IPR2023-00724
`U.S. Patent 10,335,462
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
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`MYLAN PHARMACEUTICALS, INC.,
`Petitioner
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`v.
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`NOVO NORDISK A/S,
`Patent Owner
`______________________
`Case IPR2023-00724
`Patent 10,335,462
`______________________
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`EXPERT DECLARATION OF GEORGE L. BAKRIS, M.D.
`IN SUPPORT OF PATENT OWNER’S RESPONSE TO
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 10,335,462
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`U.S. Patent 10,335,462
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
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`MYLAN PHARMACEUTICALS, INC.,
`Petitioner
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`v.
`
`NOVO NORDISK A/S,
`Patent Owner
`______________________
`Case IPR2023-00724
`Patent 10,335,462
`______________________
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`EXPERT DECLARATION OF GEORGE L. BAKRIS, M.D.
`IN SUPPORT OF PATENT OWNER’S RESPONSE TO
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 10,335,462
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`IPR2023-00724
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`I, George L. Bakris, hereby declare under penalty of perjury:
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`INTRODUCTION
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`I.
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`1.
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`I have been retained by Groombridge, Wu, Baughman & Stone LLP,
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`on behalf of Novo Nordisk A/S (“Novo Nordisk”) to provide assistance regarding
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`U.S. Patent No. 10,335,462 (“the ’462 patent”). Specifically, I have been asked to
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`provide my opinions regarding certain objective indicia of non-obviousness for the
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`’462 patent. Except as otherwise indicated, I have personal knowledge of the facts
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`and opinions set forth in this declaration, and believe them to be true. If called upon
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`to do so, I would testify competently thereto.
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`2.
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`I am being compensated for my time at a rate of $700 per hour. I will
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`be reimbursed for any expenses that I incur during the course of this work. My
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`compensation is not contingent upon the results of my study, the substance of my
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`opinions, or the outcome of any proceeding involving the Challenged Claims (claims
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`1-10). I have no financial interest in the outcome of this matter or in the pending
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`litigations involving Novo Nordisk A/S and Novo Nordisk Inc.
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`II. BACKGROUND AND QUALIFICATIONS
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`3.
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`I offer statements and opinions on behalf of Novo Nordisk, generally
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`regarding certain objective indicia of non-obviousness, specifically unexpected
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`results related to the ’462 patent.
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`4.
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`I am a nephrologist with expertise in treating diabetes-related kidney
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`disease. I am currently a tenured Professor of Medicine at University of Chicago
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`Medicine and the Director of the Comprehensive Hypertension Center at the
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`University of Chicago.
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`5.
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`I received by BA in Biology and Psychology from Indiana University
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`in 1974, my MA is in Human Development from the University of Chicago in 1975,
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`and my MD from Rosalind Franklin University of Medicine and Science in 1981.
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`6.
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`From 1981 to 1982 I completed my internship in Internal Medicine at
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`the Mayo Graduate School of Medicine. From 1982 to 1983 I did a residency year
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`in Psychiatry at the Washington University School of Medicine.
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`7.
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`From 1983 to 1984 I was a research fellow in Renal Physiology and
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`Hypertension at the Mayo Graduate School of Medicine and from 1984 to 1986 I
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`completed my residency in Internal Medicine at the University of Illinois, Chicago.
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`8.
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`I completed my fellowship in Nephrology at University of Chicago
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`Medicine from 1986 to 1988 and my fellowship in Clinical Pharmacology from 1986
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`to 1987, also at University of Chicago Medicine.
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`9.
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`Following my fellowships, from 1988 to 1991 I was a staff nephrologist
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`at the Ochsner Clinic in New Orleans, LA, and Assistant Professor in the Department
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`of Medicine at Tulane University. I was also an Adjunct Assistant Professor in the
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`Departments of Physiology and Pharmacology at Tulane University.
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`10. From 1991 to 1993 I was an Assistant Professor of Medicine and
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`Pharmacology in the Division of Nephrology and Director of the Renal Fellowship
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`Program at the University of Texas Health Science Center at San Antonio, Texas.
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`11. From 1993 to 1996 I was an Assistant Professor in the Departments of
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`Preventive Medicine and Internal Medicine at Rush University Medical Center.
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`12. From 1994 to 2006 I was a Lecturer in the Division of Nephrology at
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`the University of Illinois Medical Center at Chicago.
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`13. From 1996 to 1998 I was an Associate Professor and from 1999 to 2006
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`I was a Professor in the Departments of Preventive Medicine and Internal Medicine
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`at Rush University Medical Center.
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`14. Beginning in 2006, I accepted a position as Professor of Medicine at
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`University of Chicago Medicine, a position I still hold today.
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`15.
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`I have been a principal investigator or on the steering committees of
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`numerous trials and member of guideline committees involving diabetic kidney
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`disease, I have published over 1000 articles, about 500 in diabetic kidney disease.
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`For example, the ARTS-DN trial (Bakris GL, et.al. JAMA, 314(9):884-894 (2015))
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`and the FIDELITY program involving two outcome trials (FIDELIO (Bakris GL,
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`et.al. N Engl J Med., 383(23):2219-2229 (2020)) and FIGARO (Pitt B, Filippatos
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`G, Agarwal R, Anker SD, Bakris GL, et al. N Engl J Med., 385(24):2252-2263
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`(2021)) as well as a pooled analysis of these trials (Agarwal R, Filippatos G, Pitt B,
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`et.al…. and Bakris GL Eur Heart J., 43(6):474-484 (2022)).
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`16.
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`I have also served on many guidelines committees and most recently
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`completed a two year term (2020-2022) on the American Diabetes Association
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`Clinical Practice Guideline Committee. I am also a member of the American Heart
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`Association panel that is working on updating resistant hypertension guidelines. I
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`am the past president of the American College of Clinical Pharmacology and the
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`American Society of Hypertension.
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`17.
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`I have authored over 1000 peer-reviewed articles and have written over
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`130 textbook chapters covering diabetic kidney disease, hypertension, and
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`nephropathy progression and editor of 23 books on these topics.
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`18.
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`I have also received numerous awards, including the Lifetime
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`Achievement Luminary Award in Cardiometabolic Medicine at the 7th Annual
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`Heart in Diabetes Conference in 2023, the National Kidney Foundation of Illinois
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`Lifetime Service Award in 2021, and the Irwin Page and Alma Bradley Lifetime
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`Achievement Award by the American Heart Association Blood Pressure Counsel in
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`2019. Additionally, in 2021 I was listed as number 76 in Stanford University’s list
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`of the top 2% most cited scientists in the world.
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`19.(cid:3) Attached hereto as Appendix A is a true and correct copy of my(cid:3)
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`Curriculum Vitae describing my background and experience. It includes a list of my
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`publications(cid:3)(cid:68)(cid:81)(cid:71) presentations.
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`III. PRIORITY DATE
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`20.
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`I understand that the priority date of the ’462 patent is no later than July
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`1, 2012, which I understand is the date that the application to which the ’462 patent
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`claims priority was filed.
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`IV. LEGAL STANDARDS
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`21.
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`I understand that a patent claim may be invalid under 35 U.S.C.
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`§ 103(a) as obvious if the differences between the claimed invention and the prior
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`art are such that the claimed invention, as a whole, would have been obvious to a
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`hypothetical person of ordinary skill in the art in view of a prior art reference or in
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`view of a combination of prior art references at the time the claimed invention was
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`made.
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`22.
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`I understand that in an obviousness analysis, certain objective factors,
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`if present, may indicate that an invention is non-obvious. I further understand that
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`objective indicia of non-obviousness include evidence of unexpected results.
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`23.
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`I understand that evidence of “unexpected results” is evidence that a
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`claimed invention exhibits some superior property or advantage that would have
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`been surprising or unexpected to a person of ordinary skill in the relevant art.
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`24.
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`I understand that a person of ordinary skill in the art is a hypothetical
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`person who is presumed to have known the relevant art at the time of the invention. I
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`understand that a person of ordinary skill in the art is also a person of ordinary
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`creativity, who in many cases will be able to fit the teachings of multiple patents or
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`printed publications together. I understand that a person of ordinary skill in the art
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`is not a specific real person, but rather is a hypothetical person having the qualities
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`reflected by the above-discussed factors. I further understand that a person of
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`ordinary skill in the art would have knowledge from the teachings of the prior art,
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`including the art cited herein.
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`25.
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`I further understand that evidence of objective indicia of non-
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`obviousness does not need to pre-date the issuance of a patent to be relevant.
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`26.
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`I also understand that for objective indicia of non-obviousness to be
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`given weight, there must be a nexus between the claimed invention and the objective
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`indicia of non-obviousness and that the evidence must be reasonably commensurate
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`with the scope of the claims. The nexus between a patented invention and the
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`objective indicia can be based on benefits that do not need to be expressly recited in
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`the claims. I further understand that there is no requirement that evidence of
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`objective indicia be tied exclusively to claim elements that are not disclosed in a
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`particular prior art reference.
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`V. MATERIALS RELIED UPON
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`27.
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`In reaching the conclusions described in this declaration, I have relied
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`on the documents and materials cited in this Declaration and those identified in
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`Appendix B. These materials are patents, related documents, and printed
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`publications. Each of these is a type of document that experts in my field would
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`reasonably rely upon when forming their opinions.
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`28. My opinions are also based on my education, training, knowledge, and
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`personal and professional experience.
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`VI. BACKGROUND ON CHRONIC KIDNEY DISEASE
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`29.
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`Insulin is a naturally occurring hormone that is secreted by the
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`pancreas. One of the functions of insulin is to help blood sugar enter the body’s cells
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`to be used as energy. In healthy people, the body is able to make enough insulin to
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`control blood sugar and keep it at a healthy level.
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`30. Diabetes is a chronic condition that occurs when the body either does
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`not make enough insulin or does not use insulin as efficiently as it should. As a
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`result, blood sugar cannot get into cells and instead builds up in the blood, causing
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`hyperglycemia (high blood sugar). High blood sugar can cause serious health
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`problems including nerve damage, heart disease, and kidney disease.
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`31. There are three main types of diabetes, one of which is called type 2
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`diabetes. Type 2 diabetes occurs when the body either does not make enough insulin
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`or does not use insulin well enough to keep blood sugar at normal levels.
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`32. Type 2 diabetes can cause many serious complications, including
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`chronic kidney disease (“CKD”). CKD is a serious condition in which the kidneys
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`gradually lose function due to damage caused by high blood sugar levels. CKD is
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`associated with increased morbidity and mortality, including an increased risk of
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`both kidney failure and cardiovascular events. EX2012, 3.
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`33. Each kidney contains approximately one million microscopic structures
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`called nephrons. Nephrons act as filters to remove waste and other excess substances
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`from the blood and in the process of doing so produce urine.
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`34. Over time, high blood sugar may damage nephrons as well as blood
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`vessels in the kidneys, causing them to function less efficiently at first and then, as
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`the disease progresses, the kidneys may fail completely.
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`35. Because type 2 diabetes can result in high blood sugar, which in turn
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`damages the nephrons and blood vessels in the kidneys, CKD is quite common in
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`people with type 2 diabetes, occurring in approximately 40% of those who have type
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`2 diabetes. EX2012, 3.
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`36. CKD can cause many serious complications including high blood
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`pressure, swelling due to excess fluid retention, high cholesterol, anemia (not enough
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`red blood cells), or weakened bones due to an imbalance of the hormones and
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`vitamins necessary to maintain healthy bones.
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`37. There is no cure for CKD. Instead, the goal of treatment of CKD is to
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`reduce complications and slow progression of the disease. Treatments for
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`complications of CKD include high blood pressure medications, medications to
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`reduce swelling, cholesterol-lowering medications, medications to treat anemia, and
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`supplements such as calcium and vitamin D to promote bone health.
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`38. Other treatments for CKD in certain people with type 2 diabetes and
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`cardiovascular disease or at high risk of cardiovascular disease include long-acting
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`glucagon-like peptide-1 (GLP-1) receptor agonists with proven cardiovascular
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`benefits in order to lower glucose levels and reduce the risk of cardiovascular events.
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`EX2012, 3.
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`39. Additionally, people with late-stage CKD may need dialysis (use of a
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`machine to remove waste products from the blood) or a kidney transplant.
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`40. Lifestyle changes such as increasing exercise, quitting smoking,
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`reducing salt intake, reducing alcohol intake, and losing weight may help slow
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`progression of the disease, but will not stop it completely.
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`VII. OBJECTIVE INDICIA OF NON-OBVIOUSNESS
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`41. The ’462 patent relates to “improved uses of GLP-1 peptides in
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`therapy.” EX1001 (’462 patent) at 1:17-18. Claim 1 of the ’462 patent claims “[a]
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`method for treating type 2 diabetes, comprising administering semaglutide once
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`weekly in an amount of 1.0 mg to a subject in need thereof.” Id. at 35:42-44. Claim
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`2 of the ’462 patent requires “[t]he method according to claim 1, wherein the
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`semaglutide is administered by parenteral administration.” Id. at 35:45-46. Claim
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`3 of the ’462 patent requires “[t]he method according to claim 2, wherein the solution
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`is administered by subcutaneous injection.” Id. at 35:47-48. I understand that once-
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`weekly subcutaneous 1.0 mg semaglutide when administered to treat people with
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`type 2 diabetes practices at least claims 1-3 of the ’462 patent.
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`42.
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`I am familiar with semaglutide and have prescribed it to people with
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`type 2 diabetes.
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`43. Semaglutide is a GLP-1 receptor agonist that has been shown to
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`improve HbA1c levels and lower body weight in people with type 2 diabetes.
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`EX2012, 1. These benefits indirectly reduce the risk of CKD and help to slow the
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`progression of the disease in people with type 2 diabetes. It is my opinion that once-
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`weekly subcutaneous 1.0 mg semaglutide also directly affects CKD in patients with
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`type 2 diabetes and that these direct benefits were unexpected based on what was
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`known before the ’462 patent about semaglutide and other GLP-1 receptor agonists,
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`including liraglutide. In fact, as I discuss below, the reasons for the direct benefits
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`related to CKD that we have recently seen with semaglutide are still being debated
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`by experts in the field.
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`A. Unexpected Results Treating CKD With Once-Weekly 1.0 mg
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`44.
`In my opinion, there is significant evidence showing that once-weekly
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`subcutaneous semaglutide provides kidney-protective effects in people with type 2
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`diabetes and chronic kidney disease. It is also my opinion that these kidney-
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`protective effects are unexpected and were not previously observed in what I
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`understand Mylan asserts is the closest prior art in this proceeding (semaglutide itself
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`and liraglutide). For example, these kidney-protective effects are unexpected and
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`not previously observed in GLP-1 receptor agonists such as liraglutide or in
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`semaglutide itself prior to the ’462 patent. In fact, much of the evidence supporting
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`once-weekly 1.0 mg semaglutide’s kidney-protective effects has only emerged
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`recently and has surprised even the foremost experts in the field.
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`45. Semaglutide and certain other GLP-1 receptor agonists have been
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`shown to reduce the risk of major adverse cardiovascular events in certain people
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`with type 2 diabetes. EX2012, 3. Additionally, meta-analyses of prior trials of
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`semaglutide and other GLP-1 receptor agonists have “suggest[ed] potential kidney-
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`protective effects of GLP-1RAs, with some (liraglutide, dulaglutide, semaglutide
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`and efpeglenatide) associated with reductions in secondary composite kidney
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`outcomes (macroalbuminuria, substantial loss of kidney function, kidney failure and
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`death due to kidney). However, these benefits were driven by a lower risk of
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`persistent macroalbuminuria.” EX2012, 3 (citations omitted). Albuminuria is a
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`condition in which albumin (a protein normally found in the blood) is present in the
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`urine. The condition indicates a high risk of kidney function decline because the
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`kidneys, if properly functioning, should not allow albumin into the urine. EX2013,
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`3.
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`46.
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`Importantly, the results I discuss below were observed specifically with
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`use of once-weekly 1.0 mg semaglutide in patients with type 2 diabetes. As I
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`mentioned, the ability to use once-weekly semaglutide to treat CKD in patients with
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`type 2 diabetes is clinically meaningful, as studies have shown that the use of once-
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`weekly GLP-1 receptor agonists “was associated with an 11% lower risk of non-
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`adherence compared to once-daily dosing.” EX2014, 1 (emphasis added).
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`Additionally, the ability to administer semaglutide in an amount that is tolerable (1.0
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`mg) while also achieving direct effect on CKD also improves adherence, without
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`which a medication would be much less useful and effective for treating CKD.
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`EX2014, 5 (“medication non-adherence is associated with poorer disease control,
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`increased hospitalisations, higher healthcare costs and even mortality among
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`individuals with type 2 diabetes”).
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`1.
`The SUSTAIN 6 Trial
`47. For example, a post-hoc analysis of the results of the SUSTAIN 6
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`(once-weekly subcutaneous semaglutide 0.5 mg and 1.0 mg) and the LEADER
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`(once-daily 1.8 mg liraglutide) studies stated that “we demonstrate the benefit of
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`using once-weekly semaglutide and once-daily liraglutide on a number of clinically
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`important kidney outcomes: changes in albuminuria, annual slope of estimated
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`glomerular filtration rate [a measure of how well the kidneys are working] change,
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`time to persistent proportional estimated glomerular filtration rate reductions of 40%
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`and 50% from baseline, and a composite end point (time from randomization to first
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`occurrence of kidney failure/death or proportional estimated glomerular filtration
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`rate decline).” EX2015, 2.
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`48. The analysis further explained that “[t]he data also suggest differences
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`between agents, with the largest magnitude of protective effects observed for
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`semaglutide 1.0 mg,” EX2015, 8, and that “[t]he larger magnitude of effect of the
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`semaglutide 1.0 mg dose compared with both the semaglutide 0.5 mg dose and
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`liraglutide on both albuminuria and eGFR, along with likely benefits on substantial
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`reductions in kidney function, suggests that this agent in particular might have an
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`important role in protecting kidney function in diabetes. This may be especially
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`relevant in people with existing [diabetic kidney disease].” EX2015, 9.
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`49. Specifically, the analysis found that although both semaglutide and
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`liraglutide lowered albuminuria compared with placebo, the magnitude of reductions
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`were greater with once-weekly semaglutide 1.0 mg than with once-weekly
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`semaglutide 0.5 mg or once-daily liraglutide 1.8 mg: “Both semaglutide and
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`liraglutide lowered albuminuria compared with placebo (Figure 1). At 2 years after
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`randomization, on the basis of the placebo-corrected geometric mean ratios of
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`relative change from baseline, semaglutide 0.5 mg lowered albuminuria by 20%
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`compared with placebo (95% CI, 10%–28%; P<0.001) and the 1.0 mg dose lowered
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`albuminuria by 33% compared with placebo (95% CI, 24%–40%; P<0.001). At 2
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`years after randomization, albuminuria was 23% lower in liraglutide-treated patients
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`compared with placebo (95% CI, 18%–27%; P<0.001). The effect of the
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`semaglutide 1.0 mg dose was statistically greater than that of liraglutide (P=0.024)
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`at 2 years after randomization.” EX2015, 5.
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`50. The analysis further found that “[i]n the overall population, patients
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`randomized to semaglutide 0.5 mg had a nonsignificant reduction in eGFR slope
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`versus placebo (difference 0.33 mL/min/1.73 m2/y; P=0.14), whereas randomization
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`to semaglutide 1.0 mg slowed kidney function loss by 0.87 mL/min/1.73 m2/y versus
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`placebo (P<0.0001; Figure 2). Kidney function in patients randomized to liraglutide
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`declined an average of 0.26 mL/min/1.73 m2/y slower compared with placebo
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`(P<0.001).” EX2015, 5.
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`51. Notably, the analysis also explained that “[t]he mechanisms for the
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`potential protective effect of semaglutide and liraglutide on the kidneys are
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`uncertain. Possible contributing mechanisms include natriuresis, oxidative stress
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`reduction, reduced
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`inflammation and fibrosis, and hemodynamic effects.
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`Alternative possible mechanisms include the indirect modification of kidney risk
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`through lowering glucose levels, body weight, and blood pressure. However, the
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`latter indirect effects likely only play a minor role according to mediation analyses,
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`and the effects on blood pressure are modest. In a recent post hoc analysis of
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`LEADER and SUSTAIN 6, HbA1c mediated 25% and 26%, respectively, of the
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`kidney protective effect associated with liraglutide and semaglutide, whereas the
`
`mediatory effects of systolic blood pressure and body weight were lower at 9% and
`
`22% and 9% and 0%, respectively.” EX2015, 9 (citations omitted).
`
`2.
`The STEP 1, 2, and 3 Trials
`52. Additionally, an exploratory analysis from the STEP 1, 2, and 3 trials
`
`found that in people who are overweight or obese and have type 2 diabetes
`
`“semaglutide reduced albuminuria by 30% and improved urine albumin-to-
`
`creatinine ratio status but did not affect estimated glomerular filtration rate in people
`
`with overweight/obesity with or without type 2 diabetes.” EX2013, 1.
`
`53.
`
`In particular, the exploratory analysis found that in the once-weekly
`
`subcutaneous semaglutide 1.0 mg dose group, urine albumin-to-creatinine ratio
`
`(UACR) “changed from baseline by –14.8%” and “changes in urinary albumin
`
`concentration from baseline to week 68 were –8.6% in the semaglutide 1.0 mg
`
`treatment group” versus 18.1% in the placebo group. EX2013, 4-5.
`
`16
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`Novo Nordisk Exhibit 2011
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00016
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`
`
`54. Additionally, “[a] higher proportion of patients on semaglutide 2.4 mg
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`IPR2023-00724
`U.S. Patent 10,335,462
`
`
`
`and semaglutide 1.0 mg had normoalbuminuria by week 68 compared with those
`
`receiving placebo (87.1% vs. 84.9% vs. 72.8%, respectively)” and “[t]he percentage
`
`of patients with microalbuminuria and macroalbuminuria at week 68 was lower in
`
`the semaglutide 2.4 mg and 1.0 mg treatment groups compared with placebo (11.5%
`
`and 1.4% vs. 12.2%, and 2.9% vs. 22.4% and 4.8%, respectively).” EX2013, 5.
`
`55. Although it appears that at least some of the effect of semaglutide on
`
`albuminuria is due to semaglutide’s effects on HbA1c, body weight, and blood
`
`pressure, “some of the benefit in lowering albuminuria does not appear to be
`
`explained or accounted for by changes in these parameters alone.” EX2013, 9. At
`
`the 1.0 mg dose, it is clear that HbA1c improvement and weight loss contributed to
`
`albuminuria reduction. It is also clear that the higher weight loss at the 2.4 mg dose
`
`and additional improvement in glycemic control accounted for a greater reduction in
`
`albuminuria at the 2.4 mg dose. Hence, the analysis from the STEP trials
`
`demonstrate substantive benefit at both doses, however, a greater benefit at 2.4 mg
`
`due to additional weight loss. In my opinion, many people in my field would think
`
`this albuminuria reduction is all due to weight loss. However, the benefit seen with
`
`1.0 mg once-weekly subcutaneous semaglutide on kidney outcomes is far beyond
`
`what could be accounted for with the weight loss typically seen at that dose and
`
`speaks to the reduced inflammatory properties of semaglutide at that once-weekly
`
`17
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`Novo Nordisk Exhibit 2011
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00017
`
`
`
`
`dose. In contrast, a significant portion of the albuminuria reduction seen following
`
`IPR2023-00724
`U.S. Patent 10,335,462
`
`the 2.4 mg dose is likely related to greater weight loss spilling over into great
`
`reductions in blood pressure and greater reduction in inflammation secondary to
`
`weight reduction. Thus, the ability to achieve direct kidney benefit using the lower
`
`1.0 mg dose is clinically meaningful, in comparison with 2.4 mg, in particular for
`
`patients for whom the higher 2.4 mg dose is not tolerable.
`
`56.
`
`Indeed, the analysis found that “[s]emaglutide may also reduce
`
`albuminuria through direct means that may lead to beneficial effects on endothelial
`
`function or the endothelial glycocalyx, and increased natriuresis, either through
`
`inhibition of the sodium–hydrogen transporter or through anti-inflammatory or
`
`antifibrotic effects.” EX2013, 9 (citations omitted); see also EX2012, 9-10. These
`
`results were surprising to me and to many in my field.
`
`*
`
`*
`
`*
`
`57. The surprising and unexpected nature of these results, particularly those
`
`showing that semaglutide may have anti-inflammatory properties sufficient to
`
`provide a direct benefit in patients with type 2 diabetes and CKD, is shown by the
`
`fact that, even today, there is not a consensus in the field as to the mechanism by
`
`which semaglutide provides direct benefit in CKD. It is possible, for example, that
`
`semaglutide’s direct beneficial effects (which are separate and additional to
`
`semaglutide’s effects on HbA1c, body weight, and blood pressure) are due to anti-
`
`18
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`Novo Nordisk Exhibit 2011
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00018
`
`
`
`
`inflammatory properties. EX2016, 11-12. In fact, the potential anti-inflammatory
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`IPR2023-00724
`U.S. Patent 10,335,462
`
`effects of semaglutide have created a new frontier in the treatment of CKD and
`
`potentially many other diseases.
`
`3.
`The FLOW Trial
`58. The surprising results seen in the above-discussed analyses are further
`
`supported by the recent stoppage of Novo Nordisk’s FLOW trial due to superior
`
`efficacy of once-weekly subcutaneous semaglutide 1.0 mg over placebo for treating
`
`CKD in people with type 2 diabetes.
`
`59. Novo Nordisk’s FLOW
`
`trial
`
`is a randomized, double-blind,
`
`multinational phase 3b trial. EX2012, 1. In the FLOW trial, 3,534 participants with
`
`type 2 diabetes and CKD were randomized to once-weekly semaglutide 1.0 mg (with
`
`dose escalation starting at 0.25 mg/week for four weeks and then 0.5 mg for four
`
`weeks) or matched placebo. EX2012, 1. The composite primary endpoint of the
`
`FLOW trial was time to first kidney failure, persistent > 50% reduction in estimated
`
`glomerular filtration rate (eGFR, which is a measure of how well the kidneys are
`
`working) or death from kidney or cardiovascular causes. EX2012, 1.
`
`60. The FLOW trial was designed “to provide evidence on the effects of
`
`semaglutide on kidney outcomes.” EX2012, 1. As of 2019, data about potential
`
`kidney-protective effects of GLP-1 receptor agonists “have mostly been derived
`
`from cardiovascular (CV) outcome or glycaemic control trials featuring populations
`
`19
`
`Novo Nordisk Exhibit 2011
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00019
`
`
`
`
`not selected for chronic kidney disease (CKD) and/or with kidney disease events as
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`IPR2023-00724
`U.S. Patent 10,335,462
`
`secondary outcomes.” EX2012, 1. Moreover, as of 2019, “reduction of CKD
`
`progression by GLP-1RAs is yet to be confirmed and requires dedicated trials of
`
`kidney outcomes with GLP-1” receptor agonists. EX2012, 1.
`
`61. The FLOW trial began in 2019 and was expected to be completed in
`
`late 2024. The protocol for the FLOW study provides, however, that “[s]topping the
`
`trial for superiority is allowed if a stopping boundary is crossed and the [Data
`
`Monitoring Committee] makes the decision to recommend early trial termination.”
`
`EX2012, 7. This type of pre-specified procedure is put into place in part because
`
`continued administration of placebo to study participants becomes unethical when
`
`the candidate drug (here, semaglutide) is shown, before conclusion of the trial, to be
`
`effective as compared to placebo.
`
`62. That is what happened in the FLOW trial. In October 2023, Novo
`
`Nordisk announced that the independent Data Monitoring Committee concluded
`
`“that the results from an interim analysis met certain pre-specified criteria for
`
`stopping the trial early for efficacy.” EX2017, 1. That is, the FLOW trial was
`
`stopped early because the study subjects receiving once-weekly subcutaneous 1.0
`
`mg semaglutide were doing unexpectedly well. In my experience, a stoppage of this
`
`type is very rare and was certainly not expected at the outset of the trial.
`
`20
`
`Novo Nordisk Exhibit 2011
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00020
`
`
`
`63. Due to interim results showing that treatment with semaglutide was
`
`IPR2023-00724
`U.S. Patent 10,335,462
`
`
`
`effective as compared to placebo with respect to certain CKD outcomes, it became
`
`unethical to continue administering placebo to the patients who had originally been
`
`randomized to that arm of the trial. In my experience, the Food and Drug
`
`Administration prefers that outcome trials not be terminated early and strongly
`
`encourages long-term follow-up. Data Safety Monitoring Committees are well
`
`aware of this and thus, to stop a trial early must sustain the highest ethical and
`
`statistical rigor. Again, in my experience, a stoppage of this type is very rare.
`
`Although the results are not yet public, the publicly announced stoppage of this trial
`
`further shows that once-weekly subcutaneous semaglutide 1.0 mg provides direct
`
`and unexpected benefits as to CKD progression in people with type 2 diabetes.
`
`VIII. CONCLUSION
`
`64.
`
`It is my opinion that once-weekly subcutaneous 1.0 mg semaglutide has
`
`demonstrated unexpected results in providing direct, beneficial effects on chronic
`
`kidney disease in patients with type 2 diabetes.
`
`65.
`
`I reserve the right to supplement my opinions in the future and to
`
`respond to any arguments that Petitioner or its expert(s) may raise and to take into
`
`account any new information as it becomes available to me.
`
`66.
`
`I have been warned that willful false statements and the like are
`
`punishable by fine or imprisonment, or both. I make this declaration of my own
`
`21
`
`Novo Nordisk Exhibit
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