`
`
`
`
`IPR2023-00724
`U.S. Patent 10,335,462
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`MYLAN PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`NOVO NORDISK A/S,
`Patent Owner
`______________________
`Case IPR2023-00724
`Patent 10,335,462
`______________________
`
`EXPERT DECLARATION OF JULIO ROSENSTOCK, M.D.
`IN SUPPORT OF PATENT OWNER’S RESPONSE TO
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 10,335,462
`
`
`
`1
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`
`TABLE OF CONTENTS
`I. 
`INTRODUCTION ......................................................................................... 2 
`BACKGROUND AND QUALIFICATIONS .............................................. 2 
`II. 
`III.  PRIORITY DATE AND ONE OF ORDINARY SKILL ........................... 6 
`IV.  MATERIALS RELIED UPON .................................................................... 8 
`V. 
`LEGAL STANDARDS .................................................................................. 9 
`A.  Anticipation ........................................................................................... 9 
`B. 
`Obviousness ......................................................................................... 10 
`VI.  BACKGROUND ON THE STATE OF THE ART AND THE
`CHALLENGED CLAIMS .......................................................................... 14 
`A. 
`The Invention of the ’462 Patent ......................................................... 14 
`B. 
`Ozempic® (Semaglutide) .................................................................... 21 
`C. 
`Overview of the Prior Art .................................................................... 23 
`1.  WO421 (EX1011) ..................................................................... 23 
`2. 
`Lovshin (EX1012)..................................................................... 26 
`3. 
`NCT657 (EX1013) .................................................................... 31 
`4. 
`NCT773 (EX1014) .................................................................... 32 
`5.  WO537 (EX1015) ..................................................................... 34 
`6. 
`The ’424 Publication (EX1016) ................................................ 35 
`References Showing the State of the Art ............................................ 35 
`1. 
`“Systematic Review of Animal Experiments Demonstrate
`Poor Contributions Toward Human Healthcare”
`(EX2005) (Published May 2008) .............................................. 35 
`“Phase II failures: 2008–2010” (EX2006) (Published May
`2011) ......................................................................................... 37 
`“Novo Nordisk Annual Report 2010”
`(EX2065)
`(Published February 1, 2011) .................................................... 38 
`“Report on
`the Deliberation Results” (Liraglutide)
`(EX2067) (Published December 3, 2009) ................................ 40 
`“Differences in Drug Pharmacokinetics Between East
`Asians and Caucasians and
`the Role of Genetic
`Polymorphisms” (EX2066) (Published October 2004) ............ 41 
`
`D. 
`
`5. 
`
`i
`
`2. 
`
`3. 
`
`4. 
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`6. 
`
`7. 
`
`8. 
`
`E. 
`
`IPR2023-00724
`U.S. Patent 10,335,462
`“Potential of Albiglutide, a Long-Acting GLP-1 Receptor
`Agonists, in Type 2 Diabetes” (EX2062) (Published
`October 2009) ........................................................................... 42 
`“Improved Glycemic Control With No Weight Increase in
`Patients With Type 2 Diabetes After Once-Daily
`Treatment With the Long-Acting Glucagon-Like Peptide
`1 Analog Liraglutide (NN2211)” (EX2075) (Published
`June 2004) ................................................................................. 44 
`“Experimental Diabetes Drug Taspoglutide Late-Stage
`Trials Suspended” (EX2061) (Published September 13,
`2010) ......................................................................................... 46 
`Other References that Drs. Bantle and Jusko Contend Inform
`POSITA’s Knowledge ......................................................................... 48 
`1. 
`Lund (EX1035) ......................................................................... 48 
`2. 
`Seino (EX1038) ......................................................................... 53 
`3. 
`Tamimi (EX1047) ..................................................................... 54 
`4. 
`FDA Exposure Response 2003 (EX1048) ................................ 55 
`Background on Diabetes and Its Treatment ........................................ 56 
`F. 
`Failed and Withdrawn GLP-1 Receptor Agonists .............................. 60 
`G. 
`VII.  CLAIM CONSTRUCTION ........................................................................ 63 
`VIII.  GROUNDS 1-2: CLAIMS 1-3 ARE NOT ANTICIPATED .................... 65 
`A.  Ground 1: WO421 Does Not Anticipate Claims 1-3 .......................... 65 
`1. 
`POSITA Would Have Understood that WO421’s “Range”
`Disclosure Is Not a Disclosure of a 1.0 mg Dose ..................... 66 
`POSITA Would Not Have At Once Envisaged the
`Claimed 1.0 mg Once-Weekly Semaglutide Dose from
`WO421 ...................................................................................... 68 
`Semaglutide’s FDA-Approved Dosing Shows That
`POSITA Would Not Have Rejected Doses Other Than
`Exactly One Tenth of a Milligram ............................................ 73 
`The 1.0 mg Once-Weekly Dose Is Critical ............................... 74 
`4. 
`5.  WO421 Does Not Anticipate Claims 2-3 ................................. 82 
`Ground 2: Lovshin Does Not Anticipate Claims 1-3 .......................... 84 
`1. 
`Lovshin Does Not Anticipate Claims 2-3 ................................. 92 
`
`B. 
`
`2. 
`
`3. 
`
`ii
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`2. 
`
`IPR2023-00724
`U.S. Patent 10,335,462
`IX.  GROUNDS 3-5: CLAIMS 1-10 ARE NOT OBVIOUS ........................... 94 
`A.  No Motivation to Combine ................................................................. 94 
`B. 
`No Reasonable Expectation of Success ............................................100 
`1. 
`Dr. Bantle and Dr. Jusko Fail To Show POSITA Would
`Have Had a Reasonable Expectation of Success in
`“Optimizing” to Reach a 1.0 mg Once-Weekly Dose ............102 
`Dr. Bantle and Dr. Jusko Fail To Show a Reasonable
`Expectation of Success That a 1.0 mg Once-Weekly Dose
`of Semaglutide Would Have Been Safe, Effective, and
`Tolerable .................................................................................109 
`Ground 3: No Obviousness Based on WO421 In View of ’424
`Publication (Claims 1-10) .................................................................126 
`D.  Ground 4: No Obviousness Based on WO537 In View of
`Lovshin ..............................................................................................127 
`Ground 5: No Obviousness Based on NCT657 and NCT773 In
`View of the ’424 Publication ............................................................130 
`1. 
`Ground 5 Does Not Render Obvious the Challenged
`Claims .....................................................................................131 
`X.  CONCLUSION .......................................................................................... 137 
`
`C. 
`
`E. 
`
`
`
`
`
`iii
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`I, Julio Rosenstock, hereby declare under penalty of perjury:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by Groombridge, Wu, Baughman & Stone LLP,
`
`on behalf of Novo Nordisk A/S (“Novo Nordisk”) to provide assistance regarding
`
`U.S. Patent No. 10,335,462 (“the ’462 patent”). Specifically, I have been asked to
`
`provide my opinions regarding the validity of claims 1-10 of the ’462 patent (the
`
`“Challenged Claims”). Except as otherwise indicated, I have personal knowledge
`
`of the facts and opinions set forth in this Declaration. All statements herein made of
`
`my own knowledge are true and all statements made on information and belief are
`
`believed to be true. If called upon to do so, I would testify competently thereto.
`
`2.
`
`I am being compensated for my time at a rate of $1000 per hour which
`
`is my standard consulting fee for this legal work. I will be reimbursed for any
`
`expenses that I incur during the course of this work. My compensation is not
`
`contingent upon the results of my review of the evidence, the substance of my
`
`opinions, or the outcome of any proceeding involving the Challenged Claims. I have
`
`no financial interest in the outcome of this matter or in the pending litigations
`
`involving Novo Nordisk A/S and Novo Nordisk Inc.
`
`II. BACKGROUND AND QUALIFICATIONS
`
`3.
`
`I offer statements and opinions on behalf of Novo Nordisk, generally
`
`regarding the validity, novelty, prior art, obviousness considerations, and
`
`2
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`understanding of a person of ordinary skill in the art as it relates to the Challenged
`
`Claims.
`
`4.
`
`I am a board certified endocrinologist and have extensive experience
`
`designing and conducting clinical trials related to type 2 diabetes.
`
`5.
`
`I am currently the Medical Director of Velocity Clinical Research,
`
`Dallas and a Senior Scientific Advisor for Velocity Research, a position I have held
`
`since 2022. As part of my duties as Director of Velocity Clinical Research I help
`
`design and oversee numerous clinical trials for the treatment of type 2 diabetes.
`
`6.
`
`I am also in the honorary faculty as a Clinical Professor in the
`
`Department of Internal Medicine at the University of Texas Southwestern Medical
`
`Center at Dallas, a position I have held since 1998.
`
`7.
`
`Over the course of my over 30-year career I have conducted, reported
`
`on, and published on hundreds of clinical trials testing medications for the treatment
`
`of type 2 diabetes. These include numerous clinical trials related to type 2 diabetes
`
`and in particular GLP-1 receptor agonists for the treatment of type 2 diabetes.
`
`8.
`
`For example, I have conducted and published on trials of GLP-1
`
`receptor agonists for the treatment of type 2 diabetes such as albiglutide, lixisenatide,
`
`taspoglutide, exenatide, efpeglenatide,
`
`tirzepatide,
`
`retatrutide, survodutide,
`
`liraglutide, and semaglutide. As reflected in my Curriculum Vitae, I have written
`
`numerous peer-reviewed articles about these GLP-1 receptor agonists.
`
`3
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`I have also worked on trials and published on the oral GLP-1 receptor
`
`9.
`
`agonist orforglipron for treatment of obesity and oral semaglutide for the treatment
`
`of type 2 diabetes and more recently on higher doses exploring the treatment of
`
`obesity.
`
`10.
`
`I received my degree in Premedical Studies from the University of
`
`Costa Rica in 1969 and my Doctorate of Medicine and Surgery from the University
`
`of Costa Rica in 1975.
`
`11.
`
`In 1974 I completed my rotating internship in Pediatrics, Obstetrics,
`
`Gynecology, General Surgery, and Internal Medicine at the Mexico Hospital and
`
`National Children’s Hospital. From 1976-1979 I completed my residency in Internal
`
`Medicine and was Chief of Residents and Interns of Medicine from 1978-1979, also
`
`at the Mexico Hospital in San Jose, Costa Rica.
`
`12. From 1981-1983 I was an attending physician in Endocrinology and
`
`Diabetes at the Mexico Hospital in San Jose, Costa Rica.
`
`13. From 1979-1981 I completed my Fellowship in Endocrinology and
`
`Diabetes at the Royal Postgraduate Medical School at Hammersmith Hospital in
`
`London.
`
`14. From 1983-1984 I was a Fellow in Endocrinology and Diabetes at the
`
`University of Texas Southwestern Medical Center at Dallas, and from 1984-1986 I
`
`was a Member of the Executive Committee, General Clinical Research Center there.
`
`4
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`15. From 1984-1988 I was an Assistant Professor, from 1988-1993 I was a
`
`Clinical Assistant Professor, and from 1993-1998 a Clinical Associate Professor—
`
`all in the Department of Internal Medicine, University of Texas Southwestern
`
`Medical Center at Dallas.
`
`16. From 1990 until August 2016 I was also the Director of the Dallas
`
`Diabetes and Endocrine Center (in clinical practice) and from 1990 until 2022, I was
`
`also the Director of the Dallas Diabetes Research Center.
`
`17.
`
`I am also a member of numerous professional societies including the
`
`American Diabetes Association, the Endocrine Society, and the American
`
`Association of Clinical Endocrinologists.
`
`18.
`
`I have also served on numerous professional committees, including the
`
`National Board of Directors of the American Diabetes Association (ADA) from
`
`2019-2020, the ADA Scientific Sessions Annual Meeting Planning Committee as
`
`Co-Chair of Therapeutics/New Technology Content in 2018, the ADA Scientific and
`
`Medical Programs Oversight Committee from 2012-2016, and the ADA Medicine,
`
`Scient & Health Care Awards Committee from 2013-2015
`
`19.
`
`I was also a member of the Hormone Foundation Committee of the
`
`Endocrine Society from 2009-2012.
`
`20.
`
`I have also served on numerous editorial boards, including the editorial
`
`boards of Diabetes Care, Cardiovascular Diabetology, and Practical Diabetes.
`
`5
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`21. Attached hereto as Appendix A is a true and correct copy of my
`
`Curriculum Vitae describing my background and experience and includes a list of
`
`my publications and scientific presentations.
`
`III. PRIORITY DATE AND ONE OF ORDINARY SKILL
`
`22.
`
`I understand that a person of ordinary skill in the art is a hypothetical
`
`person who is presumed to have known the relevant art at the time of the invention.
`
`I understand that a person of ordinary skill in the art is also a person of ordinary
`
`creativity, who in many cases will be able to fit the teachings of multiple patents or
`
`printed publications together. I further understand that the factors that may be
`
`considered in determining the level of ordinary skill in a particular field of art include
`
`(1) the level of education and experience of those working in the field, (2) the types
`
`of problems encountered in the field, and (3) the sophistication of the technology at
`
`the time of the invention, which I understand is March 17, 2010, or at least May 28,
`
`2010, as to claims 1-3 but in any event no later than July 1, 2012, for claims 1-3, and
`
`July 1, 2012, as to claims 4-10 (my opinions herein would be the same under all of
`
`these dates). I understand that not every factor may be present in every case. I
`
`understand that a person of ordinary skill in the art is not a specific real person, but
`
`rather is a hypothetical person having the qualities reflected by the above-discussed
`
`factors. I further understand that a person of ordinary skill in the art would have
`
`knowledge from the teachings of the prior art, including the art cited herein.
`
`6
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`In my opinion, on or before each of March 17, 2010, May 28, 2010, and
`
`23.
`
`July 1, 2012, a person of ordinary skill in the art to which the ’462 patent pertains
`
`would have an M.D. or, alternatively, a Ph.D. or equivalent degree in Pharmacology,
`
`Pharmaceutics, Biopharmaceutics, or a related field. The M.D. or Ph.D. would have
`
`3-5 years of experience conducting clinical research in the field of diabetes
`
`treatments, including in the design of dosing regimens and dosage forms for type 2
`
`diabetes treatments, or would have 3-5 years of research or industry experience
`
`relating to developing pharmaceutical formulations and/or dosing regimens.
`
`Alternatively, the individual would be a highly skilled scientist lacking a Ph.D. or
`
`M.D., but would have more than 5 years of experience conducting clinical research
`
`in the field of diabetes treatments. The person of ordinary skill would consult, as
`
`appropriate with others having specific expertise in pharmaceutical development,
`
`formulation, and manufacturing. Based on my education and experience, I meet and
`
`exceed this definition.
`
`24.
`
`I understand
`
`that Mylan Pharmaceuticals,
`
`Inc.
`
`(“Mylan” or
`
`“Petitioner”) contends that a person that a person having ordinary skill in the art to
`
`which the ’462 patent pertains would have (1) an M.D., Pharm.D., or Ph.D. in
`
`pharmacy, chemical engineering, bioengineering, chemistry, or related discipline;
`
`(2) at least two years of experience in protein or peptide therapeutic development
`
`and/or manufacturing or diabetes treatments; and (3) experience with the
`
`7
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00010
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`development, design, manufacture, formulation, or administration of therapeutic
`
`agents, and the literature concerning protein or peptide formulation and design, or
`
`diabetes treatments. Based on my education and experience, I meet this definition.
`
`25. My opinions would not change if Mylan’s definition of POSITA, rather
`
`than my definition, was applied.
`
`26. Well before each of March 17, 2010, May 28, 2010, and July 1, 2012,
`
`my level of skill in the art was at least that of POSITA under either my definition or
`
`Mylan’s definition. I am qualified to provide opinions concerning what POSITA
`
`would have known and understood as of the priority date of the ’462 patent, and
`
`unless otherwise stated, my analysis and conclusions herein are from the perspective
`
`of POSITA as of March 17, 2010. My opinions herein would be the same if the
`
`priority date were, instead, May 28, 2010, or July 1, 2012.
`
`IV. MATERIALS RELIED UPON
`
`27.
`
`In reaching the conclusions described in this declaration, I have relied
`
`on the documents and materials cited in this Declaration and those identified in
`
`Appendix B. These materials are patents, related documents, and printed
`
`publications. Each of these is a type of document that experts in my field would
`
`reasonably rely upon when forming their opinions.
`
`28. My opinions are also based on my education, training, knowledge, and
`
`personal and professional experience.
`
`8
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00011
`
`

`

`V. LEGAL STANDARDS
`
`IPR2023-00724
`U.S. Patent 10,335,462
`
`A. Anticipation
`29.
`I understand that a claim is anticipated pursuant to 35 U.S.C. § 102 if
`
`someone else has already made the same invention. I understand that if an invention
`
`is not new, then the invention has been “anticipated” by the prior art.
`
`30.
`
`I understand that a claim is anticipated only if each and every limitation
`
`of the claim is disclosed, arranged as in the claim, in a single prior art reference.
`
`31.
`
`I further understand that a prior art reference can disclose a claim
`
`feature because the feature is expressly described, or because the feature is inherent
`
`in the disclosure. I understand that something is inherent in a prior art reference only
`
`if the missing descriptive matter must necessarily be present, and it would be so
`
`recognized by a person of ordinary skill in the art. I also understand that inherency
`
`cannot be established by probabilities or possibilities, and that the mere fact that
`
`something may result from a given set of circumstances is not sufficient to show
`
`inherency.
`
`32.
`
`I also understand that a prior art reference may be deemed to disclose
`
`each member of a genus when, reading the reference, POSITA can at once envisage
`
`each member of the entire genus, such as when the genus discloses only a limited
`
`class.
`
`9
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00012
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`I also understand that although it is not proper in an anticipation
`
`33.
`
`analysis to look to another document to fill in gaps in the allegedly anticipatory
`
`reference, it is permissible to look to other references for any light they shed on what
`
`the allegedly anticipatory reference would have meant to those skilled in the art.
`
`B. Obviousness
`34.
`I understand that a claim is obvious pursuant to 35 U.S.C. § 103 if,
`
`before the earliest filing date of the claimed invention, the differences between the
`
`claimed invention and the prior art are such that the claimed invention, as a whole,
`
`would have been obvious to a hypothetical person of ordinary skill in the art to which
`
`the claimed invention pertains. I understand that a claim is valid unless the
`
`differences between the claimed invention and the prior art are such that the subject
`
`matter as a whole would have been obvious at the time of the invention to persons
`
`of skill.
`
`35.
`
`I understand that the analysis of whether a claimed invention would
`
`have been obvious should be considered in light of: (i) the scope and content of the
`
`prior art; (ii) the level of ordinary skill in the art; (iii) the differences between the
`
`claimed invention and the prior art; and (iv) other “objective indicia” of non-
`
`obviousness.
`
`36.
`
`I also understand that for a claim to be found obvious, each element
`
`must be disclosed in the prior art. I understand, however, that when support for
`
`10
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00013
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`obviousness is argued based on a combination of prior art references, an invention
`
`is not shown to be obvious merely by demonstrating that each of the elements in the
`
`claim was independently known in the prior art.
`
`37.
`
`Instead, I understand that for obviousness, there must be a reason or
`
`motivation that would have prompted persons of skill in the relevant field to combine
`
`or modify the elements in the way the claimed invention does. I understand that
`
`using the claimed invention as a blueprint to piece together various elements in the
`
`prior art amounts to “hindsight” and is prohibited.
`
`38.
`
`I also understand that, for a patent to be obvious, POSITA must have
`
`had, in addition to a motivation to combine, a reasonable expectation of success in
`
`practicing the claimed invention based on the prior art. I understand that whether
`
`POSITA would have had a reasonable expectation of success in practicing the claims
`
`is determined based on the degree of unpredictability in the art as well as the
`
`guidance provided by the art.
`
`39.
`
`I further understand that, in making a determination as to whether or
`
`not the claimed invention would have been obvious to POSITA, the Board must
`
`consider certain “objective indicia” or factors, such as commercial success (e.g., the
`
`profitability of the claimed method or device practicing the claims), long-felt but
`
`unmet need, unexpected results, skepticism, and praise by others in the field. The
`
`presence of such factors is evidence of non-obviousness. I also understand that a
`
`11
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00014
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`connection, or nexus, must exist between the objective factor and the claimed
`
`invention. My conclusions of non-obviousness herein do not depend on
`
`consideration of objective indicia of non-obviousness, which I understand are being
`
`addressed elsewhere.
`
`40.
`
`I understand that evidence of “unexpected results” is evidence that a
`
`claimed invention exhibits some superior property or advantage that would have
`
`been surprising or unexpected.
`
`41.
`
`I understand that evidence of an invention satisfying a “long-felt, unmet
`
`need” is shown where there was an articulated, identified problem as of the invention
`
`date and there were efforts to solve that problem. To satisfy a long-felt, unmet need,
`
`a claimed invention does not need to completely eliminate a problem. Evidence that
`
`a claimed invention reaches results superior to prior available options can show
`
`satisfaction of a long-felt, unmet need. I further understand that in the
`
`pharmaceutical context, a claimed drug can still satisfy a long-felt, unmeet need that
`
`existed as of the priority date of the invention even if that need no longer existed by
`
`the time the claimed drug was marketed.
`
`42.
`
`I understand that evidence of “skepticism” is evidence that industry
`
`participants or skilled artisans were skeptical about whether or how a problem could
`
`be solved or the workability of the claimed solution. Such skepticism need not be
`
`premised on whether the claimed invention is technically infeasible, unworkable, or
`
`12
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00015
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`impossible to be relevant. A range of opinions can constitute skepticism, including
`
`evidence that third parties were worried or surprised by the invention.
`
`43.
`
`I understand that “praise by others” is evidence that those in the
`
`industry have praised a claimed invention or a product that embodies the claims of
`
`the patent.
`
`44.
`
`I further understand that evidence of objective indicia of non-
`
`obviousness does not need to pre-date the issuance of a patent to be relevant.
`
`45.
`
`I also understand that for objective indicia of non-obviousness to be
`
`given weight, there must be a nexus between the claimed invention and the objective
`
`indicia of non-obviousness and that the evidence must be reasonably commensurate
`
`with the scope of the claims. The nexus between a patented invention and the
`
`objective indicia can be based on benefits that do not need to be expressly recited in
`
`the claims. I further understand that there is no requirement that evidence of
`
`objective indicia be tied exclusively to claim elements that are not disclosed in a
`
`particular prior art reference. I understand that nexus is presumed where the
`
`objective indicia of non-obviousness is tied to a specific product and that product
`
`embodies the claimed features and is coextensive with them. I further understand
`
`that even if the presumption of nexus does not apply, nexus may be proven by
`
`showing that the evidence of objective indicia is the direct result of the unique
`
`characteristics of the claimed invention.
`
`13
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00016
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`I further understand that, among other things, the Board has instituted
`
`46.
`
`an inter partes review of claims 1-10 of the ’462 Patent. I understand that the
`
`instituted grounds are as follows: Ground 1 challenges claims 1-3 and of the ’462
`
`patent as unpatentable as anticipated by WO421 (EX1011), Ground 2 challenges
`
`claims 1-3 as unpatentable as anticipated by Lovshin (EX1012), Ground 3
`
`challenges claims 1-10 as unpatentable as obvious over WO421 (EX1011) in view
`
`of the ’424 publication (EX1016), Ground 4 challenges claims 1-10 as unpatentable
`
`as obvious over WO537 (EX1015) in view of Lovshin (EX1012), and Ground 5
`
`challenges claims 1-10 as unpatentable as obvious over NCT657 (EX1013),
`
`NCT773 (EX1014), and the ’424 publication (EX1016).
`
`47.
`
`I understand that for inter partes review, invalidity must be shown
`
`under a preponderance of the evidence standard. I understand that to establish
`
`something by a preponderance of the evidence one needs to prove it is more likely
`
`true than not.
`
`VI. BACKGROUND ON THE STATE OF THE ART AND THE
`CHALLENGED CLAIMS
`A. The Invention of the ’462 Patent
`48. The ’462 patent relates to “improved uses of GLP-1 peptides in
`
`therapy.” EX1001 (’462), 1:17-18. Specifically, claim 1 of the ’462 patent is
`
`directed to “[a] method for treating type 2 diabetes, comprising administering
`
`14
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00017
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`semaglutide once weekly in an amount of 1.0 mg to a subject in need thereof.”
`
`EX1001 (’462), 35:42-44.
`
`49. The ’462 patent discloses the results of a 12-week, randomized, double-
`
`blind, placebo-controlled trial in 411 participants with type 2 diabetes. EX1001,
`
`21:20-23:26. I understand that certain aspects of the protocol for this study design
`
`are described in NCT657 (however, NCT657 does not disclose any results). The
`
`study tested six once-weekly semaglutide doses: 0.1 mg, 0.2 mg, 0.4 mg, 0.8 mg,
`
`0.8 mg titrated in weekly increments of 0.4 mg, and 1.6 mg titrated in weekly
`
`increments of 0.4 mg. EX1001, 21:22-31. Those six doses were compared to
`
`corresponding placebo doses as well as 1.2 mg once-daily liraglutide and 1.8 mg
`
`once-daily liraglutide. EX1001, 21:22-31.
`
`50. The primary endpoint of the study was change in HbA1c (a measure of
`
`blood sugar) from baseline. The study also examined the “proportion of subjects
`
`reaching [the American Diabetes Association’s] HbA1c target (<7%) and change in
`
`body weight” and the proportion of subjects that reached the <6.5% HbA1c target
`
`of the American Association of Clinical Endocrinologists. EX1001, 2:21-22, Fig.
`
`3A.
`
`51. The ’462 patent discloses that “the methods of the present invention
`
`provide[] surprisingly [] improved reduction of HbA1c and reduction of body
`
`weight.” EX1001, 2:56-58. The ’462 patent repeatedly and consistently states that
`
`15
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00018
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`its embodiments include those in which the minimum dose of semaglutide is at least
`
`0.7 mg. For example, the ’462 patent states that “[i]n one embodiment the invention
`
`relates to a method for reduction of HbA1c or for prevention or treatment of type 2
`
`diabetes… said method comprising administration of a GLP-1 agonist to a subject
`
`in need thereof in an amount of at least 0.7 mg per week, such an amount equivalent
`
`to at least 0.7 mg semaglutide per week.” EX1001, 2:63-3:2; see also EX1001, 3:19-
`
`25 (discussing use of “at least 0.7 mg per week” for “reducing body weight”), 3:41-
`
`47, 4:7-16, 16:58-64, 17:20-23, 17:29-34, 20:18-22, 20:31-38.
`
`52. The ’462 patent discloses that not all doses in the 0.1 mg to 1.6 mg
`
`range were effective in lowering HbA1c as compared to placebo. Specifically, 0.1
`
`mg did not reduce HbA1c from baseline as compared to placebo. E.g., EX1001, Fig.
`
`1 (no asterisk):
`
`16
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00019
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`
`
`
`
`
`
`
`53. The ’462 patent also discloses that only doses of 0.8 mg and above
`
`brought subjects’ HbA1c to the level recommended by the American Association of
`
`Clinical Endocrinologists (AACE) as compared to placebo. EX1001, Fig. 3A (only
`
`semaglutide once-weekly doses 0.8 mg or greater (groups E-G) showed statistically
`
`significant improvement (denoted by 1-3 asterisks) over placebo in the number of
`
`subjects reaching HbA1c < 6.5%):
`
`17
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00020
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`
`
`
`
`54. The ’462 patent also states that certain doses showed statistically
`
`significant improvement over placebo, and repeatedly discloses that only once-
`
`weekly doses of 0.8 mg or greater showed improvements over once-daily
`
`liraglutide: “The results (see e.g. FIG. 1) show[] that treatment with semaglutide 0.8
`
`mg, 0.8 mg T [titrated in .04 mg weekly increments], or 1.6 mg T improved
`
`reduction of HbA1c compared to treatment with [once-daily] liraglutide 1.2 mg or
`
`1.8 mg….” EX1001, 22:12-15;1 see also EX1001, 22:21-25, EX1001, 23:19-23.
`
`
`
` 1
`
` Unless otherwise stated, all emphases are added.
`
`18
`
`Novo Nordisk Exhibit 2010
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00021
`
`

`

`IPR2023-00724
`U.S. Patent 10,335,462
`55. The ’462 patent also explains that “nausea and vomiting increased with
`
`dose.” EX1001, 23:5-6.
`
`56. Thus, the ’462 pa