`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_________________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_________________________
`
`MERCK SHARP & DOHME CORP.
`Petitioner
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`_________________________
`
`Case PGR-Unassigned
`
`U.S. Patent No. 10,626,174
`_________________________
`
`
`
`
`
`DECLARATION OF DR. JAMES M. McDONNELL IN SUPPORT OF
`PETITION FOR POST GRANT REVIEW OF U.S. PATENT NO. 10,626,174
`
`
`
`
`
`
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`TABLE OF CONTENTS
`
`Page
`
`Introduction ...................................................................................................... 1
`I.
`Qualifications ................................................................................................... 1
`II.
`III. Materials Considered ....................................................................................... 4
`IV. The Anti-PD-1 Antibodies Disclosed In The ’174 Patent Do Not
`Share Significant Sequence Homology With One Another Or With
`Other Anti-PD-1 Antibodies ............................................................................ 4
`The Anti-PD-L1 Antibodies Disclosed In The ’174 Patent Do Not
`Share Significant Sequence Homology Homology With One Another
`Or With Other Anti-PD-L1 Antibodies ......................................................... 11
`VI. The Anti-TIGIT Antibodies Disclosed In The ’174 Patent Do Not
`Share Significant Sequence Homology With Each Another Or With
`Other Anti-TIGIT Antibodies ........................................................................ 17
`VII. Conclusion ..................................................................................................... 20
`
`V.
`
`
`
`
`i
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`I.
`
`Introduction
`
`1.
`
`I, James M. McDonnell, Ph.D., have been retained as an expert by
`
`counsel for Merck Sharp & Dohme Corp. (“Merck”). I have prepared this
`
`declaration in connection with Merck’s related petition for Post Grant Review
`
`(“PGR”) of U.S. Patent No. 10,626,174 (“the ’174 patent,” Ex. 1001), which I am
`
`informed is being filed concurrently with this declaration. I have been asked to
`
`provide certain opinions relating to anti-PD-1, anti-PD-L1, and anti-TIGIT
`
`antibodies.
`
`II. Qualifications
`
`2.
`
`I am a Professor of Molecular Immunology in the Randall Centre for
`
`Cell & Molecular Biophysics at King’s College London. I have been researching
`
`immunoglobulins (antibodies) and cytokines involved in immunological and
`
`inflammatory disorders for over 20 years. My research focuses on allergy and lung
`
`biology. In the course of that research, I have had numerous occasions to not only
`
`evaluate cytokine structure and biology, but also to design, use, and evaluate
`
`monoclonal antibodies and their biological impact on immune and inflammatory
`
`diseases, including consulting on clinical development of therapeutic antibodies.
`
`In the course of that work, I have gained extensive experience in antibody
`
`screening and engineering, including those targeting IgE to modify allergic
`
`
`
`1
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`responses. I am currently collaborating with UCB on one such anti-IgE antibody
`
`that is in development for clinical trials.
`
`3.
`
`I obtained my B.S. in Microbiology from the University of
`
`Massachusetts at Amherst and my Ph.D. in 1993 from the Department of
`
`Immunology at Thomas Jefferson University. From 1993 to 1996, I did my
`
`postdoctoral research at King’s College London, conducting biophysical analyses
`
`of IgE-receptor interactions. From 1996 to 2000, I worked as a Senior Research
`
`Associate at The Rockefeller University, studying the molecular structures and
`
`interactions of proteins by NMR spectroscopy. From 2000 to 2010, I was a
`
`University Lecturer in the Department of Biochemistry at the University of
`
`Oxford. In 2010, I joined King’s College London as a Professor of Molecular
`
`Immunology and continued my research on molecular recognition and intervention
`
`in pathological immune responses.
`
`4.
`
`I have published about 100 scholarly articles. Approximately 70 of
`
`these are primary papers in peer-reviewed journals, while the others are invited
`
`review papers, book chapters, and meeting reports. Several of my publications
`
`focus on the three-dimensional structures of immunoglobulins, their binding
`
`properties and their therapeutic applications. I sit on the editorial boards of several
`
`scientific journals, including Frontiers of Molecular Biosciences, Biomedical
`
`Spectroscopy and Imaging, and Spectroscopy. I am also currently a reviewer of
`
`
`
`2
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`numerous prestigious journals on structural biology and drug development,
`
`including Current Opinions in Chemical Biology, FEBS Letters, European
`
`Biophysics Journal, Journal of Biological Chemistry, Nature Reviews Drug
`
`Development, and PLoS ONE.
`
`5.
`
`I have lectured, organized, and taught multiple courses on antibody
`
`structure and function, protein structure, molecular interactions, and structure-
`
`based drug design. Based on my research and publications, I have been awarded
`
`numerous funding grants from national scientific organizations including the
`
`Medical Research Council, the Biotechnology and Biological Sciences Research
`
`Council, the Wellcome Trust, and the National Institutes for Health to investigate,
`
`among other topics, antibody structure and function, asthma, and allergy pathways.
`
`6. My professional qualifications are described in further detail in my
`
`curriculum vitae, which is attached as Appendix A.
`
`7.
`
`I am being compensated for my work on this case at my customary
`
`rate of £325 per hour plus expenses. My compensation does not depend in any
`
`way on my opinions, my performance, or the outcome of the case. I have no
`
`current or past financial ties with Genentech, nor with Merck outside of my
`
`engagement in this proceeding. I have not testified in a U.S. court or in any U.S.
`
`administrative proceeding over the past ten years.
`
`
`
`3
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`III. Materials Considered
`
`8.
`
`I provide the opinions in this declaration based on my education,
`
`training, background, and experience, as well as the documents I have reviewed to
`
`date. Those documents, and the other materials cited in this declaration, are listed
`
`in Appendix B. To the extent I am provided with additional documents or
`
`information, including any declarations in this proceeding, I reserve the right to
`
`modify or expand upon my opinions based on any new information that may arise
`
`and in response to any additional reports and testimony.
`
`IV. The Anti-PD-1 Antibodies Disclosed In The ’174 Patent Do Not Share
`Significant Sequence Homology With One Another Or With Other
`Anti-PD-1 Antibodies
`
`9.
`
`I was asked to determine the amino acid sequence homology for the
`
`variable regions of the following anti-PD-1 antibodies disclosed in the ’174 patent:
`
`MDX-1106 (nivolumab), Merck 3745 (lambrolizumab, which was later renamed
`
`pembrolizumab), and CT-011 (pidilizumab). I have not formed any opinion as to
`
`whether these antibodies meet any of the limitations of the claims of the ’174
`
`patent.
`
`10. Although the ’174 patent does not disclose the sequences of MDX-
`
`1106 (nivolumab), Merck 3745 (lambrolizumab/pembrolizumab), or CT-011
`
`(pidilizumab), the sequences have been published in the International
`
`
`
`4
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`Immunogenetics Information System known as “IMGT.” Ex. 1047; Ex. 1048; Ex.
`
`1049.1
`
`11.
`
`I aligned the variable region sequences of MDX-1106 (nivolumab),
`
`Merck 3745 (lambrolizumab/pembrolizumab), and CT-011 (pidilizumab) using the
`
`Clustal Omega web server. Table 1 below provides the resulting alignment of the
`
`heavy chain variable region sequences, while Table 2 below provides the resulting
`
`alignment of the light chain variable region sequences.
`
`Table 1
`
`
`
`Table 2
`
`
`
`
`
`
`1 The heavy chain variable region and light chain variable region of MDX-1106
`(nivolumab) also correspond to Figures 4A and 4B, respectively, of
`WO2006/121168, which is cited by the ’174 patent as describing this antibody.
`Ex. 1001, 64:36-38; Ex. 1050. The heavy chain variable region and light chain
`variable region of CT-011 (pidilizumab) correspond to SEQ ID NOS 22 and 18,
`respectively, of WO2009/101611, which is cited by the ’174 patent as describing
`this antibody. Ex. 1001, 64:40-42; Ex. 1051.
`
`
`
`5
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`12. Using the sequence alignments of Table 1, I then calculated the
`
`percent pairwise identities for the heavy chain variable region sequences for each
`
`antibody, which is reported in Table 3 below. As reflected in the table, the heavy
`
`chain variable regions of MDX-1106 (nivolumab) and Merck 3745
`
`(lambrolizumab/pembrolizumab) share 53.1% sequence identity. The heavy chain
`
`variable regions of Merck 3745 (lambrolizumab/pembrolizumab) and CT-011
`
`(pidilizumab) share 64.1% sequence identity. The heavy chain variable regions of
`
`MDX-1106 (nivolumab) and CT-011 (pidilizumab) share 58.41% sequence
`
`identity.
`
`Antibody H_MDX-1106 H_Merck-3745 H_CT-011
`
`
`
`
`H_MDX-1106 100.00
`53.10
`58.41
`
`H_Merck-3745 53.10
`100.00
`64.10
`
`H_CT-011 58.41
`64.10
`100.00
`
`
`Table 3: Percent Pairwise Identity Matrix
`for Heavy Chain Variable Region
`
`13. Using the sequence alignments of Table 2, I then calculated the
`
`percent pairwise identities for the light chain variable region sequences for each
`
`antibody, which is reported in Table 4 below. As reflected in the table, the light
`
`chain variable regions of MDX-1106 (nivolumab) and Merck 3745
`
`(lambrolizumab/pembrolizumab) share 85.98% sequence identity. The light chain
`
`variable regions of Merck 3745 (lambrolizumab/pembrolizumab) and CT-011
`
`(pidilizumab) share 67.92% sequence identity. The light chain variable regions of
`
`
`
`6
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`MDX-1106 (nivolumab) and CT-011 (pidilizumab) share 66.98% sequence
`
`identity.
`
`Antibody L_MDX-1106 L_Merck-3745 L_CT-011
`
`
`
`
`L_MDX-1106 100.00
`85.98
`66.98
`
`L_Merck-3745 85.98
`100.00
`67.92
`
`L_CT-011 66.98
`67.92
`100.00
`
`
`Table 4: Percent Pairwise Identity Matrix
`for Light Chain Variable Region
`
`14. The sequence differences between MDX-1106 (nivolumab), Merck
`
`3745 (lambrolizumab/pembrolizumab), and CT-011 (pidilizumab) are particularly
`
`pronounced in the complementarity-determining regions (“CDRs”) of the
`
`antibodies, which is significant because these regions are primarily responsible for
`
`an antibody’s antigen-binding functionality. I have indicated the approximate
`
`positions of the CDR sequences in blue in Tables 1 and 2 above.
`
`15.
`
`I was also asked to compare the amino acid sequences of the variable
`
`regions of the anti-PD-1 antibodies disclosed in the ’174 patent to the same regions
`
`of other anti-PD-1 antibodies. I located the sequences of the following anti-PD-1
`
`antibodies from the IMGT database: cemiplimab, dostarlimab, retifanlimab,
`
`sasanlimab, spartalizumab, and tislelizumab. Ex. 1052; Ex. 1054; Ex. 1055; Ex.
`
`1056; Ex. 1077; Ex. 1078. Each of these antibodies has been found to bind PD-1
`
`and inhibit its interaction with one or more of its binding partners, PD-L1 and/or
`
`PD-L2. Ex. 1079; Ex. 1080; Ex. 1081; Ex. 1082; Ex. 1083; Ex. 1084.
`
`
`
`7
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`16.
`
`I aligned the variable region sequences of MDX-1106 (nivolumab),
`
`Merck 3745 (lambrolizumab/pembrolizumab), CT-011 (pidilizumab), cemiplimab,
`
`dostarlimab, retifanlimab, sasanlimab, spartalizumab, and tislelizumab using the
`
`Clustal Omega web server. I also included in the alignment two antibodies—an
`
`anti-TNFα antibody called adalimumab and an anti-SARS-CoV-2 antibody called
`
`COV2-2240—that bind target antigens other than PD-1 and for which there are no
`
`data of which I am aware indicating any cross-reaction with PD-1. (Ex. 1096; Ex.
`
`1097.) Table 5 below provides the resulting alignment of the heavy chain variable
`
`region sequences, while Table 6 below provides the resulting alignment of the light
`
`chain variable region sequences.
`
`Table 5
`
`
`
`
`
`
`
`8
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`Table 6
`
`17. Using the sequence alignments of Tables 5 and 6, I then calculated the
`
`percent pairwise identities for the respective heavy and light chain variable region
`
`sequences for each antibody. The results for the heavy chain variable region
`
`sequences are reported in Table 7 below, while the results for the light chain
`
`variable region sequences are reported in Table 8 below.
`
`Table 7: Percent Pairwise Identity Matrix for Heavy Chain Variable Region
`
`
`Table 8: Percent Pairwise Identity Matrix for Light Chain Variable Region
`
`18. As seen in Tables 7 and 8, certain of the anti-PD-1 antibodies share
`
`greater sequence identity with one of the antibodies that binds a completely
`
`
`
`9
`
`
`
`
`
`
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`different target than they do with other antibodies that inhibit PD-1. For example,
`
`MDX-1106 has a heavy chain variable region that shares greater sequence identity
`
`with the anti-TNFα antibody and the anti-SARS-CoV-2 antibody than it does with
`
`the other anti-PD-1 antibodies disclosed in the ’174 patent, Merck-3745 and CT-
`
`011. Similarly, CT-011 has a light chain variable region that shares more sequence
`
`identity with the anti-TNFα antibody and the anti-SARS-CoV-2 antibody than it
`
`does with the other anti-PD-1 antibodies disclosed in the ’174 patent, MDX-1106
`
`and Merck-3745. Other anti-PD-1 antibodies—like cemiplimab and dostarlimab—
`
`have light chain variable regions that share greater sequence similarity with the
`
`anti-TNFα antibody and the anti-SARS-CoV-2 antibody than they do with any of
`
`the anti-PD-1 antibodies sequenced in Table 8, including the ones disclosed in the
`
`’174 patent. Likewise, cemiplimab, dostarlimab, and tislelizumab have heavy
`
`chain variable regions that share greater sequence similarity with the anti-TNFα
`
`antibody and the anti-SARS-CoV-2 antibody than they do with one or more of the
`
`anti-PD-1 antibodies disclosed in the ’174 patent. And sasanlimab, spartalizumab,
`
`and tislelizumab have light chain variable regions that share greater sequence
`
`similarity with the anti-TNFα antibody and the anti-SARS-CoV-2 antibody than
`
`they do with one or more of the anti-PD-1 antibodies disclosed in the ’174 patent.
`
`
`
`10
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`V. The Anti-PD-L1 Antibodies Disclosed In The ’174 Patent Do Not Share
`Significant Sequence Homology Homology With One Another Or With
`Other Anti-PD-L1 Antibodies
`
`19.
`
`I was asked to determine the amino acid sequence homology for the
`
`variable regions of the following anti-PD-L1 antibodies disclosed in the ’174
`
`patent: MPDL3280A (now, atezolizumab), MDX-1105 (BMS-936559), and
`
`MEDI 4736 (now, durvalumab). I have not formed any opinion as to whether
`
`these antibodies meet any of the limitations of the claims of the ’174 patent.
`
`20. Although the ’174 patent does not disclose the sequences of
`
`MPDL3280A (atezolizumab), MDX-1105 (BMS-936559), or MEDI 4736
`
`(durvalumab), I was able to determine the sequences from other sources. The
`
`sequences for MPDL3280A (atezolizumab) and MEDI 4736 (durvalumab) have
`
`been published in the IMGT database. Ex. 1059; Ex. 1060. The heavy chain
`
`variable region and light chain variable region of MDX-1105 (BMS-936559)
`
`correspond to Figures 2A and 2B, respectively, of WO2007/005874, which is cited
`
`by the ’174 patent as describing this antibody. Ex. 1001, 64:31-33; Ex. 1085.2
`
`21.
`
`I aligned the variable region sequences of MPDL3280A
`
`(atezolizumab), MDX-1105 (BMS-936559), and MEDI 4736 (durvalumab) using
`
`the Clustal Omega web server. Table 9 below provides the resulting alignment of
`
`
`2 Figures 2A and 2B of WO2007/005874 describe an antibody called 12A4. Ex.
`1085 at 126-127. A later patent filing, WO2017/007985, by the company that
`acquired the applicant company of WO2007/005874 confirms this antibody was
`later designated as MDX-1105 and BMS-936559. Ex. 1086 at 16; Ex. 1087.
`
`
`
`11
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`the heavy chain variable region sequences, while Table 10 below provides the
`
`resulting alignment of the light chain variable region sequences.
`
`Table 9
`
`
`
`Table 10
`
`
`
`
`
`22. Using the sequence alignments of Table 9, I then calculated the
`
`percent pairwise identities for the heavy chain variable region sequences for each
`
`antibody, which is reported in Table 11 below. As reflected in the table, the heavy
`
`chain variable regions of MPDL3280A (atezolizumab) and MDX-1105 (BMS-
`
`936559) share 57.63% sequence identity. The heavy chain variable regions of
`
`MDX-1105 (BMS-936559) and MEDI 4736 (durvalumab) share 50% sequence
`
`identity. The heavy chain variable regions of MPDL3280A (atezolizumab) and
`
`MEDI 4736 (durvalumab) share 80.51% sequence identity.
`
`
`
`12
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`Antibody H_MPDL3280A H_MDX-1105 H_MEDI-4736
`
`
`H_MPDL3280A 100.00
`57.63
`80.51
`
`H_MDX-1105 57.63
`100.00
`50.00
`
`H_MEDI-4736 80.51
`50.00
`100.00
`
`
`Table 11: Percent Pairwise Identity Matrix
`for Heavy Chain Variable Region
`
`23. Using the sequence alignments of Table 10, I then calculated the
`
`percent pairwise identities for the light chain variable region sequences for each
`
`antibody, which is reported in Table 12 below. As reflected in the table, the light
`
`chain variable regions of MPDL3280A (atezolizumab) and MDX-1105 (BMS-
`
`936559) share 71.7% sequence identity. The light chain variable regions of MDX-
`
`1105 (BMS-936559) and MEDI 4736 (durvalumab) share 91.51% sequence
`
`identity. The light chain variable regions of MPDL3280A (atezolizumab) and
`
`MEDI 4736 (durvalumab) share 71.03% sequence identity.
`
`L_MPDL3280A L_MDX-1105 L_MEDI-4736
`
`Antibody
`L_MPDL3280A 100.00
`71.70
`71.03
`
`L_MDX-1105 71.70
`100.00
`91.51
`
`L_MEDI-4736 71.03
`91.51
`100.00
`
`
`Table 12: Percent Pairwise Identity Matrix
`for Light Chain Variable Region
`
`24. The sequence differences between MDX-1105 (BMS-936559), MEDI
`
`4736 (durvalumab), and MPDL3280A (atezolizumab) are particularly pronounced
`
`in the CDRs of the antibodies, which is significant because these regions are
`
`primarily responsible for an antibody’s antigen-binding functionality. I have
`
`
`
`13
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`indicated the approximate positions of the CDR sequences in blue in Tables 9 and
`
`10 above.
`
`25.
`
`I was also asked to compare the amino acid sequences of the variable
`
`regions of the anti-PD-L1 antibodies disclosed in the ’174 patent to the same
`
`regions of other anti-PD-L1 antibodies. I located the sequences of the following
`
`anti-PD-L1 antibodies from the IMGT database: avelumab, cosibelimab, and
`
`sugemalimab. Ex. 1088; Ex. 1089; Ex. 1090. Each of these antibodies has been
`
`found to bind PD-L1 and inhibit its interaction with one or more of its binding
`
`partners, PD-1 and/or B7-1. Ex. 1091; Ex. 1092; Ex. 1093.
`
`26.
`
`I aligned the variable region sequences of MDX-1105 (BMS-936559),
`
`MEDI 4736 (durvalumab), MPDL3280A (atezolizumab), avelumab, cosibelimab,
`
`and sugemalimab using the Clustal Omega web server. I also included in the
`
`alignment two antibodies—an anti-TNFα antibody called adalimumab and an anti-
`
`SARS-CoV-2 antibody called COV2-2240—that bind target antigens other than
`
`PD-L1 and for which there are no data of which I am aware indicating any cross-
`
`reaction with PD-L1. (Ex. 1096; Ex. 1097.) Table 13 below provides the resulting
`
`alignment of the heavy chain variable region sequences, while Table 14 below
`
`provides the resulting alignment of the light chain variable region sequences.
`
`
`
`14
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`Table 13
`
`
`
`Table 14
`
`27. Using the sequence alignments of Tables 13 and 14, I then calculated
`
`the percent pairwise identities for the respective heavy and light chain variable
`
`region sequences for each antibody. The results for the heavy chain variable
`
`region sequences are reported in Table 15 below, while the results for the light
`
`chain variable region sequences are reported in Table 16 below.
`
`Table 15: Percent Pairwise Identity Matrix for Heavy Chain Variable Region
`
`
`
`
`15
`
`
`
`
`
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`Table 16: Percent Pairwise Identity Matrix for Light Chain Variable Region
`
`
`
`28. As seen in Tables 15 and 16, certain of the anti-PD-L1 antibodies
`
`share greater sequence identity with one of the antibodies that binds a completely
`
`different target than they do with other antibodies that inhibit PD-L1. For
`
`example, MPDL3280A has a light chain variable region that shares greater
`
`sequence identity with the anti-TNFα antibody and the anti-SARS-CoV-2 antibody
`
`than it does with the other anti-PD-L1 antibodies disclosed in the ’174 patent,
`
`MDX-1105 and MEDI-4736. MPDL3280A also has a heavy chain variable region
`
`that shares greater sequence identity with the anti-TNFα antibody and the anti-
`
`SARS-CoV-2 antibody than it does with MDX-1105. Similarly, the heavy chain
`
`variable region of MEDI-4736 shares more sequence identity with the anti-TNFα
`
`antibody and the anti-SARS-CoV-2 antibody than it does with MDX-1105. Other
`
`anti-PD-L1 antibodies—like avelumab and cosibelimab—have light chain variable
`
`regions that share greater sequence similarity with the anti-TNFα antibody than
`
`they do with any of the anti-PD-L1 antibodies disclosed in the ’174 patent.
`
`Likewise, avelumab and sugemalimab have heavy chain variable regions that share
`
`greater sequence similarity with the anti-TNFα antibody and the anti-SARS-CoV-2
`
`
`
`16
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`antibody than they do with MDX-1105, and in the case of sugemalimab, MEDI-
`
`4736 as well.
`
`VI. The Anti-TIGIT Antibodies Disclosed In The ’174 Patent Do Not Share
`Significant Sequence Homology With Each Another Or With Other
`Anti-TIGIT Antibodies
`
`29.
`
`I was asked to compare the amino acid sequences of the variable
`
`regions of two anti-TIGIT antibodies disclosed in the ’174 patent (10A7 and 1F4)
`
`to the same regions of other anti-TIGIT antibodies. I have not formed any opinion
`
`as to whether these antibodies meet any of the limitations of the claims of the ’174
`
`patent.
`
`30. The heavy and light chain sequences of 10A7 and 1F4 are disclosed in
`
`the ’174 patent. Ex. 1001, 84:42-85:51.
`
`31.
`
`I located the amino acid sequences of the following anti-TIGIT
`
`antibodies from the IMGT database: etigilimab, tiragolumab, and vibostolimab.
`
`Ex. 1100; Ex. 1101; Ex. 1102. I also located the variable domain amino acid
`
`sequence of the antibody called BMS-986207 from WO 2016/106302.3 Ex. 1105
`
`at [0032], SEQ ID NOS 7, 9. Each of these antibodies has been found to bind
`
`TIGIT and interfere with its normal functioning. Ex. 1099; Ex. 1103; Ex. 1104;
`
`Ex. 1105 at [00388-390], [00397].
`
`
`3 BMS-986207 corresponds to 22G2 in WO 2016/106302, as confirmed by a later
`patent application filed by the same applicant. Ex. 1105 at [0032]; Ex. 1106 at
`[0013].
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`17
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`32.
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`I aligned the variable region sequences of 10A7, 1F4, etigilimab,
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`tiragolumab, vibostolimab, and BMS-986207 using the Clustal Omega web server.
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`I also included in the alignment two antibodies—an anti-TNFα antibody called
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`adalimumab and an anti-SARS-CoV-2 antibody called COV2-2240—that bind
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`target antigens other than TIGIT and for which there are no data of which I am
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`aware indicating any cross-reaction with TIGIT. (Ex. 1096; Ex. 1097.) Table 17
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`below provides the resulting alignment of the heavy chain variable region
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`sequences, while Table 18 below provides the resulting alignment of the light
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`chain variable region sequences.
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`Table 17
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`Table 18
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`18
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`33. Using the sequence alignments of Tables 17 and 18, I then calculated
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`the percent pairwise identities for the respective heavy and light chain variable
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`region sequences for each antibody. The results for the heavy chain variable
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`region sequences are reported in Table 19 below, while the results for the light
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`chain variable region sequences are reported in Table 20 below.
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`Table 19: Percent Pairwise Identity Matrix for Heavy Chain Variable Region
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`Table 20: Percent Pairwise Identity Matrix for Light Chain Variable Region
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`34. As seen in Tables 19 and 20, certain of the anti-TIGIT antibodies
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`share greater sequence identity with one of the antibodies that binds a completely
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`different target than they do with other antibodies that bind TIGIT. For example,
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`10A7 has a heavy chain variable region that shares greater sequence identity with
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`the anti-TNFα antibody and the anti-SARS-CoV-2 antibody than it does with any
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`of the other anti-TIGIT antibodies. 10A7 also has a light chain variable region that
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`shares greater sequence identity with the anti-SARS-CoV-2 antibody than it does
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`with any of the other anti-TIGIT antibodies and that shares greater sequence
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`19
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`identity with the anti-TNFα antibody than it does with many of the other anti-
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`TIGIT antibodies. Similarly, the light chain variable regions of vibostolimab,
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`tiragolumab, and etigilimab share greater sequence identity with either the anti-
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`TNFα antibody or the anti-SARS-CoV-2 antibody than they do with any of the
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`other anti-TIGIT antibodies. And the light chain variable regions of vibostolimab,
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`BMS-986207, tiragolumab, and etigilimab share greater sequence identity with
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`both the anti-TNFα antibody and the anti-SARS-CoV-2 antibody than they do with
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`either 10A7 or 1F4. Likewise, the heavy chain variable regions of BMS-986207,
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`tiragolumab, and etigilimab share greater sequence identity with both the anti-
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`TNFα antibody and the anti-SARS-CoV-2 antibody than they do with either 10A7
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`or 1F4.
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`VII. Conclusion
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`35.
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` I declare that all statements made herein of my own knowledge are
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`true and that all statements made on information and belief are believed to be true,
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`and further that these statements were made with the knowledge that willful false
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`statements and the like so made are punishable by fine or imprisonment, or both,
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`under Section 1001 of Title 18 of the United States Code.
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`Executed this 20th day of January 2021.
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`
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` ____________________________
` James M. McDonnell, Ph.D.
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`APPENDIX A: Curriculum Vitae
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`James M. McDonnell, PhD
`Professor of Molecular Immunology
`Randall Centre for Cell & Molecular Biophysics, King's College London
`Email: james.mcdonnell@kcl.ac.uk Tel. +44 207 848 6970
`
`
`
`
`Research Experience
` 2010-present Molecular recognition and intervention in pathological immune responses
`
`
`Professor of Molecular Immunology, Centre for Molecular Biophysics
`
`
`King's College London
`
` 2000-2010 Molecular interactions and signal transduction
`
`
`University Lecturer, Department of Biochemistry
`
`
`University of Oxford
`
` 1996-2000 Molecular structure and interaction analysis by NMR spectroscopy
`
`
`Senior Research Associate, Laboratory of Physical Biochemistry
`
`
`The Rockefeller University
`
` 1993-1996 Biophysical analysis of IgE-receptor interactions
`
`
`Postdoctoral Fellow, Biophysics Unit
`
`King’s College London
`
` 1989-1993
`Structure/function studies of peptide analogs of CD4
`
`
`PhD Student, Department of Immunology
`
`Thomas Jefferson University
`
`
`
`
`Research Interests
`immunological
`Understanding how specific molecular recognition events regulate
`disorders. Detailed analysis of molecular interactions, conformation and dynamics using
`structural, biophysical and chemical biology approaches. Application of this information in
`the development of inhibitors of molecular interactions, using either structure-based design
`or library screening methods.
`
`
`
`Summary of Grant Funding
`Medical Research Council: Project Grant (2021-2024); Programme Grant (2012-2017), Capital
`Award (2013-2014), Project Grant (2005-2008), Career Establishment Grant (2002-2007),
`Cooperative Grant (2003-2008); five PhD studentships
`The Wellcome Trust: Capital Award Grants (2009-2015, 2017-2022), Programme Grant (2007-
`2012), Equipment Grant (2005-2010), Project Grant (2003-2007); five PhD studentships
`Biotechnology and Biological Sciences Research Council: Equipment Grant (2021-2025),
`Project Grant (2017-2021), one PhD studentship
`National Institute for Health Research: Biomedical Research Centre Project Grant (2012-2018)
`European Union: FP6 Consortium Grant (2004-2009)
`Arthritis Research Campaign: Studentship Grant (2008-2011)
`Asthma UK: Foundation Grant (2010-2011)
`E.P. Abraham Research Fund: Project Grant (2001-2002)
`The Royal Society: Equipment Grant (2001-2002)
`The Darwin Trust: two PhD studentship grants (2016-2020, 2018-2022)
`US Army: Breast Cancer Research Award (1999-2000)
`Burroughs Wellcome Fund: Hitchings-Elion Fellowship (1993-1996)
`Industrial support [details confidential] (2010-2021)
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`Publications
`
`
`S.V. Benjamin, P.I. Creeke, A.J. Henry and J.M. McDonnell (2020) NMR backbone
`assignment of the Cε4 domain of immunoglobulin E. Biomolecular NMR Assignments
`14:1-5 (doi: 10.1007/s12104-020-09936-9)
`R.M. Hoffmann, S. Mele, A. Cheung, D. Larcombe-Young, G. Bucaite, E. Sachouli, I.
`Zlatareva, H.O.J. Morad, R. Marlow, J.M. McDonnell, M. Figini, K.E. Lacy, A.J.N. Tutt,
`J.F. Spicer, D.E. Thurston, S.N. Karagiannis and S. Crescioli (2020) Rapid Conjugation of
`Antibodies to Toxins to Select Candidates for the Development of Anticancer Antibody-
`Drug Conjugates (ADCs). Scientific Reports 10(1):8869 (doi: 10.1038/s41598-020-
`65860-x)
`A.N. Mitropoulou, T. Ceska, J.T. Heads, A.J. Beavil, A.J. Henry, J.M. McDonnell, B.J.
`Sutton and A.M. Davies (2020) Engineering the Fab Fragment of the anti-IgE
`Omalizumab to Prevent Fab Crystallization and Permit IgE-Fc Complex Crystallization.
`Acta Crystallogr F 76:116-129 (doi: 10.1107/S2053230X20001466)
`G. Bucaite, T. Kang-Pettinger, J. Moreira, H.J. Gould, J.K. James, B.J. Sutton, and J.M.
`McDonnell (2019) Interplay between Affinity and Valency in Effector Cell Degranulation:
`A Model System with Polcalcin Allergens and Human Patient-Derived IgE Antibodies. J.
`Immunol., 203:1693-1700 (doi: 10.4049/jimmunol.1900509)
`S. Dimeloe, L.V. Rice, H. Chen, C. Cheadle, J. Raynes, P. Pfeffer, P. Lavender, D.F.
`Richards, M.P. Nyon, J.M. McDonnell, C. Kemper, B. Gooptu and C.M. Hawrylowicz
`(2019) Vitamin D (1,25(OH)2D3) induces α-1-antitrypsin synthesis by CD4+ T cells,
`which is required for 1,25(OH)2D3-driven IL-10. J Steroid Biochem Mol Biol 189:1-9
`(doi: 10.1016/j.jsbmb.2019.01.014)
`K. Hansen, A.M.C. Lau, K. Giles, J.M. McDonnell, W.B. Struwe, B.J. Sutton and A. Politis
`(2018) A mass spectrometry-based modelling workflow for accurate prediction of IgG
`the gas phase. Angew Chem 57:17194-17199 (doi:
`antibody conformations
`in
`10.1002/anie.201812018)
`J.B. Chen, F. Ramadani, M.O.Y. Pang, R.L. Beavil, M.D. Holdom, A.N. Mitropoulou, A.J.
`Beavil, H.J. Gould, T.W. Chang, B.J. Sutton, J.M. McDonnell and A.M. Davies (2018)
`Structural basis for selective inhibition of immunoglobulin E-receptor interactions by an
`anti-IgE antibody. Scientific Reports, 8:11548 (doi: 10.1038/s41598-018-29664-4)
`K.A. Doré, J. Kashiwakura, J.M. McDonnell, H.J. Gould, T. Kawakami, B.J. Sutton and
`A.M. Davies (2018) Crystal structures of murine and human Histamine-Releasing Factor
`(HRF/TCTP) and a model for HRF dimerisation in mast cell activation. Molecular
`Immunology, 93:216-222 (doi: 10.1016/j.molimm.2017.11.022)
`D. Pollpeter, M. Parsons, A.E. Sobala. S. Coxhead, R.D. Lang, A.M Bruns, S. Papaioannou,
`J.M. McDonnell, L. Apolonia, J.A. Chowdhury, C.M. Horvath and M.H. Malim (2018)
`Deep sequencing of HIV-1 reverse transcripts reveals the multifaceted antiviral functions
`of APOBEC3G. Nature Microbiology, 3:220-233 (doi: 10.1038/s41564-017-0063-9)
`K.A. Doré, A.M. Davies, N. Drinkwater, A.J.