UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`TWINSTRAND BIOSCIENCES, INC.
`Petitioner,
`v.
`GUARDANT HEALTH, INC.
`Patent Owner.
`
`___________________
`
`No. IPR2022-01400
`Patent No. 11,149,306
`___________________
`
`DECLARATION OF ALEKSANDAR RAJKOVIC, M.D., PH.D. IN
`SUPPORT OF PETITIONER’S REPLY
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`TwinStrand EX1099
`TwinStrand Biosciences v. Guardant Health
`IPR2022-01400
`
`
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`TWINSTRAND BIOSCIENCES, INC.
`Petitioner,
`v.
`GUARDANT HEALTH, INC.
`Patent Owner.
`
`___________________
`
`No. IPR2022-01400
`Patent No. 11,149,306
`___________________
`
`DECLARATION OF ALEKSANDAR RAJKOVIC, M.D., PH.D. IN
`SUPPORT OF PETITIONER’S REPLY
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`TwinStrand EX1099
`TwinStrand Biosciences v. Guardant Health
`IPR2022-01400
`
`
`
`Case IPR2022-01400
`Declaration of Aleksandar Rajkovic, M.D., Ph.D.
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ....................................................................................... 1
`I.
`II. MY BACKGROUND AND QUALIFICATIONS ....................................... 2
`III. LIST OF DOCUMENTS CONSIDERED .................................................... 4
`IV. PERSON OF ORDINARY SKILL IN THE ART ........................................ 6
`V. A POSA WOULD HAVE BEEN MOTIVATED TO APPLY
`SCHMITT’S METHODS TO SEQUENCE CELL-FREE DNA
`CONTRARY TO DR. HAGEMANN’S OPINION. ..................................... 7
`A. Dr. Hagemann improperly requires Schmitt to disclose testing
`for cancer mutations in a clinical setting. ........................................... 7
`VI. DR. HAGEMANN’S ALLEGED CONCERNS ABOUT BLOOD
`DRAW REQUIREMENTS ARE MERITLESS. ........................................ 10
`A. A POSA would have understood that collecting 21 to 36
`milliliters of blood from patients was reasonable and perfectly
`clinically acceptable. .........................................................................10
`Clinical laboratories are capable of processing 21 to 36
`milliliters of blood. ...........................................................................15
`A POSA would not have been concerned with subjecting
`patients with hospital-acquired anemia as a result of collecting
`21 to 36 milliliters of blood. ..............................................................17
`
`B.
`
`C.
`
`
`
`
`
`- i -
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`
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
`
`I, Aleksandar Rajkovic, hereby declare as follows.
`
`I.
`
`INTRODUCTION
`I have been retained on behalf of Twinstrand Biosciences, Inc.
`1.
`
`(“Twinstrand” or “Patent Owner”) for the above-captioned inter partes review
`
`proceeding to provide my expert opinions and expert knowledge. I understand that
`
`this proceeding involves U.S. Patent No. 11,149,306 (“the ’306 patent”) titled
`
`“Methods and Systems for Detecting Genetic Variants,” and that the ’306 patent is
`
`currently assigned to Guardant Health, Inc. (“Guardant” or “Patent Owner”).
`
`2.
`
`I understand that in response to a Petition submitted by Twinstrand, an
`
`inter partes review of claims 1-29 of the ’306 patent was instituted by the Patent
`
`Trial and Appeal Board (“the Board”) on February 8, 2023.
`
`3.
`
`In preparing this Declaration, I have reviewed and am familiar with all
`
`of the documents cited herein. I confirm that to the best of my knowledge the
`
`accompanying exhibits are true and accurate copies of what they purport to be, and
`
`that an expert in the field would reasonably rely on them to formulate opinions
`
`such as those set forth in this declaration.
`
`4.
`
`I am being compensated at my customary rate of $500 per hour for
`
`my work on this case. My compensation is not dependent upon my opinions, my
`
`testimony, or the outcome of this case.
`
`1
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`
`
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
`
`II. MY BACKGROUND AND QUALIFICATIONS
`I am the Distinguished Professor of Pathology and
`5.
`
`Obstetrics/Gynecology and Reproductive Sciences at the University of California,
`
`San Francisco (UCSF) School of Medicine. I also serve as the UCSF Chief
`
`Genomics Officer and the Medical Director and Chief of the Center for Genetic
`
`and Genomic Medicine (CGGM) that organizes, coordinates and oversees Clinical
`
`Genetics and Genomics Services across the entire UCSF Health System. In
`
`addition to these positions, I also serve as the Director of the Genomic Medicine
`
`Initiative, a position I have held since 2018.
`
`6.
`
`In 1985, I received my Bachelor of Science in Chemistry from Johns
`
`Hopkins University. In 1992, I received an M.D. and Ph.D. in Molecular Biology
`
`at Case Western Reserve University. After receiving my M.D. and Ph.D., I
`
`completed my internship in general medicine in 1993 and my residency in
`
`Obstetrics and Gynecology in 1997 at Metrohealth Medical Center in Cleveland,
`
`Ohio. I also completed a fellowship in Maternal Fetal Medicine at Metrohealth
`
`Medical Center. Additionally, I completed a residency in Medical Genetics at
`
`Baylor College of Medicine in Houston, Texas in 1999.
`
`7.
`
`The primary area of my research is the genetic underpinnings of the
`
`formation and differentiation of gametes and reproductive tract, their role of these
`
`genes in human disease, embryo lethality and origin of heritable human disorders.
`
`2
`
`
`
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
`
`My lab also focused on investigating the genetic underpinnings of uterine
`
`leiomyomas, better known as fibroid tumors and understanding the numerous
`
`genomic rearrangements that associate with this tumor. My lab is at the forefront
`
`of applying state of the art technologies to diagnosing infertility, gonadal
`
`dysgenesis, and prenatal disorders, including the use of genome-wide detection of
`
`copy number variants in prenatal diagnosis among others.
`
`8.
`
`I am licensed to practice medicine in California. I am also Board
`
`Certified in Obstetrics and Gynecology and Clinical Genetics.
`
`9. My work has been published in more than 170 peer-reviewed
`
`scientific articles, which have been cited more than 15,000 times. One paper
`
`discussing the results of a genome-wide association study identifying variants in
`
`the ABO locus associated with susceptibility to pancreatic cancer has been cited
`
`over 700 times. My published work also includes publications on cell-free DNA,
`
`including several papers that studied screening maternal cell-free DNA or maternal
`
`plasma for fetal microdeletion syndrome. I have also received grant funding to
`
`continually support my research from multiple organizations, including the
`
`National Institutes of Health and the Eunice Kennedy Shriver National Institute of
`
`Child Health and Human Development.
`
`10.
`
`I am an active member of the American Society for Clinical
`
`Investigation, the Association of American Physicians, the American
`3
`
`
`
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
`
`Gynecological and Obstetrical Society (ACOG), and the National Academy of
`
`Medicine. I also serve on the Board of Directors of the ACMG Foundation for
`
`Genetic and Genomic Medicine and serve on the ACOG Committee on Genetics.
`
`11. My Curriculum Vitae is attached to this declaration (EX1100), and
`
`contains additional details on my education, honors and awards, publications,
`
`professional activities, and qualifications to deliver an expert opinion in this
`
`matter.
`
`12.
`
`In preparing this declaration, I have reviewed the declaration of Dr.
`
`Ian Hagemann (EX2016). As detailed below, I disagree with Dr. Hagemann’s
`
`conclusions.
`
`III. LIST OF DOCUMENTS CONSIDERED
`In formulating my opinions, I have reviewed all the references and
`13.
`
`documents cited herein, including those listed below.
`
`Exhibit # Description
`
`1001
`
`1002
`
`1040
`
`1050
`
`Talasaz, A. and Mortimer, S.A.W., “Methods And Systems For
`Detecting Genetic Variants,” U.S. Patent No. 11,149,306 (filed July
`31, 2020; issued October 19, 2021)
`Declaration of Paul T. Spellman, Ph.D.
`
`Crowley, E., et al., ”Liquid biopsy: monitoring cancer-genetics
`in the blood,” Nat. Rev. Clin. Oncol. 10: 472-484 (2013)
`Dawson, S-J., et al., “Analysis of Circulating Tumor DNA to Monitor
`Metastatic Breast Cancer,” N Engl J Med 368(13): 1199-1209 (2013)
`with Supplementary Appendix
`
`4
`
`
`
`
` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
`
`Exhibit # Description
`
`Chan, K.C.A., et al., “Cancer Genome Scanning in Plasma: Detection
`of Tumor-Associated Copy Number Aberrations, Single-Nucleotide
`Variants, and Tumoral Heterogeneity by Massively Parallel
`Sequencing,” Clin. Chemistry 59(1): 211–224 (2013)
`Leary, R.J., et al., “Detection of Chromosomal Alterations in the
`Circulation of Cancer Patients with Whole-Genome Sequencing,” Sci
`Transl Med. 4(162): 1-12 (2012)
`Narayan et al., “Ultrasensitive Measurement of Hotspot Mutations in
`Tumor DNA in Blood Using Error-Suppressed Multiplexed Deep
`Sequencing,” Cancer Research, 72(14):3492-3498 (2012)
`U.S. Provisional Application No. 61/625,623, filed on April 17, 2012
`
`1051
`
`1052
`
`1082
`
`1083
`
`1093
`
`1094
`
`Brooks, J. D., et al., “DNA Methylation in Pre-Diagnostic Serum
`Samples of Breast Cancer Cases: Results of a Nested Case-Control
`Study,” Cancer Epidemiol, 34(6): 717-723 (Dec. 2010)
`Atamaniuk, J., et al., “Apoptotic Cell-Free DNA Promotes
`Inflammation in Haemodialysis Patients,” Nephrol Dial Transplant,
`27:902-905 (2012)
`Uppaluri, R., et al., “Neoadjuvant and Adjuvant Pembrolizumab in
`Resectable Locally Advanced, Human Papillomavirus-Unrelated Head
`and Neck Cancer: A Multicenter, Phase II Trial,”Clin. Cancer Res.,
`26(19):5141-5152 (Oct. 2020)
`1096 Deposition Transcript of Dr. Ian Hagemann, Aug. 3, 2023
`
`1095
`
`1097
`
`Deposition Transcript of John Quackenbush, Ph.D., Aug. 15, 2023
`
`1102
`
`2016
`
`2019
`
`“Expedited Review: Categories of Research that may be Reviewed
`Through an Expedited Review Procedure (1998),” U.S. Department of
`Health and Human Services, Web Page Capture on September 1, 2023
`Declaration of Dr. Ian Hagemann
`
`Zhu et al., “Sensitivity, Specificity, Accuracy, Associated Confidence
`Interval and ROC Analysis with Practical SAS® Implementations”
`(2010)
`
`5
`
`
`
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
`
`Exhibit # Description
`
`2023
`
`Dr. Ian Hagemann CV
`
`2025
`
`2026
`
`2029
`
`2030
`
`QIAGEN Sample & Assay Technologies – “QIAamp DNA Blood
`Mini Kit” Third Edition (2012)
`QIAGEN Sample & Assay Technologies – “QIAamp DNA Micro Kit”
`Second Edition (2010)
`Thavendiranathan et al., “Do Blood Tests Cause Anemia in
`Hospitalized Patients?” Journal of General Internal Medicine (2004)
`Salisbury et al., “Diagnostic Blood Loss From Phlebotomy and
`Hospital-Acquired Anemia During Acute Myocardial Infarction”
`American Medical Association (2011)
`2031 M. Levi, “Twenty-five million liters of blood into the sewer” Journal
`of Thrombosis and Haemostasis (2014)
`
`
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`I understand that a person of ordinary skill in the art (“POSA”) is a
`14.
`
`hypothetical person who is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art and is a person of ordinary creativity.
`
`15.
`
`I understand that Dr. Spellman provided a definition of a POSA in his
`
`declaration:
`
`A POSA relevant to the ’306 patent would have had knowledge of the
`scientific literature concerning methods of DNA manipulation and
`analysis,
`including DNA sample preparation
`for sequencing,
`amplification, methods of DNA sequencing (including NGS and related
`sequencing methods), and bioinformatics methods for raw data
`analysis.
`
`6
`
`
`
`
` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
`
`A POSA may have also worked as part of a multidisciplinary team and
`drawn upon not only his or her own skills, but also taken advantage of
`certain specialized skills of others on the team, e.g., to solve a given
`problem.
`
`Typically, a POSA would [] have had (i) a Ph.D., in molecular biology,
`genetics, bioinformatics, or a related field, and have at least about two
`years of experience in the use and development of sequencing
`technologies; or (ii) a Master’s degree in one of the same fields with at
`least about five years of the same experience.
`
`EX1002, ¶¶27-30.
`
`16.
`
`I understand that Dr. Hagemann has applied this same definition of a
`
`POSA in his analysis. EX2016, ¶13. I have applied the same POSA definition in
`
`my own analysis.
`
`V. A POSA WOULD HAVE BEEN MOTIVATED TO APPLY
`SCHMITT’S METHODS TO SEQUENCE CELL-FREE DNA
`CONTRARY TO DR. HAGEMANN’S OPINION.
`A. Dr. Hagemann improperly requires Schmitt to disclose testing for
`cancer mutations in a clinical setting.
`17. Dr. Hagemann opines that “while a POSA might view Schmitt as an
`
`interesting laboratory protocol, a POSA would not view Schmitt as a reliable test
`
`for cancer mutation detection in a clinical setting.” EX2016, ¶¶27-34. I disagree.
`
`18.
`
`I understand from Dr. Hagemann’s deposition transcript that he
`
`admitted that there are clear differences between performing a sequencing test in a
`
`7
`
`
`
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
`
`“clinical setting” versus performing such a test in a research setting. Indeed, Dr.
`
`Hagemann confirmed at his deposition that the “clinical setting would be a setting
`
`in which patient care is being delivered by physicians or other providers who are
`
`relying potentially on laboratory testing to guide their clinical decision making.”
`
`EX1096, 38:11-15. Dr. Hagemann further testified that detecting a cancer mutation
`
`in a clinical setting would require skills that are “consistent with the standard of
`
`care” where the “doctor or other provider also needs to be able to counsel the
`
`patient as to the accuracy of the test that they’re using to guide the patient’s care.”
`
`EX1096, 39:11-24.
`
`19. Dr. Hagemann also stated that detecting cancer mutations in a clinical
`
`setting would require “an appropriate mix or combination of sensitivity and
`
`specificity” that is “ideally as high as possible” so as to “promote its clinical
`
`acceptability to the patient.” EX1096, 38:8-15, 41:4-13. Thus, Dr. Hagemann’s
`
`“clinical setting” standard appears to be that of a clinical diagnostics or screening
`
`test.
`
`20.
`
`In contrast, Dr. Hagemann admitted that a “research setting does not
`
`necessarily require the highest level of specificity” and that there are some research
`
`settings which would require a lower sensitivity to a clinical setting. EX1096,
`
`41:23-42:8; 45:19-25. Dr. Hagemann further testified that “there are legal
`
`requirements imposed on labs that perform clinical testing,” while the same
`8
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
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`requirements are not imposed in a research setting. EX1096, 45:19-25, 47:23-48:13
`
`(emphasis added).
`
`21. Narayan itself does not disclose testing in a “clinical setting.” In fact,
`
`Narayan discloses a clinical study, which a POSA would understand to be for
`
`research purposes. I understand that Guardant’s other expert, Dr. Quackenbush,
`
`admitted that Narayan disclosed a “research study.” EX1097, 92:2-21, 86:15-87:6.
`
`Indeed, Narayan discloses that its findings suggest that the deep sequencing
`
`approach “may be applied to the development of a practical diagnostic test that
`
`measures tumor-derived DNA levels in blood.” EX1082, Abstract.
`
`22. Furthermore, Narayan teaches that the features of its deep sequencing
`
`approach “suggest a potential application of this technology that takes advantage
`
`of the cancer specificity of mutant ctDNA” for early cancer detection. EX1082, 6
`
`(emphasis added). Narayan further discloses that such an assay “would have to
`
`include analysis of mutations in a larger panel of genes to maximize the probability
`
`of detecting ctDNA” in order to “be practically useful for cancer screening.”
`
`EX1082, 6. Narayan also discloses that “much work remains to be done” and that
`
`the test is not yet suitable to “guide clinical decisions.” EX1082, 6. Thus, a POSA
`
`would have understood that Narayan was a research study. EX1097, 92:2-21,
`
`86:15-87:6. And in my opinion, a POSA would have viewed Schmitt’s error
`
`correction methods as useful in research studies such as Narayan’s.
`9
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
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`23. Dr. Spellman’s declaration testimony is consistent with my
`
`understanding. When discussing the many cfDNA references in his Declaration,
`
`including Narayan, Dr. Spellman stated that “these studies have demonstrated that
`
`sequencing and detecting cfDNA has numerous clinical and research applications
`
`that can be used to ‘evaluate this approach on a large cohort of cancers of multiple
`
`types.’” EX1002, ¶73 (quoting Chan 2013, EX1051, 222-223) (emphasis added).
`
`Moreover, Chan 2013 (EX1051) discloses that its disclosed cancer genome
`
`scanning has “numerous clinical and research applications.” EX1051, 223
`
`(emphasis added).
`
`24.
`
`In view of the above, a POSA would have been motivated to combine
`
`Schmitt and Narayan to perform at least developmental research testing because
`
`that is exactly the type of testing performed in Narayan’s study. Thus, contrary to
`
`Dr. Hagemann, a POSA would not have understood the combination of Narayan
`
`and Schmitt to be useful only in a clinical diagnostic setting.
`
`VI. DR. HAGEMANN’S ALLEGED CONCERNS ABOUT BLOOD
`DRAW REQUIREMENTS ARE MERITLESS.
`A. A POSA would have understood that collecting 21 to 36 milliliters
`of blood from patients was reasonable and perfectly clinically
`acceptable.
`25. Dr. Hagemann opines that “[w]hile it is possible to obtain 21 to 36
`
`[milliliters] of blood from a patient, this amount is greater than what is deemed
`
`reasonable or clinically acceptable.” EX2016, ¶¶36-38. I disagree with Dr.
`10
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
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`Hagemann’s opinions. As discussed below, a POSA would not have been
`
`concerned with drawing 21-36 milliliters of blood from a patient.
`
`26. First, Example 1 of the ’306 patent discloses collecting “10-30 mL” of
`
`blood and then using routine techniques to extract the cfDNA from those blood
`
`samples to detect copy number variations. EX1001, 53:54-56. I understand from
`
`reviewing Dr. Hagemann’s deposition transcript that Dr. Hagemann admitted as
`
`such. EX1096, 58:23-59:13. Nowhere in the ’306 patent does it caution against or
`
`discourage collecting up to 30 milliliters of blood for fear that it was not clinically
`
`acceptable.. Thus, a POSA would not have been concerned with collecting up to 30
`
`milliliters of blood.
`
`27. Second, while Dr. Hagemann is correct that, in general, physicians
`
`prefer to draw as little blood as possible to minimize patient discomfort or any
`
`potential side effects, a volume of 21 to 36 milliliters of blood is within the
`
`medically acceptable range for research studies even for cancer patients. In fact,
`
`physicians draw upwards of 30 milliliters of blood or more from cancer patients on
`
`a routine basis. For example, Brooks 2009, a study on DNA methylation in serum
`
`samples, collected “30 ml of non-fasting peripheral venous blood” from a cohort of
`
`14,274 women between the ages of 35 and 65 who were enrolled at a breast cancer
`
`screening clinic. EX1093, 3 (emphasis added). Similarly, Atamaniuk 2012
`
`obtained “10 ml plasma samples using the Qiamp Blood Maxi Kit” from 23
`11
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
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`hemodialysis patients with end-stage renal disease to study the effects of cfDNA
`
`on human monocytes. EX1094, 1-2 (emphasis added). As was well-known in the
`
`field and admitted to by Dr. Hagemann himself, 10 milliliters of plasma is would
`
`typically be obtained from about 30 milliliters of blood. EX1040, 473; EX1096,
`
`59:22-60:5, 78:4-7; EX2016, ¶23.
`
`28. Other references taught extracting cfDNA in standard blood draws of
`
`30 or more milliliters of blood. Dawson 2013, for example, disclosed extracting
`
`cfDNA from 30 milliliters of blood from 30 women with metastatic breast cancer
`
`who were receiving systemic therapy. EX1050, Suppl. Appx., 4. Leary 2012
`
`sequenced cfDNA from “4-18 ml” of plasma collected from 10 healthy
`
`individuals, 7 patients with colorectal cancer, and 3 patients with breast cancer.
`
`EX1052, 2, 8. A POSA would have known that 4 - 18 milliliters of plasma would
`
`be obtained from, at most, about 12 - 54 milliliters of blood. EX1040, 473. Neither
`
`Dawson nor Leary disclosed any potential issues collecting 30 or more milliliters
`
`of blood from cancer patients, including ones with late-stage metastatic cancer.
`
`29.
`
`Indeed, I understand that Dr. Hagemann himself has participated in
`
`clinical reseach studies that drew 30 milliliters of blood from cancer patients. In a
`
`paper Dr. Hagemann co-authored in 2021 titled, “Neoadjuvant and Adjuvant
`
`Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-
`
`Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial,” 30 milliliters of
`12
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
`
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`blood were “collected in 3 purple top EDTA tubes” from patients suffering from
`
`Stages III and IV head and neck cancer. EX1095, Suppl. Info, 41. I understand that
`
`Dr. Hagemann confirmed at his deposition that Uppaluri studied patients with
`
`recurrent or metastatic head and neck cancer, which are considered “advanced
`
`cases of cancer in general.” EX1096, 79:21-80:22. Dr. Hagemann also confirmed
`
`that the study protocol used in Uppaluri 2021 was “approved by the Institutional
`
`Review Board at each participating site and registered nationally” at
`
`clinicaltrials.gov (NCT02296684). EX1096, 84:21-86:3, 87:11-14. Dr. Hagemann
`
`also agreed that Uppaluri 2021 followed ethical guidelines of the Declaration of
`
`Helsinki, Belmont Report, and the U.S. Common Rule. EX1096, 81:13-82:2,
`
`84:21-86:3, 87:11-14. Lastly, I understand that Dr. Hagemann confirmed that 30
`
`milliliters of blood were collected from late-stage cancer patients in the Uppaluri
`
`2021 study. EX1096, 86:16-24. Accordingly, Dr. Hagemann’s own work has
`
`involved drawing 30 mls of blood, even from late stage cancer patients.
`
`30. Furthermore, the Office for Human Research Protections of the U.S.
`
`Department of Health and Human Services disclosed in its 1998 Categories of
`
`Research That May Be Reviewed by the Institutional Review Board (IRB) through
`
`an Expedited Review Procedure that for “healthy, nonpregnant adults who weigh
`
`at least 110 pounds,” the amounts drawn “may not exceed 550 ml in an 8 week
`
`13
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` Declaration of Aleksandar Rajkovic, M.D., Ph.D
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`period.” EX1102.1
`
`31.
`
`I further understand from his deposition transcript that Dr. Hagemann
`
`admitted that healthy volunteers willing to donate blood to the American Red
`
`Cross blood donor center can donate “about 500 milliliters.” EX1096, 92:24-93:15.
`
`32. While Dr. Hagemann does correctly point out that larger blood draws
`
`can be uncomfortable for the patient, patient compliance largely depends on the
`
`potential benefit of the test, the doctor-patient relationship, and patient education.
`
`EX2016, ¶41.
`
`33. Dr. Hagemann’s concern that large-volume peripheral blood draws
`
`may harm patients by causing injury to the vein from which blood is drawn is over
`
`stated. EX2016, ¶45. Every blood draw, regardless of number of tubes drawn, has
`
`a risk which includes pain, bruising, infection, and lightheadedness. However, Dr.
`
`Hagemann provides no evidence that multiple tube draws are associated with
`
`
`1 EX1102 is a PDF version of a webpage found at the following URL:
`
`https://www.hhs.gov/ohrp/regulations-and-policy/guidance/categories-of-research-
`
`expedited-review-procedure-1998/index.html. I have visited this webpage and
`
`verified that the PDF is a true and accurate copy of the material presented on the
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`webpage. EX1102 is also a reference that an expert would rely on to form an
`
`opinion on the amount of blood that can be drawn over an 8-week period.
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`14
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
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`increased frequency of collapsed veins. As such, a POSA would not have been
`
`concerned that a blood draw of 21 to 36 milliliters would cause injury to the
`
`patient’s veins.
`
`34. Therefore, in view of the above, a POSA would not have found
`
`collecting a 30 milliliter quantity “out of the ordinary” and instead would have
`
`deemed such a practice both reasonable and clinically acceptable even in patients
`
`with late-stage cancer during hospital stays.
`
`B. Clinical laboratories are capable of processing 21 to 36 milliliters
`of blood.
`35. Dr. Hagemann argues that clinical laboratories are “generally not
`
`equipped to track multiple vials to be analyzed together as inputs to a common
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`test” and that “introducing multiple vials would introduce new risks that are
`
`avoided by normal hospital procedures.” EX2016, ¶¶38-40. Dr. Hagemann further
`
`opines that representative commercial blood analysis kits, such as the DNA Micro
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`Kit or the Mini Kit from Qiagen “are not designed to or even capable of handling
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`the quantities of blood or plasma” EX2016, ¶40. Dr. Hagemann is wrong on all
`
`counts. Any standard laboratory is equipped to handle and analyze blood volumes
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`of 21 to 36 milliliters.
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`36. First, the ’306 patent expressly discloses using the QiaAMP Mini
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`Blood kit for bloods samples of “up to 30 ml” in quantity. EX1001, 53:59-62. Dr.
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`15
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
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`Hagemann agrees. EX1096, 60:22-61:19. The art also taught that larger sized kits
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`were available to accommodate larger quantities of blood. Indeed, Qiagen’s own
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`QIAamp DNA Mini and Blood Mini Handbook, an exhibit cited by Dr. Hagemann
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`himself, discloses that the “QIAamp DNA Blood Midi and Maxi Kits are available
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`for purification of DNA from up to 2 ml and 10 ml of blood, respectively.”
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`EX2025, 10. A POSA would have understood that if one desired collecting 30
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`milliliters of blood, it would only require using three of these Maxi Kits to test
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`such a quantity of blood.
`
`37.
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`Second, Dr. Hagemann wrongly argues that collecting 30 milliliters of
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`blood “would require four tubes to be drawn, assuming that they were completely
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`filled and that the full volume were available for testing” and that clinical
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`laboratories would have no equipment to analyze such large quantities of blood.
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`EX2016, ¶38. As discussed above, Uppaluri 2021, a paper co-authored by Dr.
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`Hagemann, teaches collecting 30 milliliters of blood in three purple top EDTA
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`tubes and reported no problems with securing the proper clinical laboratory
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`equipment to handle such “large quantities of blood.” EX1095, Suppl. Info, 41. Dr.
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`Hagemann admitted that he was unaware of any deviations from protocol in the
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`Uppaluri study. EX1096, 86:16-87:14.
`
`38. Third, several prior art references, including Brooks 2009 and
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`Atamaniuk 2012, did not discuss having any issues analyzing larger quantities of
`16
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
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`blood or explain how there were any difficulties processing “multiple collection
`
`tubes” in parallel. Furthermore, neither reference ever discussed how doing so
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`“introduce[d] new risk that are avoided by normal hospital procedures, such as the
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`risk that vials from different patients could be mistakenly combined and analyzed
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`together.” EX2016, ¶38.
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`39. Dr. Hagemann himself admitted that the art, specifically Brooks and
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`Atamaniuk, taught how to utilize a variety of commercial kits and reagents for
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`handling larger volumes of blood. EX1096, 66:2-17, 69:9-18, 70:4-12; EX1093, 3;
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`EX1094, 2.
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`40. Thus, contrary to Dr. Hagemann’s opinions, a POSA would have
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`understood that clinical laboratories are readily capable of processing 21 to 36
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`milliliters of blood.
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`C. A POSA would not have been concerned with subjecting patients
`with hospital-acquired anemia as a result of collecting 21 to 36
`milliliters of blood.
`41. Dr. Hagemann next argues that a POSA would have been concerned
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`about “iatrogenic anemia, i.e., a shortage of blood due to the quantities extracted
`
`during hospitalization.” EX2016, ¶¶42-45. I disagree. Dr. Hagemann’s concerns
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`are again, over stated.
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`42. First, although excessive blood drawing can cause iatrogenic anemia,
`
`the likelihood of anemia is dependent on several factors, including the patient's
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`17
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` Case IPR2022-01400
` Declaration of Aleksandar Rajkovic, M.D., Ph.D
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`overall health, nutritional status, and the frequency of blood draws. The risk must
`
`be weighed against the potential benefits of a potentially life-saving cancer
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`diagnosis. In my opinion as a practicing physician, the likelihood of iatrogenic
`
`anemia resulting from a one-time blood draw of 21 to 36 milliliters is extremely
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`low.
`
`43.
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`Second, each reference that Dr. Hagemann cites to relate only to a
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`very specific subset of hospitalized patients with hospital-acquired anemia.
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`Thavendiranathan 2005 (EX2029) studied whether phlebotomy contributes to
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`changes in hemoglobin and hematocrit levels in hospitalized general internal
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`medicine patients. EX2029, 520. Similarly, Salisbury 2011 studies hospital-
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`acquired anemia in patients with acute myocardial infarction. EX2030, 1646. Levi
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`2014 discusses the potential risk of patients developing hospital-acquired anemia
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`when too much blood is collected during a hospital stay. A POSA would
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`understand that for a large majority of hospitalized patients, blood collection does
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`not result in hospital-acquired anemia. Moreover, a POSA interested in applying
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`Schmitt’s error-correction methods in a clinical research study such as Narayan’s
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`would not be required to perform testing on hospitalized patients.
`
`44. Furthermore, both Thavendiranathan 2005 and Salisbury
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