UNITED STATES PATENT AND TRADEMARK OFFICE … · A. Scope and Content of the Prior Art ... I...

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UNITED STATES PATENT AND TRADEMARK OFFICE

BEFORE THE PATENT TRIAL AND APPEAL BOARD

Petitioner, v.

Genentech, Inc. Patent Owner

Patent No. 7,892,549

Title: TREATMENT WITH ANTI-ERbB2 ANTIBODIES

Inter Partes Review No. IPR2017-01122

DECLARATION OF ROBERT EARHART, M.D., Ph.D. IN SUPPORT OF CELLTRION’S PETITION FOR INTER PARTES REVIEW OF

U.S. PATENT NO. 7,892,549

1 of 97 Celltrion, Inc., Exhibit 1002

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Table of Contents

Page

I. INTRODUCTION ........................................................................................... 4

II. SUMMARY OF OPINIONS ........................................................................... 4

III. QUALIFICATIONS AND EXPERIENCE ..................................................... 5

IV. LEGAL PRINCIPLES ................................................................................... 11

V. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 13

VI. SCIENTIFIC BACKGROUND .................................................................... 13

A. Breast Cancer and its Treatment as of December 1996 ...................... 13

B. Development of Cancer Therapies ...................................................... 20

C. HER2+ Breast Cancer and Its Treatments .......................................... 22

1. Baselga 1996 (Ex. 1020) ........................................................... 24

2. Seidman 1996 (Ex. 1011) ......................................................... 26

3. Pegram 1995 (Ex. 1022) ........................................................... 28

4. Preclinical Studies ..................................................................... 30

D. Combination Therapy for Breast Cancer ............................................ 36

E. Measurements of Efficacy for Cancer Treatments ............................. 41

VII. U.S. PATENT NO. 7,892,549 ....................................................................... 44

A. The Specification of the ’549 Patent ................................................... 44

B. The Claims of the ’549 Patent ............................................................. 46

C. Prosecution History of the ’549 Patent ............................................... 49

VIII. CLAIM CONSTRUCTION .......................................................................... 54

IX. OBVIOUSNESS ANALYSIS ....................................................................... 58

A. Scope and Content of the Prior Art ..................................................... 58

B. Level of Ordinary Skill in the Art ....................................................... 58

C. Differences Between the Claims and the Prior Art and Conclusion of Obviousness ......................................................................................... 59

D. Response To The Sliwkowski Declaration ......................................... 72


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1. A Person of Ordinary Skill in the Art Would Not Have Expected an Antagonistic Interaction Between Paclitaxel and Trastuzumab .............................................................................. 72

2. Xenograft Data is a Helpful Tool for Developing Combination Therapies ................................................................................... 79

E. Claim-by-Claim Analysis of Obviousness .......................................... 83

F. Secondary Considerations ................................................................... 90

1. Dr. Hellmann Did Not Point to Data that Established that the Combination of Paclitaxel and Trastuzumab Results in Synergy ................................................................................................... 91

2. The Combination of Trastuzumab and Doxorubicin Did Not Result in Unexpected Toxicity and is Not Relevant to the Claimed Combination ............................................................... 95

X. CONCLUSION .............................................................................................. 97


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1. I, Robert Earhart, M.D., Ph.D., declare as follows:

I. INTRODUCTION

2. I have been retained by Celltrion, Inc. (“Celltrion”) in this matter.

3. I understand that Celltrion is seeking to challenge the patentability of

the claims of U.S. Patent No. 7,892,549 (“the ’549 patent”) in inter partes review

proceedings before the before the Patent Trial and Appeal Board (“PTAB”) of the

United States Patent and Trademark Office.

4. Celltrion has asked me analyze the state of the art and the scope and

content of the prior art as of December 12, 1996, and to provide my expert opinion

about whether claims 1-11 and 14-17 of the ’549 patent would have been obvious

to a person of ordinary skill in the art at that time.

5. I am being compensated at my standard rate for my time spent

preparing this Declaration, and my compensation is not contingent on the opinions

I provide or on the outcome of this matter. I have no financial interest in the

outcome of this matter.

II. SUMMARY OF OPINIONS

6. The statements, analysis and opinions that I provide in this

Declaration are my own and are based on my own personal knowledge, my many

years of experience in the field of cancer research, and the materials I reviewed in

connection with preparing this Declaration.


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7. Based on my analysis, knowledge and experience, it is my opinion

that claims 1-11 and 14-17 of the ’549 patent would have been obvious to a person

of ordinary skill in the art at the relevant time in light of the prior art references

Baselga 1996, Pegram 1995, Seidman 1996, and the 1995 Physicians’ Desk

Reference (“PDR”) entry for Taxol® (paclitaxel), in view of the knowledge of the

person of ordinary skill in the art. Each of these references is defined and analyzed

in more detail below.

8. More specifically, as of December 6, 1996, the person of ordinary

skill in the art would have been motivated by the prior art to administer a

combination of trastuzumab, cisplatin and paclitaxel to treat a human patient with

metastatic HER2+ breast cancer in amounts that would be effective to extend the

patient’s time to disease progression, and would have had a reasonable expectation

of success in so doing. As discussed in more detail below, claims 1-11 and 14-17

of the ’549 patent would have been obvious to a person of ordinary skill in the art.

III. QUALIFICATIONS AND EXPERIENCE

9. I graduated from Northwestern University in Chicago, Illinois with a

B.S. in Medicine in 1966. I subsequently earned an M.D. in 1972 and a Ph.D. in

pharmacology in 1975, both from Northwestern University.

10. I have worked in academia and in industry as a physician and clinical

pharmacologist since 1976. I also conducted research in pharmacokinetics and


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radioimmunoassay development at the University of Michigan with Prof. John

Wagner from summer 1976 through spring 1978.

11. From 1978 through 1982, I worked at the Wisconsin Clinical Cancer

Center (WCCC), where I was involved in research, clinical care and teaching.

While at WCCC, I established an Analytical Instrumentation Laboratory and

directed Phase I clinical and pharmacokinetic trials under a National Cancer

Institute (NCI) Phase I contract. My laboratory provided analytical chemistry

(HPLC, GC, GC-mass spectrometry, atomic absorption) and pharmacokinetic

support as well as protocol development and execution of NCI contract Phase I

trials of PCNU, DON, ICRF-187, carboplatin, acivicin, and combinations of

cyclophosphamide + misonidazole and cisplatin + amifostine, all of which are

chemotherapeutic agents.

12. I was a member of the New Agents and Pilot Studies Committee, and

chaired the Pharmacology Subcommittee of Eastern Cooperative Oncology Group,

an NCI-sponsored national consortium of US cancer centers. I designed and

supervised the conduct of multiple group-wide Phase II studies of the most

promising of these agents and regimens.

13. As a WCCC faculty medical oncologist, I conducted an outpatient

clinic year-round, and served as an Attending Faculty physician for several month-

long assignments in the University Hospital and the associated VA Hospital. I also


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taught cancer pharmacology course segments in the School of Pharmacy, and

developed and taught a graduate-level course in Pharmacology of Anticancer

Agents for the Department of Human Oncology.

14. In 1982, I joined The Upjohn Company as a Physician-Scientist, and

established a new in-house program of Phase I trials in cancer patients, resulting in

(1) the first induction of interferon in man by oral bropirimine, (2) optimization of

administration schedule for acivicin, (3) investigation of a suspension formulation

of bropirimine, and (4) development of a method to prevent dose-limiting CNS

toxicity of acivicin while potentiating peripheral antitumor activity of the drug,

resulting in doubling of the clinically tolerated dose.

15. While at Upjohn, I monitored Phase I and II extramural evaluation of

the oral anthracycline menogaril, which resulted in the identification of the Phase

II working dose and showed clinical activity in breast cancer. I also designed

strategy for clinical development through registration with the FDA.

Simultaneously, I designed clinical strategy for the new anticancer drugs

ormaplatin and adozelesin, which entered clinical trials in 1990, as well as

bizelesin and carzelesin. I also chaired the Drug Development Team which

organized the preclinical and clinical evaluation of acivicin.

16. I passed the first offered subspecialty examination of the American

Board of Clinical Pharmacology in 1991, and was thereby board-certified in the


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newly-emerging discipline of Clinical Pharmacology (#91406). Briefly, clinical

pharmacologists conduct research to optimize the use of therapeutic agents in

patients, both to understand and predict the results of clinical treatment and to

investigate the effects of human pathophysiology, concomitant treatments and

other factors on the use of drugs in the clinical setting.

17. In 1995, I joined Rhône-Poulenc Rorer as Associate Director of

Oncology Medical Affairs. While at the company, I was responsible for Phase

I/II/III/IV clinical trials of docetaxel (Taxotere®) which led to broadened use of this

drug after market introduction in 1996. In medical affairs, clinical trials known as

investigator-sponsored trials are routinely conducted after a cancer drug has been

approved for marketing. Every drug company with an FDA-approved product has

a medical affairs unit whose role, among others, is to consider whether to approve

or disapprove investigator-sponsored trials. These units review many such

proposals, although the exact number will vary depending on the size of the

company. By way of example, in the month of September 1996, while at Rhone

Poulenc Rorer, I personally reviewed 27 proposals for such studies. The purpose

of these activities is to fulfil the company’s ethical responsibility to develop valid

medical evidence that can inform clinical decisions involving the product, and to

guide its use to minimize patient risk, maximize patient benefit, and answer

important questions in clinical studies. Not all of the proposals were approved but


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many were, and some resulted in improvement in the clinical treatment of cancer

patients, and developed the basic information that led to FDA approval for

Taxotere® in additional oncology indications. I therefore have had substantial

experience in evaluating the information that is required to conduct clinical studies

in oncology with due regard to scientific, safety, efficacy and ethical concerns.

18. In late 1999, I worked as Senior Director of U.S. Bioscience. In

2000, U.S. Bioscience became MedImmune Oncology, where I was Vice President

of Clinical Oncology. There, I was responsible for Phase I clinical and

pharmacokinetic trials of Vitaxin® (a humanized monoclonal antibody against

human α-V β-3 integrin, an antiangiogenesis agent) in America and Europe, and a

Phase III product line extension trial of amifostine (Ethyol®) for prevention of

acute esophagitis in patients with stage III non-small-cell lung carcinoma

undergoing chemoradiotherapy. I formed and chaired Project Teams for both

Vitaxin® and Ethyol® to conduct these programs.

19. In 2003, I joined Cell Therapeutics in Seattle as Vice President of

Global Medical Affairs. I became responsible for planning, staffing, budgeting

and execution of Medical Affairs activities that supported Cell Therapeutics’

marketed product Trisenox® (arsenic trioxide), and late-phase development

products Xyotax® (paclitaxel polyglumex) and pixantrone.


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20. In 2005, I founded Arrowsmith Oncology LLC. This company

provides consultative services to the pharmaceutical industry in the areas of

strategic planning, process development, medical writing, staff training, medical

affairs support, clinical meeting organization and business development.

21. In March 2008, I joined Poniard Pharmaceuticals as Senior Director

of Clinical Development. Poniard needed a full-time physician/monitor to

supervise their Phase II combination (colorectal and prostate cancer), oral

bioavailability and QTc trials of their drug candidate, picoplatin. During my time

at Poniard, I continued some consultancy activity for Arrowsmith Oncology,

primarily teaching activities. In 2010, I returned to full-time consultative activities

at Arrowsmith Oncology, which I have being doing ever since. As a voting

member of the Institutional Review Board for the Cancer Research and

Biostatistics (CRAB®) nonprofit Contract Research Organization, I continue to

review scientific, clinical and ethical aspects of studies involving patients with

cancer.

22. I am a member of the American Society for Clinical Oncology

(“ASCO”), which I joined in 1998. I am also a member of the American

Association for Cancer Research (“AACR”), which I joined in 1982, and a

member of the American Society for Clinical Pharmacology and Therapeutics,


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which I joined in 1991. I have published over 40 peer reviewed research and

review articles and 60 abstracts in the field of oncology and drug development.

23. A copy of my curriculum vitae is provided as Exhibit 1003.

IV. LEGAL PRINCIPLES

24. Counsel has advised me of the following legal standards regarding

obviousness to assist me in preparing this declaration.

25. I am advised that the following four elements should be considered in

conducting an obviousness analysis: (1) the scope and content of the prior art;

(2) the differences between the prior art and the claim; (3) the level of ordinary

skill in the art; and (4) secondary considerations/objective indicators of

nonobviousness. I am advised that a patent claim is unpatentable for obviousness

if the differences between the subject matter sought to be patented and the prior art

are such that the subject matter as a whole would have been obvious at the time the

invention was made to a person of ordinary skill in the art to which the subject

matter pertains. I am further advised that a patent claim is obvious if a person of

ordinary skill in the art would have been motivated to combine the elements of the

claim, in view of the prior art and the state of the art, and would have had a

reasonable expectation of success in doing so. I am advised that the law requires

only a reasonable expectation of success, and does not require absolute certainty of

success.


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26. I am advised that the combination of known elements according to

known methods is likely to be obvious when it does no more than yield predictable

results, and that any need or problem known in the art at the time of the alleged

invention can provide a reason for combining elements. I am further advised that

obviousness is assessed via a common sense approach that is flexible, rather than

adherent to rigid application of legal standards or tests.

27. It is my understanding that obviousness is viewed through the eyes of

a person of ordinary skill in the art as of the time of the invention in question. I am

advised that, for purposes of this proceeding, I should consider only “prior art” in

the form of patents and printed publications which were publicly available and

were published more than a year before the filing date of the earliest application

for the patent. Here, the ’549 patent was filed on February 3, 2003, but is a

continuation of U.S. Patent No. 7,846,441 (“the ’441 patent”), which was filed on

December 10, 1998, and claims priority to Provisional Application No.

60/069,349, which was filed on December 12, 1997. For purposes of this

declaration, I have been asked to assume that patents and printed publications that

were published before December 12, 1996 constitute prior art to the ’549 patent

and may be considered as part of an obviousness analysis in this proceeding.


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V. LEVEL OF ORDINARY SKILL IN THE ART

28. I am advised that in defining a POSA the following factors may be

considered: (1) the educational level of the inventor; (2) the type of problems

encountered in the art; (3) prior art solutions to those problems; (4) rapidity with

which innovations are made; (5) sophistication of the technology; and (6)

educational level of active workers in the field.

29. In my opinion, a person of ordinary skill in the art as of December

1996 would have been an M.D. with subspecialty training in oncology and

substantial experience treating breast cancer patients and/or a Ph.D. with

substantial experience in researching and developing oncologic therapies. Such an

individual would also have had substantial experience in the design and/or

implementation of clinical trials for breast cancer treatments, and/or an active

research role relating to breast cancer treatments.

VI. SCIENTIFIC BACKGROUND

A. Breast Cancer and its Treatment as of December 1996

30. Cancers, including breast cancers, are characterized by the

uncontrolled and often rapid division of cells, caused by mutations in various genes

that are responsible for coordinating cellular processes, including cell division,


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cellular metabolism, and cell death. (Ex. 1005,1 at 1256.) The dividing cells form

a tumor, or a solid mass. The original tumor is called the primary tumor. (Id. at

1258.) Benign tumors are confined to the primary site; malignant tumors have the

ability to “metastasize,” in which some of the tumor cells leave the primary site

and form secondary tumors in other parts of the body. (Id. at 1256.) Cancers that

have metastasized are called “metastatic” or “advanced” cancers.

31. Most breast cancers are carcinomas, which are cancers derived from

epithelial cells.

32. As of December 1996, breast cancer was treated with a

multidisciplinary approach involving pharmaceuticals, radiation and/or surgery.

(Ex. 1016 (Abellof’s)2 at 201-206.) These approaches were often used in

combination. (Id. at 204.) The pharmaceutical treatments used in treating breast

cancer primarily included chemotherapy and hormone therapy. Note that the

treatment of advanced (metastatic) breast cancer is in some ways different from

neoadjuvant treatment (given prior to surgery with the intent of improving the

surgical outcome) or adjuvant treatment (given after surgical resection with the

1 ALBERTS, BRUCE et al., MOLECULAR BIOLOGY OF THE CELL 1255-1294 (3rd. ed.

New York: Garland Publishing, Inc., 1994) (“Albert’s”).

2 Excerpts from CLINICAL ONCOLOGY (Martin D. Abeloff et al., eds., New

York: Churchhill Livingstone, 1995) (“Abeloff’s”).


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intent of eliminating or delaying recurrence of disease). The end points (criteria

for success) will be different in each of these settings.

33. The goal in using most chemotherapeutic agents is to slow the growth

rate or decrease the size of the tumor, either by killing cancer cells by forcing the

cells to undergo a process called “apoptosis,” or by stopping cellular processes,

such as cell division. Apoptosis is the process of programmed cell death that

eliminates damaged or unwanted cells from multicellular organisms. (Ex. 1005 at

1268-1269.) It is also a common mechanism by which cancer drugs kill cancer

cells. Cellular pathways caused by genetic mutations often block apoptosis in

cancer cells, thereby increasing their survival even in the face of abnormalities that

would normally be recognized as cell damage and would therefore normally spur a

cell to undergo apoptosis.

34. Biochemical events of apoptosis lead to characteristic changes in cell

appearance and death. These include loss of cell membrane asymmetry and

attachment, cell shrinkage, nuclear fragmentation, chromatin condensation and

chromosomal DNA fragmentation. Although chemotherapeutics as a class are

designed to attack cells, different chemotherapy drugs achieve this goal in different

ways. Clinical experience has shown that some cancer histotypes respond to some

types of chemotherapies and other histotypes respond to other types of


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chemotherapies. Often, it is the type of cellular mutation that determines which

chemotherapy will work on a given cell.

35. As of December 1996, the following classes of chemotherapeutic

agents were commonly used to treat breast cancer: alkylating agents, including

cyclophosphamide, cisplatin and carboplatin3; antimetabolites, including 5-

fluorouracil and methotrexate; antibiotics, including doxorubicin and epirubicin;

and plant alkaloids, including the taxoids paclitaxel and docetaxel. (Ex. 1016 at

210.) Common use does not necessarily mean that the drug was FDA approved for

treating the specific histotype. Due to medical need, publication of trial results

sometimes outstrips formal drug development and approval processes, and

oncologists sometimes use promising regimens based on robust published data.

36. Each of the above chemotherapy classes has a different mechanism of

action and induces cell death in a different way. Doxorubicin, epirubicin, cisplatin,

paclitaxel and docetaxel were all FDA approved prior to December 1996.

Approval implies that the agent is commercially available for clinical use at the

discretion of the practitioner.

37. The taxoids paclitaxel (Taxol®) and docetaxel (Taxotere®) were FDA-

approved in December 1992 and May 1996, respectively, and were considered

3 Note that in terms of mechanism of antitumor activity, cisplatin and carboplatin

are highly similar; they differ somewhat in clinical toxicity, however.


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among the most promising chemotherapies in the mid-1990s. Taxoids were shown

to successfully treat some cancers that were refractory (non-responsive) to

anthracyclines. (See, e.g., Ex. 1010 (Seidman 1995)4 at 108.) Paclitaxel had anti-

cancer activity in many metastatic breast cancer patients. (Ex. 1010 at 108-111.)

Paclitaxel was used as monotherapy and as part of a combination of active agents

(such as cisplatin) in the treatment of metastatic breast cancer. (Ex. 1013

(Tolcher)5 at 37; Ex. 1007 (Abrams)6 at 1164.)

38. The 1995 Physician’s Desk Reference (“PDR”) entry for TAXOL®

(Ex. 1012 (1995 PDR)7) bears a copyright date of 1995. (Ex. 1012 at 2.) In my

experience, the PDR is a periodical distributed to physicians, which contains

4 A. Seidman et al., Memorial Sloan-Kettering Cancer Center Experience with

Paclitaxel in the Treatment of Breast Cancer, 22(5) SEMINARS ONCOLOGY

(SUPPLEMENT), 108-116 (Oct. 1995). (“Seidman 1995”).

5 Anthony W. Tolcher, Paclitaxel Couplets with Cyclophosphamide or Cisplatin in

Metastatic Breast Cancer, 23(1) Suppl. 1 SEMINARS ONCOLOGY 37-43 (Feb. 1996).

6 J. Abrams et al., New Chemotherapeutic Agents for Breast Cancer, 74(3)

INTERDISCIPLINARY INT. J. AM. CANCER SOC. (SUPPLEMENT), 1164-1176 (Aug.

1994). (“Abrams”).

7 Taxol® (Paclitaxel) for Injection Concentrate, in PHYSICIANS’ DESK REFERENCE,

682-685 (49th ed. 1995). (“1995 PDR”).


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safety, efficacy, and dosing information for drugs approved by the FDA. The

information contained in the PDR is the exact text of the most recent “package

insert” or “label” that has been exhaustively reviewed and approved by the FDA; it

is the most authoritative drug prescribing information available. The PDR is

published annually, and in my experience becomes publicly available to physicians

as of its publication date. In other words, a PDR that bears a copyright date of

1995—like the Taxol excerpt marked as Exhibit 1012—becomes available in 1995.

39. The 1995 PDR entry for Taxol® (paclitaxel) stated that the drug was

“indicated for the treatment of breast cancer after failure of combination

chemotherapy for metastatic disease or relapse within 6 months of adjuvant

chemotherapy. Prior therapy should have included an anthracycline unless

clinically contraindicated.” (Ex. 1012 at 683.) The recommended dosage of

paclitaxel to treat breast cancer was 175 mg/m2, administered intravenously over

the course of three hours, every three weeks. (Id. at 685.) “Mg/m2” and “mg/kg”

are two commonly used measurements of drugs that are dosed based on the surface

area and weight of the patient. Chemotherapeutic and other anti-cancer drugs are

often dosed by mg/m2 or mg/kg.

40. Chemotherapies are designed to kill cells or inhibit cellular functions.

Accordingly, chemotherapeutic agents, by their very nature, are toxic and can

cause a variety of side effects, ranging from minor to severe. Most of these are


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dose-related (more common or severe at higher doses of the drug) and among

these, some toxic effects are cumulative (more common or severe with repeated

treatments with the agent).

41. On the more severe side, the anthracycline class was known to cause

dose-related cumulative toxicity to the heart muscle, or cardiomyopathy. (Ex.

1016 at 810.) The risk of cardiomyopathy caused by anthracyclines was known to

increase with total lifetime dose. (Id.) Clinical evidence of cardiomyopathy

caused by anthracyclines may present immediately upon treatment with the

anthracycline or even years after treatment has stopped. Based on this knowledge,

treating physicians knew to limit the total amount of anthracycline that a patient

receives over a lifetime. (Id. at 813.) Careful monitoring for changes in cardiac

function (LVEF, or left ventricular ejection fraction) by ultrasound was used as a

means of identifying the rare patient whose cardiac function was compromised

earlier in the treatment program at low cumulative doses, or the patient with pre-

existing cardiac dysfunction who would not be a good candidate for anthracycline

treatment. (Id. at 812.)

42. Chemotherapies are most often administered to patients as part of a

regimen of therapies, given over a time period called a treatment cycle. A regimen

of a single agent may consist of infusions or oral doses of that drug on a set

schedule, such as at daily, weekly or monthly intervals. For example, for treating


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metastatic breast cancer, the Taxol® prescribing information recommended a

paclitaxel dose of 175 mg/m2 based on the calculated body surface area of the

patient (a function of height and weight), administered intravenously over the

course of three hours, every three weeks. (Ex. 1012 at 685.) For some regimens,

each infusion may use a different amount of a drug, adjusted depending on how the

patient tolerates the treatment. Regimens of combinations of drugs may consist of

infusions of each of the drugs, each with its own schedule and dosage, but with the

schedules overlapping with each other.

B. Development of Cancer Therapies

43. Before being administered to humans, anticancer drugs are developed

in the laboratory to evaluate their potential safety, efficacy and other properties.

Typically, drug candidates are first assessed in vitro, such as in cell lines and tissue

samples, for potential activity against a target or for potential toxicity. If in vitro

data are promising, the drug may be tested in living animals (e.g., mice, rats, dogs,

etc.) to determine potential toxicity in a live model.

44. “Xenografts” are an in vivo preclinical study method conducted in

living, immunocompromised mice, designed to model a human cancer patient as

closely as possible. (Ex. 1026 (Fiebig)8 at 343-346.) The immunocompromised

8 H.H. Fiebig et al., Comparison of Tumor Response in Nude Mice and in the

Patients, 74 BEHRING INST. MITTEILUNGEN, 343-352 (1984). (“Fiebig”).


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mice are injected with human cancer cells, which are able to grow unabated

because the mice’s immune systems are partially deficient. (Id.) This process

results in mice with “human” tumors, which maintain many features of the human

histotype from which they arose. (Id.) The tumor cells in the mouse undergo the

same cellular processes as the human tumor cells and exhibit the same genetic

mutations that caused the cells to be cancerous in humans. (Id.) Moreover, the

host animal will experience many of the dose-limiting toxic effects of the drug and

will eliminate the drug by processes that are similar to those of the human “species

of interest.” (Id.) Thus, xenografts provide a relatively reliable platform on which

to experiment with new therapies. (Id.)

45. By administering experimental anticancer drugs or drug combinations

to a xenograft animal model, researchers can evaluate activity and toxicity against

the target “human” tumor in a living organism. Thus, xenograft results provide a

“high[ly] correct prediction for resistance and sensitivity of a tumor” to a particular

agent. (Ex. 1026 at 349.) Because this predictive power is reproducible, the

mouse xenograft system validates “human tumor xenografts as tumor models to

test new drugs and combinations.” (Id. at 343; see also, Ex. 1028 (Mattern)9 at

9 Mattern, et al., Human Tumor Xenografts as Model for Drug Testing, 7 CANCER

AND METASTASIS REVIEWS, 263-284 (1988). (“Mattern”).


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279-80 (concluding that xenografts have strong predictive value for testing new

anticancer agents).)

46. Although xenografts are not conclusive evidence of efficacy or

toxicity in humans, they serve as a helpful tool that can provide further evidence of

efficacy or safety that researchers may find informative in developing new

treatments or designing clinical studies. This was true as of December 1996 and

still is today.

C. HER2+ Breast Cancer and Its Treatments

47. By December 1996, it was understood that some breast cancers have a

mutation in the “HER2” gene (also known as the “erbB2” gene). (Ex. 1020

(Baselga 1996)10 at 737.) This mutation causes the cancer cells to “overexpress” a

protein called the “HER2 receptor” (or “ErbB2” receptor). Healthy cells have

many protein receptors on the cell surface, including a limited number of the

HER2 receptor, whereas a cancer cell that “overexpresses” the HER2 receptor has

more copies of the HER2 receptor on the cell surface than a normal cell does.

10 J. Baselga et al., Phase II Study of Weekly Intravenous Recombinant Humanized

Anti-p185HER2 Monoclonal Antibody in Patients with HER2/neu-Overexpressing

Metastatic Breast Cancer, 14(3) J. CLINICAL ONCOLOGY 737-744 (Mar. 1996).

(“Baselga 1996”).


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Breast cancers in which the cancerous cells overexpress the HER2 receptor are

commonly called “HER2+ breast cancer.”

48. As of December 1996, HER2+ breast cancer was understood to

account for 25% to 30% of human breast cancers and known to be aggressive,

associated with a worse prognosis, and particularly difficult to treat with traditional

anti-cancer agents. (Ex. 1020 (Baselga 1996) at 737.)

49. In the 1980s and 1990s, researchers began to focus on antibody

therapy for cancer. (Ex. 1015 (Pietras 1994)11 at 1829-1830.) Other chemotherapy

drugs kill cells by interrupting normal cellular processes, and are therefore not

specifically targeted to cancer cells. In contrast, antibody therapy is targeted to

specific proteins that may be abnormally overexpressed in a given histotype of

cancerous cells.

50. First developed in late 1980s, trastuzumab is an antibody that targets

the HER2 receptor. Trastuzumab is a humanized version of 4D5, a murine

(mouse) antibody against the HER2 receptor that had been found, in vitro and in

xenograft models, to be a potent inhibitor of growth of HER2+ human breast

cancer cells. (Ex. 1020 (Baselga 1996) at 737.) Because murine antibodies are

11 R. J. Pietras et al., Antibody to HER-2/neu Receptor Blocks DNA Repair After

Cisplatin in Human Breast and Ovarian Cancer Cells, 9 ONCOGENE, 1829-1838

(1994). (“Pietras).


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immunogenic in humans and therefore of limited clinical use, 4D5 was

“humanized” to facilitate clinical investigations and use. (Id.) Trastuzumab,

which was at the time was commonly known as “rhuMAb HER2” or “humanized

4D5,” was found to be safe in two phase I clinical trials before 1996. (Id.)

51. As discussed below, as of December 1996, the prior art had reported

that both trastuzumab and paclitaxel were clinically effective against metastatic

HER2+ breast cancer, preclinical studies of this combination against this type of

cancer were very promising, and clinical trials of this combination were already

underway.

52. Trastuzumab was ultimately approved by the FDA in 1998 as

Herceptin® for the treatment of metastatic HER2+ breast cancer, either as a single

agent or in combination with chemotherapeutic drugs.

1. Baselga 1996 (Ex. 1020)

53. In March 1996, researchers at Memorial Sloan Kettering Cancer

Center (“MSKCC”) and Genentech published an article, Baselga 1996, in the

Journal of Clinical Oncology that reported the results of a phase II clinical trial of

trastuzumab. (Id. at 737.) In 1996, I was personally familiar with the Journal of

Clinical Oncology. It was directed to cancer researchers. It published monthly,

with issues becoming available during the month of their publication. For

example, the March 1996 issue became available to readers in March 1996. In


25

1996, this journal was widely available to and consulted by POSAs around the

world, including in the United States.

54. The clinical trial in Baselga 1996 included 46 patients who had

extensive metastatic breast carcinoma, “one of the most dire prognostic

characteristics regarding response to therapy.” (Id. at 741.) All of the patients’

cancers were HER2+ breast cancer. (Id. at 738.) The patients were treated with an

initial dose of 250 mg of trastuzumab on day 0, and beginning on day 7, 100 mg of

trastuzumab weekly for a total of 10 doses. (Id. at 738.)

55. The study reports that 43 of the 46 patients were “assessable” (one

had died, one had developed a bacterial infection that precluded treatment, and one

declined treatment). Of these, five patients had tumor responses, including one

complete remission and four partial remissions. “Two patients had minor

responses and 14 patients had stable disease at day 77… The median time to

progression for the patients with either minor or stable disease was 5.1 months.”

(Id. at 740.)

56. Baselga 1996 reports that “[t]reatment with rhuMAb HER2 [i.e.,

trastuzumab] was remarkably well tolerated.” (Id. at 739.) The study reported

adverse events of fever and chills, pain at tumor site, diarrhea, nausea and emesis.

Of these, most were “moderate,” with a rating of “Grade 2,” and one was “severe,”

with a rating of “Grade 3.” (Id. at 740.)


26

57. Baselga 1996 states that “[t]hese data are specially interesting in light

of the absence of significant toxicity observed here, for in a setting in which

palliation is a main objective, quality of life while on treatment should be a main

end point.” (Id. at 741.)

58. Baselga 1996 concludes: “In preclinical studies, both in vitro and in

xenografts, rhuMAb HER2 [i.e., trastuzumab] markedly potentiated the antitumor

effects of several chemotherapeutic agents, including cisplatin, doxorubicin, and

paclitaxel, without increasing their toxicity. Laboratory studies of the mechanism

of this effect and clinical trials of such combination therapy are currently in

progress.” (Id. at 743.) Baselga 1996 cites Baselga Abstract 53, discussed further

below, in support of this statement about the preclinical results for the

trastuzumab/paclitaxel and trastuzumab/doxorubicin combinations. (Id.)

2. Seidman 1996 (Ex. 1011)

59. Some of the same researchers from MSKCC published data on

paclitaxel’s clinical activity against HER2+ breast cancer in an abstract, Seidman

199612 (Ex. 1011), that was submitted for the 32nd Annual Meeting of the

American Society of Clinical Oncology (“ASCO”) in May 1996 and published in

12 A. Seidman et al., Over-Expression and Clinical Taxane Sensitivity: A

Multivariate Analysis in Patients with Metastatic Breast Cancer (MBC), 15 PROC.

AM. SOC. CLINICAL ONCOLOGY 104, abs. 80 (Mar. 1996). (“Seidman 1996”).


27

the Programs/Proceedings book for the meeting in May 1996. I am very familiar

with the annual ASCO meetings, which thousands of oncology specialists and

cancer researchers attend each year. I typically attend the ASCO annual meeting,

and know that copies of the Programs/Proceedings book are distributed to

attendees during or before the meetings. I submitted an abstract for the May 1996

ASCO meeting, and attended the meeting. I, along with other persons of ordinary

skill in the art, received a copy of Programs/Proceedings book during or prior to

that meeting, which is before the December 1996 date that is important to this

proceeding.

60. Seidman 1996 reports on treatment of metastatic breast cancer

patients with paclitaxel. Fifty-one of the 126 (40.5%) patients studied had HER2+

breast cancer, while the others had cancer that did not overexpress the HER2

protein. (Id.) Thirty of the 51 (58.8%) patients with HER2+ breast cancer

responded to treatment with paclitaxel. (Id.) Twenty-nine of the 75 (38.7%)

patients with non-HER2+ breast cancer responded to treatment. (Id.) That is, a

higher percentage of patients were found to respond to treatment with paclitaxel

for HER2+ breast cancer than for non-HER2+ breast cancer. Seidman 1996

concludes: “Thus, HER2 over-expression in MBC [metastatic breast cancer] seems

to confer sensitivity rather than resistance to taxanes, in spite of a positive


28

correlation of HER2 positivity with poor prognostic features. Cellular mechanisms

for this effect are under investigation.” (Id.)

3. Pegram 1995 (Ex. 1022)

61. In 1995, some of the same researchers from MSKCC and Genentech,

together with researchers from other institutions including UCLA, published data

on the clinical activity of the combination of trastuzumab and cisplatin against

HER2+ breast cancer. This data was submitted in an abstract, Pegram 199513 (Ex.

1022), for the 31st Annual Meeting of ASCO in May 1995 that was published in

the Programs/Proceedings book for the meeting in March 1995. I submitted an

abstract for the May 1995 ASCO meeting, and attended the meeting. I, along with

other persons of ordinary skill in the art received a copy of Programs/Proceedings

book during or prior to that meeting, which is before the December 1996 date that

is important to this proceeding.

62. Pegram 1995 begins by explaining that “[p]hase I studies conducted at

UCLA show that rhuMAb HER-2 [i.e., trastuzumab] has no substantial toxicity at

any dose level and localizes to malignant cells overexpressing the HER-2 receptor

13 M. Pegram et al., Phase II Study of Intravenous Recombinant Humanized Anti-

p185 HER-2 Monoclonal Antibody (rhuMAb HER-2) Plus Cisplatin in Patients

with HER-2/NEU Overexpressing Metastatic Breast Cancer, 14 PROC. AM. SOC.

CLINICAL ONCOLOGY 106, abs. 124 (Mar. 1995). (“Pegram 1995”).


29

protein.” (Ex. 1022 (Pegram 1995).) The abstract then states that “[i]n preclinical

studies, therapy with this antibody plus cisplatin (CDDP) elicits a synergistic and

cytocidal effect on tumor cells which overexpress p185HER-2/neu.” (Id.)

63. Pegram 1995 reports a phase II, open-label, multicenter clinical trial

of the combination of trastuzumab and cisplatin in patients with metastatic HER2+

breast cancer. (Ex. 1022.) The patients received 75 mg/m2 of cisplatin on days 1,

29, and 57, and received a 250-mg loading dose of trastuzumab followed by

weekly doses of 100 mg for 8 weeks. (Id.) This trastuzumab regimen in this trial

was the same as that used in the Baselga 1996 trastuzumab-only trial (except that

the patients were treated for 10 weeks total in Baselga 1996, but 9 weeks total in

Pegram 1995). (Id.; Ex. 1020 (Baselga 1996) at 738.)

64. Of 36 patients treated in the study, one had a complete response and

seven had partial responses. (Ex. 1022 (Pegram 1995).) Pegram 1995 further

reports: “The toxicity profile was that expected from [cisplatin], and there were no

acute serious adverse events recorded following treatment with rhuMAb HER-2

[i.e., trastuzumab].” (Id.)

65. Pegram 1995 concludes that the “use of rhuMAb HER-2 [i.e.,

trastuzumab] plus CDDP [i.e., cisplatin] in patients with HER2/neu overexpressing

MBC [metastatic breast cancer] resulted in response rates above that expected from

CDDP alone, and the combination showed no apparent increase in toxicity.” (Id.)


30

4. Preclinical Studies

66. In addition to the clinical evidence of efficacy for treating metastatic

HER2+ breast cancer of (1) trastuzumab alone, (2) paclitaxel alone, and (3) the

trastuzumab/cisplatin combination, preclinical data in mouse xenograft models also

supported the combined use of trastuzumab and paclitaxel for metastatic HER2+

breast cancer.

a. Baselga Abstract 53 (Ex. 1019)

67. In 1994, some of the same researchers from MSKCC and Genentech,

submitted an abstract, Baselga Abstract 5314 (Ex. 1019), for the 30th Annual

Meeting of ASCO in May 1994 that was published in the Programs/Proceedings

book for the meeting in May 1994. I submitted an abstract for the May 1994

ASCO meeting and attended that meeting. I, along with other persons of ordinary

skill in the art received a copy of Programs/Proceedings book during or prior to

that meeting, which is before the December 1996 date that is important to this

proceeding.

68. Baselga Abstract 53 reports a study of “humanized anti-HER2 4D5

against HER2” (i.e., trastuzumab) and other chemotherapeutic agents, alone and in

14 J. Baselga et al., Anti HER2 Humanized Monoclonal Antibody (MAb) Alone and

in Combination with Chemotherapy Against Human Breast Xenografts, 13 PROC.

AM. SOC. CLINICAL ONCOLOGY 63, abs 53 (Mar. 1994). (“Baselga Abstract 53”).


31

various combinations, against HER2+ breast carcinoma xenografts. (Ex. 1019

(Abstract 53).) Baselga Abstract 53 reports the following results:

Treatment Result As Compared to Placebo Trastuzumab 35% growth inhibition at 5 weeks

Paclitaxel 35% growth inhibition at 5 weeks Doxorubicin 27% growth inhibition at 5 weeks

Trastuzumab and paclitaxel 93% growth inhibition at 5 weeks Trastuzumab and doxorubicin 70% growth inhibition at 5 weeks

69. As indicated above, each of trastuzumab and paclitaxel, when used

alone, inhibited tumor growth by 35%. The combination of

trastuzumab/paclitaxel, however, “resulted in a major antitumor activity with 93%

inhibition of growth” inhibited tumor growth by 93%. (Id.) The

trastuzumab/paclitaxel results were more promising than for the

trastuzumab/doxorubicin combination, which resulted in 70% tumor inhibition,

though “[c]omplete tumor eradication was seen in both groups.” (Id.) As a

possible explanation for the better results seen with the combinations, the authors

postulate that “[t]hese observations suggest that dual insults to cell cycle

transversal through checkpoints (MAb-mediated growth factor deprivation, and

drug mediated damage to DNA or tubulin) may activate cell death in tumor cells

which can survive either treatment given singly.” (Id.)

70. Baselga Abstract 53 further states that “MAb 4D5 [i.e., trastuzumab]

did not increase the toxicity of paclitaxel or doxorubicin in animals as determined

by animal survival and weight loss.” (Id.)


32

71. Baselga Abstract 53 concludes: “In summary, anti HER2 MAbs can

eradicate well established tumors and enhance the activity of paclitaxel and

doxorubicin against human breast cancer xenografts. Clinical trials are underway.”

(Id.)

b. Baselga Abstract 2262 (Ex. 1021)

72. The MSKCC and Genentech researchers also published this same

xenograft study in an abstract, Baselga Abstract 226215 (Ex. 1021), for the 85th

Annual Meeting of the American Association for Cancer Research in April 1994

that was published in the Proceedings book for the meeting in March 1994. I am

very familiar with the annual AACR meetings and I often attend those meetings,

including prior to 1994. In 1994 and today, this meeting is well-attended by

oncology specialists and cancer researchers. I know that copies of the

Programs/Proceedings book are distributed to attendees during or before the

meetings. I also know that copies of the Programs/Proceedings book are available

once published by contacting the AACR. In the case of Baselga Abstract 2262, the

Programs/Proceedings book was also available for purchase as of April 1994,

15 J. Baselga et al., Antitumor Activity of Paclitaxel in Combination with Anti-

growth Factor Receptor Monoclonal Antibodies in Breast Cancer Xenografts, 35

PROC. AM. ASSOC. CLINICAL CANCER RES. 380, abs. 2262 (Mar. 1994). (“Baselga

Abstract 2262”).


33

which is before the December 1996 date that is important to this proceeding. (See

Ex. 1021 at 2, copyright notice.) Based on my experience attending AACR

meetings, I believe that all registered attendees at that March 1994 meeting, many

of whom were persons of ordinary skill in the art, received copies of the

Programs/Proceedings book at or prior to that meeting.

73. Baselga Abstract 2262 reports the same xenograft data that were

published in Baselga Abstract 53.16 With regard to the combinations in the study,

Baselga Abstract 2262 states: “The combined treatment with paclitaxel plus 4D5

[i.e., trastuzumab] resulted in a major antitumor activity with 93% inhibition of

growth. This result was markedly better than doxorubicin plus 4D5 (70%

inhibition).” (Exhibit 1021.)

74. Baselga Abstract 2262 additionally states: “Thus, equipotent doses of

paclitaxel and doxorubicin differed in their combined effect with ARMAs [anti-

16 Baselga Abstract 2262 does not specify that the antibody was the humanized

version of 4D5. However, in my opinion, a POSA would have known that Baselga

Abstract 2262 was reporting results of a study using humanized 4D5. The study

reported in Baselga Abstract 2262 is the same study reported in Baselga Abstract

53, which does specify the use of the humanized antibody. The results reported in

the two abstracts are identical.


34

growth factor receptor monoclonal antibodies, which includes 4D5], which

suggests synergy between paclitaxel and 4D5.” (Id.)

75. Like Baselga Abstract 53, Baselga Abstract 2262 also reports:

“ARMAs did not increase the toxicity of paclitaxel in animals as determined by

animal survival and weight loss.” (Id.)

76. Baselga Abstract 2262 concludes: “The antitumor effects of

paclitaxel can be markedly enhanced by the addition of ARMAs. Mechanisms are

being explored.” (Id. (emphases added).)

c. Seidman 1995 (Ex. 1010)

77. The MSKCC researchers also published an article, Seidman 1995 (Ex.

1010), in Seminars in Oncology in October 1995. The Seminars in Oncology

journal, published every two months, is well respected in the field of oncology and

has been since before December 1996.

78. Seidman 1995 primarily concerns the development of paclitaxel,

including the development via routine trial and error of the optimal dosing

schedule for paclitaxel given as a single agent. (Ex. 1010 (Seidman 1995) at 110-

111.)

79. Seidman 1995 also discusses the development of paclitaxel-based

combination therapies, including combinations of paclitaxel with doxorubicin,

cisplatin, and trastuzumab. (Id. at 111-112.) Citing references including Baselga


35

Abstract 2262 (ref. 21), Seidman 1995 states: “Since 1992, we and others have

developed strong experimental data suggesting that combining maximally tolerated

doses of chemotherapeutic agents with MoAb-mediated blockade of either EGFR

or HER-2/neu receptors [e.g., trastuzumab] can eradicate well-established human

tumor xenografts that were resistant to either treatment given singly.” (Id. at 112.)

Seidman 1995 further states: “Striking antitumor effects are observed when

paclitaxel is given in human breast cancer xenografts in combination with either

anti-EGFR or anti-HER-2 MoAbs [e.g., trastuzumab]. This strong synergy is

achieved with no increased toxicity in the animal model.” (Id.)

80. That section of Seidman 1995 concludes: “While mechanisms for the

apparent synergy are being explored, these data provide a lead for translation into

the clinic. Indeed, future clinical trials combining paclitaxel with anti-growth

factor receptor MoAbs [(e.g., trastuzumab)] are being planned.” (Id.)

81. In summary , Seidman 1995 states that the “striking antitumor”

effects, “strong synergy” and “no increased toxicity” of paclitaxel and trastuzumab

in xenograft models “provide a lead for translation into the clinic” and that such

“future clinical trials” of the trastuzumab/paclitaxel combination “are being

planned.” (Id.)


36

D. Combination Therapy for Breast Cancer

82. Treating cancer with a combination of therapeutic agent has been

established and common practice since the 1960s. (Ex. 1006 (DeVita) at 278-279;

Ex. 1016 at 208.)

83. A person of ordinary skill in the art understood that different cancers

respond to different types of therapies. A person of ordinary skill in the art also

understood that tumors can exhibit “intra-tumor heterogeneity,” in which, within a

single tumor, different cells may have different mutations that support the cancer

phenotype. (See, e.g., Ex. 1005 at 1271; Ex. 1020 at 738 (“Tumors were

considered to overexpress HER2 if at least 25% of tumor cells” were shown to

overexpress that receptor.).) Therefore, the different cells within a single tumor

may respond to different types of therapy.

84. Further, a person of ordinary skill in the art understood that tumors

that may initially respond to one type of therapy may develop “resistance” to that

therapy and no longer respond, simply due to the selection and preferential survival

of resistant cells. (Ex. 1005 at 1267, 1271-1273.) These resistant cells may

become sensitized to respond to different therapies in a process called “collateral


37

sensitivity.” (Ex. 102517 at 246.) Another resistance-related phenomenon is

“cross-resistance,” whereby prolonged treatment with one anticancer drug can also

cause the cancer to develop resistance, not just to the drug being administered, but

also to other drugs within the same class. (Id.)

85. The following is a hypothetical for illustration purposes: A single

tumor includes cancerous cells, 90% of which are responsive to “type A”

chemotherapy, but 10% of which are resistant. In the best case scenario, therefore,

only 90% of the cells in the tumor will be killed by treatment with “type A”

chemotherapy, and 10% will survive. In a more realistic scenario, even some of

the 90% of cells that should respond to “type A” chemotherapy do not respond.

These cells, via a “resistance mechanism,” adapt to treatment with “type A,” and

mutate such that they are no longer of the type that would respond to “type A”

chemotherapy. These cells may also develop sensitivity to “type B”

chemotherapy. The 10% of cells that do not respond to “type A” and the small

fraction of the 90% that mutated continue to replicate, and the tumor grows with

cells that are resistant to “type A” chemotherapy. Therefore, treatment with just

17 Dorris J. Hutchison, Cross Resistance and Collateral Sensitivity Studies in

Cancer Chemotherapy, in 7 ADVANCES IN CANCER RESEARCH 235-348 (Alexander

Haddow and Sidney Wienhouse eds., Academic Press 1963). (“Hutchinson”).


38

one type of chemotherapy is often not sufficient to kill all of the cells in a given

tumor and to stop the tumor from growing.

86. Because of the various mutations that may occur in a tumor and that

may arise in a tumor as a result of treatment, it is very uncommon for a single

treatment to be effective in killing all of the cells of the tumor. (Ex. 1006 at 279-

281.)

87. This complicated web of mutations and resistance mechanisms arises

in cells in a dynamic process that is interactive with treatment. A person of

ordinary skill in the art would have understood that combination therapy gave

patients their best chance of surviving cancer because a combination of drugs

allows the therapy to attacks cells in different ways at the same time. (Ex. 1016 at

204 (“The optimal exploitation of the chemotherapy strategies discussed earlier

requires the use of combination chemotherapy, because with rare exceptions single

agents do not cure cancer…The superior results achieved by combination

chemotherapy can be explained in several ways. Resistance to any given single

agent is almost always present, even in clinically responsive tumors, at

diagnosis. Tumors that are initially ‘sensitive’ rapidly acquire resistance to single

agents either as a result of selection of a pre-existing clone of resistant tumor cells

or due to an increased rate of mutation leading to drug resistance. Combination

chemotherapy theoretically addresses both important phenomena by providing a


39

broader range of coverage of initially resistant clones of cells and preventing or

slowing the development of resistant clones.”).)

88. Thus, physicians and researchers use combinations of drugs to treat

cancer, based on the understanding that within a single tumor, the different cells

will respond to different drugs, and total efficacy of the combination will be

greater than the efficacy of single agents used alone. (Ex. 1006 at 208.) This was

true as of December 1996, and remains true today.

89. In developing new combinations of drugs, a person of ordinary skill in

the art relied on a set of four reasoned principles. (Ex. 1016 at 204-205.) First,

each drug in the combination should have exhibited efficacy in the target

population (histotype) when used alone. This principle ensures that only drugs that

are expected to work are used in combinations. (Id.) Second, the drugs in the

combinations should have non-overlapping toxicities. This principle ensures, as

much as possible, that any particular type of toxicity is not unduly severe or

frequent; ideally, this allows full doses of each of the drugs to be combined in the

regimen. (Id.) Third, the drugs in the combination should have different

mechanisms of action (addressing different oncogenic abnormalities), and fourth,

the drugs in the combination should have different resistance mechanisms. The

third and fourth principles ensure that the combination treatment is effective

against cells with as many types of cellular mutations as possible, whether those


40

mutations were within original tumor cells, or arose via a resistance mechanism.

(Id.) I have lectured extensively on the development of combination therapies and

these principles, before December 1996 and continuing through today.

90. These principles of combination therapy are generally applicable to

anti-cancer drugs. The principles apply to all types of anti-cancer therapy

(including antibody therapy) in the same way that they apply to chemotherapy.

Some scientific literature in the early to mid-1990s focused on developing

combination therapies with paclitaxel, and illustrates the use of these principles.

For example, Arbuck 1994, a review article, succinctly describes the principles

behind combination therapy: “The best therapeutic results in cancer chemotherapy

are usually achieved with combinations of two or more drugs. When possible,

efforts are made to combine full doses of non-cross resistant drugs with single-

agent activity, differing mechanisms of action, and nonoverlapping toxicity.” (Ex.

102418 at 130-131 (emphasis added to point out the four principles of combination

therapy); see also, Ex. 1013 at 37 (“[p]aclitaxel combined with either

cyclophosphamide or cisplatin has several potential advantages: cisplatin and

cyclophosphamide are active single agents against previously untreated metastatic

breast cancer, colony-stimulating factors can modulate overlapping toxicities like

18 S. Arbuck et al., Paclitaxel (Taxol) in Breast Cancer, 8(1) HEMATOLOGY

ONCOLOGY CLINICS NORTH AM., 121-140 (Feb. 1994). (“Arbuck 1994”).


41

myelosuppression, and no mechanisms of cross-resistance between paclitaxel and

these agents are yet known.”) (emphasis added).) Once paclitaxel had been shown

to be effective in treating metastatic breast cancer, “the logical progression for the

clinical development of this agent includes combination studies of paclitaxel and

other drugs that possess proven activity against breast cancer.” (Id.) The

development of combination therapies with paclitaxel was “logical” because

persons of skill in the art understood that cancer is most effectively treated with

combinations of more than one drug.

91. Consistent with the development of combination therapies for

paclitaxel in the years following the initial positive results with that drug,

combination therapies for trastuzumab were also under development as of

December 1996, following the initial positive clinical results for the individual

agent and positive preclinical results for the combinations, including the

trastuzumab/paclitaxel combination. For example, Baselga 1996, Abstract 2262

and Seidman 1995 report that clinical trials with the combination of trastuzumab

and chemotherapeutic agents, including paclitaxel, were underway or being

planned.

E. Measurements of Efficacy for Cancer Treatments

92. Cancer treatments are typically evaluated for efficacy using one or

more of the following clinical endpoints in clinical trials: (1) Overall Survival


42

(“OS”), which measures the median survival time of the treated population, and is

the “gold standard” of efficacy; this is not to be confused with point estimates of

survival rate, the percentage of patients alive at a defined time after initiation of the

treatment (for example, one-year or five-year survival rate). (2) Progression Free

Survival (“PFS”), which measures the median time from initiation of treatment

until progression , death or loss to follow-up; PFS incorporates all deaths

regardless of cause and is a preferred surrogate end-point for OS. (3) Time to

Tumor Progression (“TTP”), which measures the median time from diagnosis or

start of treatment until tumor progression, but censors deaths that are not related to

cancer, and also censors loss to follow-up or withdrawal of the patient from the

study. (4) Disease-Free Survival (“DFS”), which measures the median time from a

potentially curative intervention (such as surgery) until recurrent cancer is seen or

until death or loss to follow-up. (5) Response Rate (“RR”), which measures the

percentage of patients whose tumor is reduced in size by a specified amount

following treatment. (Ex. 1023 (ASCO Guidelines)19 at 671-677.) OS, PFS, TTP

and DFS parameters are collectively called “time-to-event” end points, and are

thus more or less dependent on the determination of the specific event involved.

19 Outcomes of Cancer Treatment for Technology Assessment and Cancer

Treatment Guidelines, 14(2) J. CLINICAL ONCOLOGY, 671-679 (Feb. 1996). (“ASCO

Guidelines”).


43

93. The World Health Organization (“WHO”) system that was in use

prior to 2000 classifies responses of solid tumors as either (1) Complete Response

(“CR”), characterized by the disappearance of all clinical evidence of disease and

normalization of disease symptoms and clinical markers, shown on two

measurements taken at least 4 weeks apart; (2) Partial Response (“PR”), defined as

a reduction of ≥50% in the sum of the cross products (the products of the longest

dimension times the longest perpendicular dimension) of all measurable tumor

masses, and no new lesions appearing; (3) Progressive Disease (“PD”), defined as

an increase of 25% or more in the sum of the cross products of all measurable

tumor masses, or new lesions; and (4) Stable Disease (“SD,” also called Minor

Response or “MR”), characterized by tumor size which over a pre-defined period

(usually two cycles) does not change enough to be classified as PR or PD. (Ex.

102920 at 211-212.) It was common to report clinical trial results in terms of

Objective Response Rate (“ORR”), which is the sum of the CR rate and the PR

rate. Reporting “clinical benefit,” the sum of CR, PR and MR, is sometimes done.

Special considerations are applied to lesions in bone or to lesions that are not

bidimensionally measurable.

20 Miller, A. B. et al., Reporting Results of Cancer Treatment, 47 CANCER, 207-

214 (Jan. 1981). (“Miller”)


44

94. Overall survival is an ideal endpoint for showing efficacy, but it can

be difficult to establish due to the short duration of a clinical trial. For Phase 2

studies, which have the purpose of detecting useful clinical activity that can be

confirmed by definitive Phase 3 trials, response rate is normally employed.

Progression-free survival and time to disease progression are often used as

surrogates for overall survival, depending on the setting. Historical data has shown

that an increase in progression free survival or time to disease progression often

(but not always) correlates with an increase in overall survival. (Id. at 212.)

VII. U.S. PATENT NO. 7,892,549

A. The Specification of the ’549 Patent

95. The abstract of the ’549 patent states: “The present invention

concerns the treatment of disorders characterized by the overexpression of ErbB2.

More specifically, the invention concerns the treatment of human patients

susceptible to or diagnosed with cancer overexpressing ErbB2 with a combination

of an anti-ErbB2 antibody and a chemotherapeutic agent other than an

anthracycline, e.g., doxorubicin or epirubicin.” (Ex. 1001,21 Abstract.)

96. The specification states that Baselga 1996 showed that trastuzumab

“has been clinically active in patients with ErbB2-overepressing metastatic breast

cancers.” (Id., 3:36-42.) Further, overexpression of ErbB2 “is commonly regarded

21 U.S. Patent No. 7,892,549.


45

as a predictor of a poor prognosis…and has been linked to sensitivity and/or

resistance to hormone therapy and chemotherapeutic regimens.” (Id., 3:43-52.)

However, according to the specification, HER2+ patients were three times as more

likely to respond to treatment with taxanes than patients whose tumors did not

overexpress HER2. (Id., 3:52-56.) Preclinical studies had shown that trastuzumab

enhanced the activity of each of paclitaxel and doxorubicin in mouse xenografts,

an in vivo test that closely models human cancers. (Id., 3:56-61.)

97. The specification includes an Example that describes a study in which

patients with HER2+ breast cancer were treated with one of four treatment

regimens: (1) anthracycline + cyclophosphamide (“AC”); (2) anthracycline +

cyclophosphamide + trastuzumab (“AC + H”); (3) paclitaxel (“T”); (4) paclitaxel +

trastuzumab (“T + H”). (Id., 26:34-30:25.) The patent reports the following

results for TTP in months, RR in percent, and AE (adverse events) in percent:22

Treatment Number of patients

TTP (months) RR (%) AE(%)

AC 145 6.5 42.1. 71 AC + H 146 9.0 64.9 68

T 89 4.2 25.0 59 T + H 89 7.1 57.3 70

22 The patent also reports results for “CRx” (chemotherapy) and “CRx + H.”

“CRx” is the combined data for “AC” and “T,” and “CRx + H” is the combined

data for “AC + H” and “T + H.”


46

(Id., 29:11-30:12.) The specification states that “[a] syndrome of myocardial

dysfunction similar to that observed with anthracyclines was reported more

commonly with a combined treatment of AC+H (18% Grade 3/4) than with AC

alone (3%), T (0%), or T+H (2%).” (Id. at 30:13-25.) The specification states that

the results favor the combination of trastuzumab and paclitaxel:

These data indicate that the combination of anti-ErbB2 antibody

treatment with chemotherapy markedly increases the clinical benefit,

as assessed by response rates and the evaluation of disease

progression. However, due to the increased cardiac side-effects of

doxorubicin or epirubicin, the combined use of anthracyclines with

anti-ErbB2 antibody therapy is contraindicated. The results, taking

into account risk and benefit, favor the combined treatment with

HERCEPTIN® and paclitaxel (TAXOL).

(Id.)

B. The Claims of the ’549 Patent

98. The ’549 patent has 17 claims. Claims 1, 5, and 16 are independent

claims. Claims 2-4 depend from claim 1, claims 6-15 depend from claim 5, and

claim 17 depends from claim 16. I understand that Celltrion’s Petition for inter

partes review challenges all of the claims other than claims 12 and 13. Claims 1-

11 and 14-17 are reproduced below.


47

1. A method for the treatment of a human patient with breast cancer

that overexpresses ErbB2 receptor, comprising administering a

combination of an antibody that binds ErbB2, a taxoid, and a further

growth inhibitory agent to the human patient in an amount effective to

extend the time to disease progression in the human patient, wherein

the antibody binds to epitope 4D5 within the ErbB2 extracellular

domain sequence.

2. The method of claim 1 wherein the antibody is a humanized 4D5

anti-ErbB2 antibody.

3. The method of claim 1 wherein the antibody cross-blocks binding

of 4D5 to the ErbB2 extracellular domain sequence.

4. The method of claim 1 wherein the antibody binds to amino acid

residues in the region from about residue 529 to about residue 625 of

the ErbB2 extracellular domain sequence.

5. A method for the treatment of a human patient with breast cancer

characterized by overexpression of ErbB2 receptor, comprising

administering an effective amount of a combination of an anti-ErbB2

antibody which binds epitope 4D5 within the ErbB2 extracellular

domain sequence, a taxoid, and a further therapeutic agent, to the

human patient.

6. The method of claim 5 wherein the breast cancer is metastatic

breast carcinoma.


48

7. The method of claim 5 wherein the antibody is a humanized 4D5

anti-ErbB2 antibody.

8. The method of claim 7 wherein the antibody is administered as a 4

mg/kg dose and then weekly administration of 2 mg/kg.

9. The method of claim 5 wherein the taxoid is paclitaxel.

10. The method of claim 5 wherein efficacy is measured by

determining the time to disease progression or the response rate.

11. The method of claim 5, wherein the further therapeutic agent is

selected from the group consisting of: another ErbB2 antibody, EGFR

antibody, ErbB3 antibody, ErbB4 antibody, vascular endothelial

growth factor (VEGF) antibody, cytokine, and growth inhibitory

agent.

14. The method of claim 5 wherein the further therapeutic agent is a

growth inhibitory agent.

15. The method of claim 14 wherein the growth inhibitory agent is a

DNA alkylating agent.

16. A method for the treatment of a human patient with ErbB2

overexpressing breast cancer, comprising administering a combination

of an antibody that binds epitope 4D5 within the ErbB2 extracellular


49

domain sequence, a taxoid and a further growth inhibitory agent, in

the absence of an anthracycline derivative, to the human patient in an

amount effective to extend the time to disease progression in the

human patient.

17. The method of claim 16 wherein the breast cancer is metastatic

breast carcinoma.

C. Prosecution History of the ’549 Patent

99. Below, I describe the obviousness arguments presented by the

Examiner, as well as the pertinent details of (1) a declaration by one of the ’549

patent’s named inventors, Susan D. Hellmann, M.D., M.P.H. (“Hellmann

Declaration” (Ex. 1008)), that Patent Owner submitted in the parent application

(for the ’441 patent) on August 25, 2000, and again relied on in the prosecution of

the ’549 patent on September 12, 2006 in response to the Examiner’s first

obviousness rejection of the application’s claims, and (2) a declaration from a

Genentech employee, Mark X. Sliwkowski, Ph.D.23 (“Sliwkowski Declaration”

(Ex. 1009)), that Patent Owner submitted on October 15, 2009 to respond to the

Examiner’s fourth (and last) obviousness rejection of the application’s claims.

23 Declaration of Mark X. Sliwkowski, Ph. D. (Dec. 10, 1998). (“Sliwkowski

Declaration”).


50

100. Based on my reading of the prosecution history of the ’549 patent (Ex.

1004),24 I understand that (1) the Examiner did not ultimately find the arguments in

the Hellmann Declaration persuasive, and that the ’549 patent did not issue as a

result of the Hellmann Declaration (Ex. 1008; see also Ex. 1004 at 1550), and (2)

that the Examiner withdrew the obviousness rejections and ultimately issued the

’549 patent as a result of the statements made in the Sliwkowski Declaration (Ex.

1009; see also Ex. 1004 at 2351).

101. The claims of the ’549 patent are similar to the claims that were

pending for most of the prosecution of the patent application. In general, those

claims were drawn to a method of treating a human patient who has HER2+ breast

cancer with a combination of trastuzumab, paclitaxel, and a third anti-cancer agent.

I understand that during prosecution, the Patent Owner elected to treat carboplatin

as the third anti-cancer agent for examination purposes (Ex. 1004 at 1396

(02/16/2006 Office Action at 2); 1406 (03/16/2006 Response at 5)), and so the

Examiner concentrated on the combination of trastuzumab, paclitaxel, and

carboplatin for many of the rejections (id. at 1419, 1788, 1839 (Office Actions

dated 06/02/2006, at 2; 06/26/2008, at 2; 03/20/2009, at 2)).

102. In a series of rejections, the Examiner rejected the claims on a number

of grounds, including as obvious over the prior art. Although the exact

24 Ex. 1004 is the Prosecution History of the ’441 patent.


51

combination of prior art references that the Examiner relied on as the basis of the

obviousness rejections sometimes differed from one rejection to the next, the

obviousness rejections were all very similar. First, the Examiner found that it was

known in the prior art that trastuzumab had shown anti-tumor efficacy in clinical

studies with patients who were suffering from HER2+ breast cancer. Second, it

was known in the prior art that the combination of trastuzumab and paclitaxel had

resulted in a synergistic antitumor response in preclinical mouse xenograft studies.

Third, the examiner found that it was known that the combination of paclitaxel and

carboplatin may be used to treat patients with advanced breast cancer. Therefore,

according to the Examiner, it would have been obvious to a person of ordinary skill

in the art to combine the therapies of trastuzumab, paclitaxel, and carboplatin and

to use that combination to treat human patients who had HER2+ breast cancer.

103. In response to these obviousness rejections, the Patent Owner relied

upon and resubmitted the Hellmann Declaration from the parent application. (Ex.

1008; see also Ex. 1004 at 1456, 1522-25, 1550-615.) In that declaration, Dr.

Hellmann opined that the claimed combination of drugs produced a synergistic

clinical response in human patients and that this response was unexpected. (Ex.

1008 at ¶¶ 3-6.) She also opined that the combination of trastuzumab and

doxorubicin resulted in unacceptable increased cardiac toxicity, and that the

absence of such increased toxicity with the trastuzumab/paclitaxel combination


52

was unexpected. (Id., ¶ 7.) The Patent Owner argued that these two allegedly

unexpected results rendered the claims non-obvious and should overcome the

examiner’s obviousness rejection. (Ex. 1004 at 1456, 1522-25, 1822-26.)

104. Dr. Hellmann cited the following data in support of her assertions that

the combination of trastuzumab and paclitaxel resulted in synergy when tested in

humans:

Time (Months) to Disease Progression (Median) Herceptin +

AC (N = 143)

AC Alone (N = 138)

Herceptin + Paclitaxel (N = 92)

Paclitaxel Alone

(N = 96)

Herceptin Alone

(N = 58) 7.8

(95% Confidence Interval 7.3-

9.4)

6.1 (95%

Confidence Interval 4.9-7.1)

6.9 (95%

Confidence Interval 5.3-

9.9)

2.8 (95%


4.3)

3.5 (95%


5.5)

(Ex. 1008 at Exhibit B and C.)

105. With respect to the “unexpected results” regarding the toxicity of the

trastuzumab and doxorubicin combination, Dr. Hellmann cited the results

presented in the patent specification:

Myocardial Dysfunction of Grade 3 or 4 Severity Herceptin +

anthracycline (N = 146)

Anthracycline alone

(N = 145)

Taxol alone (N = 89)

Herceptin + Taxol (N = 89)

18% 3% 0% 2%

(Ex. 1001 at 30:13-16.)


53

106. The examiner did not agree with Patent Owner that the “unexpected

results” discussed in Dr. Hellmann’s declaration supported non-obviousness

because (1) any synergy between trastuzumab and paclitaxel would not have been

unexpected because that combination had exhibited synergy in mouse xenografts;

and (2) the unacceptable toxicity caused by trastuzumab and doxorubicin was not

relevant to the claimed invention, and was not unexpected, given the known

cardiotoxicity caused by anthracycline therapy. (Ex. 1004 at 1506-09, 1837,

1976.)

107. After failing in several responses to convince the examiner to drop the

obviousness rejections based on the opinions in Dr. Hellmann’s declaration, the

Patent Owner submitted a declaration from a Genentech employee, Dr. Mark X.

Sliwkowski (Ex. 1009; see also Ex. 1004 at 2351).

108. Dr. Sliwkowski opined first that a person of ordinary skill in the art

would not have been motivated to combine trastuzumab and paclitaxel because

paclitaxel would not be expected to provide any additional benefit over

trastuzumab alone because paclitaxel induces cell arrest at a later point in the cell

life cycle than trastuzumab. Therefore, according to Dr. Sliwkowski, a person of

ordinary skill in the art would have expected that administering trastuzumab would

arrest the cell cycle and prevent paclitaxel from working later in the cell cycle, and

that “[a]n antagonistic interaction between trastuzumab and paclitaxel would have


54

been viewed as a reasonable possibility.” (Ex. 1009 at ¶¶ 7-8.) Dr. Sliwkowski

based this theory on purported antagonism reported in the prior art for a different

combination (tamoxifen and anthracyclines). (Id.) Second, Dr. Sliwkowski opined

that the synergistic response to the combination of trastuzumab and paclitaxel in

mouse xenografts would not have motivated a person of ordinary skill in the art to

use that combination in humans, or have led a person of ordinary skill in the art to

a reasonable expectation of success, because mouse xenografts are not predictive

of results in humans. (Id. at ¶ 9.) The only reference that Dr. Sliwkowski cited to

support this argument was published in 2001, more than four years after the

application for the parent application (for the ’441 patent) was filed.

109. In response to the Sliwkowski Declaration and Patent Owner’s related

arguments, the Examiner withdrew the obviousness rejections, but without

substantively responding to the Sliwkowski Declaration. (Ex. 1004 at 1978-79

(12/28/2009 Office Action at 2-3).) After resolution of a remaining rejection for

double patenting, the Examiner allowed the claims. (Id. at 2016-20 (10/08/2010

Notice of Allowance).)

VIII. CLAIM CONSTRUCTION

110. I have been informed by counsel that the challenged claims should

be given their broadest reasonable construction in light of the specification of the

patent. The following terms in the claims of the ’549 patent are explicitly defined


55

in the specification and should therefore be construed in accordance with those

explicit definitions:

a. The term “humanized” (claims 2 and 7) means “contains

minimal sequence derived from non-human immunoglobulin.” (Ex. 1001, 9:17-

22.)

b. The term “epitope 4D5” (claims 1, 5 and 16) means “the region

in the extracellular domain of ErbB2 to which the antibody 4D5 binds.” (Id., 5:26-

28.)

c. The terms “overexpresses ErbB2 receptor” (claim 1) /

“overexpression of ErbB2 receptor” (claim 5) / “ErbB2 overexpressing” (claim

16) mean having significantly higher than normal ErbB2 receptor/ErbB2 levels

compared to a noncancerous cell of the same tissue type. Cancers with these

characteristics are termed HER2+ cancers., i.e., these terms refer to HER2+ breast

cancer. (Id., 5:59-61.)

d. The term “growth inhibitory agent” (claims 1, 11, 14, 15 and

16) means “a compound or composition which inhibits growth of a cell, especially

an ErbB2-overexpressing cancer cell either in vitro or in vivo.” (Id. at 11:20-40.)

“Growth inhibitory agent” includes, for example, cisplatin, a DNA alkylating

agent. (Id.)


56

111. The following terms, while not explicitly defined in the specification,

have meanings derived from the specification based on the knowledge of one of

ordinary skill in the art:

a. The term “therapeutic agent” (claims 5, 11 and 14) means “an

agent with efficacy in the treatment of cancer.” (See Ex. 1001 at 11:4-19, 10:41-

50.) The specification expressly defines “chemotherapeutic agent” as “a chemical

compound useful in the treatment of cancer.” (Id. at 11:4-19.) Based on claim 5,

which requires administering “an effective amount of a combination of an anti-

ErbB2 antibody …, a taxoid, and a further therapeutic agent,” the “further

therapeutic agent” must have efficacy in treating cancer, as opposed to simply

general efficacy in treating any condition. This conclusion is supported by the

specification, which defines “therapeutically effective amount” as “an amount

having antiproliferative effect.” (Id. at 10:41-50.) “Therapeutic agent” includes,

for example, cisplatin, a DNA alkylating agent. (Id. at 11:4-19.)

b. The term “time to disease progression” (claims 1, 10 and 16)

means the “time period calculated from the beginning of therapy until the disease

worsens.” (Id.. at 29:3-9; see also Ex. 1004 at 2304 (’441 patent prosecution

history, Response to Office Action dated Sep. 22, 2008 at 7 (citing National

Cancer Institute Definition “measure of time after a disease is diagnosed (or

treated) until the disease starts to get worse.”)).)


57

c. The term “response rate” (claim 10) means the percentage of

patients whose disease responds to treatment. (See, e.g., Ex. 1001, col. 28, lines

46-67; col. 29, lines 11-30:20.)

d. The term “extend the time to disease progression in the

human patient” (claims 1 and 16) is a relative term. Based on the specification,

the appropriate comparison is to compare the claimed combination treatment

versus treatment with a taxoid alone. This is supported by the Example in the

specification, which begins at Col. 26, line 34. The Example reports a clinical

study in which patients received either paclitaxel alone, or paclitaxel together with

humanized anti-ErbB2 antibody (Herceptin®). (Id. at col. 28, lines 3-6 and 15-23.)

The specification shows that the comparisons of time to disease progression and

evaluations of adverse events for the taxoid/antibody combination were made

based on the combination of the taxoid (Taxol®) with the anti-ErbB2 antibody

(Herceptin®) versus treatment with the taxoid (Taxol®) alone. (Id. at col. 29, line 9

– col. 30, line 25.)

I note that, during prosecution of the ’549 patent’s parent application,

Application No. 09/208,649 (now the ’441 patent), Patent Owner asserted that the

appropriate comparison for the term “extend the time to disease progression” is to

compare the claimed combination treatment to no treatment at all. For example, in

response to an indefiniteness rejection based on the ambiguity of this claim term,


58

Patent Owner stated: “Clearly, the combination of anti-ErbB2 antibody and taxoid

is administered in an amount effective to extend the time to disease progression

relative to an untreated patient.” (Ex. 1004 at 416 (Response dated Jan. 17, 2002 at

3).) In my opinions in this declaration, I have considered this alternate claim

construction as well, but it does not impact my analysis.

IX. OBVIOUSNESS ANALYSIS

112. It is my opinion that claims 1-11 and 14-17 of the ’549 patent would

have been obvious to a person of ordinary skill in the art in view of the following

combination of prior art references: Baselga 1996 (Ex. 1020), Seidman 1996 (Ex.

1011), Pegram 1996 (Ex. 1022), and the 1995 PDR entry for Taxol® (Ex. 1012).

113. As indicated above in Section IV above (Legal Principles), I

understand that there are four factual inquiries that go into an obviousness analysis.

A. Scope and Content of the Prior Art

114. I described the scope and content of the prior art above, including the

disclosures of Baselga 1996, Seidman 1996, Pegram 1995, and the 1995 PDR entry

for Taxol®. The scope and content of the prior art also includes the discussion in

this section on obviousness.

B. Level of Ordinary Skill in the Art

115. I described the level of ordinary skill in the art in Section V above.


59

C. Differences Between the Claims and the Prior Art and Conclusion of Obviousness

116. Claims 1-11 and 14-17 of the ’549 patent are generally directed to the

administration of an effective amount of a combination of an anti-ErbB2 antibody

(which can be trastuzumab), a taxoid (which can be paclitaxel), and a third agent

(which can be cisplatin) to treat a human patient with metastatic HER2+ breast

cancer. Claims 1-4 and 16-17 require the effective amount of the combination to

be “an amount effective to extend the time to disease progression in the human

patient,” whereas claims 5-11 and 14-15 require simply an “effective amount.”

117. The prior art teaches that each of trastuzumab alone (Baselga 1996),

the combination of trastuzumab and cisplatin (Pegram 1995), and paclitaxel alone

(Seidman 1996) is clinically effective for the treatment of humans with metastatic

HER2+ breast cancer. The prior art (Baselga 1996) also taught that, following

promising preclinical data that showed major antitumor activity and synergy of the

trastuzumab/paclitaxel combination for this type of cancer without increasing

toxicity relative to paclitaxel alone, clinical trials of the trastuzumab/paclitaxel

combination were already underway. The prior art also disclosed regimens of

trastuzumab-alone (Baselga 1996), the trastuzumab/cisplatin combination (Pegram

1995), and paclitaxel alone (1995 PDR) that were known to be clinically effective

against metastatic breast cancer.


60

118. Based on these teachings, Baselga 1996, Pegram 1995, and Seidman

1996 would have provided a person of ordinary skill in the art with a motivation to

combine trastuzumab, cisplatin and paclitaxel to treat human patients with

metastatic HER2+ breast cancer with a reasonable expectation that the

combination would be effective. A person of ordinary skill in the art would have

been motivated by Pegram 1995 and the 1995 PDR to use the doses of

trastuzumab, cisplatin, and paclitaxel that were known in the prior art to be

effective against metastatic breast cancer. Based on the teaching in Baselga 1996

that trastuzumab was “remarkably well tolerated,” lacked “significant toxicities,”

and did not increase the toxicity of either cisplatin (when combined in clinical

trials) or paclitaxel (when combined in preclinical studies), a person of ordinary

skill in the art would have reasonably expected the prior art amounts of

trastuzumab, cisplatin, and paclitaxel to extend the time to disease progression.

119. As I explained above, as of December 1996, combination therapy

was a well-established approach for treating cancer. In the natural progression of

cancer research, a new agent is typically tested in combination with others after the

new agent has proven clinical efficacy in a target population. Particularly for the

population of metastatic HER2+ breast cancer patients, which typically had a

worse prognosis than other cancer patients and had been underserved in the past

because this cancer often did not respond to traditional anti-cancer therapies, a


61

person of ordinary skill in the art would have been interested in testing

combinations with any drug that had proven efficacy for metastatic HER2+ breast

cancer. Baselga 1996, Pegram 1995, and Seidman 1996 respectively report the

clinical efficacy of trastuzumab, trastuzumab/cisplatin, and paclitaxel in the

metastatic HER2+ breast cancer population, and therefore provided a strong

motivation to test those drugs in combination in human metastatic HER2+ breast

cancer patients.

120. The clinical data in Baselga 1996, which demonstrated that

trastuzumab had clinical efficacy in treating patients with metastatic HER2+ breast

cancer, would have motivated a person of ordinary skill in the art to combine

trastuzumab with other anti-cancer drugs to treat patients with this disease with a

reasonable expectation of success. As explained, it was well-known that cancers

are not homogeneous with respect to the cellular mutations that are responsible for

the cancer. Therefore, if a particular cancer overexpresses the HER2 receptor, that

cancer likely also has other mutations that would make some cells of that cancer

susceptible to other treatments. (See, e.g., Baselga 1996 (Ex. 1020) at 738

(“Tumors were considered to overexpress HER2 if at least 25% of tumor cells

exhibited characteristic membrane staining for p185HER2.”).) The established

efficacy of trastuzumab in treating patients with metastatic HER2+ breast cancer

would have motivated a person of skill in the art to use trastuzumab in combination


62

with other therapies that had proven efficacy in all types of metastatic breast

cancer, and cisplatin and paclitaxel were particularly attractive options.

121. Pegram 1995 discloses that the trastuzumab/cisplatin combination is

clinically effective against metastatic HER2+ breast cancer, and reports that adding

trastuzumab to cisplatin resulted in elevated response rates, with no apparent

increase in toxicity, relative to what was expected for cisplatin-alone. (Ex. 1022.)

Based on this knowledge, a person of ordinary skill in the art would have been

motivated to develop combination therapies for metastatic HER2+ breast cancer

that included trastuzumab and cisplatin.

122. Seidman 1996 reports that paclitaxel is clinically effective against

metastatic HER2+ breast cancer. (Ex. 1011.) Based on this disclosure, combined

with the knowledge of a person of ordinary skill in the art that paclitaxel had

efficacy in patients with metastatic breast cancer regardless of whether or not the

cancer overexpress HER2, a person of ordinary skill in the art would have been

motivated to develop combination therapies for metastatic HER2+ breast cancer

that included paclitaxel. This made paclitaxel an ideal candidate for combination

with trastuzumab/cisplatin for this patient population. Accordingly, a person of

ordinary skill in the art would have been motivated to add paclitaxel to the

established trastuzumab/cisplatin combination and would have reasonably


63

expected this three-drug combination to effectively treat metastatic HER2+ breast

cancer.

123. The motivation and reasonable expectation of success for the

trastuzumab/cisplatin/paclitaxel combination would have been reinforced by the

knowledge of a person of ordinary skill in the art that the underlying two-drug

combinations (trastuzumab/cisplatin, trastuzumab/paclitaxel, and

paclitaxel/cisplatin) were already being administered by persons of ordinary skill

in the art to treat metastatic breast cancer patients. Indeed, a person of ordinary

skill in the art knew from the prior art that:

the trastuzumab/cisplatin combination was clinically effective

against metastatic HER2+ breast cancer and reasonably safe (Pegram

1995 (Ex. 1022));

the trastuzumab/paclitaxel combination was already undergoing

clinical trials to treat metastatic HER2+ breast cancer as stated in

Baselga 1996: (Baselga 1996 (Ex. 1020) at 743); and

the paclitaxel/cisplatin combination was already being used

successfully, including to treat patients with metastatic breast cancer

(1995 TAXOL PDR (Ex. 1012) at 683; Ex. 1013 (Tolcher) at 37; Ex.

1014 (Gelmon 1996) at 1185).


64

This knowledge would have confirmed that persons of skill in the art were already

motivated to combine these drugs for the treatment of metastatic breast cancer,

including metastatic HER2+ breast cancer, and based on their willingness to

administer the combination to humans and their ethical responsibilities to use only

treatments that are likely to succeed, reasonably expected success with the

combination.

124. Further, the ongoing clinical studies of the trastuzumab/paclitaxel

combination were supported by promising preclinical data. Baselga 1996 reported

that in preclinical xenografts studies of HER2+ breast cancer, trastuzumab

“markedly potentiated the antitumor effects of several chemotherapeutic agents,

including … paclitaxel, without increasing their toxicity.” (Ex. 1020 at 743.)

Baselga 1996 cites Baselga Abstract 53, from which a person of ordinary skill in

the art would have already known that the trastuzumab/paclitaxel combination

exhibited “major antitumor activity” with 93% inhibition of growth, demonstrating

better results than the trastuzumab/doxorubicin combination, and that trastuzumab

did not increase the toxicity of paclitaxel when combined. (Id.) The xenograft

data would have further reinforced the motivation to combine trastuzumab and

paclitaxel for the treatment of metastatic HER2+ breast cancer and the reasonable

expectation that the combination would work.


65

125. The combination of trastuzumab, cisplatin, and paclitaxel also made

logical sense based on the four guiding principles of combination therapy.

126. First, trastuzumab, cisplatin, and paclitaxel each had proven clinical

efficacy in the target population, metastatic HER2+ breast cancer patients.

(Baselga 1996 (Ex. 1020); Pegram 1995 (Ex. 1022); Seidman 1996 (Ex. 1011).)

Indeed, as reported in Seidman 1996, paclitaxel was clinically effective in both the

sub-population of metastatic HER2+ breast cancer patients and the larger

population of metastatic breast cancer patients, which made it a strong choice to

combine with trastuzumab/cisplatin to treat metastatic HER2+ breast cancer,

particularly based on the known concept of intra-tumor heterogeneity. Therefore,

the trastuzumab/cisplatin/paclitaxel combination satisfied the first principle of

combination therapy.

127. Second, trastuzumab, cisplatin, and paclitaxel were not known to have

any significant overlapping toxicities. Trastuzumab was reported to have

“remarkably [good] tolerability” with an “absence of significant toxicities.”

(Baselga 1996 (Ex. 1020).) When trastuzumab was combined with cisplatin in

clinical trials, the combination showed no increase in toxicity compared with

cisplatin alone (Pegram 1995 (Ex. 1022)), which would have suggested to a person

of ordinary skill in the art that trastuzumab and cisplatin do not have any

significant overlapping toxicities.


66

128. A person of ordinary skill in the art also would have known that the

dose-limiting toxicity (i.e., the toxicity that determines the maximum dose of a

drug that may be administered to a patient) of paclitaxel was myelosuppression.

(Ex. 1018 (Gelmon 1994)25 at 24.) The prior art did not associate trastuzumab with

myelosuppression. (Baselga 1996 (Ex. 1020) at 739, 741.) Based on the lack of

toxicity observed in the xenografts with the combination of trastuzumab and

paclitaxel, a person of ordinary skill in the art, going into clinical trials, would have

reasonably expected to be able to administer the two agents at full effective doses

in combination without creating serious safety or tolerability concerns. A person

of ordinary skill in the art would also have known from clinical studies reported in

the prior art that myelosuppression associated with the paclitaxel/cisplatin

combination could be minimized by adjusting the sequencing of administration,

and other adverse events were tolerable. (Ex. 1012 at 683; Ex. 1013 at 38.)

129. Based on their toxicity profiles, a person of ordinary skill in the art

would have reasonably expected trastuzumab, cisplatin, and paclitaxel to work

well together in combination. Therefore, the trastuzumab/cisplatin/paclitaxel

combination satisfied the second principle of combination therapy.

25 Karen A. Gelmon, Biweekly Paclitaxel (Taxel) and Cisplatin in Breast and

Ovarian Breast Cancer, 21(5) SEMINARS ONCOLOGY (SUPPLEMENT), 24-28 (Oct.

1994). (“Gelmon 1994”).


67

130. Third, trastuzumab, cisplatin, and paclitaxel were known to have

different mechanisms of action. Trastuzumab is a growth factor receptor targeted

antibody, and paclitaxel is a cytotoxic chemotherapeutic agent. Cisplatin and

paclitaxel are non-specific chemotherapeutic agents that treat cancer in different

ways. Cisplatin is a DNA alkylating agent that acts by modifying cellular DNA.

Paclitaxel is plant alkaloid that acts on the cell’s microtubules. (Ex. 1018 at 24.)

Because these agents have different mechanisms of action, a person of ordinary

skill in the art would have reasonably expected them to work well together.

Therefore, the trastuzumab/cisplatin/paclitaxel combination satisfied the third

principle of combination therapy.

131. Fourth, a person of ordinary skill in the art would have reasonably

expected that trastuzumab, cisplatin, and paclitaxel would not exhibit any cross-

resistance with one another because they have very different mechanisms of action.

Indeed, paclitaxel and cisplatin were already known not to exhibit cross-resistance

with one another. Ex. 1013 at 37 (“[C]isplatin … [has no] known mechanisms of

cross-resistance with paclitaxel.”); Ex. 1014 at 1185 (“We were also interested in

combining the new agent [paclitaxel] with a non-cross-resistant drug with a

different spectrum of toxicity. Cisplatin seemed to be an appropriate choice.”).

Because there are virtually no common mechanisms through which targeted

antibodies like trastuzumab and chemotherapies like paclitaxel and cisplatin induce


68

apoptosis or otherwise kill cells, a person of ordinary skill in the art would not

believe that these agents have the potential to exhibit cross-resistance with one

another. (Ex. 1016 at 113.) Therefore, the trastuzumab/cisplatin/paclitaxel

combination satisfied the fourth principle of combination therapy.

132. With respect to the effective amount of the combination, a person of

ordinary skill in the art would have been motivated to target the known effective

regimens of trastuzumab/cisplatin and paclitaxel when used as single agents. A

bedrock principle of combination therapy is that, when possible, the drugs in a

combination should be administered at their full doses at which they are known to

be effective individually, to maximize the anticancer effects. Therefore, a person

of ordinary skill in the art would have been motivated to use the

trastuzumab/cisplatin dosing regimen that Pegram 1995 reported to be effective in

treating metastatic HER2+ breast cancer (Ex. 1022.), and the dosing regimen for

paclitaxel that was recommended in the 1995 PDR entry for Taxol® as being

effective for treating metastatic breast cancer. (Ex. 1012 at 685.) A person of

ordinary skill in the art would have been motivated to use these regimens and

would have reasonably expected these combined regimens to extend the time to

disease progression, without increasing overall severe adverse events, relative to

paclitaxel alone, based on many factors, including (a) the promising clinical results

reported for these drugs in Baselga 1996, Pegram 1995 and Seidman 1996, (b) the


69

good tolerability and absence of significant toxicities associated with trastuzumab

reported in Baselga 1996, (c) the report in Baselga 1996 that trastuzumab did not

increase the toxicity of paclitaxel, (d) the report in Pegram 1995 that adding

trastuzumab to cisplatin increased the response rates in metastatic HER2+ breast

cancer patients with no apparent increase in toxicity relative to that expected from

cisplatin alone, and (e) the lack of known significant overlapping toxicities

between trastuzumab and paclitaxel.

133. If a person of ordinary skill in the art discovered, upon administering

the combination to a patient, that the amounts of trastuzumab, cisplatin, or

paclitaxel needed adjustment, it would have been a routine matter for a person of

ordinary skill in the art to optimize the combined regimen for maximal tolerability

and efficacy to arrive at amounts that extend the time to disease progression.

134. A person of ordinary skill in the art would have known how to

optimize that combined dose, via routine and conventional techniques, for both a

standard “recommended” dosage amount, and for individual patients’ needs, if

necessary. Routine dose finding studies normally follow one of two possible

patterns: either the dose of one or more agents is held constant while the dose of

the other agent is increased, or the dosages of all agents are increased by the same

multiplicative factor. In both cases, the increase is stopped when the adverse

effects of the treatment become unacceptable.


70

135. Indeed, the conclusion that a person of ordinary skill in the art would

have known how to optimize the dosage amount is admitted by the ’549 patent

specification, which describes the amount of paclitaxel, cisplatin. or other

chemotherapeutic agent to use in combination with trastuzumab as follows:

“Preparation and dosing schedules for such chemotherapeutic agents may be used

according to manufacturers’ instructions or as determined empirically by the

skilled practitioner.” (Ex. 1001, col. 25, lines 1-19.) In discussing the amount of

trastuzumab to administer in the combination, the specification provides a broad

range (15,000-fold) of possible dosages—“about 1 μg/kg to 15 mg/kg (e.g. 0.1-20

mg/kg)”—“[d]epending on the type and severity of the disease.” (Id. at col. 25,

lines 43-54.) The specification acknowledges that there are many possible

regimens by which trastuzumab may be administered and that physicians routinely

optimize the dose, based on many well-known factors, stating that “progress of this

therapy is easily monitored by conventional techniques and assays.” (Id.)

136. In summary, by using the known effective amounts of each

component of the combination, a person of skill in the art would have reasonably

expected that the trastuzumab/cisplatin/paclitaxel combination would be effective

in extending the time to disease progression. As explained, it is rare for a single

drug to kill all of the cancerous cells in a patient’s tumors. With a combination of

different agents, the expectation is that more of the cells will be killed and


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therefore, the time to disease progression and other measures of efficacy, including

the response rate, would improve.

137. These measures of efficacy would also improve relative to no

treatment, in accordance with the alternate claim construction presented in Section

VIII. A person of ordinary skill in the art would have known that treatment with

paclitaxel alone resulted in extension of time to disease progression and a higher

response rate than no treatment. Therefore, an extension of time to disease

progression and increase in response rate relative to treatment with paclitaxel,

logically also results in an extension of time to disease progression and increase in

response rate relative to no treatment. A person of ordinary skill in the art would

have also expected that the treatment of trastuzumab, cisplatin, and paclitaxel in

combination would not have resulted in any unacceptable toxicities, based on the

known toxicity profiles of each of those drugs when given alone or in two-drug

combinations.

138. A person of skill in the art would have been motivated to use the triple

combination of trastuzumab/paclitaxel/cisplatin because that combination was

obvious based on the principles of combination therapy, as explained above.

Further, a person of ordinary skill in the art would have excluded an anthracycline

derivative from the combination in order to avoid the cardiotoxicity that is

associated with that class of drugs. Anthracyclines were known to cause


72

irreversible cardiotoxicity, a phenomenon associated with the total lifetime dose a

patient receives. (Ex. 1016 at 813.) While treating patients with anthracyclines is

often unavoidable in the course of a patient’s cancer treatment, limiting the total

dose of an anthracycline is a goal. (Id. at 810, 813; see also Ex. 1020 at 740

(stating that a patient died of congestive heart failure due to doxorubicin treatment

during treatment with trastuzumab.) A person of ordinary skill in the art would

have expected that many patients had previous anthracycline treatment, given that

anthracyclines were a first-line therapy for breast cancer. (Ex. 1016 at 1693.)

Therefore, particularly for patients who had already been treated with an

anthracycline, it would have been obvious not to include the drug in the

combination of trastuzumab and paclitaxel.

139. For these reasons, a person of ordinary skill in the art would have

been motivated to avoid administering further anthracycline derivatives to the

many patients who had already been treated with this class of drug. (Id.)

D. Response To The Sliwkowski Declaration

1. A Person of Ordinary Skill in the Art Would Not Have Expected an Antagonistic Interaction Between Paclitaxel and Trastuzumab

140. In his declaration, Dr. Sliwkowski argues that “a skilled scientist

would have anticipated that paclitaxel would provide little or no additional benefit

to treatment with trastuzumab alone” because trastuzumab arrests the cell cycle at


73

the G1 phase, which precedes the G2/M phase at which paclitaxel purportedly

arrests the cell cycle. (Ex. 1009 at ¶ 7.) Based on this theory, Dr. Sliwkowski

argues that combining trastuzumab with paclitaxel “would provide little or no

additional benefit,” because trastuzumab would “arrest cell cycle before it reaches

the G2/M phase, where taxoids exert their apoptotic antitumor activity.” (Ex. 1009

(Sliwkowski Dec.), ¶ 7.)

141. I disagree with Dr. Sliwkowski’s theory and reasoning because they

are based on several false assumptions about how these agents work to treat

cancer, and are contradicted by the data available in the prior art, which predicted a

favorable interaction between trastuzumab and paclitaxel, rather than antagonism.

142. First, Dr. Sliwkowski’s theory wrongly assumes that because

paclitaxel causes cell death by attacking microtubules, it only acts when a cell is in

the phase of its cell cycle in which microtubules are active. A person of ordinary

skill in the art would have known, however, that paclitaxel exerts its anticancer

effects during all phases of the cell cycle, and not only while the microtubules were

active in the G2/M phase. (Ex. 1007 at 1165; Ex. 1006 (De Vita) at 415.) A

person of ordinary skill in the art would have known that the cellular component

on which paclitaxel exerts its effect is tubulin, a component of microtubules, as Dr.

Sliwkowski acknowledges. (Ex. 1009 at ¶ 7.) However, a person of ordinary skill

in the art would have known that an injury to the microtubules causes a cell to


74

undergo apoptosis (i.e., cell death) regardless of whether the microtubules are

active at the time of the injury. In other words, paclitaxel does not work only

during one phase of the cell cycle, and therefore, cycle arrest caused by

trastuzumab would not preempt the activity of paclitaxel. (See, e.g., Ex. 1007 at

1165.)

143. As support for his assertion that paclitaxel lead to “an arrest of the

cells in the G2/M phase” of the cell cycle, Dr. Sliwkowski cites to C.M. Woods et

al., Taxol-Induced Mitotic Block Triggers Rapid Onset of a p53-Independent

Apoptotic Pathway, 1(5) MOLECULAR MEDICINE 506-526 (1995) (“Woods”). (Ex.

1009, ¶ 7, Exhibit B.) Woods, however, does not support Dr. Sliwkowski’s

statement that paclitaxel works only during the G2/M phase of the cell cycle (i.e.,

at the end of interphase and the beginning of prophase). Woods clearly states that

paclitaxel induces two types of apoptosis, one in prophase (i.e., the G2/M phase),

and another in the earlier G1 phase of the cell cycle. (Ex. 1009, Exhibit B at 21;

see also Ex. 1006 (De Vita) at 60-66.) Dr. Sliwkowski’s declaration does not

mention or otherwise account for the knowledge in the prior art that he cited that

paclitaxel induces apoptosis in this earlier G1 phase of the cell cycle. Dr.

Sliwkowski’s failure to mention paclitaxel’s anticancer effects at the G1 phase is

an important omission, given that Dr. Sliwkowski asserts in his declaration that

trastuzumab exerts its anti-tumor effects at the G1 phase. (Ex. 1009, ¶ 8.) A


75

person of ordinary skill in the art would have known that trastuzumab and

paclitaxel work at the same phase of the cell cycle. This information is a

significant flaw in Dr. Sliwkowski’s theory.

144. Second, Dr. Sliwkowski’s theory wrongly assumes that tumors are

homogenous—that all cells in a tumor have the same mutations, behave in the

same way, and exist at precisely the same phase in the cell cycle as one another.

(Id., ¶ 109.) A person of ordinary skill in the art, however, would have known that

tumors are typically heterogeneous and contain of cancer cells having a variety of

mutations and growing at different stages. Therefore, even if it were true that

trastuzumab and paclitaxel only exert their effects at different phases of the cell

cycle, a person of ordinary skill in the art would have known that the cells in the

tumor would exist at different cell cycle phases and could be attacked by both

trastuzumab and paclitaxel. (Id., ¶ 109.)

145. Third, and relatedly, Dr. Sliwkowski’s theory wrongly assumes that

trastuzumab will kill all of the cells in the tumor when they are in the G1 phase.

However, a person of ordinary skill in the art would understand that drugs are

typically not 100% effective. That is, trastuzumab would not be expected to kill

every single cancer cell in the tumor, and paclitaxel would still be able to attack the

remaining cells in the phase of G2/M. Indeed, because trastuzumab targets HER2+

cancer cells, it would not be expected to kill every cell in a HER2+ tumor. In the


76

prior art, a breast carcinoma was considered to be HER2+ if at least 25% of tumor

cells exhibited the HER2 receptor. (See, e.g., Ex. 1020 at 738 (“Tumors were

considered to overexpress HER2 if at least 25% of tumor cells exhibited

characteristic membrane staining for p185HER2.”).) That means that a HER2+

breast cancer tumor will very likely contain a significant proportion of cells that

are not individually HER2+. As explained, a person of ordinary skill in the art

would want to combine trastuzumab with one or more drugs with proven efficacy

in all types of metastatic breast cancer (such as paclitaxel and cisplatin) that could

target cells that are not HER2+. Dr. Sliwkowski’s theory simply does not work in

the context of HER2+ breast cancer.

146. Dr. Sliwkowski’s theory that “an antagonistic interaction between

trastuzumab and paclitaxel would have been viewed as a reasonable possibility”

was based on the purported observation in the prior art that tamoxifen, a hormone

that causes antitumor effects at the G0-G1 cell cycle phase, exhibited an

antagonistic interaction when combined with anthracyclines, which act later in the

cell cycle. (Ex. 1009, ¶ 8.)

147. Based on the prior art, a person of ordinary skill in the art would have

had no basis to believe that Dr. Sliwkowski’s theory based on the

tamoxifen/doxorubicin combination would be applicable to the unrelated

combination of trastuzumab/paclitaxel.


77

148. First, in my opinion, the activity of the tamoxifen/anthracycline

combination provides information only about that particular combination and

cannot be reasonably extrapolated to other combinations of drugs. Indeed,

according to the articles cited by Dr. Sliwkowski in support of his analogy to the

tamoxifen/doxorubicin combination, the antagonism that is seen with tamoxifen

and doxorubicin may not be extrapolated even to combinations of tamoxifen with

other chemotherapeutic drugs. (See, e.g., Ex. 1009, Exhibit F (Osborne) at 715)

(“The antagonism is drug specific and even alkylating agent specific.”).) The

articles cited by Dr. Sliwkowski also note that antagonism between tamoxifen and

doxorubicin is not always seen (Ex. 1009, Exhibit F (Osborne) at 715; Exhibit G

(Woods) at 1449), and that any antagonism may be due to many factors, not only

to the particular combination of tamoxifen and doxorubicin. (Exhibit G (Woods)

at 1450-1451.) These articles therefore do not provide any information to a person

of ordinary skill in the art regarding why or even if an antagonistic relationship

exists between tamoxifen and doxorubicin; and they certainly do not provide

information regarding other combinations. Further, a person of ordinary skill in

the art would have known that tamoxifen is an anti-estrogen hormone therapy and

that trastuzumab is an antibody against a growth factor receptor. These agents

work in very different ways, and analogies between them should not be drawn

without reference to specific similarities between those drugs.


78

149. Second, the prior art discloses combinations that are more analogous

to trastuzumab/paclitaxel than tamoxifen/doxorubicin that contradict Dr.

Sliwkowski’s theory. For example, the prior art disclosed the combination of

trastuzumab and cisplatin. (Pegram 1995 (Ex. 1022).) Like paclitaxel, cisplatin

was known to arrest the cell cycle at the G2/M phase. (Ex. 1027 (Sorenson).)26 If

Dr. Sliwkowski’s theory were correct that trastuzumab would arrest the cell cycle

of every cancer cell at the G1 phase, and prevent a chemotherapy that acts later in

the cell cycle from exerting its anticancer effects, then one would expect that

trastuzumab would have antagonized cisplatin and caused cisplatin to “provide

little or no additional benefit to treatment with trastuzumab alone.” (Ex. 1009, ¶

7.) But Pegram 1995 reports that (a) the trastuzumab/cisplatin combination

exhibited synergistic effects against HER2+ cancer cells in vitro, (b) that the

combination was clinically effective in humans with metastatic HER2+ breast

cancer, and (c) the response rates for the combination were above those that were

expected from cisplatin alone. (Ex. 1022 (Pegram 1995).) This prior experience

using a more analogous combination in the very system of interest (metastatic

HER2+ breast cancer) would have dispelled for a person of ordinary skill in the art

26 Christine M. Sorenson et al., Analysis of Events Associated with Cell Cycle

Arrest at G2 Phase and Cell Death Induced by Cisplatin, 82 JOURNAL OF THE

NATIONAL CANCER INSTITUTE 9, 749-755 (1990) (“Sorenson”)


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any concerns based on Dr. Sliwkowski’s theory. Dr. Sliwkowski’s declaration

does not mention Pegram 1995 or the trastuzumab/cisplatin combination.

150. Third, with regard to the specific combination of

trastuzumab/paclitaxel, prior experience in preclinical xenograft studies informed a

person of ordinary skill in the art that trastuzumab was not preventing paclitaxel

from working. (See, e.g., Ex. 1021.) That is, in live human cancer cells in live

animals, trastuzumab did not antagonize paclitaxel and, indeed, did just the

opposite and exhibited synergistic antitumor effects. (Id.) The favorable results

and synergy reported for the combination of trastuzumab/paclitaxel in the prior art

would have dispelled any theoretical concern about potential antagonism with this

particular combination. Furthermore, a person of ordinary skill in the art would

have known that, following these favorable preclinical studies, the

trastuzumab/paclitaxel combination was undergoing clinical trials, which would

have confirmed that other persons of skill in the art were motivated to combine

these drugs with a reasonable expectation of success. In summary, a person of

ordinary skill in the art had no basis to anticipate that the trastuzumab-paclitaxel

combination would behave antagonistically.

2. Xenograft Data is a Helpful Tool for Developing Combination Therapies

151. Dr. Sliwkowski asserted in his declaration that xenograft models are

not predictive of clinical efficacy for breast cancer and therefore a person of


80

ordinary skill in the art would not have reasonably expected success for the

trastuzumab-paclitaxel combination based on the xenograft data reported in the

prior art. (Ex. 1004 at ¶ 9.) While it is true that xenografts are not predictive in the

sense that results seen in xenografts are not identical to results that are seen in

patients, it is my experience that positive xenograft data can forecast positive

results in humans, and were considered valuable in developing cancer drugs for the

clinic as of December 1996, and remain valuable today. (Ex. 1028 at 279

(“Xenografts of a particular tumor type are often able to identify agents of known

clinical activity against that disease.”).) If not, there would be no reason to burden

preclinical drug development programs with the cost and effort involved in such

activities. In no case would such results be disregarded by persons of ordinary

skill in the art.

152. In vivo animal studies such as xenografts, when available, can be

valuable tools in developing an experimental therapy or designing a clinical trial.

Such studies can be designed to test specific hypotheses related to a proposed

human study. For example, if during the development of new combination

therapies, a concern is raised that a particular combination might be antagonistic,

xenograft studies may be used to test that hypothesis. Favorable results with the

combination, such as those reported for trastuzumab and paclitaxel in Baselga

Abstract 53 and Abstract 2262, would have supported a reasonable level of


81

confidence in the ethical validity and potential success of proceeding with

developing the combination in clinical trials.

153. Based on the finding in Abstract 2262 and Baselga Abstract 53 of a

93% growth inhibition for the trastuzumab-paclitaxel combination, compared to a

70% growth inhibition for the trastuzumab-doxorubicin combination, a person of

ordinary skill in the art would reasonably have given a higher priority to the former

regimen, if a choice needed to be made. Such a higher priority is expressly

suggested in the prior art: “The combined treatment with paclitaxel plus 4D5

resulted in a major antitumor activity with 93% inhibition of growth. This result

was markedly better than doxorubicin plus 4D5 (70% inhibition). Thus, equipotent

doses of paclitaxel and doxorubicin differed in their combined effect with ARMAs,

which suggests synergy between paclitaxel and 4D5.” (Ex. 1021.) The favorable

xenograft results of the trastuzumab-paclitaxel combination against HER2+ breast

cancer pointed the way to an obvious next step in the drug development process:

clinical trial of the trastuzumab-paclitaxel combination for patients with HER2+

breast cancer. Indeed, the prior art stated that those clinical trials were already

underway. (Ex. 1020 at 743.)

154. I also note that Dr. Sliwkowski submitted his declaration in 2009,

which is more than ten years after the date that the application for the ’441 patent

was filed. As support for his assertions, he relied on an article published in 2001,


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which is also later than the date that the application was filed. However, in 1999

(which is later than the filing date of the patent but earlier than Dr. Sliwkowski’s

2009 declaration and earlier than the 2001 article upon which Dr. Sliwkowski

relied), Dr. Sliwkowski co-authored an article that explicitly relied upon xenograft

data “to determine how best to use this antibody both as a single agent and in

combination with established cancer therapeutics.” (Ex. 101727 at 2242.) Dr.

Sliwkowski’s research in xenografts was aimed at demonstrating that some

combinations are “rational” to test in “human clinical trials.” (Id. at Abstract.) In

that article, Dr. Sliwkowski reports that in order to test a hypothesis that

trastuzumab is synergistic with chemotherapeutic agents, he tested the drugs

together in vitro and then, as a confirmatory tool, he tested the drugs in mouse

tumor xenografts. (Id.)

155. Dr. Sliwkowski’s assertions that a person of ordinary skill in the art

would not have predicted synergistic results between trastuzumab and paclitaxel

based on xenografts rings hollow in the face of his reliance on xenografts to test for

synergy. Dr. Sliwkowski’s published xenograft testing and reliance in 1999 is

aligned with the understanding of a person of ordinary skill in the art as of

27 M. Pegram et al., Inhibitory Effects of Combinations of HER-2.neu Antibody and

Chemotherapeutic Agents Used for Treatment of Human Breast Cancers, 18

ONCOGENE, 2241-2251 (1999). (“Pegram 1999”).


83

December 1996. His declaration, submitted in 2009, and relying on art from 2001,

is not.

E. Claim-by-Claim Analysis of Obviousness

156. Independent claim 1 claims a method for the treatment of a human

patient with a breast cancer that overexpresses ErbB2 receptor with the

combination of an antibody which binds to epitope 4D5 within the ErbB2

extracellular domain sequence, a taxoid, and a further growth inhibitory agent in an

amount that is effective to extend the time to disease progression.

157. The patient described in claim 1 has a HER2+ breast cancer. The

antibody described in claim 1 is directed to epitope 4D5 within the ErbB2

extracellular domain, and therefore, may be trastuzumab. Paclitaxel is a taxoid.

As I explained above, cisplatin is a growth inhibitory agent within the meaning of

the patent claims. Baselga 1996, Seidman 1996, Pegram 1995, and the 1995 PDR

entry for Taxol® would have motivated to a person of ordinary skill in the art to

administer trastuzumab, paclitaxel and cisplatin to treat metastatic HER2+ breast

cancer patients with a reasonable expectation of success that the combination

would extend the time to disease progression, as discussed in Section IX.C

above.28 With regard to the amount of each drug in the combination to use, a

28 To the extent the phrase “extend the time to disease progression” is construed to

mean relative to an untreated patient, as opposed to meaning relative to treatment


84

person of ordinary skill in the art would have used the reported effective amounts

of each agent (i.e., for trastuzumab, a loading dose of 250 mg, followed by 100 mg

per week, see Ex. 1020 at 738-39, Ex. 1022; for paclitaxel, 135 mg/m2 or 175

mg/m2, see Ex. 1012 at 685; and for cisplatin, 75 mg/m2 , see Ex. 1022) as a

starting point. To the extent that the amount of any drug needed to be adjusted for

a “generic” recommendation or for a specific patient, a person of ordinary skill in

the art would have known how to adjust and optimize the dosage amounts using

routine and conventional techniques. Therefore, claim 1 is obvious over Baselga

1996, Seidman 1996, Pegram 1995, and the 1995 PDR entry for Taxol®.


patient with breast cancer characterized by overexpression of ErbB2 receptor with

an anti-ErbB2 antibody which binds epitope 4D5 within the ErbB2 extracellular

domain sequence, a taxoid, and a further therapeutic agent, in an effective amount.

159. The patient population defined in claim 5 is the HER2+ breast cancer

population, and the antibody, directed against the HER2 receptor, may be

with a taxoid alone, my opinion is still the same because a person of ordinary skill

in the art would have known that treatment with paclitaxel extends the time to

disease progression relative to no treatment. By extension, a treatment that extends

the time to disease progression relative to paclitaxel also must extend the time to

disease progression relative to no treatment.


85

trastuzumab. Paclitaxel is a taxoid. Cisplatin, a chemotherapeutic agent, is within

the definition of the term “further therapeutic agent” as defined above. As I

explained above, Baselga 1996, Seidman 1996, Pegram 1996, and the 1995 PDR

entry for Taxol® would have motivated person of ordinary skill in the art to use the

claimed combination to treat patients in the claimed population, in amounts that

would provide a reasonable expectation of success in treating the cancer. With

regard to the amount of each drug in the combination to use, a person of ordinary

skill in the art would have used the reported effective amounts of each agent as a

starting point, as discussed above for claim 1. To the extent that the amount of any

drug needed to be adjusted for a “generic” recommendation or for a specific

patient, a person of skill in the art would have known how to adjust and optimize

the dosage amounts using routine and conventional techniques. Therefore, claim 5

is obvious over Baselga 1996, Seidman 1996, Pegram 1995, and the 1995 PDR

entry for Taxol®.


patient with ErbB2 overexpressing breast cancer with an antibody that binds

epitope 4D5 within the ErbB2 extracellular domain sequence, a taxoid, and a

further growth inhibitory agent, in the absence of an anthracycline derivative, in an

amount that is effective to extend the time to disease progression. The patient

population described in this claim has HER2+ cancer that has the potential to


86

metastasize, and the antibody, directed against the HER2 receptor, may be

trastuzumab. Paclitaxel is a taxoid. Cisplatin is a further growth inhibitory agent

within the meaning of the ’549 patent claims as defined above. Baselga 1996,

Seidman 1996, Pegram 1995, and the 1995 PDR entry for Taxol®, would have

motivated a person of ordinary skill in the art to use the claimed combination, in

amounts that would provide a reasonable expectation of success in meeting the

efficacy limitation of the claim. With regard to the amount of each drug in the

combination to use, a person of ordinary skill in the art would have used the

reported effective amounts of each agent as a starting point, as discussed above

with respect to claim 1. To the extent that the amount of any drug needed to be

adjusted for a “generic” recommendation or for a specific patient, a person of skill

in the art would have known how to adjust and optimize the dosage amounts using

routine and conventional techniques.

161. With respect to the limitation in claim 16 requiring “the absence of an

anthracycline derivative,” a person of skill in the art would have been motivated to

exclude an anthracycline derivative from the combination in order to avoid the

cardiotoxicity that is associated with that class of drugs. While treating patients

with anthracyclines is often unavoidable in the course of a patient’s cancer

treatment, limiting the total dose of an anthracycline is a goal. Therefore,

particularly for patients who had already been treated with an anthracycline or


87

those with pre-existing cardiomyopathy regardless of cause, it would have been

obvious to not include the drug in the combination of trastuzumab and paclitaxel.

A person of ordinary skill in the art would have expected that many patients had

previous anthracycline treatment, given that anthracyclines were a first line therapy

for breast cancer. (Ex. 1016 at 1693.) Indeed, paclitaxel was indicated for use

only after first-line therapy that included anthracycline. (1995 TAXOL PDR (Ex.

1012) at 683.) Therefore, claim 16 is obvious over Baselga 1996, Seidman 1996,

Pegram 1995, and the 1995 PDR entry for Taxol®.

162. Claims 2-4 depend from claim 1and therefore incorporate all of the

limitations in claim 1. Claim 7 depends from independent claim 5 and therefore

incorporates all of the limitations of claim 5. Claim 2 further requires that the

antibody is a humanized 4D5 anti-ErbB2 antibody; claim 3 further requires that the

antibody crossblocks binding of 4D5 to the ErbB2 extracellular domain sequence;

claim 4 further requires that the antibody binds to amino acid residues in the region

from about residue 529 to about residue 625 of the ErbB2 extracellular domain

sequence; and claim 7 requires that the antibody is a humanized 4D5 anti-ErbB2.

These requirements are all properties of trastuzumab. Therefore, it is my opinion

that claims 2-4 and 7 would have been obvious over Baselga 1996, Seidman 1996,

Pegram 1995, and the 1995 PDR entry for Taxol® for the same reasons that

independent claims 1 and 5 would have been obvious.


88

163. Claim 6 depends from independent claim 5 and therefore incorporates

all of the limitations from claim 5. Claim 17 depends from independent claim 16

and therefore incorporates all of the limitations of claim 16. Claims 6 and 17 each

further require that the breast cancer is metastatic breast carcinoma (another word

for tumor). Therefore, it is my opinion that claims 6 and 17 would have been

obvious over Baselga 1996, Seidman 1996, Pegram 1995, and the 1995 PDR entry

for Taxol® for the same reasons that independent claims 5 and 16 would have been

obvious.

164. Claim 8 depends from claim 7, which depends from claim 5. Claim 8

further requires that the antibody is administered as a 4 mg/kg dose and then

weekly administration of 2 mg/kg. The dose of the trastuzumab that was shown to

be clinically effective when used alone and when used in combination with

cisplatin was a 250 mg loading dose followed by weekly 100-mg doses. (Baselga

1996 (Ex. 1020); Pegram 1995 (Ex. 1022).) For an average patient of about 62.5

kg (approximately 143 pounds), the dose described in Baselga 1996 and Pegram

1995 is the same as a 4 mg/kg loading dose, followed by 1.6 mg/kg weekly doses.

The dose in Baselga 1996 and Pegram 1995 would have been the starting point for

a POSA designing a combination therapy with trastuzumab, cisplatin, and

paclitaxel. A POSA would have been motivated to optimize this regimen for

efficacy using routine and conventional techniques and would have arrived at the


89

claimed dosage amounts. Therefore, it is my opinion that claim 8 would have been

obvious over Baselga 1996, Seidman 1996, Pegram 1995, and the 1995 PDR entry

for Taxol® for the same reasons that independent claim 5 would have been

obvious.

165. Claim 9 depends from independent claim 5 and therefore incorporates

all of the limitations in claim 5. Claim 9 further requires that the taxoid is

paclitaxel. As explained, the combination of trastuzumab/paclitaxel/cisplatin

would have been obvious. Therefore, it is my opinion that claim 9 would have

been obvious over Baselga 1996, Seidman 1996, Pegram 1995, and the 1995 PDR

entry for Taxol® for the same reasons that independent claim 5 would have been

obvious.

166. Claim 10 depends from independent claim 5 and therefore

incorporates all of the limitations from claim 5. Claim 10 further requires that

“efficacy is measured by determining the time to disease progression or the

response rate.” As discussed above in Section VI.E, person of ordinary skill in the

art would have been well aware of both time to disease progression and response

rate as part of a clinical trial and would have measured efficacy with both of those

metrics as a matter of course. Therefore, it is my opinion that claim 10 would have

been obvious over Baselga 1996, Seidman 1996, Pegram 1995, and the 1995 PDR


90

entry for Taxol® for the same reasons that independent claim 5 would have been

obvious.

167. Claims 11, 14, and 15 depend directly or indirectly from independent

claim 5 and therefore incorporate all of the limitations from claim 5. Claim 11

further specifies types of agents that may be the “further therapeutic agent.” One

of the listed types of agents is a “growth inhibitory agent.” Claim 14 further

requires that the further therapeutic agent is a growth inhibitory agent. Claim 15

further requires that the growth inhibitory agent is a DNA alkylating agent.

Cisplatin is a growth inhibitory agent within the express definition given in the

patent, and is a DNA alkylating agent. Therefore, it is my opinion that claims 11,

14, and 15 would have been obvious over Baselga 1996, Seidman 1996, Pegram

1995, and the 1995 PDR entry for Taxol® for the same reasons that independent

claim 5 would have been obvious.

F. Secondary Considerations

168. As I noted above, I understand that objective indications of non-

obviousness, such as purported unexpected results or the fulfillment of a long-felt

need, must be considered in an obviousness analysis. Patent Owner submitted the

Hellmann Declaration during prosecution of the application for the ’549 patent.

This declaration alleged two unexpected results: (1) that the combination of

paclitaxel and trastuzumab resulted in unexpected synergy, and (2) that the


91

combination of trastuzumab and doxorubicin resulted in unexpected toxicity. I

disagree with both of these assertions.

1. Dr. Hellmann Did Not Point to Data that Established that the Combination of Paclitaxel and Trastuzumab Results in Synergy

169. Dr. Hellmann opined in her declaration that the combination of

trastuzumab and paclitaxel is “surprisingly synergistic with respect to extending

TTP” because it achieves a therapeutic effect in terms of TTP which is greater than

that expected by the simple addition of the effects of the component drugs.” (Ex

1008, ¶ 6.) I do not agree that this result is surprising in view of the prior art, nor

do I agree that the data she cited demonstrated clinical synergy of the claimed

combination.

170. As an initial matter, Dr. Hellmann’s alleged synergy is limited to the

two-drug combination of trastuzumab/paclitaxel and she did not allege any

evidence of synergy of the claimed combination of an anti-ErbB2 antibody, a

taxoid and a third agent. Therefore, regardless of whether Dr. Hellmann

demonstrated synergy and regardless of whether synergy would have been

expected, Dr. Hellmann offered no evidence about the combinations that are

claimed in the ’549 patent. Still, below I address the evidence of synergy that Dr.

Hellmann alleged in her declaration.


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171. Practically speaking, the outcome of interest to a person of ordinary

skill in the art in a clinical trial of a two-drug combination is whether the results

show that patients are more likely to benefit from the combination (in terms of

either the duration or quality of response) than they are from treatment with the

single agents, either individually or sequentially. With respect to the combination

of trastuzumab and paclitaxel, while a person of ordinary skill in the art would not

have been able to predict with complete accuracy the clinical efficacy results based

on the available single agent clinical data, single agent preclinical data, and

combination preclinical data, a person of ordinary skill in the art would not have

found the clinical efficacy results Dr. Hellmann reported to be surprising in light of

the data that were available in the prior art.

172. The efficacy results Dr. Hellmann reported were reasonably expected

based on the known clinical efficacy of each of trastuzumab and paclitaxel as

single agents in patients with metastatic HER2+ breast cancer, and based on the

known activity of the combination in mouse xenografts. (Ex. 1020; Ex. 1011; Ex.

1019.) Xenograft studies were performed using live cancer cells in live organisms,

and were considered a reasonably accurate model for predicting clinical activity, as

I explained above in Section VI.C.4. The xenografts studies for the trastuzumab-

paclitaxel combination provided a meaningful level of assurance that significant

and synergistic anti-cancer activity could be achieved in human patients.


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173. The efficacy results Dr. Hellmann reported were also reasonably

expected based on the general principles supporting the use of combination therapy

against cancer: that multiple drugs will kill more cancer cells than a single drug

alone, provided the combination therapy can be tolerated. This understanding of

combination therapy includes an expectation of improved outcome with

concomitant administration of two active agents because of the collateral

sensitivity and resistance mechanisms that are inherent in a cancer/treatment

system. As explained, treatment with some agents prime cells to be particularly

sensitive to treatment with other agents; if two agents are given at the same time, it

is expected that the second agent will then be able to kill more cells than it would

have, had it been given alone.

174. Moreover, reliance on the data presented in the Exhibits to the

Hellmann Declaration is flawed, and a conclusion of synergy from those data is not

possible. Dr. Hellmann asserted that Exhibit B attached to her declaration

provided the results of the H0648 trial in which patients were treated with

HERCEPTIN® and paclitaxel. (Id.) She further asserted that Exhibit C attached

to her declaration provided the results of the H0650 study, in which patients were

treated with HERCEPTIN® as a single agent at the same dose as in the H0648

trial. (Id.) According to Dr. Hellmann, these data show that paclitaxel alone

extended TTP by 2.8 months and HERCEPTIN® alone extended TTP by 3.5


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months (for a combined TTP of 2.8 + 3.5, or 6.3 months), whereas the combination

of HERCEPTIN® and paclitaxel extended TTP by 6.9 months. (Id.) Dr.

Hellmann concludes that “the combination is surprisingly synergistic with respect

to extending TTP.” (Id.)

175. The data presented in the Hellmann declaration are insufficient to

draw a conclusion of synergy. For example, the trastuzumab only and

trastuzumab/paclitaxel combination studies were different. (See Ex. 1008

(Hellmann Dec. at 13-14 (Exhibits A- C).) Dr. Hellmann did not provide any

information to conclude that a comparison of values across these separate studies,

which presumably used different protocols and included different patient

populations, would be proper.

176. Further, Dr. Hellmann cited only the median TTP, but ignored the

95% confidence interval data reported for TTP. (Id.) When factoring in the 95%

confidence intervals—as is proper—the TTP values for monotherapy groups

overlap with the values for the trastuzumab-plus-paclitaxel group. Specifically, in

the H0650 study, the patients who received only Herceptin® had a median TTP of

3.5 months, with a 95% confidence interval of 2.8 – 5.5 months. (Hellmann Dec.

at 13 (Exhibit B).) In the H0648 study, the patients who received only paclitaxel

had a median TTP of 2.8 months, with a 95% confidence interval of 1.6 – 5.4

months. (Hellmann Dec. at 14 (Exhibit C).) In that same study, the patients who


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received Herceptin® plus paclitaxel had a median TTP of 6.9 months, with a 95%

confidence interval of 5.3 – 9.9 months. (Hellmann Dec. at 14 (Exhibit C).)

177. Even assuming that TTP is properly additive (i.e., assuming that it is

meaningful to add the Herceptin®-only and paclitaxel-only TTPs together), and

properly compared across studies, given the overlap in the confidence intervals, no

conclusion can be drawn about relative TTPs. The data show that the TTP for the

Herceptin®-only group was somewhere in the range of 2.8 – 5.5 months; the TTP

for the paclitaxel-only group was 1.6 – 5.4 months, and the TTP for the

Herceptin/paclitaxel group was 5.3 – 9.9. months. Given these data, the TTP for

each group could be the same, e.g., 5.3, or 5.4, or even 5.5 months. This means

that based on the data presented by Dr. Hellmann, one is unable to discern whether

there is actually any meaningful difference between TTP for trastuzumab alone

versus the trastuzumab/paclitaxel combination.

178. For at least these reasons, the Hellmann Declaration does not show a

synergistic relationship between trastuzumab and paclitaxel in humans.

2. The Combination of Trastuzumab and Doxorubicin Did Not Result in Unexpected Toxicity and is Not Relevant to the Claimed Combination

179. Dr. Hellmann also opined that combining trastuzumab with

anthracycline/cyclophosphamide (AC) chemotherapy unexpectedly “resulted in a

syndrome of myocardial dysfunction (similar to that observed with anthracyclines)


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substantially more commonly than with AC alone.” (Ex. 1008 at ¶ 4.) Regardless

of this observed result, unexpected or not, as discussed above, a person of ordinary

skill in the art would have been motivated to pursue a combination treatment that

excluded doxorubicin in order to treat the many patients who had already been

treated with first-line-agent doxorubicin.

180. Further, I fail to see the connection between an adverse event that is

observed with a combination of trastuzumab and doxorubicin on the one hand, and

the claimed combination of an anti-ErbB2 antibody, a taxoid and a third agent on

the other. It is my opinion that Dr. Hellmann’s assertions are not relevant to the

claims of the ’549 patent.

181. Further, whether the increased myocardial dysfunction was expected

or not, it does not affect whether a person of ordinary skill of the art would have

been motivated to combine trastuzumab and paclitaxel or reasonably expected

success with that combination for the target population.

182. I am not aware of any other objective indicators of non-obviousness

that could be connected to the claims of the ’549 patent. The prior art indicates

that the combination of paclitaxel and trastuzumab had already been contemplated

before the application was filed, and therefore, any indicators would be a result of

those earlier disclosures in the prior art, and not a result of the disclosure in the


'549 patent. I reserve the right to respond to any assertions of secondary

considerations that Patent Owner alleges during this proceeding.

X. CONCLUSION

183. For all of the reasons discussed above, it is my opinion that claims 1-

11 and 14-17 of the '549 patent are obvious in view of the prior art.

184. I hereby declare that all statements made herein of my own

knowledge are true and that all statements made on information and belief are

believed to be true; and further that these statements were made with the

knowledge that willful false statements and the like so made are punishable by fine

or imprisonment, or both, under Section 1001 of Title 18 of the United States

Code.

Dated: 2 J N fl(lCH 2 0 J 7 By: Robert Earhart, M.D., Ph.D.

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