UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`WOCKHARDT BIO AG, TEVA PHARMACEUTICALS USA, INC.
`and AUROBINDO PHARMA U.S.A. INC.,
`Petitioners,
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2015-01340
`Patent No. RE44,186 E1
`
`_____________________________
`
`
`
`DECLARATION OF ROBERT J. TANENBERG, M.D., FACP
`
`
`
`1 Petitioners Wockhardt (IPR2016-01209), Teva (IPR2016-01122), and
`
`Aurobindo (IPR2016-01117) have been joined as Petitioners to this proceeding.
`
`MYLAN - EXHIBIT 1041
`Mylan et al. v. AstraZeneca
`IPR2015-01340
`
`
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`WOCKHARDT BIO AG, TEVA PHARMACEUTICALS USA, INC.
`and AUROBINDO PHARMA U.S.A. INC.,
`Petitioners,
`
`v.
`
`ASTRAZENECA AB,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2015-01340
`Patent No. RE44,186 E1
`
`_____________________________
`
`
`
`DECLARATION OF ROBERT J. TANENBERG, M.D., FACP
`
`
`
`1 Petitioners Wockhardt (IPR2016-01209), Teva (IPR2016-01122), and
`
`Aurobindo (IPR2016-01117) have been joined as Petitioners to this proceeding.
`
`MYLAN - EXHIBIT 1041
`Mylan et al. v. AstraZeneca
`IPR2015-01340
`
`
`
`Table of Contents
`
`
`
`I.
`
`Qualifications.......................................................................................... 1
`
`II.
`
`Scope of Work ........................................................................................ 4
`
`III. Overview of the ’186 Patent ................................................................... 4
`
`IV. Legal Principles ...................................................................................... 6
`
`V.
`
`The State of Diabetes and Anti-diabetic Treatment in the Late
`1990s and Early 2000s, Through Today .................................................. 7
`
`VI. Targeting DPP-4 Inhibitors as Anti-diabetic Therapeutics ...................... 9
`
`VII.
`
`Interchangeability of the Four FDA-Approved DPP-4 Inhibitors .......... 11
`
`VIII. No Long-felt but Unmet Need .............................................................. 14
`
`IX. No Failure of Others in the Prior Art to Fulfill This Need ..................... 17
`
`X. No Unexpected Results of the Claimed Compound .............................. 23
`
`XI. Concluding Statements ......................................................................... 24
`
`XIII. Appendix – List of Exhibits .................................................................. 26
`
`
`
`
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`-1-
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`
`
`I, Robert J. Tanenberg, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1. My name is Robert J. Tanenberg. I have held my current position as a
`
`Professor of Medicine at East Carolina University in Greenville, North Carolina
`
`since 1998. I also serve as Program Director for the Diabetes Clinical Fellowship
`
`and as Medical Director for the Diabetes and Obesity Institute, both at East
`
`Carolina University, and as Director of the Inpatient Diabetes Programs at Vidant
`
`Medical Center (formerly Pitt County Memorial Hospital) in Greenville, North
`
`Carolina.
`
`2.
`
`Among other things, I am professionally certified by the American
`
`Board of Internal Medicine, I am a certified diplomat of the American Board of
`
`Endocrinology & Metabolism, and I have been repeatedly recognized as a provider
`
`for the delivery of quality diabetes care by the American Diabetes Association. I
`
`was elected as a fellow of the American College of Physicians in 1982. I have
`
`been treating patients with diabetes for more than forty years.
`
`3.
`
`After receiving my M.D. from the University of Illinois, I completed a
`
`medical internship at Northwestern University Hospital in Chicago, Illinois, and a
`
`residency in internal medicine at the Mayo Graduate School of Medicine in
`
`Rochester, Minnesota. I then completed a fellowship in endocrinology and
`
`-1-
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`
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`metabolism at the University of Minnesota Hospital, followed by a fellowship in
`
`diabetes and metabolism at the Joslin Diabetes Center in Boston, Massachusetts.
`
`4.
`
`I served as a Major in the United States Air Force. I was stationed at
`
`the Malcolm Grow Medical Center at Andrews Air Force Base, where I served as
`
`Chief of the Section of Endocrinology. From 1977-1979, I served as an Instructor
`
`of Medicine and then as Assistant Professor of Medicine in the Uniformed
`
`Services Division at the University of Health Sciences in Bethesda, Maryland.
`
`From 1979-1984, I served first as the Director of the Diabetes Clinic, and then the
`
`Chief of the Metabolic and Nutritional Service unit, of the U.S. Soldiers and
`
`Airmen’s Home Health Care Facility in Washington, D.C.
`
`5.
`
`From 1980-1998, I also worked in various capacities at Georgetown
`
`University Hospital and Georgetown University School of Medicine in
`
`Washington, D.C. My titles there included Clinical Assistant Professor of
`
`Medicine, Clinical Associate Professor of Medicine, Medical Director of the
`
`Diabetes Treatment Center, and Attending Physician.
`
`6.
`
`From 1988-1998, I also filled various roles at the Washington
`
`Hospital Center in Washington, D.C. These roles included serving as Acting Chief
`
`of Endocrinology, as Medical Director of the Diabetes Treatment Center, and as a
`
`Senior Attending Physician.
`
`
`
`-2-
`
`
`
`7.
`
`In addition to the forgoing experience, I spent nearly twenty years
`
`leading a private practice group of endocrine and diabetes specialists in the
`
`Washington, D.C. area. I continue to treat diabetes patients today through my
`
`clinical practice at East Carolina University and through the Inpatient Diabetes
`
`Programs at Vidant Medical Center (formerly Pitt County Memorial Hospital).
`
`8.
`
`During my career I have authored or co-authored more than 100
`
`articles and abstracts, and have given hundreds of invited lectures and
`
`presentations on the management of diabetes and diabetic complications. I am also
`
`significantly involved in various professional organizations. For example, I have
`
`served on the Board of Directors and on various committees of the D.C. Area
`
`Affiliate of the American Diabetes Association. I have also served as an editor or
`
`advisory board member for various publications of the American Diabetes
`
`Association and have provided peer-review for articles in various journals. I have
`
`also participated as an investigator in many clinical trials. I direct the East Carolina
`
`University-Diabetes Research Center for Clinical Trials where I have been a
`
`principal investigator for over 60 diabetes research studies. These include clinical
`
`trials of oral hypoglycemic and injectable agents and insulins for Type 1 and Type
`
`2 diabetes.
`
`9. My CV, attached as EX1042, provides a summary of my education,
`
`experience, publications, and other qualifications.
`
`
`
`-3-
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`
`
`II.
`
`SCOPE OF WORK
`
`10.
`
`I understand that the Patent Trial and Appeal Board has instituted
`
`inter partes review of U.S. Patent RE 44,186 (“the ’186 patent,” EX1001). I have
`
`been retained by the Petitioner in that proceedings and have been asked to review
`
`the August 2, 2016 Declaration of M. James Lenhard, M.D. (EX2057) and to
`
`provide my opinions with respect to what Dr. Lenhard has written in his
`
`declaration. In addition to the Lenhard Declaration, I have also reviewed and
`
`considered the ’186 patent and various other documents cited in this declaration in
`
`arriving at my opinions. Documents cited in this declaration are listed in the
`
`Appendix in Section XIII.
`
`11.
`
`I am being compensated for my time in this matter at the rate of
`
`$600/hour. I have no financial interest in the outcome of this matter.
`
`III. OVERVIEW OF THE ’186 PATENT
`
`12. The ’186 patent is entitled “Cyclopropyl-fused pyrrolidine-based
`
`inhibitors of dipeptidyl peptidase IV and method.” EX1001 at cover. The patent
`
`states that it resulted from a patent application that was filed on December 1, 2011,
`
`and is a reissue of an application that was filed on February 16, 2001. Id. The
`
`patent identifies a provisional patent application that was filed on March 10, 2000.
`
`Id. I understand from Dr. Lenhard’s declaration that AstraZeneca claims that
`
`saxagliptin was invented in October 2000. EX2057, ¶17.
`
`
`
`-4-
`
`
`
`13.
`
`I understand that the claims of a patent define the scope of the
`
`invention. The ’186 patent contains 41 claims. EX1001 at 86:24-92:52. The ’186
`
`patent claims depict several chemical structures. For example, claim 8 depicts
`
`eight chemical structures. Id. at 88:42-89:28. I understand that claims 25 and 32,
`
`for example, depict a chemical structure representing the compound saxagliptin.
`
`Id. at 91:18-33, 91:50-92:16. Claim 32 recites a method for treating diabetes in a
`
`mammal by administering a pharmaceutical composition containing saxagliptin. I
`
`am familiar with saxagliptin and other DPP-4 inhibitors through my years of
`
`practice treating patients with diabetes. None of the claims recite administering a
`
`claimed compound to humans, recite elements regarding clinical data, or recite
`
`elements regarding regulatory approval, including FDA approval.
`
`14. The patent describes a large number of compounds and teaches that
`
`they can be used to treat Type 2 diabetes. E.g., EX1001 at 3:52-4:2. The patent
`
`states that “DP4 inhibitor activity of the compounds of the invention may be
`
`determined by use of an in vitro assay system which measures the potentiation of
`
`inhibition of DP4,” and describes how to measure inhibition constants for DPP-4
`
`inhibitors. Id. at 22:13-17, 54. However, the patent does not appear to describe
`
`any in vivo data for any of the claimed compounds. In particular, the patent does
`
`not appear to describe any data showing safety or efficacy in humans.
`
`
`
`-5-
`
`
`
`IV. LEGAL PRINCIPLES
`
`15.
`
`I understand that an objective of this proceeding is to determine
`
`whether subject matter of certain claims of the ’186 patent that encompass
`
`saxagliptin would have been obvious at the time of the invention to “a person
`
`having ordinary skill in the art.” I am informed 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. As discussed above, I understand that the time period of
`
`the alleged invention is the 2000-2001 timeframe.
`
`16.
`
`I understand that a panel of administrative patent judges on the Patent
`
`Trial and Appeal Board will reach a legal determination regarding the obviousness
`
`of the claims based on underlying factual findings. I have been instructed that the
`
`judges may weigh “secondary considerations” against evidence of obviousness
`
`where appropriate. I understand that such secondary considerations may include:
`
`(i) commercial success of a product due to the merits of the claimed invention;
`
`(ii) a long-felt, but unsatisfied need for the invention; (iii) failure of others to find
`
`the solution provided by the claimed invention; (iv) deliberate copying of the
`
`invention by others; (v) unexpected results achieved by the invention; (vi) praise of
`
`the invention by others skilled in the art; (vii) lack of independent simultaneous
`
`invention within a comparatively short space of time; and (viii) teaching away
`
`
`
`-6-
`
`
`
`from the invention in the prior art. I am informed that secondary considerations are
`
`relevant where there is a nexus between the evidence and the claimed invention.
`
`V. THE STATE OF DIABETES AND ANTI-DIABETIC TREATMENT IN THE LATE
`1990S AND EARLY 2000S, THROUGH TODAY
`
`17.
`
`I have reviewed Dr. Lenhard’s description of the increase in diabetes
`
`diagnoses throughout the 1990s and through today, as well as his discussion of the
`
`state of anti-diabetic treatment in the late 1990s. I agree with Dr. Lenhard that the
`
`rate of diabetes diagnoses increased significantly in the 1990s and 2000s, including
`
`from 2009 through today. In fact, according to a CDC report on long-term trends
`
`in diabetes in the United States, there were approximately 6.2 million patients
`
`diagnosed with diabetes in 1990, 12 million in 2000, and 22 million today. Ling-
`
`term Trends in Diabetes, CDC’s Division of Diabetes Translation (April 2016)
`
`(EX1039) at 5-6.
`
`18.
`
`I also reviewed Dr. Lenhard’s statements suggesting that there were
`
`serious safety concerns with each of the available treatment options for diabetes in
`
`the 1999-2001 timeframe. E.g., EX2057, ¶¶33-34. However, Dr. Lenhard
`
`overstates these safety concerns. Contrary to his suggestions, serious safety
`
`concerns for the available anti-diabetic treatments were rare.
`
`19.
`
`Indeed, each of the classes of anti-diabetic treatments identified by Dr.
`
`Lenhard as being available in the United States prior to the first FDA-approved
`
`DPP-4 inhibitor (sitagliptin) is still approved for use, and indeed is still used,
`
`-7-
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`
`
`today. For example, sulfonylureas continue to be used today despite its non-
`
`serious or rare side effects because of its excellent efficacy and low cost. Kabadi,
`
`Sulfonylurea Glimepiride: A Proven Cost Effective, Safe and Reliable War Horse
`
`in Combating Hyperglycemia in Type 2 Diabetes, 5 JOURNAL OF DIABETES
`
`MELLITUS 211 (2015) (EX1040) at 211-12. I continue to prescribe sulfonylureas in
`
`my own practice. In fact, the World Health Organization lists one sulfonylurea
`
`(gliclazide) in its current List of Essential Medicines for the treatment of diabetes.
`
`World Health Organization List of Essential Medicines,19th Edition,
`
`http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINA
`
`L_amended_NOV2015.pdf?ua=1 (2015) (EX1043) at 34. For comparison,
`
`saxagliptin is not listed.
`
`20. As another example, Dr. Lenhard identifies metformin and appears to
`
`imply that it was disfavored because some compounds in the biguanide class can
`
`cause lactic acidosis. E.g., EX2057, ¶34. However, Dr. Lenhard elsewhere
`
`conceded, as he must, that metformin not only continues to be used to treat
`
`diabetes long after the introduction of FDA-approved DPP-4 inhibitors into the
`
`market, but it is actually the primary first-line therapy for diabetes in the United
`
`States. Id. at ¶62. Again, I continue to prescribe metformin in my own practice.
`
`21.
`
`Indeed, metformin has been known in the field of endocrinology for
`
`my entire career. Metformin is well-known and has an accepted side effect profile.
`
`
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`-8-
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`
`
`Metformin may also advantageously provide added cardiovascular and anticancer
`
`benefits. In 2000-2001 and still today, no other oral treatment for Type 2 diabetes
`
`is more frequently prescribed than metformin. American Diabetes Association,
`
`Standards of Medical Care in Diabetes, 2016, 39, DIABETES CARE S1 (Jan. 2016)
`
`(EX2065) at 60. In my opinion, there is no drug (including saxagliptin) that stands
`
`out above the others as the second best choice alternative to metformin. Indeed,
`
`metformin is also listed in the WHO List of Essential Medicines for the treatment
`
`of diabetes. EX1043 at 34. Again, saxagliptin is not.
`
`VI. TARGETING DPP-4 INHIBITORS AS ANTI-DIABETIC THERAPEUTICS
`
`22. Dr. Lenhard admits that DPP-4 inhibition was a known target for
`
`treatment of Type 2 diabetes in the 1990’s, noting that GLP-1 was a recognized
`
`target for treatment of type 2 diabetes and that DPP-4 inhibition was understood to
`
`treat diabetes by preventing cleavage of GLP-1 into a GLP-1 receptor antagonist.
`
`EX2057, ¶¶35-36. But Dr. Lenhard seems to suggest that there was heavy
`
`skepticism about the potential of DPP-4 inhibitors for anti-diabetic treatment and
`
`that drug developers were therefore discouraged from drug development efforts
`
`directed towards DPP-4 inhibition. Id. at ¶¶37-41.
`
`23. Dr. Lenhard’s supposition about how a person of ordinary skill in the
`
`art would have weighed these risks runs contrary to history, both before and after
`
`the claimed invention date of saxagliptin. Indeed, there was an explosion of
`
`
`
`-9-
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`
`
`interest in DPP-4 inhibitors in the mid- to late-1990s. See, e.g., Ashworth, D. M.,
`
`et al., 4-Cyanothiazolidides as Very Potent, Stable Inhibitors of Dipeptidyl
`
`Peptidase IV, 6 BIOORG. & MED. CHEM. LETT. 2745 (1996) (EX2001); Holst, J. J.,
`
`et al., Inhibition of the Activity of Dipeptidyl-Peptidase IV as a Treatment of Type
`
`2 Diabetes, 47 DIABETES 1663 (1998) (EX2005); Augustyns, K., et al., The Unique
`
`Properties of Dipeptidyl-Peptidase IV (DPP IV / CD26) and the Therapeutic
`
`Potential of DPP IV Inhibitors, 6 CURR. MED. CHEM. 311 (1999) (EX2007); Pauly,
`
`R. P., et al., Improved Glucose Tolerance in Rats Treated with the Dipeptidyl
`
`Peptidase IV (CD26) Inhibitor Ile-Thiazolidide, 48 METAB. 385 (1999) (EX2009);
`
`Hughes, T. E., et al., NVP-DPP728: (1-[[[2-[(5- Cyanopyridin-2-
`
`yl)amino]ethyl]amino ]acetyl]-2-cyano-(S)-pyrrolidine ), a Slow-Binding Inhibitor
`
`of Dipeptidyl Peptidase IV, 38 BIOCHEM. 11597 (1999) (EX2016); Balkan, B., et
`
`al., Inhibition of Dipeptidyl Peptidase IV with NVP-DPP728 Increases Plasma
`
`GLP-1(7-36 Amide) Concentrations and Improves Oral Glucose Tolerance in
`
`Obese Zucker Rats, 42 DIABETOLOGIA 1324 (1999) (EX2168). Even Dr. Lenhard
`
`concedes that promising clinical data for Phase I trials of two different DPP-4
`
`inhibitors had already been published by the year 2000. EX2057, ¶¶40-41 (citing
`
`Rothenberg, P., et al., Abstract, Treatment with a DPP-IV Inhibitor, NVP-DPP728,
`
`Increases Prandial Intact CLP-1 Levels and Reduced Glucose Exposure in
`
`Humans, 49 DIABETES 160-OR (2000) (EX2012); Demuth, Hans-U, et al.,
`
`
`
`-10-
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`
`
`Abstract, Single Dose Treatment of Diabetic Patients by the DP IV Inhibitor
`
`P32/98, 49 DIABETES 413-P (2000) (EX2010). Subsequent publications confirm
`
`that many different drug development teams did, in fact, view DPP-4 inhibition as
`
`an attractive target for diabetes treatment prior to the claimed invention date of
`
`saxagliptin. See, e.g., Weber, A. E., Dipeptidyl Peptidase IV Inhibitors for the
`
`Treatment of Diabetes, 47 J. MED. CHEM. 4135 (2004) (EX2098); Nabeno, M., et
`
`al., A Comparative Study of the Binding Modes of Recently Launched Dipeptidyl
`
`Peptidase IV Inhibitors in the Active Site, 434 BIOCHEM. & BIOPHYS. RESEARCH
`
`COMMC’NS 191 (2013) (EX2176).
`
`VII. INTERCHANGEABILITY OF THE FOUR FDA-APPROVED DPP-4 INHIBITORS
`
`24. Dr. Lenhard appears to suggest that doctors who prescribe Onglyza do
`
`so because of some advantage provided by saxagliptin over the three other FDA-
`
`approved DPP-4 inhibitors sitagliptin, linagliptin and alogliptin. EX2057, ¶¶54-
`
`56, 62. However, as explained by Dr. Lenhard each of these compounds operates
`
`through the same mechanism of action (inhibiting peptidase cleavage of GLP-1
`
`circulating in the blood). Id. at ¶¶35-36.
`
`25. Not only are these four compounds interchangeable with respect to
`
`their mechanism of action and resulting clinical effect, but they also have very
`
`similar and favorable side effect profiles, once-daily dosing, and potent efficacy.
`
`Onglyza® Prescribing Info., revised Aug. 2015 (EX2047) at 2-6 and 16; Januvia®
`
`
`
`-11-
`
`
`
`Prescribing Info., revised Mar. 2015 (EX2049) at 2-6 and 13; Tradjenta®
`
`Prescribing Info., revised Aug. 2015 (EX2077) at 2-4 and 8; Nesina® Prescribing
`
`Info., revised Aug. 2015 (EX2079) at 2-7, 16. Indeed, as one who has treated
`
`countless diabetes patients for decades and who treated many patients over the
`
`years with each of these DPP-4 inhibitors, in my opinion there is no meaningful
`
`difference in the side effect profile of the DPP-4 inhibitors on the market, with two
`
`possible exceptions.
`
`26. One such exception is that the FDA now requires the product labels
`
`for saxagliptin and alogliptin to provide a warning for an increase in
`
`hospitalization for congestive heart failure in patients taking these particular DPP-4
`
`inhibitors. FDA Drug Safety Communication: FDA adds warnings about heart
`
`failure risk to labels of type 2 diabetes medicines containing saxagliptin and
`
`alogliptin (2016) (EX1032, (JTX-146)); ONGLYZA Label (2016) (EX1033). By
`
`way of comparison, sitagliptin does not have a similar warning. EX2049 at 2-3.
`
`This FDA warning is something that a doctor must take into account as being both
`
`significant and clinically relevant when making prescribing decisions. In my
`
`opinion, if this warning had issued in 2009, at least some doctors who prescribed
`
`saxagliptin would have prescribed sitagliptin instead.
`
`
`
`-12-
`
`
`
`27. Another such exception is that all the compounds except linagliptin
`
`have different indicated dosages depending on whether or not the patient has
`
`chronic kidney disease. EX2049 at 1.
`
`28. Despite these difference, based on my years of experience treating
`
`diabetes and applying the prescription guidelines for each of the four FDA-
`
`approved DPP-4 inhibitors, it is my opinion that there is no medically indicated
`
`reason to prescribe saxagliptin more frequently than any other DPP-4 inhibitor on
`
`the market. I disagree with, and see no basis for, Dr. Lenhard’s assertion (EX2057,
`
`¶62) that saxagliptin has a side effect profile that is superior to that of the other
`
`second-line treatment options, which include the other FDA-approved DPP-4
`
`inhibitors sitagliptin, linagliptin, and alogliptin.
`
`29.
`
`In my own experience treating countless patients using DPP-4
`
`inhibitors, the prescription choice between the FDA-approved DPP-4 inhibitors
`
`(including Onglyza) is most frequently based on how favorably the patients’
`
`insurance treats the particular compound, such as through its formulary pricing. In
`
`other words, these decisions are most commonly based on private contractual
`
`arrangements and market forces, not on any alleged clinical superiority of
`
`saxagliptin over sitagliptin, linagliptin, or alogliptin.
`
`30.
`
` Dr. Lenhard states that physicians prescribe saxagliptin based on its
`
`therapeutic properties and advantages, including its safety, efficacy, mechanism of
`
`
`
`-13-
`
`
`
`action, and favorable side effect profile, which he says are tied directly to the
`
`active pharmaceutical ingredient, saxagliptin. EX2057, ¶¶54-56. I agree with Dr.
`
`Lenhard that physicians in the United States could not legally prescribe saxagliptin
`
`for use in the United States if the FDA had not granted regulatory approval for
`
`such use, and that such regulatory approval is granted based on an analysis of
`
`clinical studies regarding the safety, efficacy and side effects of the compound.
`
`However, the FDA has also deemed each of sitagliptin, linagliptin, and alogliptin
`
`safe and effective. EX2049 at 2; EX2077 at 2; EX2079 at 2. Because saxagliptin
`
`has not positively distinguish itself clinically or therapeutically from the remaining
`
`FDA-approved DPP-4 inhibitors to any significant degree, its therapeutic
`
`properties and “advantages” are unlikely in my experience to provide any
`
`significant motivation for prescribing saxagliptin over another member of this
`
`class.
`
`VIII. NO LONG-FELT BUT UNMET NEED
`
`31. Dr. Lenhard repeatedly asserts that saxagliptin filled a long-felt but
`
`unmet need, but he appears to describe the need in several different ways. At one
`
`point, Dr. Lenhard refers to a long-felt need for the claimed invention. EX2057,
`
`¶58. Subsequently, Dr. Lenhard calls it a long-felt need for an alternative
`
`treatment for type 2 diabetes that was both safe and effective. EX2057, ¶59. To
`
`the extent Dr. Lenhard relies on a long-felt need for an alternative treatment for
`
`
`
`-14-
`
`
`
`type 2 diabetes treatment that is both safe and effective, such a need continues to
`
`exist today and was not resolved by the synthesis of saxagliptin in 2000 or 2001.
`
`In other words, the synthesis of saxagliptin in 2000 or 2001 did not satisfy the need
`
`for an alternative type 2 diabetes treatment that was both safe and effective.
`
`32. Dr. Lenhard concedes that other DPP-4 inhibitors (e.g., vildagliptin)
`
`were invented before the earliest claimed invention date of saxagliptin. EX2057,
`
`¶¶60 (“Saxagliptin was the first invented FDA-approved DPP-4 inhibitor”), 63
`
`(“Other DPP-4 inhibitors in the prior art were never approved in the United
`
`States.”), 76 (stating that other FDA-approved DPP-4 inhibitors were not invented
`
`as of February 16, 2001, or by October 2000, and vildagliptin was never approved
`
`by the FDA). But Dr. Lenhard argues that vildagliptin did not satisfy the need for a
`
`safe and effective DPP-4 inhibitor because vildagliptin has not been approved by
`
`the FDA in the United States. Id. at ¶76.
`
`33. Dr. Lenhard similarly argues that sitagliptin, the first FDA-approved
`
`DPP-4 inhibitor, did not satisfy the need for a safe and effective DPP-4 inhibitor
`
`because “whether a long-felt need is unmet must be judged as of the filing date of
`
`the claimed invention and not as of the date that the patented product is first
`
`introduced into the market if that date of market entry is later.” Id. at ¶58.
`
`However, saxagliptin had not been shown to be safe and effective “as of the
`
`invention date.” Indeed, Dr. Lenhard concedes that saxagliptin did not receive
`
`
`
`-15-
`
`
`
`FDA approval until 2009, years after the claimed invention date. Id. at ¶47. Even
`
`then, the FDA later determined that patients should receive additional safety
`
`warnings regarding saxagliptin, as discussed in more detail in paragraph 26 above.
`
`34. Moreover, the claims of the ’186 patent do not recite a “safe and
`
`effective DPP-4 inhibitor” or an “FDA-approved DPP-4 inhibitors” having the
`
`chemical structure of saxagliptin. EX1001, 86:24-92:52. Indeed, the ’186 patent
`
`provides no clinical efficacy data at all and no in vivo data whatsoever. Thus, Dr.
`
`Lenhard redefines the long-felt need to avoid the fact that saxagliptin was not the
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`first-discovered DPP-4 inhibitor, and then redefines the “claimed invention” to
`
`avoid the fact that saxagliptin was not the first DPP-4 inhibitor administered to
`
`humans in the clinic or even the first FDA-approved DPP-4 inhibitor.
`
`35.
`
`In short, the invention of saxagliptin failed to fill any need in diabetes
`
`treatment in 2000 or 2001, in the same way that Dr. Lenhard opines that
`
`vildagliptin failed to meet that need, because neither compound was available to
`
`doctors (in the sense of having received regulatory approval) in 2000 or 2001 to
`
`treat diabetes patients.
`
`36. Similarly, the FDA-approval of saxagliptin in 2009 did not fill any
`
`need for an alternative treatment option for type 2 diabetes that was both safe and
`
`effective because sitagliptin was already available to doctors wishing to prescribe a
`
`DPP-4 inhibitor. The fact that sitagliptin, not saxagliptin, is still the primary
`
`
`
`-16-
`
`
`
`choice of doctors and patients for use as a DPP-4 inhibitor eight years after
`
`saxagliptin’s arrival in the U.S. treatment market confirms that saxagliptin did not
`
`fill any clinical need for a safe and effective DPP-4 inhibitor. Mushtaq et al., A
`
`Study of the Current Prescribing Patterns of Dipeptidyl Peptidase 4 Inhibitors in a
`
`Multi Specialty Hospital Outpatient Setting, 7 ASIAN J. PHARM. CLIN. RES. 134
`
`(2014) (EX1038) at 135 (article on prescribing patterns of DPP-4 inhibitors).
`
`37. To the extent any drug first filled the need of the prescribing physician
`
`to employ, or the patient to receive, an FDA-approved, safe, and effective DPP-4
`
`inhibitor in the United States (EX2057, ¶61), that drug was sitagliptin, not
`
`saxagliptin. Indeed, sitagliptin, not saxagliptin, was the first potent DPP-4
`
`inhibitor that was approved by the FDA and shown to be effective, weight neutral,
`
`and have a low risk of side effects.
`
`IX. NO FAILURE OF OTHERS IN THE PRIOR ART TO FULFILL THIS NEED
`
`38. Dr. Lenhard seems to suggest that the saxagliptin is a unique drug
`
`because no more than three other DPP-4 inhibitors have received FDA approval in
`
`the United States. EX2057, ¶66. From the perspective of one who has actually
`
`prescribed these drugs to thousands of patients, it is my opinion that the demand
`
`for an FDA-approved DPP-4 inhibitors has been substantially satisfied by
`
`sitagliptin, which has been and remains the overwhelming choice of doctors and
`
`patients. As additional DPP-4 inhibitors have been approved, these later-approved
`
`
`
`-17-
`
`
`
`compounds (including saxagliptin) have had to rely primarily on marketing and
`
`distribution relationships (such as insurance contracts) to gain a piece of the
`
`continually expanding diabetes treatment market because they are unable to
`
`advertise any clinical benefit over sitagliptin.
`
`39. Dr. Lenhard also suggests vildagliptin failed as a safe and effective
`
`DPP-4 inhibitor because it was approved in Europe and sold outside United States
`
`as Galvus® but was not approved by the FDA for sale in the United States.
`
`EX2057, ¶¶67, 76. However, vildagliptin can be administered as a monotherapy
`
`twice a day in Europe, and has been approved for administration in more than 100
`
`countries around the world. Annex I, Summary of Product Characteristics for
`
`Galvus® 50 mg Tablets (EX2080) at 33; Novartis 2013 Annual Report (EX1049) at
`
`148. Vildagliptin is also available for sale as a combination therapy with
`
`metformin, sold as Eucreas®. Id. Thus, vildagliptin has necessarily been deemed
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`safe and effective by a variety of regulatory bodies around the world and is, in fact,
`
`being used successfully as a DPP-4 inhibitor to treat diabetes. In other words, Dr.
`
`Lenhard’s categorization of vildagliptin as a failure appears to be based on
`
`regulatory disparities between different countries, as opposed to failure of
`
`vildagliptin in a technical sense.
`
`40. Moreover, the regulatory approvals of vildagliptin were also based on
`
`human clinical trial data, which found that both 50 mg and 100 mg dosages of
`
`
`
`-18-
`
`
`
`vildagliptin resulted in significant reductions in A1C levels. Reduction in A1C
`
`level is associated in improvement of outcomes in diabetes patients. EX2080 at 11
`
`and Table 8. These studies also found significant decreases in A1C levels, fasting
`
`plasma glucose levels, and prandial glucose levels for a 25 mg dose administered
`
`twice daily. Id.
`
`41. Dr. Lenhard states that vildagliptin has dose-dependent liver toxicity
`
`that he says other DPP-4 inhibitors lack. EX2057, ¶¶68-70. Dr. Lenhard relies on
`
`a November 6, 2007 report of Phase III trials showing that 0.86% of patients
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`receiving a 100 mg dose of vildagliptin once daily, 0.34% of patients receiving 50
`
`mg of vildagliptin twice daily, and 0.21% of patients receiving 50 mg of
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`vildagliptin once daily had elevated liver enzymes. Id. Dr. Lenhard states that
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`Novartis sells vildagliptin in Europe for administration in a twice-daily 50 mg dose
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`(EX2057, ¶¶67, 76), and suggests that this “twice-daily” administration constitutes
`
`a failure. However, I note that neither the 2007 test results nor vildagliptin’s
`
`approved dosing regimen could have been known in 2000 or early 2001 at the time
`
`of the claimed invention of saxagliptin. In other words, at the time saxagliptin was
`
`invented, vildagliptin would not have been considered a failure (any more than
`
`saxagliptin could have been viewed as a success). The future discovery of an
`
`infrequent liver side effect thus could not have influenced anyone’s decision to
`
`pursue DPP-4 inhibitors in 2000-2001.
`
`
`
`-19-
`
`
`
`42. Moreover, as discussed above, these side effects did not prevent
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`vildagliptin from being deemed safe and effective in Europe and more than 100
`
`countries or from being widely used to treat diabetes in those countries. EX1049 at
`
`148. Widespread administration of vildagliptin as a DPP-4 inhibitor throughout
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`the world (with the exception of in the United States) does not make vildagliptin a
`
`failure from a therapeutic perspective.
`
`43. To the extent Dr. Lenhard suggests that twice-daily administration of
`
`vildagliptin makes that drug a failure, I disagree. First of all, Dr. Lenhard does not
`
`identify where the claimed invention specifies a dosing frequency. The ’186 itself
`
`expressly contemplates dosing 1-4 times a day. EX1001, 21:67-22:3.
`
`44. Second, as conceded by Dr. Lenhard (EX2057, ¶68), vildagliptin can
`
`be given once a day in combination with sulfonylurea. EX2080 at 3. As discussed
`
`above, sulfonylurea is still an essential, commonly prescribed and administered
`
`anti-diabetic medication.
`
`45. Third, twice-daily dosing alone does not make a drug a failure. Many
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`successful drugs are administered twice daily, such as Advair (EX1036 at 1),
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`Cymbalta (EX1037 at 1), as well as metformin (EX1012) at 48. Moreover, though
`
`Dr. Lenhard points to a single study to support his assertion that once-daily dosing
`
`results in statistically significant differences in reductions of A1C levels, EX2057,
`
`¶82, these differences are very small and are not likely to be clinically significant.
`
`
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`-20-
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`
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`46. Moreover, Dr. Lenhard notes that metformin is not dosed once-daily
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`as monotherapy. As mentioned above, however, metformin is the primary anti-
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`diabetic
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