have a
`human tumor in an immuno-compromised mouse, or you may have a
`human tumor in an immune-competent mouse. So there are lots of
`preclinical in vivo models. Here I just say “other promising activity.” There
`are many, and I don’t specify here, and it is not part of my opinion.
`
`Q. So other promising activities would be if they passed those specific tests
`that you just were talking about in preclinical models; is that correct?
`
`A. Many drugs would pass those and still fail, correct.
`
`Q.
`
`(BY MR. COBLENTZ) And that would be failures in Phase I, Phase II, or Phase
`III?
`
`A. Correct.
`
`Q. But they would pass the preclinical models?
`
`A. Correct. We’re on the same page.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 38:12-39:12
`
`Petitioners’ Reply at pp. 14-15
`
`32
`
`
`
`Definitions of a POSA
`
`Ex. 1002, Dr. Giaccone Declaration at ¶52
`
`Petitioners’ Reply at pp. 4-5; Patent Owner’s Response at p. 26
`
`33
`
`Ex. 1002, Dr. Giaccone Declaration at ¶22
`
`
`
`OSI’s Definition of a POSA is Overly Broad
`
`Q. Now, you understand that one of the claims of the 221
`patent that is at issue in this proceeding is directed to
`treatment solely of NSCLC; is that correct?
`A. Correct.
`
`Q. And you would agree with me that in your declaration
`you have only opined about the treatment of NSCLC, not
`the other cancers that were present in claim 44; is that
`correct?
`That’s correct.
`
`A.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 15:1-10
`
`Petitioners’ Reply at p.4
`
`34
`
`
`
`OSI’s Definition of a POSA is Overly Broad
`
`Q. But there are thoracic oncologists that specifically treat
`lung cancer --
`A. Correct.
`
`-- is that correct?
`Q.
`A. Correct.
`
`specialize in using
`Q. Thoracic oncologists, do they
`medications in therapies effective for
`treating lung
`cancer?
`Yes, sir.
`
`A.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 16:10-18
`
`Petitioners’ Reply at p.5
`
`35
`
`
`
`The Person of Ordinary Skill in the Art
`
`Petition at p. 13; Petitioners’ Reply at pp. 4-5
`
`36
`
`Ex. 1002, Dr. Giaccone Declaration at ¶52
`
`
`
`The Person of Ordinary Skill in the Art
`
`Case Law
`– Ex Parte Hiyamizu, 10 USPQ2d 1393, 1394
`(Bd. Pat. App. & Inter. 1988)
`• “The statutory ‘person having ordinary skill in the art’
`created by Congress
`to provide a standard of
`patentability is a hypothetical person presumedly
`[p]ossessing knowledge in the field to which the
`claimed ‘subject matter pertains,’ . . . .”
`
`Petitioners’ Reply at p. 5
`
`37
`
`
`
`The PTAB Is Not Bound by
`a District Court’s Definition of a POSA
`
`Case Law
`– Novartis AG v. Noven Pharmaceuticals, Inc., 853 F.3d 1289, 1293
`(Fed. Cir. 2017)
`
`• “Novartis alleges that a fundamental legal error pervades
`the PTAB's Final Written Decisions: the PTAB unlawfully
`reached different conclusions than our court and the U.S.
`District Court for the District of Delaware (“Delaware District
`Court”), which addressed the “same” arguments and the
`“same” evidence and found the Asserted Claims nonobvious
`in two prior opinions. . . . Novartis’s argument fails on
`factual and legal grounds. As an initial matter, the record
`here differed from that in the prior litigation, meaning that
`Novartis’s argument rests on a faulty factual predicate.”
`
`Petitioners’ Reply at pp. 5-6
`
`38
`
`
`
`“therapeutically effective amount”
`
`Q. Yes. Now, on the 221 patent, column 4, lines 31
`through 37, the patent specifically defines
`what a therapeutically effective amount is;
`isn’t that correct?
`
`A. It gives a range, correct.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 52:8-13
`
`Petitioners’ Reply at p. 9
`
`39
`
`
`
`“therapeutically effective amount”
`
`Q. Looking at the Schnur patent, I want you to look at column
`15, lines 55 through 62, and I want you to go down to line
`58. It says here, However, an effective dosage is in the
`range of approximately 0.001-100 milligrams per kilogram,
`preferably 1 to 35 milligrams, slash, kilogram in single or
`divided doses. Do you see that?
`I do.
`
`A.
`
`Q. That’s the same language we saw in the 221 patent for
`effective dosage and therapeutically effective amount; is
`that correct?
`A. They look the same to me.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 54:11-55:2
`
`Petitioners’ Reply at p. 9
`
`40
`
`
`
`The Same “therapeutically effective amount” is
`Disclosed in Schnur and the ’221 Patent
`
`Schnur
`
`’221
`Patent
`
`Petition at p. 25; Petitioners’ Reply at p. 9
`
`41
`
`Ex. 1009, ’498 Patent at Col. 15:55-62
`
`Ex. 1001, ’221 Patent at Col. 4:27-33
`
`
`
`“therapeutically effective treatment”
`Is Not a Limitation of the Challenged Claims
`
`Q.
`
`...But there is no term that is specifically
`“therapeutically effective treatment?”
`“treatment” is in one part of the claim
`and “therapeutically effective amount” is
`in another part of the claim correct?
`
`A. That would be my understanding.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 58:21-59:6
`
`Petitioners’ Reply at p. 7
`
`42
`
`
`
`The Specification of the ’221 Patent Does Not Describe
`a “therapeutically effective treatment”
`
`Q. Correct. But that data, the full Phase II clinical trial
`data, was not present in the 221 patent; isn’t that
`correct?
`A. That’s what I said.
`
`Q. So the data that’s present in the 221 patent, there was
`still a high likelihood of failure of erlotinib being a
`therapeutically effective treatment
`for the NSCLC
`based off the data presented in the 221 patent,
`correct?
`I don’t disagree with your statement.
`
`A.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 67:2-13
`
`Petitioners’ Reply at p. 7
`
`43
`
`
`
`Requiring a “therapeutically effective treatment”
`Is an Incorrect Heightened Standard to Assess Obviousness
`
`Q. (BY MR. COBLENTZ) Is it your opinion, Dr. Bunn,
`that a reasonable expectation of success requires
`a specific disclosure of use and vetted scientific
`data?
`
`A.
`
`In general that would be correct.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 94:2-8
`
`Petitioners’ Reply at p. 7
`
`44
`
`
`
`Reasonable Expectation of Success
`
`Case Law
`– In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988)
`• “Obviousness does not require absolute predictability of success.”
`• “For obviousness under § 103, all that is required is a reasonable
`expectation of success.”
`– Impax Labs., In. v. Aventis Pharma, Inc., 468 F.3d 1366, 1383
`(Fed. Cir. 2006)
`• “proof of efficacy is not required for a prior art reference to be
`enabling”
`– Amgen, Inc. v. Hoeschest Marion Roussel, Inc., 314 F.3d 1313,
`1357 (Fed. Cir. 2003)
`• “however, a reference need not be enabled; it qualifies as a prior
`art, regardless, for whatever is disclosed therein.”
`
`Petitioners’ Reply at p. 8
`
`45
`
`
`
`Paul Bunn Declaration: Motivation to Combine
`
`Ex. 2021, Paul Bunn Declaration at 96
`
`Petitioners’ Reply at p. 10
`
`46
`
`
`
`The Patent Owner Admits a POSA Would Have Been
`Motivated to Combine Schnur and OSI’s 10-K
`
`Paper 20, Patent Owner’s Response at p. 65
`
`Petitioners’ Reply at p. 12; Patent Owner’s Response at p. 65
`
`47
`
`
`
`Motivation to Combine Schnur and OSI’s 10-K
`
`Q. Are you aware of any colleagues who have done so in the
`context of their oncology research?
`I know several people who work in drug companies, and that's
`what they do all the time, to look into competitors’ portfolios.
`
`A.
`
`Ex. 2020, Giuseppe Giaccone, M.D., Ph.D. Depo. Tr. at 75:18-22
`
`Q. Are you aware of any other medical oncologists who reviewed
`this document before May -- March 30th, 2000?
`A. Yes.
`
`Q. Who?
`A. George Blackledge.
`
`Q. And who is that?
`A. AstraZeneca7.
`
`Petitioners’ Reply at p. 10
`
`48
`
`Ex. 2020, Giuseppe Giaccone, M.D., Ph.D. Depo. Tr. at 78:9-16
`
`
`
`Motivation to Combine Schnur and OSI’s 10-K
`
`Q. So you’re inferring that he must have read it, but you don’t
`know that for sure; is that right?
`I don’t know for sure.
`
`A.
`
`Q. Was he employed?
`A. But –
`
`Q. Go ahead.
`A. This is just to tell you that companies do this all the time.
`And George Blackledge is a medical oncologist, just like
`me, but working for a drug company, a competitor.
`
`Ex. 2020, Giuseppe Giaccone, M.D., Ph.D. Depo. Tr. at 79:18-80:5
`
`Petitioners’ Reply at p. 10
`
`49
`
`
`
`OSI’s Expert Admits that a POSA Could Include
`Employees at Competing Pharma Companies
`
`Q.
`
`(BY MR. COBLENTZ) Do you know whether companies that develop
`oncology drugs in general typically have medical oncologists on staff?
`A. Depending on the size, the larger ones likely do.
`
`Q.
`
`A.
`
`Q.
`A.
`
`(BY MR. COBLENTZ) And those medical oncologists would fall within
`your definition of a person of ordinary skill in the art; isn’t that correct?
`So in my definition of POSA I say somebody trained in medical oncology
`with experience -- and we can go back there. So not every medical
`oncologist, but you can go to where I talk about that.
`
`(BY MR. COBLENTZ) That would be paragraph 22 of your report?
`Thank you. Medical oncologists holding an M.D. degree completed
`several years of practice in the field of oncology. So some medical
`oncologists who work for a company would likely meet that definition
`and it’s possible that some would not.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 96:17-97:19
`
`Petitioners’ Reply at p. 10
`
`50
`
`
`
`Motivation to Combine Schnur and OSI’s 10-K
`
`Q. So that is R-A-S, ras pathway. Did you ever research
`competitors’ product development in your role as the
`senior director of cancer research at Merck?
`A. Depending on the project.
`
`Q. So is that a yes?
`A. Depending on the project, competitor information could
`be made available to us.
`
`Q. And that would be something that you would review as a
`part of your job?
`A. As it related to my project.
`
`Ex. 1049, Jackson B. Gibbs, Ph.D. Deposition Tr. at 20:13-21:1
`
`Petitioners’ Reply at p. 10
`
`51
`
`
`
`Motivation to Combine Schnur and OSI’s 10-K
`
`Case Law
`– In re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004)
`
`• “Two separate tests define the scope of analogous prior art:
`(1) whether the art is from the same field of endeavor,
`regardless of the problem addressed and, (2) if the reference is
`not within the field of the inventor’s endeavor, whether the
`reference still
`is reasonably pertinent
`to the particular
`problem with which the inventor is involved.”
`
`Petitioners’ Reply at p. 11
`
`52
`
`
`
`Motivation to Combine Schnur and OSI’s 10-K
`
`Case Law
`– Ball Aerosol v. Ltd. Brands, 555 F.3d 984, 993 (Fed. Cir. 2009)
`– KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 415-421 (2007)
`
`• “As our precedents make clear, however, the analysis need
`not seek out precise teachings directed to the specific subject
`matter of the challenged claim, for a court can take account
`of the inferences and creative steps that a person of ordinary
`skill in the art would employ.”
`
`Petitioners’ Reply at p. 11
`
`53
`
`
`
`The Patent Owner’s Allegations of Hindsight Bias
`Are Misplaced
`
`Paper 20, Patent Owner’s Response at p. 65
`
`Petitioners’ Reply at p. 12; Patent Owner’s Response at p. 65
`
`54
`
`
`
`A POSA Would Have Known that Different Names for Erlotinib in
`the Prior Art Referred to the Same Compound
`
`Patent Owner’s Response at p. 48
`
`55
`
`Paper 20, Patent Owner’s Response at p. 48
`
`
`
`A POSA Would Have Known that Different Names for Erlotinib in
`the Prior Art Referred to the Same Compound
`
`Q.
`
`I would like you to stay on page 4839 of Moyer under the
`materials and methods that we just reviewed.
`A. Okay.
`Q. And so if we look at the Schnur patent, which is Exhibit 1009, I
`want you to go to column 40, lines 1 through 2.
`Yes.
`A.
`Q. And if we look at column 40, lines 1 through 2, this chemical
`name is identical to the chemical name that is listed in Moyer
`identifying CP-358,774, correct?
`Yes, sir.
`A.
`Q. And the chemical structure for the CP-358,774 that is listed in
`Moyer has been the same since the publication of Moyer; is that
`correct? What I mean is the structure hasn't changed for CP-
`358,774; is that correct?
`A. Not my knowledge.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 92:2-92:20
`
`Petitioners’ Reply at p. 13
`
`56
`
`
`
`Different Names for Erlotinib in the Prior Art:
`Gibbs References Moyer
`
`Ex. 1016, Moyer Paper at 4839
`
`Schnur
`
`Petitioners’ Reply at p. 13
`
`57
`
`Ex. 1009, ’498 Patent at Col. 4:8-9
`
`
`
`A POSA Would Have Known that Different Names for Erlotinib in
`the Prior Art Referred to the Same Compound
`
`Butamax Advanced Biofules LLC v. Gevo, Inc.,
`IPR2014-00581, 2014 WL 5299385 at *7 n.4
`
`Butamax Advanced Biofules LLC v. Gevo, Inc.,
`IPR2014-00581, 2014 WL 5299385 at *5
`
`Petitioners’ Reply at pp. 13-14
`
`58
`
`
`
`A Consistent Name for a Erlotinib in the Prior Art is Not
`Required for Obviousness Here
`
`Case Law
`– Randall Mfg. v. Rea, 733 F.3d 1355, 1362-63
`(Fed. Cir. 2013)
`• This “expansive and flexible approach,” is
`consistent with our own pre-KSR decisions
`acknowledging that the inquiry “not only
`permits, but requires, consideration of
`common knowledge and common sense.”
`
`Petitioners’ Reply at p. 14
`
`59
`
`
`
`Pre-Clinical Studies
`
`Q. What are other examples of promising activities in preclinical models?
`
`A. Well, there are many other models, okay? So you may have a mouse
`tumor in a mouse, you may have a human tumor in a mouse, you may
`have a human tumor in an immuno-compromised mouse, or you may
`have a human tumor in an immune-competent mouse. So there are lots
`of preclinical in vivo models. Here I just say “other promising activity.”
`There are many, and I don’t specify here, and it is not part of my opinion.
`
`Q. So other promising activities would be if they passed those specific tests
`that you just were talking about in preclinical models; is that correct?
`
`A. Many drugs would pass those and still fail, correct.
`
`Q.
`
`(BY MR. COBLENTZ) And that would be failures in Phase I, Phase II, or
`Phase III?
`
`A. Correct.
`
`Q. But they would pass the preclinical models?
`
`A. Correct. We’re on the same page.
`
`Ex. 1048 , Dr. Bunn Deposition Transcript at 38:12-39:12
`
`Petitioners’ Reply at p. 14
`
`60
`
`
`
`Phase I Studies
`
`Q. Now, once you’ve completed a study of a certain drug on a
`human tumor in a mouse, is that when -- and let’s say you
`were successful in that study, is that when you would file
`an investigational new drug application with the FDA?
`
`A. Right. To get an IND you have to have toxicology, and so
`you have to know what the lethal dose in an animal was.
`You would have to have a lot of pharmacokinetic
`information about the drug. You would have to know a lot
`about drug interactions with other known enzymes
`involved in drug metabolism. So, yeah, there are a number
`of things in addition to what you mentioned that are
`required for an IND.
`
`Ex. 1048 , Dr. Bunn Deposition Transcript at 30:4-19
`
`Petitioners’ Reply at p. 14
`
`61
`
`
`
`Indications Examined in Phase I Studies
`
`Q.
`
`Isn’t it correct you have to list your targeted therapeutic
`indications in the investigator’s brochure?
`
`A. Many drugs would not be called “targeted.” So generally
`you would list the indications that you are going to study
`and the clinical trial that has to accompany, would specify
`what patients are being included, if that's what you mean.
`
`Ex. 1048 , Dr. Bunn Deposition Transcript at 32:18-33:5
`
`Petitioners’ Reply at p. 14
`
`62
`
`
`
`Patients with NSCLC Were Administered
`Erlotinib in Phase I Studies
`
`A.
`
`Q. And you did not find any evidence in those abstracts of CP-
`358,774 being administered to non-small cell
`lung cancer
`patients specifically, correct?
`THE WITNESS: So as we were discussing before, in the ASCO
`proceedings, there were two abstracts on Phase I studies of
`erlotinib. Although they did not specify non-small cell lung
`cancer there, these are Phase I studies, and most likely, they
`included non-small cell lung cancer patients.
`BY MS. WIGMORE:
`Q. And that was the inference you made, correct?
`A.
`It’s not only an inference, it’s reality.
`
`Ex. 2020, Giuseppe Giaccone, M.D., Ph.D. Depo. Tr. at 112:8-17
`
`Petitioners’ Reply at p. 15
`
`63
`
`
`
`Patients with NSCLC Were Administered
`Erlotinib in Phase I Studies
`
`Q. (BY MR. COBLENTZ) So when the patient started
`the trial, they would know what cancer type they
`had; is that correct?
`A. Yes, that’s correct.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 86:20-87:1
`
`Petitioners’ Reply at p. 15
`
`64
`
`
`
`Patients with NSCLC Were Administered
`Erlotinib in Phase I Studies
`
`Q. (BY MR. COBLENTZ) So let me back up there.
`Among the patient population in this Phase I
`trial with erlotinib were patients with NSCLC; is
`that correct?
`A. Four to be exact.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 69:19-70:1
`
`Petitioners’ Reply at p. 15
`
`65
`
`
`
`Hidalgo Confirms that Patients with NSCLC Were
`Administered Erlotinib in Phase I Studies
`
`Q. Is this the Hidalgo paper that you reference in Exhibit 2036
`as reference 64?
`A. Yes, sir.
`
`Q. So this is the paper that you reference in order to describe
`the data from the Phase I trial of erlotinib that we just
`discussed a few minutes ago; is that correct?
`A. That would be correct.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 72:19-73:4
`
`Petitioners’ Reply at pp. 14-15
`
`66
`
`
`
`Hidalgo Confirms that Patients with NSCLC Were
`Administered Erlotinib in Phase I Studies
`
`I would like to go to page 3271 of Exhibit 1031.
`Q.
`A. Yes, sir.
`
`Q. And if we look at Table 1, we see that the number of patients that were
`included in the study was 40. Do you see that?
`A. Yes, sir.
`
`Q. And if we go down further in Table 1 we see tumor type. Do you see that?
`A. Yes, sir.
`
`Q. And this says the tumor type of the patients that were treated with erlotinib
`in this Phase I study, correct?
`A. Correct.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 73:11-74:2
`
`Q. We have four patients with non-small cell lung cancer that were treated; is
`that correct?
`
`A. That’s correct.
`
`Petitioners’ Reply at pp. 14-15
`
`67
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 74:12-14
`
`
`
`Hidalgo Confirms that Patients with NSCLC Were
`Administered Erlotinib in Phase I Studies
`
`Q. Now, I would like to go to page 3274 of the Hidalgo reference, which
`is Exhibit 1031. If we look on page 3274 at the header Antitumor
`Activity, do you see where I'm at?
`I do.
`
`A.
`
`Q. And if we look at the last sentence here of the left-hand column that
`starts, In addition, two patients... Do you see where I’m at?
`A. Yes, sir.
`
`Q.
`
`A.
`
`It says, In addition, two patients with colorectal carcinoma and one
`patient each with non-small cell lung, prostate, cervical, and head
`and neck carcinomas, all of whom had progressive tumor growth
`documented immediately before treatment, experienced stable
`disease for at least five months. This included one patient with head
`and neck carcinoma who had stable disease for 15 months. Do you
`see that?
`I do.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 75:7-76:4
`
`Petitioners’ Reply at pp. 14-15
`
`68
`
`
`
`Gibbs Refers to Same Phase I Clinical Data as
`Hidalgo
`
`Q. Now I would like to go to page 3267 of the Hidalgo reference,
`which is Exhibit 1031. And if we see in the right-hand column, in
`the italicized text about three-quarters of the way down we see
`language that says, Presented in part. Do you see where I'm at?
`I do.
`It says, Presented in part at the 35th annual meeting of the
`American Society of Clinical Oncology in Atlanta, Georgia, May 15
`through 19, 1999. Do you see that?
`I do.
`
`A.
`Q.
`
`A.
`
`Ex. 1048. Dr. Bunn Deposition Transcript at 76:5-76:16
`
`Q. (BY MR. COBLENTZ) And these are the ASCO abstracts that were
`referenced in the Gibbs reference; is that correct?
`A. Correct.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 83:19-22
`
`Petitioners’ Reply at pp. 14-15
`
`69
`
`
`
`Gibbs Refers to Same Phase I Clinical Data as Hidalgo
`
`Ex. 1010, Gibbs Paper at 1
`
`Patent Owner Response at p. 22
`
`70
`
`
`
`Hidalgo and ASCO
`Refer to the Same Phase I Data
`
`Q. Now I would like to go to page 3267 of the Hidalgo reference, which
`is Exhibit 1031. And if we see in the right-hand column, in the
`italicized text about three-quarters of the way down we see
`language that says, Presented in part. Do you see where I’m at?
`I do.
`
`A.
`
`Q.
`
`A.
`
`It says, Presented in part at the 35th annual meeting of the
`American Society of Clinical Oncology in Atlanta, Georgia, May 15
`through 19, 1999. Do you see that?
`I do.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 76:5-11
`
`Petitioners’ Reply at p. 15
`
`71
`
`
`
`Phase I Study Information Was Known
`as of May 15, 1999
`
`Ex. 1031, J Clin Oncology, Vol 19, 13:3267-3279 at 3267
`3267
`
`Petitioners’ Reply at p. 15
`
`72
`
`Ex. 1031, J Clin Oncology, Vol 19, 13:3267-3279 at 3267
`3274
`
`
`
`Hidalgo and ASCO
`Refer to the Same Phase I Data
`
`Petitioners’ Reply at p. 15
`
`73
`
`Ex. 2024 at 2
`
`
`
`Hidalgo, ASCO, and Gibbs
`Refer to the Same Phase I Data
`
`Q. (BY MR. COBLENTZ) And these are the ASCO abstracts that
`were referenced in the Gibbs reference; is that correct?
`A. Correct.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 83:19-22
`
`Petitioners’ Reply at p. 15
`
`74
`
`
`
`Dr. Gibbs’ Admissions
`
`Q. And so when you’re talking about the tyrosine kinase
`inhibitors here, you’re only referencing two specific
`compounds, which is the ZD-1839 compound and the
`CP-358,774 compound, correct?
`I was referring to two compounds that had moved from
`preclinical to clinical.
`
`A.
`
`Q.
`
`A.
`
`But you would agree with me that you’re only
`mentioning two compounds here, correct?
`In this paragraph, yes.
`
`Ex. 1049, Jackson B. Gibbs, Ph.D. Deposition Tr. at 24:15-25:4
`
`Petitioners’ Reply at p. 16
`
`75
`
`
`
`Gibbs Teaches that Erlotinib Has Anticancer
`Activity in Patients with NSCLC
`
`Petitioners’ Reply at p. 16
`
`76
`
`Ex. 1010, Gibbs Paper at 2
`
`
`
`Dr. Gibbs’ Admissions
`
`Q. Okay, but you chose to particularly point out in
`this particular sentence only non-small-cell
`lung cancer. Isn’t that correct?
`
`A. Yes.
`
`Ex. 1049, Jackson B. Gibbs, Ph.D. Deposition Tr. at 28:19-29:1
`
`Petitioners’ Reply at p. 16
`
`77
`
`
`
`Dr. Gibbs’ Admissions
`
`Q. Dr. Gibbs, let’s go back to Exhibit 1010. So you never attempted to
`offer any sort of correction for this publication. Isn’t that correct?
`A. That is correct.
`Q. And you state in your declaration that you have written over 128
`articles. Isn’t that correct?
`A. That is correct.
`Q. And so you have -- you would agree with me that you have
`experience in writing articles such as this Gibbs reference. Isn’t that
`correct?
`A. That is correct.
`Q. And of the 128 articles, have you ever asked that an article be
`retracted?
`I have not.
`A.
`Q. And according to your C.V., one of your areas of expertise is that you
`have extensive journal editorial experience. Isn’t that correct?
`A. Yes.
`
`Ex. 1049, Jackson B. Gibbs, Ph.D. Deposition Tr. at 29:18-30:16
`
`Petitioners’ Reply at p. 16
`
`78
`
`
`
`A POSA’s Interpretation of Gibbs
`
`Q. Would a person of ordinary skill in the art, reading the Gibbs reference
`as of March of 2000, have looked at these abstracts that he refers to in
`the first paragraph to understand the context of the statements he
`makes in this article?
`
`A. The statement that he makes in the second page is a pretty strong and
`precise statement saying, there is activity in non-small cell lung cancer
`patients. So that’s based not only on the abstracts of the proceedings,
`but is based on the information he had at that time. Being this a peer-
`reviewed journal of high impact, and being him a reputable
`pharmacologist,
`I would trust that he was saying something very
`important here.
`
`Ex. 2020, Giuseppe Giaccone, M.D., Ph.D. Depo. Tr. at 115:12-20
`
`Petitioners’ Reply at p. 16
`
`79
`
`
`
`
`
`80
`
`Unexpected Results
`Unexpected Results
`
`( COZEN
`) O’CONNOR
`
`
`
`Unexpected Results:
`No Comparison to the Closest Prior Art
`
`Ex. 1053, Reply Declaration of Guiseppe Giaconne, M.D., PH.D. at ¶5
`
`Petitioners’ Reply at p. 17
`
`81
`
`
`
`Unexpected Results:
`No Comparison to the Closest Prior Art
`
`Q. And in this unexpected result section in paragraph
`108, do you mention a comparison of erlotinib to
`chemotherapy?
`
`A. Let me go back to 108. Well, 108 doesn’t mention
`chemotherapy.
`It mentions that
`the astounding
`results
`in people with EGFR mutations was
`unexpected.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 113:9-16
`
`Petitioners’ Reply at p. 17
`
`82
`
`
`
`Unexpected Results:
`Schnur is Closest Prior Art
`
`Q.
`
`(BY MR. COBLENTZ) Now, you would agree with me
`that erlotinib, the erlotinib compound itself, was
`patented in the Schnur patent; is that correct?
`It was one of many compounds in there, correct.
`A.
`Q. But it was patented in the Schnur patent; is that
`correct?
`A. Correct.
`Q. And the Schnur patent was and is prior art to the
`221 patent; is that correct?
`A. That’s a legal term. I would assume that would be
`correct, but I -- the legal definition of “prior art”
`would be beyond me.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 114:17-115:7
`
`Petitioners’ Reply at p. 15
`
`83
`
`
`
`Unexpected Results:
`Schnur is Closest Prior Art
`
`Q.
`
`A.
`
`(BY MR. COBLENTZ) You would agree with me it was
`known as of the filing date of the 221 patent that
`erlotinib was a tyrosine kinase inhibitor; is that correct?
`That was known, yes.
`
`Q. And it was known that -- or it was theorized that certain
`types of cancer overexpressed EGFR; is that correct?
`That’s correct, there was a theory.
`
`A.
`
`Q. And it was also theorized at that particular time that the
`mechanism of action of these TKIs like erlotinib was to
`operate on the tyrosine kinase of the EGFR receptor; is
`that correct?
`That was a theory at the time, correct.
`
`A.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 113:17-114:9
`
`Petitioners’ Reply at p. 18
`
`84
`
`
`
`Unexpected Results: Legal Standard
`
`Case Law
`– In re Merchant, 575 F.2d 865, 869 (CCPA 1978)
`• “An applicant relying upon a comparative
`showing to rebut a prima facie case must
`compare his claimed invention with the
`closest prior art.”
`
`Petitioners’ Reply at p. 17
`
`85
`
`
`
`Unexpected Results:
`Not Commensurate in Scope with the Claims
`
`Q. What percentage of NSCLC patients have these
`abnormalities?
`A. Again, would you give me the stage and the country of
`origin of the patient?
`
`(BY MR. COBLENTZ) So stage IV in the U.S.
`Q.
`A. 15 percent.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 23:19-24:4
`
`Q. And do you know what percentage in the U.S. of patients,
`approximately, would be treated by Tarceva?
`I do not. I could make a guess, if you wish.
`
`A.
`
`Q. Sure.
`A. 80 percent.
`
`Petitioners’ Reply at p. 19
`
`86
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 25:16-26:6
`
`
`
`Unexpected Results:
`Not Commensurate in Scope with the Claims
`
`A.
`
`Q. And the claims that are at issue in this proceeding are
`directed to all NSCLC patients, correct?
`It just says non-small cell lung cancer. It could be a subset
`of them.
`It could be, one, histology.
`It didn’t specify
`whether there was a subset or not in the beginning.
`
`Q.
`
`A.
`
`Q.
`
`A.
`
`(BY MR. COBLENTZ) And in the 221 patent claims that are
`at issue in this case?
`It doesn’t specify which non-small cell
`patients.
`
`lung cancer
`
`It doesn't specify that it’s a subset. It just says NSCLC
`patients, correct?
`That’s what the patent says, right.
`
`Ex. 1048, Dr. Bunn Deposition Transcript at 115:14-116:7
`
`Petitioners’ Reply at pp. 18-19
`
`87
`
`
`
`Unexpected Results:
`Not Commensurate in Scope with the Claims
`
`Ex. 1046 at 2
`
`Petitioners’ Reply at p. 19
`
`88
`
`
`
`Unexpected Results:
`Not Commensurate in Scope with the Claims
`
`Petitioners’ Reply at p. 19
`
`89
`
`Ex. 1051, J Clin Oncol 23:3235-3242 at 3238
`
`
`
`Unexpected Results:
`Not Commensurate in Scope with the Claims
`
`Petitioners’ Reply at p. 19
`
`90
`
`Ex. 1053, Reply Declaration of Guiseppe Giaconne, M.D., PH.D. at ¶7
`
`
`
`Unexpected Results:
`Not Commensurate in Scope with the Claims
`
`Q. And do you know what percentage in the U.S. of
`patients, approximately, would be treated by
`Tarceva?
`
`A. 80 percent.
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