`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 1 of 363 PageID #:
`
` 1 of 363 PageID #: 3395 5064
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE SOUTHERN DISTRICT OF INDIANA
`INDIANAPOLIS DIVISION
`
`
`
`ELI LILLY AND COMPANY,
`
`
`Plaintiffs/Counterclaim Defendants,
`
`Defendants/Counterclaimants.
`
`
`
`
`
`EXPERT REPORT OF BRUCE A. CHABNER, M.D.
`
`
`
`
`
`v.
`
`
`DR. REDDY’S LABORATORIES, LTD. and
`DR. REDDY’S LABORATORIES, INC.,
`
`
`
`
`
`
`C.A. No. 1:16-308-TWP-DKL
`
`CONFIDENTIAL – SUBJECT TO
`PROTECTIVE ORDER
`
`A953
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 2 of 363 PageID #:
`
` 2 of 363 PageID #: 3396 5065
`
`
`
`I. 
`II. 
`III. 
`IV. 
`V. 
`
`VI. 
`
`TABLE OF CONTENTS
`
`QUALIFICATIONS AND BACKGROUND. ................................................................... 1 
`THE ’209 PATENT. ........................................................................................................... 6 
`THE PERSON OF ORDINARY SKILL IN THE ART. .................................................... 7 
`CLAIM CONSTRUCTION. ............................................................................................... 8 
`INFRINGEMENT............................................................................................................... 9 
`A. 
`DRL’s NDA Products. ............................................................................................ 9 
`B. 
`Literal Infringement Analysis. .............................................................................. 15 
`1. 
`Administration of Folic Acid. ................................................................... 16 
`2. 
`Pemetrexed Disodium. .............................................................................. 20 
`Analysis of Infringement under the Doctrine of Equivalents. .............................. 28 
`1. 
`Substantially the Same Function. .............................................................. 30 
`2. 
`Substantially the Same Way. .................................................................... 31 
`3. 
`Substantially the Same Result. .................................................................. 38 
`Inducement of and Contribution to Infringement. ................................................ 39 
`D. 
`PROSECUTION HISTORY. ............................................................................................ 40 
`
`
`
`C. 
`
`A954
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 3 of 363 PageID #:
`
` 3 of 363 PageID #: 3397 5066
`
`
`
`I.
`
`QUALIFICATIONS AND BACKGROUND.
`
`1.
`
`My name is Bruce A. Chabner. I am the Clinical Director Emeritus and the Paul
`
`G. Allen Distinguished Investigator at the Massachusetts General Hospital Cancer Center. I am
`
`also a Professor of Medicine at Harvard Medical School.
`
`2.
`
`I am an expert in the field of medical oncology and in the following fields of
`
`special interest: biochemistry and pharmacology of anticancer agents, including antifolates, and
`
`the development of new anticancer agents. I have well over 40 years of experience in these
`
`areas. My curriculum vitae, which include a list of my publications, are found at Exhibit A.
`
`3.
`
`Folates and antifolates have been a major focus of my work throughout my career.
`
`I have personally engaged in preclinical research on various antifolates, have been involved with
`
`or overseen clinical trials that studied various antifolates, and have prescribed or overseen the
`
`prescription of antifolates to patients.
`
`4.
`
`After my formal education (B.A. from Yale, M.D. from Harvard), I undertook a
`
`series of postdoctoral training posts. One of these posts was as a Research Associate in the
`
`Department of Medicine and Pharmacology at Yale University School of Medicine, where I
`
`worked under the tutelage of Joseph Bertino, a pioneer in the antifolate field. In 1970-71, in Dr.
`
`Bertino’s laboratory, I studied the role of a particular enzyme (carboxypeptidase G) in cleaving
`
`folates and antifolates, including methotrexate. As part of this research, I discovered that this
`
`enzyme could rescue animals from toxicity induced by high doses of methotrexate. It is now
`
`approved by the FDA for that clinical use.
`
`5.
`
`In 1971, I joined the National Cancer Institute at the National Institutes of Health,
`
`the federal government’s principal agency for cancer research and training as a senior staff
`
`fellow, and one year later became a faculty member in the U.S. Public Health Service. While at
`
`
`
`A955
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 4 of 363 PageID #:
`
`
`
` 4 of 363 PageID #: 3398 5067
`
`
`the NCI, I maintained an active laboratory program in cancer pharmacology with a particular
`
`focus on the pharmacology and biochemistry of antifolate cancer drugs.
`
`6.
`
`One aspect of my NCI research concerned the biochemistry and pharmacological
`
`aspects of antifolate cancer drugs, including the investigation of the cellular transport and
`
`polyglutamation of antifolate drugs. My laboratory was the first to clone the folate receptor (also
`
`called the folate binding protein) and define its role in the transport of folates and antifolates.
`
`My close colleagues at NCI were the first to clone the reduced folate carrier, a second transporter
`
`of antifolates.
`
`7.
`
`My NCI research also involved the clinical evaluation of a number of antifolate
`
`cancer compounds, in particular methotrexate. I oversaw clinical studies with methotrexate in a
`
`variety of tumor types including breast cancer, ovarian cancer, and lymphomas, and investigated
`
`safety aspects of methotrexate, such as determinants of methotrexate toxicity (drug concentration
`
`and duration of exposure) to normal and malignant cells. My group published the first clinical
`
`report of drug resistance related to gene amplification, which had developed in patients treated
`
`with methotrexate, and also discovered that the process of polyglutamation (a process central to
`
`the cellular retention and mode of action of methotrexate, pemetrexed, and other antifolates)
`
`extended the drug’s action and determined treatment outcome.
`
`8.
`
`Another aspect of my NCI research involved efforts to improve the clinical utility
`
`of methotrexate. For example, we performed pharmacokinetic studies to evaluate the
`
`mechanisms by which high-dose methotrexate caused sepsis and renal failure—serious toxicities
`
`that resulted from this regimen. We discovered that methotrexate-induced renal failure resulted
`
`from precipitation of the drug (and its metabolites) in patients’ kidneys, and based on that
`
`finding, we developed an in-patient regimen of fluid administration, urine alkalinization, and
`
`2
`
`A956
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 5 of 363 PageID #:
`
`
`
` 5 of 363 PageID #: 3399 5068
`
`
`drug level monitoring that has since become a standard approach with high dose chemotherapy,
`
`preventing the frequent deaths that previously occurred with this important regimen.
`
`9.
`
`My tenure at NCI culminated in my service, from 1982 to 1995, as the Director of
`
`the Division of Cancer Treatment, the largest of the four divisions at NCI, and the one concerned
`
`with drug discovery and development. My responsibilities in that position included overseeing
`
`intramural research programs, and supporting grants, cooperative groups, and contracts for
`
`extramural anticancer drug development. Our division discovered and developed many
`
`important cancer drugs, including paclitaxel, cisplatin, and the first anti-AIDS drugs, AZT, DDI,
`
`and DDC.
`
`10.
`
`In 1995, I joined the academic faculty at Harvard Medical School as Professor of
`
`Medicine. I served as Chief of MGH’s Division of Hematology and Oncology from 1995 to
`
`2006, Clinical Director of MGH’s Cancer Center from 1995 to 2010, and Director of Clinical
`
`Research from 2010 to 2015. In addition, from 1999 to 2010, I was the Associate Director for
`
`Clinical Sciences at the Dana Farber-Harvard Cancer Center. My responsibilities at MGH have
`
`focused on supervision of cancer treatment services, cancer clinical investigations, and training
`
`of medical oncology fellows. Throughout this time, I also have served as an attending physician
`
`for the inpatient general medicine service and for oncology. I have been responsible for
`
`overseeing the prescription of ALIMTA® to patients, and have been an investigator in a high-
`
`dose ALIMTA® study for lymphomas of the central nervous system.
`
`11.
`
`I am an author of approximately 500 peer-reviewed publications, reviews,
`
`chapters, monographs, and editorials, of which a substantial number are related to antifolates. I
`
`am an editor of over twenty books and textbooks for the medical and scientific community,
`
`including the standard text, Cancer Chemotherapy and Biotherapy, now in its fifth edition. I
`
`3
`
`A957
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 6 of 363 PageID #:
`
`
`
` 6 of 363 PageID #: 3400 5069
`
`
`served as an Editor of the 12th edition of Goodman and Gilman’s textbook of pharmacology
`
`(2011), the standard text in its field. I served as a Senior Editor of the journal Clinical Cancer
`
`Research from 2001 to 2006, and I have served as the Editor-in-Chief of the journal The
`
`Oncologist from 1994 to present.
`
`12.
`
`One of the major cancer research organizations in the United States is the
`
`American Society of Clinical Oncology, also known as ASCO. ASCO is the national
`
`organization of clinical oncologists. I am privileged to have received the David A. Karnofsky
`
`Memorial Award, which is given for lifetime achievement in cancer research. I received this
`
`award in 1985 at the age of 45.
`
`13.
`
`The other major cancer research organization in the United States is the American
`
`Association for Cancer Research, also known as AACR. In 1998, I was privileged to have
`
`received the Bruce F. Cain Memorial Award, which is the main award of the AACR for drug
`
`development. I was elected to Fellowship in the AACR Academy, a major honor for cancer
`
`researchers, in 2015.
`
`14.
`
`The National Cancer Advisory Board (“NCAB”) was created in the 1970s as part
`
`of the War on Cancer. Its 18 members are appointed by the President, and they provide advice
`
`and oversight concerning cancer policy in the United States. I was a member of the NCAB from
`
`2006-2012, and served as its chair from 2010-2012.
`
`15.
`
`In September 2016, I was honored with the Distinguished Investigator Award and
`
`lectureship of the American College of Clinical Pharmacology at their annual meeting in
`
`Bethesda, Maryland.
`
`16.
`
`For my work on this matter, I am being compensated at a rate of $1,250 per hour,
`
`and $1,500 per hour for time testifying at the trial. This compensation does not depend on the
`
`4
`
`A958
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 7 of 363 PageID #:
`
`
`
` 7 of 363 PageID #: 3401 5070
`
`
`outcome of these proceedings. In forming my opinions, I have considered the materials cited in
`
`this report and/or Exhibit B, as well as my education, training, experience as a medical
`
`oncologist, including with ALIMTA®, and conversations with colleagues regarding ALIMTA®.
`
`17.
`
`In the past four years, I have testified in the following matters:
`
` Neptune Generics, LLC, et al., v. Eli Lilly & Co., IPR2016-00237 (joined with IPR2016-
`01190, IPR2016-01335, IPR2016-01341);
`
` Neptune Generics, LLC, et al., v. Eli Lilly & Co., IPR2016-00240 (joined with IPR2016-
`01191, IPR2016-01337, IPR2016-01343);
`
` Sandoz Inc., et al., v. Eli Lilly & Co., IPR2016-00318 (joined with IPR2016-01429,
`IPR2016-01393, IPR2016-01340);
`
` Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., et al., No. 10-1376 (S.D. Ind.); and
`
` Richard Hutson, et al., v. Dermatology In Clinton, LLP, et al., No. MMX-CV12-
`6007760-S (Superior Court, J.D. of Middlesex at Middletown).
`
`18.
`
`If asked, I will be prepared to present a basic tutorial to explain the terms and
`
`concepts related to the opinions set forth in my expert report, as well as to provide further
`
`background on the folic acid pathway and folate-dependent enzymes, the history of antifolate
`
`development, clinical use of antifolates, clinical use of cisplatin, the state of the art,
`
`polyglutamation, transport of antifolates into cells, the level of skill in the art, and the patent at
`
`issue. That tutorial may include demonstrative exhibits and models. In addition to the opinions
`
`and bases set forth in this report, I may supplement my opinions—including in the event of
`
`changes to the labeling for DRL’s NDA Products, as well as in response to deposition testimony
`
`from DRL witnesses—and my testimony may include responses to facts, arguments, allegations,
`
`or references raised by DRL or its experts relating to this litigation.
`
`5
`
`A959
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 8 of 363 PageID #:
`
`
`
` 8 of 363 PageID #: 3402 5071
`
`
`II.
`
`THE ’209 PATENT.
`
`19.
`
`I understand that the patent at issue in this case is Eli Lilly’s U.S. Patent No.
`
`7,772,209 (“the ’209 patent”). The ’209 patent relates to Lilly’s anticancer product ALIMTA®
`
`(pemetrexed for injection), which has as its active ingredient pemetrexed (also referred to as
`
`“pemetrexed disodium,” “LY231514” (the internal Lilly name for the compound), and “MTA”
`
`(which stands for multi-targeted antifolate)). Pemetrexed is an antifolate compound that acts by
`
`blocking the function of enzymes in the folic acid pathway. Pemetrexed is indicated for the
`
`treatment of locally advanced or metastatic nonsquamous non-small cell lung cancer and
`
`mesothelioma. The use of ALIMTA® in accordance with its labeling is covered by the claims of
`
`the ’209 patent.
`
`20.
`
`Generally speaking, the claims of the ’209 patent relate to methods of
`
`administration of folic acid and a methylmalonic acid lowering agent (such as vitamin B12) to a
`
`cancer patient prior to administration of pemetrexed disodium, as well as repeated administration
`
`of vitamin B12. The claims specify various regimens and dosages for such administration,
`
`including the additional administration of cisplatin.
`
`21.
`
`The invention claimed in the ’209 patent has benefited cancer patients, in
`
`particular cancer patients for whom administration of pemetrexed disodium without vitamin
`
`supplementation was too toxic. In other words, the invention in the ’209 patent is not
`
`pemetrexed disodium, nor is it merely a method of administering pemetrexed disodium to a
`
`cancer patient in need of chemotherapeutic treatment. This is reflected in claim 12 of the ’209
`
`patent, which refers to “[a]n improved method for administering pemetrexed disodium to a
`
`patient in need of chemotherapeutic treatment,” which I understand legally means that a method
`
`for administering pemetrexed disodium to a patient in need of chemotherapeutic treatment is
`
`deemed to be known in the prior art. Rather, as set forth in further detail in the claims, the
`
`6
`
`A960
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 9 of 363 PageID #:
`
`
`
` 9 of 363 PageID #: 3403 5072
`
`
`invention claimed in the ’209 patent relates to administration folic acid and vitamin B12 as pre-
`
`treatment, prior to administration of pemetrexed to a patient.
`
`22.
`
`ALIMTA® was approved by the U.S. Food and Drug Administration (“FDA”) for
`
`administration according to a regimen involving administering folic acid and vitamin B12 prior
`
`to and during treatment with pemetrexed disodium. This regimen is set forth in the ALIMTA®
`
`product labeling. Lilly sells ALIMTA® as a 500 mg/vial product and a 100 mg/vial product.
`
`Copies of Lilly’s current ALIMTA® labeling, as well of the patient information, can be found at
`
`http://pi.lilly.com/us/alimta-pi.pdf and http://pi.lilly.com/us/alimta-ppi.pdf, respectively.
`
`III.
`
`THE PERSON OF ORDINARY SKILL IN THE ART.
`
`23.
`
` I have been asked to provide my opinion as to the qualifications of the
`
`hypothetical “person of ordinary skill in the art” (“POSA”) to whom the inventions disclosed and
`
`claimed in the ’209 patent were directed, as of June 29, 1999, which I have been informed is
`
`more than one year prior to June 30, 2000, the filing of the first patent application related to the
`
`’209 patent.1
`
`24.
`
`In my opinion, the POSA to whom the ’209 patent is addressed is a medical
`
`doctor who specializes in oncology, specifically medical oncology. Such a person would have
`
`knowledge and experience concerning the use of chemotherapy agents, including antifolates, in
`
`the treatment of cancer, as well as knowledge and experience regarding the management of
`
`toxicities associated with such treatment.
`
`25.
`
`I understand that the POSA is a hypothetical person who can possess the skills of
`
`individuals in different disciplines. As a practical matter, medical oncologists may sometimes
`
`
`1
`My opinions regarding the qualifications of the POSA would not change if, instead, the
`date used was June 30, 2000, or if it were September 27, 2000, April 18, 2001, or June 15, 2001,
`which I have been informed are the dates of filing of subsequent patent applications related to the
`’209 patent.
`
`7
`
`A961
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 10 of 363 PageID #:
`
`
`
` 10 of 363 PageID #: 3404 5073
`
`
`need to consult with individuals with different skills and experience during the course of treating
`
`patients with chemotherapeutic agents. Such individuals can include, for example, individuals
`
`with experience in drug formulation (including salt forms of an active compound) if questions
`
`arise as relating to the dissolution of the active ingredient into solution for intravenous
`
`administration.2
`
`IV.
`
`CLAIM CONSTRUCTION.
`
`26. With respect to the first step of the infringement analysis—claim construction—I
`
`note that in the prior litigation against Teva and APP, the parties adopted the following
`
`constructions of particular claim terms. I have applied these constructions in my analysis. I
`
`understand that DRL has not challenged these constructions or proposed that they be modified:
`
`CLAIM TERM OR PHRASE
`“an effective amount of folic acid and an
`effective amount of a methylmalonic acid
`lowering agent”
`
`
`
`AGREED CONSTRUCTION
`“amounts of folic acid and a methylmalonic
`acid lowering agent that are capable of reducing
`the prevalence or severity of one or more
`toxicities associated with the administration of
`pemetrexed disodium”
`
`
`
`2
`I have been informed that, for purposes of its claim construction order in the prior
`litigation against Teva and APP, the Court found that the POSA can be “[1] a medical doctor
`who specializes in oncology or [2] a medical doctor with extensive experience in the areas of
`nutritional sciences involving vitamin deficiencies,” and that this latter individual “would need to
`have collaborated with medical oncologists who have knowledge and experience in the treatment
`of cancer through the use of antifolates.” Entry on Claim Construction, Eli Lilly & Co. v. Teva
`Parenteral Medicines, Inc., et al., No. 1:10-cv-1376-TWP-DKL, slip op. at 8 (S.D. Ind. June 20,
`2012) (emphasis added). I do not believe that this second definition accurately describes the
`POSA. Although I have been informed that the POSA is a hypothetical person, in my experience
`individuals who have expertise in nutritional sciences are not involved in decisions regarding
`cancer drug administration, let alone how to address toxicities that arise from administration of a
`cancer drug. However, whether the definition of the POSA is a medical doctor who specializes
`in oncology, or encompasses either of the persons described in the Court’s claim construction
`order in the litigation against Teva and APP, it would not change the opinions I express in this
`report, as in both cases the POSA would include a medical doctor who specializes in oncology.
`
`8
`
`A962
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 11 of 363 PageID #:
`
`
`
` 11 of 363 PageID #: 3405 5074
`
`
`“methylmalonic acid lowering agent”
`
`“an effective amount of pemetrexed
`disodium”
`
`“an agent such as vitamin B12 which can be
`used to lower the concentration of
`methylmalonic acid in a mammal”
`
`“an amount of pemetrexed disodium that is
`capable of providing a therapeutic benefit to the
`patient in need thereof”
`
`
`
`I also have been informed that the phrase “A method for administering pemetrexed disodium to a
`
`patient in need thereof” in claim 1 and the phrase “An improved method for administering
`
`pemetrexed disodium to a patient in need of chemotherapeutic treatment” in claim 12, were
`
`agreed by the parties in the litigation against Teva and APP to be limiting. I have been informed
`
`that means that this language should be included in the analysis of whether the claims have been
`
`infringed. I understand that DRL has not challenged those constructions or proposed that they be
`
`modified. I have applied these constructions in my analysis.
`
`27.
`
`In addition, I understand that the Court construed the following claim terms in the
`
`following manner in the litigation against Teva and APP, and that DRL has neither challenged
`
`these constructions nor proposed modifying them. I have applied these constructions in my
`
`analysis.
`
`CLAIM TERM
`
`“patient”
`
`“vitamin B12”
`
`
`V.
`
`INFRINGEMENT.
`
`A.
`
`DRL’s NDA Products.
`
`CONSTRUCTION ADOPTED BY THE COURT
`“human undergoing medical treatment”
`
`“cyanocobalamin”
`
`
`28.
`
`I understand that Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories,
`
`Inc. (“DRL”) have filed a New Drug Application (“NDA”) with the FDA seeking to market
`
`“Pemetrexed for injection” in a 500 mg/vial dosage form and a 100 mg/vial dosage form. I will
`
`9
`
`A963
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 12 of 363 PageID #:
`
`
`
` 12 of 363 PageID #: 3406 5075
`
`
`refer to DRL’s products individually as “DRL’s 500 mg Product” and “DRL’s 100 mg Product,”
`
`and collectively as “DRL’s NDA Products.” I have reviewed the labeling for DRL’s NDA
`
`Products, which is directed to physicians. See DRL00050499-536.3 Excerpts from the labeling
`
`for DRL’s NDA Products are discussed below. Also discussed below are corresponding excerpts
`
`from the labeling for ALIMTA®, the administration of which in accordance with its labeling is
`
`covered by the claims of the ’209 patent.
`
`29.
`
`
`
`
`
`
`3
`
`
`
`10
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A964
`
`

`

`
`
`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 13 of 363 PageID #:
`
`
` 13 of 363 PageID #: 3407 5076
`
`
`
`
`
`
`
`30.
`
`31.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`11
`
`A965
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 14 of 363 PageID #:
`
`
`
` 14 of 363 PageID #: 3408 5077
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`32.
`
`
`
`
`
`
`
`12
`
`A966
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 15 of 363 PageID #:
`
`
`
` 15 of 363 PageID #: 3409 5078
`
`
`33.
`
`34.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`13
`
`
`
`
`
`
`
`
`
`
`
`A967
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 16 of 363 PageID #:
`
`
`
` 16 of 363 PageID #: 3410 5079
`
`
`35.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`36.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`14
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A968
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 17 of 363 PageID #:
`
`
`
` 17 of 363 PageID #: 3411 5080
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`37.
`
`
`
`
`
`
`
`
`
`B.
`
`Literal Infringement Analysis.
`
`38.
`
`I have been asked to compare DRL’s NDA Products, including their labeling,
`
`with various claims of the ’209 patent. I understand that this comparison is called an
`
`infringement analysis, and that this analysis involves determining, for each claim at issue,
`
`whether the use of a given product would entail performing every step of the claimed method. In
`
`that regard, I have been asked to provide my opinion on whether the administration of DRL’s
`
`15
`
`A969
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 18 of 363 PageID #:
`
`
`
` 18 of 363 PageID #: 3412 5081
`
`
`NDA Products in accordance with the labeling for those products would infringe claims 9, 10,
`
`12, 13, 14, 15, 18, 19, 21, and 22 (the “Asserted Claims”) of the ’209 patent.
`
`39.
`
`The administration of DRL’s NDA Products in accordance with the labeling for
`
`those products would infringe each and every Asserted Claim of the ’209 patent. As reflected in
`
`the discussion in this report and in the accompanying claim chart (Exhibit C), as well as in my
`
`testimony at the infringement trial against Teva and APP (which should be considered as part of
`
`this report), see ADRL-000898-001170,4 DRL’s labeling directs and encourages the
`
`administration of DRL’s NDA Products in a manner that meets each limitation of each Asserted
`
`Claim of the ’209 patent. In addition, and as reflected in the discussion in this report, the claim
`
`chart, and my trial testimony, it is my opinion that physicians will prescribe and patients will
`
`receive DRL’s NDA Products in accordance with such directions.
`
`1.
`
`Administration of Folic Acid.
`
`40.
`
`In the litigation against Teva and APP, those companies took the position that the
`
`use of their generic pemetrexed products did not infringe the ’209 patent claims because the
`
`labeling for their generic products directed more than one person to practice the claims—i.e., the
`
`steps of the claimed methods are not performed by a single person. Specifically, Teva and APP
`
`took the position that while the physician5 will administer the pemetrexed infusion and the
`
`vitamin B12 injections, the patient will self-administer the folic acid.
`
`
`4
`My testimony at trial analyzed the labeling for ALIMTA®, which I understand the parties
`in that case agreed was representative of the labeling for Teva and APP’s generic pemetrexed
`products.
`
`When I say “physician” in this report or in the claim chart, I am including those health
`
`care providers who are acting for the physician, such as a nurse who in response to a physician’s
`instructions physically administers the intravenous injection of pemetrexed and/or the
`intramuscular injection of vitamin B12.
`
` 5
`
`16
`
`A970
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 19 of 363 PageID #:
`
`
`
` 19 of 363 PageID #: 3413 5082
`
`
`41.
`
`I disagree with the position taken by Teva and APP in the prior litigation. I also
`
`disagree with any notion that it somehow means that DRL’s NDA Products do not infringe the
`
`claims of the ’209 patent. Rather, the labeling for DRL’s NDA Products—which is essentially
`
`the same if not identical to the labeling for ALIMTA® with respect to directions regarding
`
`administration of folic acid—induces physicians to direct and control the administration of folic
`
`acid to the patient.
`
`42.
`
`I understand that whether an individual “directs and controls” a step of a method
`
`claim depends upon whether the individual (here, the physician) conditions receipt of a benefit or
`
`participation in an activity upon performance of the step of the method. With respect to DRL’s
`
`NDA Products, the benefit that is provided is administration of pemetrexed, which can provide a
`
`therapeutic benefit in terms of cancer treatment. Likewise, the activity here is the patient’s
`
`participation in the pemetrexed treatment.
`
`43.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`17
`
`A971
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 20 of 363 PageID #:
`
`
`
` 20 of 363 PageID #: 3414 5083
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`44.
`
`18
`
`A972
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 21 of 363 PageID #:
`
`
`
` 21 of 363 PageID #: 3415 5084
`
`
`
`
`
`
`45.
`
`46.
`
`
`
`19
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A973
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 22 of 363 PageID #:
`
`
`
` 22 of 363 PageID #: 3416 5085
`
`
`
`
`47.
`
`
`
`48.
`
`2.
`
`Pemetrexed Disodium.
`
`20
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A974
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 23 of 363 PageID #:
`
`
`
` 23 of 363 PageID #: 3417 5086
`
`
`49.
`
`
`
`50.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`21
`
`A975
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 24 of 363 PageID #:
`
`
`
` 24 of 363 PageID #: 3418 5087
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`51.
`
`
`
`52.
`
`22
`
`A976
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 25 of 363 PageID #:
`
`
`
` 25 of 363 PageID #: 3419 5088
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`53.
`
`
`
`23
`
`A977
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 26 of 363 PageID #:
`
`
`
` 26 of 363 PageID #: 3420 5089
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`54.
`
`
`
`
`
`
`
`
`
`
`
`24
`
`A978
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 27 of 363 PageID #:
`
`
`
` 27 of 363 PageID #: 3421 5090
`
`
`
`
`
`
`
`
`
`
`55.
`
`56.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`25
`
`A979
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 28 of 363 PageID #:
`
`
`
` 28 of 363 PageID #: 3422 5091
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`57.
`
`
`
`26
`
`A980
`
`

`

`
`Case 1:16-cv-00308-TWP-MPB Document 147-1 (Case Participants) Filed 08/31/17 PageCase 1:16-cv-00308-TWP-MPB Document 172-1 Filed 09/21/17 Page 29 of 363 PageID #:
`
`
`
` 29 of 363 PageID #: 3423 5092
`
`
`
`
`