IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In the Inter Partes Review of:
`
`Trial Number: IPR2017-00805
`
`U.S. Patent No. 7,371,379
`
`Filed:
`
`June 20, 2003
`
`Issued:
`
`May 18, 2008
`
`Inventor(s): Sharon Baughman, Steven Shak
`
`Assignee: Genentech, Inc.
`
`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.
`
`Genentech 2040
`Hospira v. Genentech
`IPR2017-00805
`
`
`
`In the Inter Partes Review of:
`
`Trial Number: IPR2017-00805
`
`U.S. Patent No. 7,371,379
`
`Filed:
`
`June 20, 2003
`
`Issued:
`
`May 18, 2008
`
`Inventor(s): Sharon Baughman, Steven Shak
`
`Assignee: Genentech, Inc.
`
`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.
`
`Genentech 2040
`Hospira v. Genentech
`IPR2017-00805
`
`
`
`TABLE OF CONTENTS
`
`I.(cid:3)
`Introduction .................................................................................................. 1(cid:3)
`II.(cid:3) Qualifications................................................................................................ 1(cid:3)
`III.(cid:3) Summary of Opinions ................................................................................... 2(cid:3)
`IV.(cid:3) Person of Ordinary Skill in the Art................................................................ 5(cid:3)
`V.(cid:3)
`Background and State of the Art ................................................................... 6(cid:3)
`A.(cid:3)
`Treatment Before Trastuzumab ........................................................... 6(cid:3)
`B.(cid:3)
`Trastuzumab Clinical Development .................................................... 9(cid:3)
`C.(cid:3)
`Success of Trastuzumab .................................................................... 13(cid:3)
`D.(cid:3)
`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. ................................................................ 13(cid:3)
`VI.(cid:3) Dr. Lipton’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. ........................................................................... 25(cid:3)
`A.(cid:3) A clinical oncologist’s primary motivating factors are efficacy
`and safety; convenience is a lesser priority. ...................................... 25(cid:3)
`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. .......... 35(cid:3)
`
`B.(cid:3)
`
`- i -
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`
`
`I.
`
`1.
`
`Introduction
`
`I have been asked to review and respond to the opinions set forth in the
`
`January 20, 2017 Declaration of Allan Lipton, M.D. and the January 20, 2017
`
`Declaration of William Jusko, PhD.
`
`II. Qualifications
`
`2.
`
`I am a Professor of Medicine at the University of British Columbia and a
`
`medical oncologist at the BC Cancer Agency. In my current roles, I serve as both
`
`a researcher and investigator for clinical trials primarily in breast cancer and as a
`
`practicing clinical oncologist. I see over 200 new patients with breast cancer per
`
`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
`
`completed my internal medicine residency at the University of British Columbia
`
`and became a Fellow of the Royal College of Physicians and Surgeons of Canada
`
`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.
`
`From that time forward, I have held faculty positions at the University of British
`
`Columbia. I did further training in clinical trials in the UK with the Medical
`
`Research Council.
`
`
`
`-1-
`
`
`
`4.
`
`I have over thirty years of experience in breast oncology and have been
`
`involved in more than 150 clinical trials. I have served as the Clinical Head of the
`
`Investigational Drug Program at the BC Cancer Agency since 1990. I am a past
`
`Co-Chair of the NCIC Clinical Trials Group Breast Site Committee and serve on
`
`the Breast International Group (BIG) Executive Board. In addition, I am a Komen
`
`Scholar and serve on the Scientific Advisory Board (SAB) of the Susan G. Komen
`
`Foundation.
`
`5.
`
`I am a co-author on more than 200 peer-reviewed articles and more than 200
`
`abstracts in the field of breast oncology. I have co-authored at least 50
`
`publications that studied trastuzumab. In addition to acting as a reviewer for grants
`
`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 in August 1999
`
`would not have been motivated to administer trastuzumab on a three-week
`
`schedule as claimed in U.S. Patent Nos. 6,627,196 (“the ’196 patent”) and
`
`7,371,379 (“the ’379 patent”). Oncologists finally had a drug that was effective in
`
`patients with a devastating type of breast cancer. Not only was trastuzumab
`
`effective, it was also exceedingly well-tolerated and patient compliance was high.
`
`- 2 -
`
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`
`
`As a monoclonal antibody therapy, the first ever approved for a solid tumor and
`
`one of the first approved to treat cancer generally, trastuzumab was a very different
`
`type of drug from the chemotherapeutic agents that oncologists regularly
`
`prescribed.
`
`7.
`
`Oncologists in August 1999 were not seeking to change trastuzumab’s
`
`dosing regimen. Petitioner asserts that convenience and ease of scheduling with
`
`paclitaxel, a chemotherapeutic agent dosed every three weeks, would have
`
`motivated such a change. However, without a compliance problem, convenience
`
`standing alone rarely motivates an oncologist to risk making a life-saving treatment
`
`less effective by altering its dosing schedule. Further, the fact that trastuzumab and
`
`paclitaxel were given in combination would not have prompted a clinical
`
`oncologist to experiment with trastuzumab’s dosing schedule to “match” it to
`
`paclitaxel’s. Instead, if an oncologist in 1999 cared to synchronize the schedules,
`
`he/she would likely have experimented with the dosing of paclitaxel, a familiar
`
`chemotherapeutic agent, instead of the dosing of the novel monoclonal antibody
`
`therapy. In 1999, oncologists were studying whether more frequent dosing of
`
`some chemotherapy agents (including paclitaxel) would be more effective, and in
`
`cancer treatment, efficacy reigns supreme.
`
`8.
`
`It is also my opinion that a skilled artisan would not have had confidence
`
`that administering trastuzumab on a three-week dosing interval would have been as
`
`
`
`- 3 -
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`
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`
`
`clinically effective as the weekly dosing based on the pharmacokinetic data
`
`presented in the 1998 Herceptin Label (Ex. 1008), Baselga ’96 (Ex. 1013), and
`
`Pegram ’98 (Ex. 1014). I know from my experience working with
`
`pharmacokineticists on clinical trials that they make mathematical models or rely
`
`on other mathematical equations to describe drug levels in a patient’s serum, and
`
`can make predictions for drug levels in a patient’s serum for an alternative dosing
`
`regimen. I also know that if a drug shows certain pharmacokinetic characteristics
`
`such as non-linearity, the pharmacokineticist cannot simply ignore the
`
`characteristic; otherwise, the pharmacokineticist’s predictions may not accurately
`
`predict the levels of drug in the patient’s body over time. The prior art provided
`
`only sparse pharmacokinetic data, and particularly for a drug with documented
`
`non-linear kinetics—a characteristic that Petitioner’s expert glosses over—it was
`
`not possible to accurately predict whether an alternative dosing regimen would
`
`maintain high enough levels of the drug in the patient’s serum to be effective. At
`
`least because of the unfamiliarity that comes with a new class of drug, and because
`
`trastuzumab was already a very effective treatment for an aggressive disease, a
`
`clinical oncologist would not have taken chances by using the new regimen on a
`
`patient with a life-threatening illness.
`
`
`
`- 4 -
`
`
`
`
`
`IV. Person of Ordinary Skill in the Art
`
`9.
`
`I understand that the Petitioner, Dr. Lipton, and Dr. Jusko defined a skilled
`
`artisan as a team including:
`
`(1)
`
`a clinical or medical oncologist specializing in breast cancer
`
`with several years of experience with breast cancer research or clinical
`
`trials, and
`(2)
`
`a person with a Ph.D. in pharmaceutical sciences or a closely
`
`related field with an emphasis in pharmacokinetics with three years of
`
`relevant experience in protein based drug kinetics.
`
`(Paper 1 at 23-24; Ex. 1002, Lipton Decl. ¶ 14; Ex. 1003, Jusko Decl. ¶ 15.)
`
`10. For the purpose of this declaration, I have applied this definition of a skilled
`
`artisan, and my opinions are offered from the perspective of a skilled artisan as that
`
`hypothetical person would have understood matters on August 27, 1999, which I
`
`understand is the relevant date for the analysis.
`
`11.
`
`In 1999, I specialized in treating breast cancer patients and had designed
`
`and/or served as a principal investigator in numerous oncology clinical trials. Also
`
`at the time of invention, I had published around 20 papers specifically on breast
`
`cancer treatment, including publications in the New England Journal of Medicine
`
`and in the Journal of Clinical Oncology. Further, I had knowledge of
`
`pharmacokinetics because of my involvement in Phase I clinical trials. I typically
`
`
`
`- 5 -
`
`
`
`
`
`consulted with a pharmacokineticist for these trials, and I have done so here by
`
`consulting with Dr. George Grass.
`
`V. Background and State of the Art
`
`A. Treatment Before Trastuzumab
`
`12. By the mid-20th century, doctors had observed that some breast cancers
`
`were clearly more aggressive than others, meaning that the cancers grew and
`
`spread more rapidly. The reason behind this difference in behavior was unknown.
`
`In the late 1980s, researchers identified a potential explanation for some breast
`
`cancers; the gene encoding the HER2 protein was amplified in a fraction of breast
`
`cancers, and the amplification was a predictor of poor overall survival and time to
`
`relapse. (Ex. 2043, Dennis J. Slamon, Human Breast Cancer: Correlation of
`
`Relapse and Survival with Amplification of the HER-2/neu Oncogene, 235 SCIENCE
`
`177 (1987) at 177; Ex. 2054, Dennis J. Slamon, Studies of the HER-2/neu Proto-
`
`oncogene in Human Breast and Ovarian Cancer, 244 SCIENCE 707 (1989) at 707.)
`
`During this period numerous other markers of prognosis were also described but
`
`HER2 amplification or overexpression was more robust than many others, which
`
`are now long forgotten. By the mid-1990s, it was increasingly recognized in the
`
`field that HER2-positive status was one predictor of aggressive cancer and poor
`
`prognosis, with a high rate of tumor recurrence and spreading to other areas of the
`
`body. (Ex. 2041, Michael S. Kopreski et al., Growth Inhibition of Breast Cancer
`
`
`
`- 6 -
`
`
`
`
`
`Cell Lines by Combinations of Anti-P185HER2 Monoclonal Antibody and Cytokines,
`
`16 ANTICANCER RES. 433 (1996) at 433; Ex. 2042, Steven Lehrer et al., Tumour
`
`HER2 Protein in Breast Cancer and Family History, 341 THE LANCET 1420 (1993)
`
`at 1420; Ex. 2043 at 179-180.) HER2-positive patients had “a shorter time to
`
`relapse as well as a shorter overall survival” even after surgery, chemotherapy,
`
`and/or radiation. (Ex. 2054 at 707; Ex. 2043 at 179-180.) Existing treatments
`
`were not effective, so the harsh reality for HER2-positive patients in 1996 was a
`
`life expectancy of “only 18 months post-diagnosis.” (Ex. 2044, David Holzman,
`
`Gene Therapy for HER-2-Related Cancer, MOLECULAR MED. TODAY, April 1996
`
`at 138; see also Ex. 2045, Russ Hoyle, Genentech Is Poised for an Anti-cancer
`
`Breakthrough, 16 NATURE BIOTECHNOLOGY 887 (1998) at 887 (“[B]reast cancer
`
`patients who overproduce HER2 can now expect to live some 10 to 12 months
`
`after metastasis begins, a horribly rapid progression compared to six or seven years
`
`for HER2- normal patients.”).)
`
`13. Many women were affected by the lack of an effective treatment for HER2-
`
`positive breast cancer. In 1998, approximately 180,000 new cases of breast cancer
`
`were being diagnosed every year in the United States, and of those 180,000
`
`diagnosed women, 25-30% had the HER2-positive subtype. (See Ex. 1011 at 1, 5;
`
`see also Ex. 1013 at 9.)
`
`
`
`- 7 -
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`
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`14. Researchers looked for ways to target the source of this deadly disease.
`
`Because HER2 protein is overexpressed on the cell surface, scientists investigated
`
`whether HER2 could serve as a target for a large macromolecule, such as a
`
`monoclonal antibody, that might interfere with the ability of HER2 protein to bind
`
`to receptors and initiate the cascade of cell signaling associated with aggressive
`
`breast cancer. (Ex. 2055, Robert M. Hudziak et al., p185HER2 Monoclonal
`
`Antibody Has Antiproliferative Effects In Vitro and Sensitizes Human Breast
`
`Tumor Cells to Tumor Necrosis Factor, 9 MOLECULAR & CELLULAR BIOLOGY
`
`1165 (1989) at 1165.) The idea of using antibodies as targeted cancer therapies
`
`had been floated for decades. (Ex. 2056, Richard P. Junghans et al., Antibody-
`
`Based Immunotherapies for Cancer, in CANCER CHEMOTHERAPY & BIOTHERAPY:
`
`PRINCIPLES AND PRACTICE 655 (1996) at 655.) Although antibodies targeting a
`
`specific antigen could be obtained from mice and other animals, the human
`
`immune system would identify these nonhuman antibodies as foreign antigens and
`
`attack them. (Id. at 683.) The resulting “antigenic” or “immunogenic” response
`
`inactivated the antibodies and resulted in rapid clearance from the body, curtailing
`
`therapeutic usefulness. (Id. at 683.) By the early 1990s, numerous antibodies had
`
`been tested in patients with different cancers, including breast cancer, but they
`
`showed “no hint of a consistent therapeutic efficacy.” (Ex. 2002, Gert Riethmüller
`
`& Judith P. Johnson, Monoclonal Antibodies in the Detection and Therapy of
`
`
`
`- 8 -
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`
`
`Micrometastatic Epithelial Cancers, 4 CURRENT OPINION IN IMMUNOLOGY 647
`
`(1992) at 649; id., Table 2 (identifying failed antibody clinical trials for
`
`gastrointestinal tumors; breast, colon, ovarian, and lung cancer; pancreatic
`
`adenocarcinoma; neuroblastoma; and melanoma).)
`
`15. Genentech collaborated with researchers at a variety of academic and
`
`research institutions including the University of California, Los Angeles and the
`
`Memorial Sloan-Kettering Cancer Center to find a solution to the daunting
`
`problem. First, researchers at Genentech developed a mouse monoclonal antibody
`
`that targeted the HER2 protein. (Ex. 2055 at 1165.) The next and crucial step was
`
`the development of a humanized version of this monoclonal antibody, which
`
`would be made up of mostly human components and very few mouse components
`
`to reduce immunogenic responses in patients. (Ex. 2057, Paul Carter et al.,
`
`Humanization of an Anti-p185HER2 Antibody for Human Cancer Therapy, 89 PROC.
`
`NAT’L ACAD. SCI. 4285 (1992).) That humanized antibody came to be known as
`
`Herceptin® (trastuzumab).
`
`B.
`
`Trastuzumab Clinical Development
`
`Phase I
`1.
`16. When the first trastuzumab clinical trials began in 1992, antibody therapies
`
`were not in favor in the oncology field. Despite theoretical promise in the lab,
`
`clinical researchers had experienced many failures when other antibody therapies
`
`
`
`- 9 -
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`
`
`
`were tested on patients. Harmful immunogenic responses were often observed in
`
`the clinic. In addition, the complexity of cell signaling pathways in the body as
`
`well as the difficulty of safely delivering effective doses of these large
`
`macromolecules posed a slew of new challenges for researchers in the field.
`
`17.
`
`In light of these challenges, Phase I pharmacokinetic trials of trastuzumab
`
`were initially conducted with a small number of patients and Genentech’s studies
`
`were not published, which is surprising considering the subsequent success of the
`
`drug. Limited information from these studies was eventually included in the 1998
`
`Herceptin Label (Ex. 1008) and described in a cursory fashion in a small handful
`
`of publications. (See, e.g., Ex. 2001 at 312; Ex. 1013 at 9-10.)
`
`2.
`
`Phase II
`
`
`18. Two Phase II studies of trastuzumab were conducted. (See Ex. 1013, Ex.
`
`1014). The results from these trials showed preliminary suggestions of
`
`trastuzumab’s activity, but needed to be validated in larger trials. Clinicians do not
`
`trust results from small trials because they may not predict whether and how the
`
`drug will work in the broader patient population. Small trials also do not have the
`
`statistical power to demonstrate any benefit of the new therapy over existing
`
`therapy. Further, many small studies are single center studies which is also a
`
`concern for clinicians as there are concerns about bias, patient selection, and the
`
`potential validation of the results. Clinical skepticism was especially high during
`
`
`
`- 10 -
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`
`
`
`
`the clinical development of trastuzumab because of the failure of prior antibody
`
`therapies.
`
`19.
`
`In one Phase II study (results published as Baselga ’96), 46 patients with
`
`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. 1013 at 9.) The results showed 1 complete and 4 partial responses
`
`among 43 evaluable patients for an objective tumor response rate of about 12%.
`
`(Id.) In the other Phase II study (results published as Pegram ’98), 37 patients with
`
`HER2-overexpressing metastatic breast cancer received trastuzumab at a dose of
`
`250 mg intravenously on week one, then 100 mg intravenously weekly for 9 weeks
`
`plus cisplatin at a dose of 75 mg/m2 on days 1, 29, and 57. (Ex. 1014 at 8.) The
`
`results showed 9 partial responses and 9 minor responses or stable disease among
`
`the 37 evaluable patients. (Id.)
`
`20. Neither of the papers that published the results of these studies—Baselga ’96
`
`and Pegram ’98 —included detailed pharmacokinetic data. For example, Baselga
`
`’96 provides serum concentration data for only two patients. (Ex. 1013 at 12.)
`
`Similarly, Pegram ’98 provides isolated mean pharmacokinetic parameters without
`
`including any of the underlying data. (Ex. 1014 at 14 (Table 6).)
`
`
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`- 11 -
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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. 2058, Melody A.
`
`Cobleigh et al., Multinational Study of the Efficacy and Safety of Humanized Anti-
`
`HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing
`
`Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic
`
`Disease, 17 J. CLINICAL ONCOLOGY 2639 (1999) at 2639; Ex. 2059, Dennis J.
`
`Slamon et al., Use of Chemotherapy Plus a Monoclonal Antibody Against HER2
`
`for Metastatic Breast Cancer That Overexpresses HER2, 344 NEW ENG. J. MED.
`
`783 (2001) at 783.) In these trials, trastuzumab was administered at an initial dose
`
`of 4 mg/kg followed by weekly maintenance doses of 2 mg/kg. The first dose of
`
`antibody was infused intravenously over 90 minutes. In the absence of significant
`
`infusion-related toxicity, subsequent doses were infused intravenously over 30
`
`minutes. Pharmacokinetic data for the Phase II single agent trial was not published
`
`until September 1999. (See Ex. 2058.) Data from the Phase III combination
`
`therapy trial was not published before August 1999.
`
`22. Slamon announced remarkable preliminary efficacy results to a packed
`
`audience at the 1998 American Society of Clinical Oncology (“ASCO”) meeting.
`
`(See Ex. 1040.) There was excitement as oncologists finally had the level of proof
`
`
`
`- 12 -
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`
`
`
`they needed that a targeted treatment was effective in aggressive HER-positive
`
`cancers.
`
`23. The FDA approved trastuzumab later that same year. (See Ex. 1011.) It was
`
`the first antibody approved to target solid tumors and the first approved to treat
`
`breast cancer. (Ex. 2003, Janice M. Reichert, Probabilities of Success for Antibody
`
`Therapeutics, 1 MABS 387 (2009) at 388.) The approved dosing regimen consisted
`
`of a 4 mg/kg loading dose followed by 2 mg/kg weekly maintenance doses. (Ex.
`
`1008 at 1; Ex. 2001 at 309-10, 314-15.)
`
`C.
`
`Success of Trastuzumab
`
`
`24. Clinical oncologists, including myself, were excited to finally have an
`
`effective targeted therapy to treat a group of patients with a poor prognosis and
`
`very high risk advanced breast cancer. When the results of the Phase III trial were
`
`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-
`
`positive diagnosis. Trastuzumab changed that. After the approval of trastuzumab,
`
`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
`
`
`
`- 13 -
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`
`
`identifying patients who could most benefit, and 2) on improving efficacy by
`
`combining trastuzumab with other chemotherapy agents. (See Ex. 2028, José
`
`Baselga, Current and Planned Clinical Trials With Trastuzumab (Herceptin), 27
`
`(SUPPL. 9) SEMIN. ONCOLOGY 27 (2000); Ex. 2046, Steven Shak, Overview of the
`
`Trastuzumab (Herceptin) Anti-HER2 Monoclonal Antibody Clinical Program in
`
`HER2-Overexpressing Metastatic Breast Cancer, 26 (SUPPL. 12) SEMIN.
`
`ONCOLOGY 71 (1999) at 76.)
`
`1.
`
`Researchers at the time wanted to identify patients who
`could most benefit from the drug.
`
`26. First, persons of skill prioritized identifying patients who could most benefit
`
`from trastuzumab, including by finding out how early the treatment should start.
`
`27. Neoadjuvant treatment is treatment given before surgery to remove
`
`cancerous lumps, intended to reduce the size of the tumor. Adjuvant treatment is
`
`treatment given after surgery to remove cancerous lumps, intended to kill
`
`remaining cancer cells. These treatments are primarily for patients with early
`
`breast cancer that has not metastasized. If trastuzumab showed efficacy in the
`
`adjuvant and neoadjuvant treatment settings, it would become available to a much
`
`broader and more treatable group of patients. (See Ex. 2046 at 76) (“It will be
`
`particularly important to perform clinical trials in patients with early breast cancer,
`
`
`
`- 14 -
`
`
`
`
`
`in which the more limited tumor burden would suggest even greater opportunities
`
`for clinical benefit.”)
`
`28.
`
`In 1998, as soon as the Phase III trastuzumab pivotal trial results were
`
`announced, Genentech signaled that it intended to study the drug in patients with
`
`early breast cancer. Large cooperative research groups had similar intent. Around
`
`the time of invention, the National Surgical Adjuvant Breast and Bowel Project
`
`(NSABP) and the North Central Cancer Treatment Group (NCCTG) were making
`
`proposals for adjuvant therapy trials that would enroll thousands of patients.
`
`2.
`
`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
`
`antibodies were a whole new world. Trastuzumab was different from anything that
`
`oncologists had been prescribing for breast cancer before, which for the last half of
`
`the twentieth century had been largely chemotherapy. During the five years
`
`following the approval of trastuzumab, hundreds of papers and abstracts were
`
`published in which researchers explored various ways to maximize use of
`
`trastuzumab, as well as more traditional chemotherapy treatments.
`
`
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`- 15 -
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`
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`
`
`a)
`
`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
`
`malignant cells, usually on the basis of nonspecific DNA damaging activity. (Ex.
`
`2060, Walter M. Stadler & Mark J. Ratain, Development of Target-based
`
`Antineoplastic Agents, 18 INVESTIGATIONAL NEW DRUGS 7 (2000) at 7.) This
`
`means that healthy, rapidly dividing cells, like hair follicles and cells lining the
`
`intestine, tend to be damaged the worst, leading to symptoms such as hair loss and
`
`gastrointestinal issues. Nausea, vomiting, and fatigue are also common. But
`
`perhaps the most alarming possible side effect is myelosuppression, which is
`
`suppression of bone marrow activity, resulting in the creation of fewer white blood
`
`cells. When the bone marrow is not able to produce enough white blood cells, the
`
`body cannot fight off infection. Neutropenia, a condition in which the patient has
`
`an abnormally low number of a particular type of white blood cell, can be life-
`
`threatening.
`
`31. The goal of most chemotherapy dosing was to deliver the largest tolerable
`
`dose that would kill the greatest number of tumor cells without causing life-
`
`threatening toxicity, such as severe myelosuppression and neutropenia. Thus, from
`
`the time chemotherapeutic agents were first prescribed up until the end of the
`
`1980s, chemotherapy agents were typically dosed in a way that allowed the
`
`patient’s bone marrow to recover and produce white blood cells between doses.
`
`
`
`- 16 -
`
`
`
`
`
`32. Despite inconvenience and toxicity, oncologists in the 1990s were pushing
`
`the bounds of chemotherapy because there was a desperate need for more effective
`
`treatment. Many of the newer chemotherapy treatment regimens carried higher
`
`risks, caused more serious side effects, and were more inconvenient than even
`
`standard chemotherapy. For example, many oncologists were studying high-dose
`
`chemotherapy plus autologous bone marrow transplant (ABMT), a treatment that
`
`involved administration of extremely high doses of chemotherapy, so high that it
`
`killed patients’ bone marrow. (See Ex. 2062, Gabriel N. Hortobagyi, Mien-Chie
`
`Hung, & Aman U. Buzdar, Recent Developments in Breast Cancer Therapy, 26
`
`(SUPPL. 12) SEMIN. ONCOLOGY 11 (1999) at 13; Ex. 2061 at 1180; Ex. 2063,
`
`William P. McGuire, High-Dose Chemotherapy and Autologous Bone Marrow or
`
`Stem Cell Reconstitution for Solid Tumors, CURRENT PROBS. IN CANCER, May/June
`
`1998 at 142.) ABMT allowed a patient to receive much higher dosages of
`
`chemotherapy than was ordinarily possible because it restored the bone marrow by
`
`reinfusing stem cells (the bone marrow cells that mature into blood cells) taken
`
`from the patient before chemotherapy. (See Ex. 2062 at 13.) The procedure
`
`carried high risks, side effects were severe, and it typically required
`
`hospitalization. (See Ex. 2064, William P. Peters et al., High-Dose Chemotherapy
`
`and Autologous Bone Marrow Support as Consolidation After Standard-Dose
`
`Adjuvant Therapy for High-Risk Primary Breast Cancer, 11 J. CLINICAL
`
`
`
`- 17 -
`
`
`
`
`
`ONCOLOGY 1132 (1993) at 1134 (“Patients were then admitted to the next available
`
`bed in the transplant unit and were cared for in private rooms with positive-
`
`pressure, high-efficiency particle filtration (HEPA) air systems. During the high-
`
`dose consolidation phase of treatment, access to patient rooms required masks,
`
`gloves, gowns, and shoe covers; a low-bacterial, low-fungal content diet was
`
`prescribed.”). “The stakes are high, but the potential payoff is well worth it if
`
`more women with breast cancer can be saved from death.” (Ex. 2063 at 156.)
`
`33. Oncologists at the time were also interested in dose-dense chemotherapy.
`
`The dose-dense hypothesis, popularized by Dr. Larry Norton and tested at many
`
`institutions in the 1990s, was that if oncologists could administer more drug per
`
`unit of time by reducing the interval between treatment cycles, they could reduce
`
`the time for tumor re-growth. (See Ex. 2065, Larry Norton, Evolving Concepts in
`
`the Systemic Drug Therapy of Breast Cancer, 24 (SUPPL. 10) SEMIN. ONCOLOGY
`
`S10-3 (1997) at S10-3, -5; Ex. 2063 at 154 (“Norton popularized the concept of
`
`dose density, which shortens the interval between treatment cycles and uses doses
`
`of single agents requiring only cytokine support rather than stem cell support, in an
`
`attempt to achieve high total dose and dose intensity simultaneously. . . . This
`
`concept of dose density is currently being evaluated.”).) Skilled artisans also
`
`theorized that shorter intertreatment intervals would allow less opportunity for the
`
`emergence of drug-resistant cancer cells and that the more sustained exposure may
`
`
`
`- 18 -
`
`
`
`
`
`permanently impair growth-promoting intracellular signaling. (Ex. 2050, Andrew
`
`D. Seidman, One-Hour Paclitaxel Via Weekly Infusion: Dose-Density with
`
`Enhanced Therapeutic Index, 12 (SUPPL. 1) ONCOLOGY 19 (1998) at 22; Ex. 2065
`
`at S10-5.) I was personally involved in several dose-dense studies in the 1990s.
`
`Dose-dense therapy showed great promise for efficacy and some of the
`
`myelotoxicity and neutropenia could be managed by administering granulocyte
`
`colony-stimulating factor (G-CSF). (See Ex. 2061 at 1179.) G-CSF facilitates
`
`bone marrow recovery and stimulates the production of white bloods cells, which
`
`in turn allows for more frequent dosing. (See Ex. 2065 at S10-5; Ex. 2066, John
`
`Crown et al., High-Intensity Chemotherapy with Hematopoietic Support In Breast
`
`Cancer, 698 ANNALS N.Y. ACAD. SCI. 378 (1993) at 383.) For example,
`
`chemotherapy in a dose-dense regimen could be administered once every week or
`
`every two weeks instead of every three weeks. (See Ex. 2062 at 13; Ex. 2065 at
`
`S10-3, -6, -7.)
`
`34. None of these treatments could be described as convenient, showing that
`
`efficacy was a higher priority than convenience for oncologists treating cancer in
`
`August 1999.
`
`
`
`- 19 -
`
`
`
`
`
`b)
`Skilled artisans recognized that the principles that
`applied for dosing chemotherapeutic agents did not apply
`for dosing trastuzumab.
`35. Compared to other intravenous cancer treatments available in August 1999,
`
`trastuzumab was exceptionally well tolerated. Trastuzumab had few and relatively
`
`mild side effects, including infusion reactions such as chills and fever after the first
`
`infusion that did not typically recur after subsequent administrations. (Ex. 2067,
`
`Charles L. Vogel & Jean-Marc Nabholtz, Monotherapy of Metastatic Breast
`
`Cancer: A Review of Newer Agents, 4 THE ONCOLOGIST 17 (1999) at 26) (“Aside
`
`from fever and chills, which generally occur only with the first dose of drug,
`
`toxicities have been rare. Patient tolerability and acceptance have been excellent,
`
`because the antibody is not associated with alopecia, significant gastrointestinal
`
`problems, or myelosuppression.”). Trastuzumab could lead to cardiotoxicity in
`
`some patients and this caused concern as the cardiac toxicity was a surprise and did
`
`not appear to be related to dose. Although it appeared to be related to combining it
`
`with cardiotoxic drugs such as anthracyclines, it also occurred sporadically which
`
`was not well understood. (Id.) Other symptoms included mild to moderate pain at
`
`the tumor site, diarrhea, and nausea. (Ex. 1008 at 2.) Trastuzumab did not cause
`
`
`
`- 20 -
`
`
`
`
`
`myelosuppression or neutropenia, and these severe, dose-related side effects were
`
`key drivers of three-weekly dosing for a number of chemotherapeutic agents.
`
`36. Another key difference between trastuzumab and chemotherapeutic agents is
`
`that trastuzumab is a targeted antibody therapy. Targeted cancer therapies interact
`
`with specific molecular targets involved in the growth, progression, and spread of
`
`cancer. The goal of antibody dosing is to maintain therapeut
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