`
`In the Inter Partes Review of:
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`Trial Number: IPR2017-01139
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`U.S. Patent No. 6,627,196
`
`Filed:
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`August 25, 2000
`
`Issued:
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`September 30, 2003
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`Inventor(s): Sharon Baughman, Steven Shak
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`Assignee: Genentech, Inc.
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`Title:
`
`Dosages for Treatment with Anti-
`ErbB2 Antibodies
`
`__________________________________________________________________
`Mail Stop Inter Partes Review
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`DECLARATION OF KAREN GELMON, M.D.
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`(cid:38)(cid:72)(cid:79)(cid:79)(cid:87)(cid:85)(cid:76)(cid:82)(cid:81)(cid:3)(cid:89)(cid:17)(cid:3)(cid:42)(cid:72)(cid:81)(cid:72)(cid:81)(cid:87)(cid:72)(cid:70)(cid:75)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:26)(cid:16)(cid:19)(cid:20)(cid:20)(cid:22)(cid:28)(cid:3)
`(cid:42)(cid:72)(cid:81)(cid:72)(cid:87)(cid:72)(cid:70)(cid:75)(cid:3)(cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87)(cid:3)(cid:21)(cid:19)(cid:21)(cid:27)
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`TABLE OF CONTENTS
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`I.
`II.
`III.
`IV.
`V.
`
`Introduction .................................................................................................. 1
`Qualifications................................................................................................ 1
`Summary of Opinions ................................................................................... 2
`Person of Ordinary Skill in the Art................................................................ 5
`Background and State of the Art ................................................................... 6
`A.
`Treatment Before Trastuzumab ........................................................... 6
`B.
`Trastuzumab Clinical Development .................................................. 10
`C.
`Success of Trastuzumab .................................................................... 14
`D.
`Trastuzumab was a breakthrough in the treatment of HER2-
`positive breast cancer, but a great deal of efficacy-focused
`research remained before oncologists could fully realize and
`utilize the drug’s potential. ................................................................ 14
`VI. Dr. Ratain’s Opinions Contradict Key Teachings in the Prior Art as Well as
`the Motivations and Reasonable Expectations of Success of Persons Skilled
`in the Art in August 1999. ........................................................................... 26
`A.
`A clinical oncologist’s primary motivating factors are efficacy
`and safety; convenience is a lesser priority. ...................................... 26
`A clinical oncologist would not reasonably expect the claimed
`dosing regimen to be effective without sufficient evidence and
`assurances from a pharmacokineticist that the regimen would
`achieve therapeutic trough serum levels, and the prior art did
`not provide adequate information to support such assurances. .......... 38
`
`B.
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`I.
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`1.
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`Introduction
`
`I have been asked to review and respond to the opinions set forth in the
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`March 22, 2017 Declaration of Mark J. Ratain, M.D.
`
`II. Qualifications
`
`2.
`
`I am a Professor of Medicine at the University of British Columbia and a
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`medical oncologist at the BC Cancer Agency. In my current roles, I serve as both
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`a researcher and investigator for clinical trials primarily in breast cancer and as a
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`practicing clinical oncologist. I see over 200 new patients with breast cancer per
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`year and treat approximately 70 breast cancer patients per week.
`
`3.
`
`I obtained my M.D. from the University of Saskatchewan in 1979. I then
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`completed my internal medicine residency at the University of British Columbia
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`and became a Fellow of the Royal College of Physicians and Surgeons of Canada
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`in Internal Medicine in 1984. I also completed my American Internal Medicine
`
`Boards. I trained in Medical Oncology and obtained my Fellowship in Medical
`
`Oncology from the Royal College of Physicians and Surgeons of Canada in 1986.
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`From that time forward, I have held faculty positions at the University of British
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`Columbia. I did further training in clinical trials in the UK with the Medical
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`Research Council.
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`4.
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`I have over thirty years of experience in breast oncology and have been
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`involved in more than 150 clinical trials. I have served as the Clinical Head of the
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`Investigational Drug Program at the BC Cancer Agency since 1990. I am a past
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`Co-Chair of the NCIC Clinical Trials Group Breast Site Committee and serve on
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`the Breast International Group (BIG) Executive Board. In addition, I am a Komen
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`Scholar and serve on the Scientific Advisory Board (SAB) of the Susan G. Komen
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`Foundation.
`
`5.
`
`I am a co-author on more than 200 peer-reviewed articles and more than 200
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`abstracts in the field of breast oncology. I have co-authored at least 50
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`publications that studied trastuzumab. In addition to acting as a reviewer for grants
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`and journals, I hold positions on the International Advisory Boards of The Lancet
`
`and The Oncologist, and have been on the editorial board of Lancet Oncology and
`
`Clinical Breast Cancer. A copy of my curriculum vitae is attached as Appendix A.
`
`III.
`
`Summary of Opinions
`
`6.
`
`It is my opinion that a person of ordinary skill in the art (“POSA”) in August
`
`1999 would not have been motivated to administer trastuzumab on a three-week
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`schedule as claimed in U.S. Patent Nos. 6,627,196 (“the ’196 patent”) and
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`7,371,379 (“the ’379 patent”). Oncologists finally had a drug that was effective in
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`patients with a devastating type of breast cancer. Not only was trastuzumab
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`effective, it was also exceedingly well-tolerated, and patient compliance was high.
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`As a monoclonal antibody therapy, the first ever approved for a solid tumor and
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`one of the first approved to treat cancer generally, trastuzumab was a very different
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`type of drug from the chemotherapeutic agents that oncologists regularly
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`prescribed.
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`7.
`
`Oncologists in August 1999 were not seeking to change trastuzumab’s
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`dosing regimen. Petitioner asserts that convenience and ease of scheduling with
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`paclitaxel, a chemotherapeutic agent dosed every three weeks, would have
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`motivated such a change. However, without a compliance problem, convenience
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`standing alone rarely motivates an oncologist to risk making a life-saving treatment
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`less effective by altering its dosing schedule. Further, the fact that trastuzumab and
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`paclitaxel were given in combination would not have prompted a clinical
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`oncologist to experiment with trastuzumab’s dosing schedule to “match” it to
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`paclitaxel’s. Instead, if an oncologist in 1999 cared to synchronize the schedules,
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`he/she would likely have experimented with the dosing of paclitaxel, a familiar
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`chemotherapeutic agent, instead of the dosing of the novel monoclonal antibody
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`therapy. In 1999, oncologists were studying whether more frequent dosing of
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`some chemotherapy agents (including paclitaxel) would be more effective, and in
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`cancer treatment, efficacy reigns supreme.
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`8.
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`It is also my opinion that a skilled artisan would not have had confidence
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`that administering trastuzumab on a three-week dosing interval would have been as
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`clinically effective as the weekly dosing based on the pharmacokinetic data
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`presented Watanabe (Ex. 1006), the Slamon Abstract (Ex. 1005), the 1998
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`Herceptin Label (Ex. 1008), Baselga ’96 (Ex. 1007), and Pegram ’98 (Ex. 1009). I
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`know from my experience working with pharmacokineticists on clinical trials that
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`they make mathematical models or rely on other mathematical equations to
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`describe drug levels in a patient’s serum, and can make predictions for drug levels
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`in a patient’s serum for an alternative dosing regimen. I also know that if a drug
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`shows certain pharmacokinetic characteristics such as non-linearity, the
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`pharmacokineticist cannot simply ignore the characteristic; otherwise, the
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`pharmacokineticist’s predictions may not accurately predict the levels of drug in
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`the patient’s body over time. The prior art provided only sparse pharmacokinetic
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`data, and particularly for a drug with documented non-linear kinetics—a
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`characteristic that Petitioner’s expert glosses over—it was not possible to
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`accurately predict whether an alternative dosing regimen would maintain high
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`enough levels of the drug in the patient’s serum to be effective. Further,
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`Petitioner’s expert relied on an admittedly inaccurate calculation to predict trough
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`serum levels that barely slide above the minimum therapeutic target. At least
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`because of the unfamiliarity that comes with a new class of drug, and because
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`trastuzumab was already a very effective treatment for an aggressive disease, a
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`clinical oncologist would not have taken chances by using the new regimen on a
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`patient with a life-threatening illness.
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`IV. Person of Ordinary Skill in the Art
`
`9.
`
`I understand that the Petitioner and Dr. Ratain defined a person of skill in the
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`art as having either an M.D. with subspecialty training in oncology and/or a Ph.D.
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`with substantial experience in oncology drug development. I also understand that
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`the Petitioner and Dr. Ratain state that a skilled artisan would have had familiarity
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`with the treatment of breast cancer and substantial experience in the design and/or
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`implementation of oncology clinical trials, as well as expertise in clinical
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`pharmacology, including pharmacokinetics. (Paper 1 at 14; Ex. 1003, Ratain Decl.
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`¶ 44.) The skilled artisan would have had access to and worked on a team with a
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`number of other individuals involved in drug development with expertise in
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`clinical pharmacology, including pharmacokinetics.
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`10. For the purpose of this declaration, I have applied this definition of a person
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`of skill in the art, and my opinions are offered from the perspective of a skilled
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`artisan as that hypothetical person would have understood matters on August 27,
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`1999, which I understand is the relevant date for the analysis.
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`11.
`
`In 1999, I specialized in treating breast cancer patients and had designed
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`and/or served as a principal investigator in numerous oncology clinical trials. Also
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`at the time of invention, I had published around 20 papers specifically on breast
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`cancer treatment, including publications in the New England Journal of Medicine
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`and in the Journal of Clinical Oncology. Further, I had knowledge of
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`pharmacokinetics because of my involvement in Phase I clinical trials. I typically
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`consulted with a pharmacokineticist for these trials, and I have done so here by
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`consulting with Dr. George Grass.
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`V. Background and State of the Art
`
`A. Treatment Before Trastuzumab
`
`12. By the mid-20th century, doctors had observed that some breast cancers
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`were clearly more aggressive than others, meaning that the cancers grew and
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`spread more rapidly. The reason behind this difference in behavior was unknown.
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`In the late 1980s, researchers identified a potential explanation for some breast
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`cancers; the gene encoding the HER2 protein was amplified in a fraction of breast
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`cancers, and the amplification was a predictor of poor overall survival and time to
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`relapse. (Ex. 2031, Dennis J. Slamon, Human Breast Cancer: Correlation of
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`Relapse and Survival with Amplification of the HER-2/neu Oncogene, 235 SCIENCE
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`177 (1987) at 177; Ex. 2032, Dennis J. Slamon, Studies of the HER-2/neu Proto-
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`oncogene in Human Breast and Ovarian Cancer, 244 SCIENCE 707 (1989) at 707.)
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`During this period numerous other markers of prognosis were also described but
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`HER2 amplification or overexpression was more robust than many others, which
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`are now long forgotten. By the mid-1990s, it was increasingly recognized in the
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`field that HER2-positive status was one predictor of aggressive cancer and poor
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`prognosis, with a high rate of tumor recurrence and spreading to other areas of the
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`body. (Ex. 2029, Michael S. Kopreski et al., Growth Inhibition of Breast Cancer
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`Cell Lines by Combinations of Anti-P185HER2 Monoclonal Antibody and Cytokines,
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`16 ANTICANCER RES. 433 (1996) at 433; Ex. 2030, Steven Lehrer et al., Tumour
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`HER2 Protein in Breast Cancer and Family History, 341 THE LANCET 1420 (1993)
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`at 1420; Ex. 2031 at 179-180.) HER2-positive patients had “a shorter time to
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`relapse as well as a shorter overall survival” even after surgery, chemotherapy,
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`and/or radiation. (Ex. 2032 at 707; Ex. 2031 at 179-180.) Existing treatments
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`were not effective, so the harsh reality for HER2-positive patients in 1996 was a
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`life expectancy of “only 18 months post-diagnosis.” (Ex. 2033, David Holzman,
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`Gene Therapy for HER-2-Related Cancer, MOLECULAR MED. TODAY, April 1996
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`at 138; see also Ex. 2034, Russ Hoyle, Genentech Is Poised for an Anti-cancer
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`Breakthrough, 16 NATURE BIOTECHNOLOGY 887 (1998) at 887 (“[B]reast cancer
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`patients who overproduce HER2 can now expect to live some 10 to 12 months
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`after metastasis begins, a horribly rapid progression compared to six or seven years
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`for HER2-normal patients.”).)
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`13. Many women were affected by the lack of an effective treatment for HER2-
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`positive breast cancer. In 1998, approximately 180,000 new cases of breast cancer
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`were being diagnosed every year in the United States, and of those 180,000
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`diagnosed women, 25-30% had the HER2-positive subtype. (See Ex. 2043 at 1, 5;
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`see also Ex. 1007 at 3.)
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`14. Researchers looked for ways to target the source of this deadly disease.
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`Because HER2 protein is overexpressed on the cell surface, scientists investigated
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`whether HER2 could serve as a target for a large macromolecule, such as a
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`monoclonal antibody, that might interfere with the ability of HER2 protein to bind
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`to receptors and initiate the cascade of cell signaling associated with aggressive
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`breast cancer. (Ex. 2044, Robert M. Hudziak et al., p185HER2 Monoclonal
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`Antibody Has Antiproliferative Effects In Vitro and Sensitizes Human Breast
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`Tumor Cells to Tumor Necrosis Factor, 9 MOLECULAR & CELLULAR BIOLOGY
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`1165 (1989) at 1165.) The idea of using antibodies as targeted cancer therapies
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`had been floated for decades. (Ex. 2045, Richard P. Junghans et al., Antibody-
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`Based Immunotherapies for Cancer, in CANCER CHEMOTHERAPY & BIOTHERAPY:
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`PRINCIPLES AND PRACTICE (1996) at 655.) Although antibodies targeting a specific
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`antigen could be obtained from mice and other animals, the human immune system
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`would identify these nonhuman antibodies as foreign antigens and attack them.
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`(Id. at 683.) The resulting “antigenic” or “immunogenic” response inactivated the
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`antibodies and resulted in rapid clearance from the body, curtailing therapeutic
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`usefulness. (Id. at 683.) By the early 1990s, numerous antibodies had been tested
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`in patients with different cancers, including breast cancer, but they showed “no
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`hint of a consistent therapeutic efficacy.” (Ex. 2002, Gert Riethmüller & Judith P.
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`Johnson, Monoclonal Antibodies in the Detection and Therapy of Micrometastatic
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`Epithelial Cancers, 4 CURRENT OPINION IN IMMUNOLOGY 647 (1992) at 649; id.,
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`Table 2 (identifying failed antibody clinical trials for gastrointestinal tumors;
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`breast, colon, ovarian, and lung cancer; pancreatic adenocarcinoma;
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`neuroblastoma; and melanoma).)
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`15. Genentech collaborated with researchers at a variety of academic and
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`research institutions including the University of California, Los Angeles and the
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`Memorial Sloan-Kettering Cancer Center to find a solution to the daunting
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`problem. First, researchers at Genentech developed a mouse monoclonal antibody
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`that targeted the HER2 protein. (Ex. 2044 at 1165.) The next and crucial step was
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`the development of a humanized version of this monoclonal antibody, which
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`would be made up of mostly human components and very few mouse components
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`to reduce immunogenic responses in patients. (Ex. 2048, Paul Carter et al.,
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`Humanization of an Anti-p185HER2 Antibody for Human Cancer Therapy, 89 PROC.
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`NAT’L ACAD. SCI. (1992).) That humanized antibody came to be known as
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`Herceptin® (trastuzumab).
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`B.
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`Trastuzumab Clinical Development
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`Phase I
`1.
`16. When the first trastuzumab clinical trials began in 1992, antibody therapies
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`were not in favor in the oncology field. Despite theoretical promise in the lab,
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`clinical researchers had experienced many failures when other antibody therapies
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`were tested on patients. Harmful immunogenic responses were often observed in
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`the clinic. In addition, the complexity of cell signaling pathways in the body as
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`well as the difficulty of safely delivering effective doses of these large
`
`macromolecules posed a slew of new challenges for researchers in the field.
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`17.
`
`In light of these challenges, Phase I pharmacokinetic trials of trastuzumab
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`were initially conducted with a small number of patients and Genentech’s studies
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`were not published, which is surprising considering the subsequent success of the
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`drug. Limited information from these studies was eventually included in the 1998
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`Herceptin Label (Ex. 1008) and described in a cursory fashion in a small handful
`
`of publications. (See, e.g., Ex. 1013 at 4; Ex. 1007 at 3-4.) Results from a
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`Japanese Phase I dose escalation study of only 18 patients were published in an
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`abstract (Watanabe) years after the Genentech Phase I studies were completed, but
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`no detailed pharmacokinetic information was included. (See Ex. 1006 at 5.)
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`Phase II
`2.
`18. Two Phase II studies of trastuzumab were conducted. (See Ex. 1007, Ex.
`
`1009.) The results from these trials showed preliminary suggestions of
`
`trastuzumab’s activity, but needed to be validated in larger trials. Clinicians do not
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`trust results from small trials because they may not predict whether and how the
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`drug will work in the broader patient population. Small trials also do not have the
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`statistical power to demonstrate any benefit of the new therapy over existing
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`therapy. Further, many small studies are single center studies which is also a
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`concern for clinicians as there are concerns about bias, patient selection, and the
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`potential validation of the results. Clinical skepticism was especially high during
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`the clinical development of trastuzumab because of the failure of prior antibody
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`therapies.
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`19.
`
`In one Phase II study (results published as Baselga ’96), 46 patients with
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`HER2-overexpressing metastatic breast cancer received trastuzumab at a dose of
`
`250 mg intravenously on week one, then 100 mg intravenously weekly for 10
`
`weeks. (Ex. 1007 at 3.) The results showed 1 complete and 4 partial responses
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`among 43 evaluable patients for an objective tumor response rate of about 12%.
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`(Id.) In the other Phase II study (results published as Pegram ’98), 37 patients with
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`HER2-overexpressing metastatic breast cancer received trastuzumab at a dose of
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`250 mg intravenously on week one, then 100 mg intravenously weekly for 9 weeks
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`plus cisplatin at a dose of 75 mg/m2 on days 1, 29, and 57. (Ex. 1009 at 2.) The
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`results showed 9 partial responses and 9 minor responses or stable disease among
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`the 37 evaluable patients. (Id.)
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`20. Neither of the papers that published the results of these studies—Baselga ’96
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`and Pegram ’98—included detailed pharmacokinetic data. For example, Baselga
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`’96 provides serum concentration data for only two patients. (Ex. 1007 at 6.)
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`Similarly, Pegram ’98 provides isolated mean pharmacokinetic parameters without
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`including any of the underlying data. (Ex. 1009 at 8 (Table 6).)
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`Phase II/III Pivotal Trials
`3.
`21. Trastuzumab was approved based on two pivotal trials in metastatic breast
`
`cancer patients: a Phase II single agent trial conducted in 222 patients and a Phase
`
`III combination therapy trial conducted in 469 patients. (See Ex. 2046, Melody A.
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`Cobleigh et al., Multinational Study of the Efficacy and Safety of Humanized Anti-
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`HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing
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`Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic
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`Disease, 17 J. CLINICAL ONCOLOGY 2639 (1999) at 2639; Ex. 2047, Dennis J.
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`Slamon et al., Use of Chemotherapy Plus a Monoclonal Antibody Against HER2
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`for Metastatic Breast Cancer That Overexpresses HER2, 344 NEW ENG. J. MED.
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`783 (2001) at 783.) In these trials, trastuzumab was administered at an initial dose
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`of 4 mg/kg followed by weekly maintenance doses of 2 mg/kg. The first dose of
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`antibody was infused intravenously over 90 minutes. In the absence of significant
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`infusion-related toxicity, subsequent doses were infused intravenously over 30
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`minutes. Pharmacokinetic data for the Phase II single agent trial was not published
`
`until September 1999. (See Ex. 2046.) Data from the Phase III combination
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`therapy trial was not published before August 1999.
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`22. Slamon announced remarkable preliminary efficacy results to a packed
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`audience at the 1998 American Society of Clinical Oncology (“ASCO”) meeting.
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`(Ex. 1005 at 5.) He also submitted an abstract for that meeting that briefly
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`summarized the Phase III study results (the Slamon Abstract). (Ex. 1005 at 5.)
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`There was excitement as oncologists finally had the level of proof they needed that
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`a targeted treatment was effective in aggressive HER-positive cancers.
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`23. The FDA approved trastuzumab later that same year. (See Ex. 2043.) It was
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`the first antibody approved to target solid tumors and the first approved to treat
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`breast cancer. (Ex. 2003, Janice M. Reichert, Probabilities of Success for Antibody
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`Therapeutics, 1 MABS 387 (2009) at 388.) The approved dosing regimen consisted
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`of a 4 mg/kg loading dose followed by 2 mg/kg weekly maintenance doses. (Ex.
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`1008 at 1; Ex. 1013 at 1-2, 6-7.)
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`C.
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`Success of Trastuzumab
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`24. Clinical oncologists, including myself, were excited to finally have an
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`effective targeted therapy to treat a group of patients with a poor prognosis and
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`very high risk advanced breast cancer. When the results of the Phase III trial were
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`announced, many of us in the oncology field shared the opinion that trastuzumab
`
`was a major breakthrough. Both patients and oncologists had dreaded a HER2-
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`positive diagnosis. Trastuzumab changed that. After the approval of trastuzumab,
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`it has become a diagnosis that indicates treatable disease.
`
`D. Trastuzumab was a breakthrough in the treatment of HER2-
`positive breast cancer, but a great deal of efficacy-focused
`research remained before oncologists could fully realize and
`utilize the drug’s potential.
`
`25. Soon after trastuzumab’s approval, researchers everywhere wanted to be
`
`involved in the drug’s future. This initial wave of research focused 1) on
`
`identifying patients who could most benefit, and 2) on improving efficacy by
`
`combining trastuzumab with other chemotherapy agents. (See Ex. 2021, José
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`Baselga, Current and Planned Clinical Trials With Trastuzumab (Herceptin), 27
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`(SUPPL. 9) SEMIN. ONCOLOGY 27 (2000); Ex. 2035, Steven Shak, Overview of the
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`Trastuzumab (Herceptin) Anti-HER2 Monoclonal Antibody Clinical Program in
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`HER2-Overexpressing Metastatic Breast Cancer, 26 (Suppl. 12) SEMIN.
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`ONCOLOGY 71 (1999) at 76.)
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`1.
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`Researchers at the time wanted to identify patients who
`could most benefit from the drug.
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`26. First, persons of skill prioritized identifying patients who could most benefit
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`from trastuzumab, including by finding out how early the treatment should start.
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`27. Neoadjuvant treatment is treatment given before surgery to remove
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`cancerous lumps, intended to reduce the size of the tumor. Adjuvant treatment is
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`treatment given after surgery to remove cancerous lumps, intended to kill
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`remaining cancer cells. These treatments are primarily for patients with early
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`breast cancer that has not metastasized. If trastuzumab showed efficacy in the
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`adjuvant and neoadjuvant treatment settings, it would become available to a much
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`broader and more treatable group of patients. (See Ex. 2035 at 76) (“It will be
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`particularly important to perform clinical trials in patients with early breast cancer,
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`in which the more limited tumor burden would suggest even greater opportunities
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`for clinical benefit.”)
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`28.
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`In 1998, as soon as the Phase III trastuzumab pivotal trial results were
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`announced, Genentech signaled that it intended to study the drug in patients with
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`early breast cancer. Large cooperative research groups had similar intent. Around
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`the time of invention, the National Surgical Adjuvant Breast and Bowel Project
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`(NSABP) and the North Central Cancer Treatment Group (NCCTG) were making
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`proposals for adjuvant therapy trials that would enroll thousands of patients.
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`2.
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`Trastuzumab was a novel, important tool for clinicians to
`add to their toolbox of cancer-fighting drugs, but
`oncologists had much to explore in terms of improving its
`efficacy and tying it in with existing treatments.
`29. Oncologists readily adopted trastuzumab, but therapeutic monoclonal
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`antibodies were a whole new world. Trastuzumab was different from anything that
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`oncologists had been prescribing for breast cancer before, which for the last half of
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`the twentieth century had been largely chemotherapy. During the five years
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`following the approval of trastuzumab, hundreds of papers and abstracts were
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`published in which researchers explored various ways to maximize use of
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`trastuzumab, as well as more traditional chemotherapy treatments.
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`a)
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`Efficacy, not convenience, was the focus of cancer
`treatment in the 1990s.
`30. Most chemotherapy drugs are cytotoxic to a broad range of normal and
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`malignant cells, usually on the basis of nonspecific DNA damaging activity. (Ex.
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`2024, Walter M. Stadler & Mark J. Ratain, Development of Target-based
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`Antineoplastic Agents, 18 INVESTIGATIONAL NEW DRUGS 7 (2000) at 7.) This
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`means that healthy, rapidly dividing cells, like hair follicles and cells lining the
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`intestine, tend to be damaged the worst, leading to symptoms such as hair loss and
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`gastrointestinal issues. Nausea, vomiting, and fatigue are also common. But
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`perhaps the most alarming possible side effect is myelosuppression, which is
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`suppression of bone marrow activity, resulting in the creation of fewer white blood
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`cells. When the bone marrow is not able to produce enough white blood cells, the
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`body cannot fight off infection. Neutropenia, a condition in which the patient has
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`an abnormally low number of a particular type of white blood cell, can be life-
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`threatening.
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`31. The goal of most chemotherapy dosing was to deliver the largest tolerable
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`dose that would kill the greatest number of tumor cells without causing life-
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`threatening toxicity, such as severe myelosuppression and neutropenia. Thus, from
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`the time chemotherapeutic agents were first prescribed up until the end of the
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`1980s, chemotherapy agents were typically dosed in a way that allowed the
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`patient’s bone marrow to recover and produce white blood cells between doses.
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`32. Despite inconvenience and toxicity, oncologists in the 1990s were pushing
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`the bounds of chemotherapy because there was a desperate need for more effective
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`treatment. Many of the newer chemotherapy treatment regimens carried higher
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`risks, caused more serious side effects, and were more inconvenient than even
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`standard chemotherapy. For example, many oncologists were studying high-dose
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`chemotherapy plus autologous bone marrow transplant (ABMT), a treatment that
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`involved administration of extremely high doses of chemotherapy, so high that it
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`killed patients’ bone marrow. (See Ex. 2050, Gabriel N. Hortobagyi, Mien-Chie
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`Hung, & Aman U. Buzdar, Recent Developments in Breast Cancer Therapy, 26
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`(SUPPL. 12) SEMIN. ONCOLOGY 11 (1999) at 13; Ex. 2049 at 1180; Ex. 2051, High-
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`Dose Chemotherapy and Autologous Bone Marrow or Stem Cell Reconstitution for
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`Solid Tumors, CURRENT PROBS. IN CANCER, May/June 1998 at 142.) ABMT
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`allowed a patient to receive much higher dosages of chemotherapy than was
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`ordinarily possible because it restored the bone marrow by reinfusing stem cells
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`(the bone marrow cells that mature into blood cells) taken from the patient before
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`chemotherapy. (See Ex. 2050 at 13.) The procedure carried high risks, side effects
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`were severe, and it typically required hospitalization. (See Ex. 2052, William P.
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`Peters et al., High-Dose Chemotherapy and Autologous Bone Marrow Support as
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`Consolidation After Standard-Dose Adjuvant Therapy for High-Risk Primary
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`Breast Cancer, 11 J. CLINICAL ONCOLOGY 1132 (1993) at 1134 (“Patients were
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`then admitted to the next available bed in the transplant unit and were cared for in
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`private rooms with positive-pressure, high-efficiency particle filtration (HEPA) air
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`systems. During the high-dose consolidation phase of treatment, access to patient
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`rooms required masks, gloves, gowns, and shoe covers; a low-bacterial, low-fungal
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`content diet was prescribed.”).) “The stakes are high, but the potential payoff is
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`well worth it if more women with breast cancer can be saved from death.” (Ex.
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`2051 at 156.)
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`33. Oncologists at the time were also interested in dose-dense chemotherapy.
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`The dose-dense hypothesis, popularized by Dr. Larry Norton and tested at many
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`institutions in the 1990s, was that if oncologists could administer more drug per
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`unit of time by reducing the interval between treatment cycles, they could reduce
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`the time for tumor re-growth. (See Ex. 2053, Larry Norton, Evolving Concepts in
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`the Systemic Drug Therapy of Breast Cancer, 24 (SUPPL. 10) SEMIN. ONCOLOGY
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`S10-3 (1997) at S10-3, -5; Ex. 2051 at 154 (“Norton popularized the concept of
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`dose density, which shortens the interval between treatment cycles and uses doses
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`of single agents requiring only cytokine support rather than stem cell support, in an
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`attempt to achieve high total dose and dose intensity simultaneously. . . . This
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`concept of dose density is currently being evaluated.”).) Skilled artisans also
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`theorized that shorter intertreatment intervals would allow less opportunity for the
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`emergence of drug-resistant cancer cells and that the more sustained exposure may
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`permanently impair growth-promoting intracellular signaling. (Ex. 2065, Andrew
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`D. Seidman, One-Hour Paclitaxel Via Weekly Infusion: Dose-Density with
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`Enhanced Therapeutic Index, 12 (SUPPL. 1) ONCOLOGY 19 (1998) at 22; Ex. 2053
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`at S10-5.) I was personally involved in several dose-dense studies in the 1990s.
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`Dose-dense therapy showed great promise for efficacy and some of the
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`myelotoxicity and neutropenia could be managed by administering granulocyte
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`colony-stimulating factor (G-CSF). (See Ex. 2049 at 1179.) G-CSF facilitates
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`bone marrow recovery and stimulates the production of white bloods cells, which
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`i