Filed on behalf of Boston Heart Diagnostics Corporation IN THE UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD

Transcription

1 Filed on behalf of Boston Heart Diagnostics Corporation By: Thomas C. Meyers, Reg. No. 36,989 Brown Rudnick LLP One Financial Center Boston, MA Tel: (617) Fax: (617) IN THE UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD BOSTON HEART DIAGNOSTICS CORPORATION Petitioner v. HEALTH DIAGNOSTIC LABORATORY, INC. Patent Owner Patent No. 8,119,358 PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,119,358 (CLAIMS 1-10) Mail Stop Patent Board Patent Trial and Appeal Board U.S. Patent and Trademark Office P.O. Box 1450 Alexandria, VA

2 TABLE OF CONTENTS I. Introduction... 1 II. Requirements of Petition and Mandatory Notices... 1 A. Grounds for Standing (37 C.F.R (a))... 1 B. Real Party-in-Interest (37 C.F.R. 42.8(b)(1))... 2 C. Related Matters (37 C.F.R. 42.8(b)(2))... 2 D. Counsel and Service Information (37 C.F.R. 42.8(b)(3)-(4))... 2 E. Power of Attorney (37 C.F.R (b))... 3 F. Inter Partes Review Fee (37 C.F.R )... 3 III. Challenge Under (b) and Relief Requested... 3 A. Claims 1-10 of the 358 patent are invalid and should be cancelled... 3 B. Table of grounds for challenge... 5 IV. Overview of the 358 patent... 6 A. The 358 patent claims methods for identifying individuals at risk for diabetes that were known... 6 B. Claim Construction under 37 C.F.R (b)(3) Claims 1 and 2 include Markush groups of Markush groups and cover many alternative biomarkers The claims should be given their broadest reasonable interpretation in light of the specification...10 i

3 C. File history of the 358 patent...15 V. Explanation of Grounds for Invalidity under 37 C.F.R (b)...17 A. Overview of grounds for invalidity...17 B. Ground 1: Claims 1-9 are anticipated by the BWH application Overview of the BWH application Overview of claims 1 and The BWH application discloses step a) of claims 1 and 2 (obtaining measurements of specific biomarkers for diabetes) The BWH application discloses step b) of claims 1 and 2 (calculating a risk score based on those measurements using a model based upon a population study) The BWH application discloses step c) of claim 1 and the preamble of claim 2 (administering a drug to an individual deemed to be at risk of diabetes) The BWH application identically discloses claim 3 (type II diabetes) The BWH application discloses claim 4 (individual has not converted to frank diabetes) The BWH application discloses claim 5 (endpoint is risk for developing a diabetic condition)...26 ii

4 9. The BWH application discloses claim 6 (endpoint is diagnosis of a diabetic condition) The BWH application discloses claim 7 (endpoint is response to a Diabetes-modulating drug) The BWH application discloses claim 8 (individual has not converted to frank diabetes; drug is for prophylaxis) The BWH application discloses claim 9 (individual has converted to frank diabetes; drug is for treatment) Claim chart summarizing the anticipation of claims 1-9 by the BWH application...28 C. Ground 2: Claim 10 is unpatentable over the combination of the BWH application and Harder Overview of Harder One of skill in the art would administer liraglutide to treat diabetes...37 D. Ground 3: Claims 1-8 are obvious over Krakoff in view of the ADA position statement Overview of Krakoff Overview of the ADA position statement...40 iii

5 3. Claims 1 and 2 are unpatentable over the combination of Krakoff and the ADA position statement Claims 3-8 are unpatentable over the combination of Krakoff and the ADA position statement...43 E. Ground 4: Claims 9 and 10 are unpatentable over the combination of Krakoff, the ADA position statement, and Harder...45 F. Ground 5: Claims 1-8 are unpatentable over the combination of Spranger and the ADA position statement Overview of Spranger Claims 1 and 2 are unpatentable over the combination of Spranger in view of the ADA position statement Claims 3-8 are unpatentable over Spranger in view of the ADA position statement...50 G. Ground 6: Claims 9 and 10 are unpatentable over the combination of Spranger, the ADA position statement, and Harder...52 VI. Conclusion...54 iv

6 TABLE OF CASES In re Slayter, 276 F.2d 408, 411, 125 USPQ 345, 347 (CCPA 1960)...8, 48 In re Trans Tex. Holdings Corp., 498 F.3d 1290, 1297 (Fed. Cir. 2007)...10 v

7 EXHIBIT LIST Exhibit 1001 Exhibit 1002 Exhibit 1003 Exhibit 1004 U.S. Patent No. 8,119,358, Diabetes-Related Biomarkers and Methods of Use Thereof (the 358 patent); earliest priority claimed Oct. 11, Summons and Proof of Service; Health Diagnostics Laboratory, Inc. v. Boston Heart Diagnostics Corporation, Civil Action 3:14-cv HEH, U.S. District Court, Eastern District of Virginia. Served December 4, WO 02/48715, Inflammatory Markers as Tools in the Detection and Prevention of Diabetes Mellitus and as Tools to Aid in the Selection of Agents to be Used for the Prevention and Treatment of Diabetes, The Brigham and Women s Hospital, Inc. ( the BWH application ); published June 20, Harder et al., The Effect of Liraglutide, a Long- Acting Glucagon-Like Peptide 1 Derivative, on Glycemic Control, Body Composition, and 24-h Energy Expenditure in Patients with Type 2 Diabetes, Diabetes Care, Vol. 27, p (2004), ( Harder ); available online August vi

8 Exhibit 1005 Exhibit 1006 Exhibit 1007 Krakoff et al., Inflammatory Markers, Adiponectin, and Risk of Type 2 Diabetes in the Pima Indian, Diabetes Care, Vol. 26, p (2003), ( Krakoff ); available online June American Diabetes Association et al., Prevention or Delay of Type 2 Diabetes, Diabetes Care, Vol. 27, Supplement 1, p. S47-S54 (2004), ( ADA position statement ); available online January Spranger et al. Adiponectin and Protection Against Type 2 Diabetes Mellitus, Lancet, Vol. 361, p (2003), ( Spranger ); January 18, Exhibit 1008 Excerpts from the prosecution history of the 358 patent. Exhibit 1009 File wrapper of U.S. 60/725,462. Exhibit 1010 U.S. Patent No. 7,723,050. vii

9 I. Introduction Boston Heart Diagnostics Corporation ( BHDX ) respectfully requests inter partes review ( IPR ) of claims 1 through 10 of U.S. Patent No. 8,119,358 ( the 358 patent ), Ex. 1001, under 35 U.S.C and 37 C.F.R & Prior art provided by the Petitioner demonstrates that the methods claimed in the 358 patent were widely known and used as of the purported priority date of the 358 patent. In particular, each element of claims 1-9 of the 358 patent are identically disclosed in WO 02/ Furthermore, claim 10 is obvious over WO 02/48715 in combination with a secondary reference teaching the specific drug (liraglutide) recited in claim 10. Finally, claims 1-10 of the 358 patent are obvious over additional prior art also provided by the Petitioner. For all of these reasons, claims 1-10 should not have issued. Petitioner, therefore, respectfully requests that the Board finds claims 1-10 of the 358 patent unpatentable and that the Board cancels claims II. Requirements of Petition and Mandatory Notices A. Grounds for Standing (37 C.F.R (a)) BHDX certifies that the 358 patent is available for inter partes review. More than nine months have passed since the issue of the 358 patent on February 21, BHDX has not previously filed a civil action challenging the validity of 1

10 a claim of the 358 patent. The present petition is being filed within one year of service against Petitioner, on December 4, 2014, of a complaint alleging infringement of the patent. See Ex. 1002, (Proof of Service). Petitioner is not barred or estopped from requesting this IPR on the grounds identified herein. B. Real Party-in-Interest (37 C.F.R. 42.8(b)(1)) The Petitioner, Boston Heart Diagnostics Corporation ( BHDX ), Framingham, Massachusetts, is the real party-in-interest. C. Related Matters (37 C.F.R. 42.8(b)(2)) The 358 patent has been asserted against BHDX in Health Diagnostic Laboratory, Inc. v. Boston Heart Diagnostics Corporation, Case No. 3:14-cv (E.D. Va. filed November 20, 2014). See Ex D. Counsel and Service Information (37 C.F.R. 42.8(b)(3)-(4)) The designations of counsel and addresses for service are: LEAD COUNSEL Thomas C. Meyers, Reg. No. 36,989 Brown Rudnick LLP One Financial Center Boston, MA Tel: (617) Fax: (617) tmeyers@brownrudnick.com BACKUP COUNSEL Brian D. Bean, Reg. No. 61,565 Brown Rudnick LLP One Financial Center Boston, MA Tel: (617) Fax: (617) bbean@brownrudnick.com Petitioner consents to service at d@brownrudnick.com and tmeyers@brownrudnick.com. 2

11 E. Power of Attorney (37 C.F.R (b)) Filed herewith is a Power of Attorney under 37 C.F.R (b). F. Inter Partes Review Fee (37 C.F.R ) This Petition requests review of ten claims of the 358 patent; accordingly, pursuant to 37 C.F.R (a), a payment of $23,000 is submitted herewith. Any additional fees required of Petitioner for purposes of this IPR may also be charged to Deposit Account No III. Challenge Under (b) and Relief Requested A. Claims 1-10 of the 358 patent are invalid and should be cancelled This Petition should be granted, and trial instituted, because there is a reasonable likelihood that Petitioner will prevail with respect to the invalidity of at least one of claims 1-10 of the 358 patent. See 35 U.S.C. 314(a). Petitioner s challenge is based on the following references: Ex. 1003: WO 02/48715, Inflammatory Markers as Tools in the Detection and Prevention of Diabetes Mellitus and as Tools to Aid in the Selection of Agents to be Used for the Prevention and Treatment of Diabetes, The Brigham and Women s Hospital, Inc. ( the BWH application ), published June 20, Ex. 1004: Harder et al., The Effect of Liraglutide, a Long-Acting Glucagon-Like Peptide 1 Derivative, on Glycemic Control, Body Composition, 3

12 and 24-h Energy Expenditure in Patients with Type 2 Diabetes, Diabetes Care, Vol. 27, p (2004), ( Harder ) available online August Ex. 1005: Krakoff et al., Inflammatory Markers, Adiponectin, and Risk of Type 2 Diabetes in the Pima Indian, Diabetes Care, Vol. 26, p (2003), ( Krakoff ), available online June Ex. 1006: American Diabetes Association et al., Prevention or Delay of Type 2 Diabetes, Diabetes Care, Vol. 27, Supplement 1, p. S47-S54 (2004), ( ADA position statement ), available online January Ex. 1007: Spranger et al. Adiponectin and Protection Against Type 2 Diabetes Mellitus, Lancet, Vol. 361, p (2003), ( Spranger ); January 18, Each of the references was publicly available at least one year before the earliest priority date claimed by the 358 patent. 4

13 B. Table of grounds for challenge Ground 358 Patent Basis for Rejection Anticipated by the BWH application under 102(b) 2 10 Unpatentable over the BWH application in view of Harder under 103(a) Unpatentable over Krakoff in view of ADA position statement under 103(a) 4 9 and 10 Unpatentable over Krakoff in view of ADA position statement and Harder under 103(a) Unpatentable over Spranger in view of ADA position statement under 103(a) 6 9 and 10 Unpatentable over Spranger in view of ADA position statement and Harder under 103(a) An explanation of how claims 1-10 of the 358 patent are unpatentable based on grounds asserted in this petition, including the identification of where each element of each claim is found in the prior art, is provided in Part V. 5

14 IV. Overview of the 358 patent A. The 358 patent claims methods for identifying individuals at risk for diabetes that were known In general terms, the claims of the 358 patent recite a) obtaining measurements of biomarkers for diabetes, b) using the measurements to calculate a diabetes risk score using a model based upon a diabetes population study, and c) administering a drug. Ex at claims 1 and 2. As is discussed in the background section of the 358 patent, many biomarkers for diabetes were known prior to the filing of the 358 patent, including blood glucose levels, glycated hemoglobin ( HBA1c ), C-Reactive Protein ( CRP ), and Interlukin-6 ( IL-6 ). Ex at 2: Additionally, it was known that a risk of diabetes could be evaluated using multivariate risk prediction algorithms validated with stratified samples from a representative population, such as the Framingham study. Ex at 3: Nonetheless, according to the background of the 358 patent, state-of-the-art predictive diabetes screening was not practical and the follow on risk calculations were difficult. Ex at 3: The 358 patent purports to solve the problems of the prior art by providing novel panels of biomarkers which can be measured and used to evaluate the risk that an individual will develop Diabetes in the future. Ex at 4: The 6

15 measurements of the biomarkers are then entered into a model that is based upon a study of a population of subjects that developed diabetes, i.e., a longitudinal study. Ex at 4: Using the model, a diabetes risk score (a.k.a. index value ) is calculated that represents a quantified risk that an individual will develop diabetes. Ex at 8: If an individual s diabetes risk score is above a predetermined value, that individual can be selected to receive a treatment regimen. Ex at 25: In some instances, the individual will have already developed diabetes, however in other instances, the individual will only be at risk for developing diabetes. Ex at 25:51-26:14. B. Claim Construction under 37 C.F.R (b)(3) 1. Claims 1 and 2 include Markush groups of Markush groups and cover many alternative biomarkers Independent claims 1 and 2 of the 358 patent include Markush groups of Markush groups. Accordingly, a reader must parse the claim language in order to determine the subject matter of the claims. In particular, Claims 1 and 2 both include six alternative sets of biomarkers [(i) (vi)] that are allegedly indicative of a risk for developing diabetes. Ex at claims 1 and 2. Because the six alternative sets of biomarkers are separated by or, they represent six alternate elements in a Markush group. See MPEP (h). It is well settled that it is not necessary for an anticipatory reference to disclose each element of a Markush 7

16 group to anticipate that claim; one element is enough. See In re Slayter, 276 F.2d 408, 411, 125 USPQ 345, 347 (CCPA 1960); MPEP Each of the six alternative biomarker sets of claims 1 and 2 invokes an additional Markush group of biomarkers within its description, thus claims 1 and 2 of the 358 patent each encompass many possible combinations of biomarkers. Ex at claims 1 and 2. Moreover, Tables 1, 2, and 3, recited in sub elements (iii) and (iv) of claims 1 and 2, include over 270 biomarkers. Id. Thus, when interpreting claims 1 and 2, a reader must choose from over 300 different biomarkers that are allegedly indicative of a risk for developing diabetes. Claim 1 illustrates the alternative biomarker sets. It recites: 1. A method comprising: (a) obtaining measurements of biomarkers from at least one biological sample isolated from an individual, wherein said biomarkers comprise: (i) at least three biomarkers, where three of the biomarkers are selected from the RDMARKER sets listed in FIG. 6A; or (ii) at least four biomarkers selected from RDMARKERS; or (iii) at least three biomarkers, where two biomarkers are selected from ADIPOQ; CRP; GLUCOSE; GPT; HBA1C; HSPA1B; IGFBP1; IGFBP2; INS, LEP; and TRIG; and one biomarker is selected from the ALLDBRISKS, CPs, and TLRFs of Table 1, Table 2, and Table 3; or 8

17 (iv) at least three biomarkers, where at least one biomarker is selected from GLUCOSE and HBA1C; at least one biomarker is selected from ADIPOQ, CRP, GPT, HSPA1B, IGFBP1, IGFBP2, INS, LEP, and TRIG; and at least one biomarker is selected from the ALLDBRISKS, CPs, and TLRFs of Table 1, Table 2, and Table 3; or (v) at least three biomarkers, where at least two biomarkers are selected from the biomarkers within the group consisting of Core Biomarkers I and Core Biomarkers II and at least a third biomarker is selected from any of the biomarkers listed in Table 4; or (vi) ADIPOQ, GLUCOSE, CRP and one biomarker selected from the group consisting of HBA1C, IGFBP1, IGFBP2, Insulin, LEP and TRIG; (b) calculating an index value from the output of a model, wherein the inputs to said model comprise said measurements, and further wherein said model was developed by fitting data from a longitudinal study of a selected population of individuals and said fitted data comprises levels of said biomarkers and an end point in said selected population of individuals, wherein said end point is selected from risk for developing a diabetic condition, the diagnosis of a diabetic condition, response to a Diabetes-modulating drugs, a surrogate diabetes endpoint, glucose class, a complication of a diabetic condition; and (c) administering to said individual a Diabetes-modulating drug. Ex at claim 1, emphasis added. Independent claim 2 is quite similar to claim 1, however instead of reciting an administering step, delivery of a 9

18 Diabetes-modulating drug is recited in the preamble. Ex at claim 2. Dependent claims 3-9 recite specific endpoints and goals for treatment with a diabetes-modulating drug. Ex at claims 3-9. Dependent claim 10 recites a specific diabetes-modulating drug, i.e., liraglutide (brand name Victoza TM manufactured by Novo Nordisk). 2. The claims should be given their broadest reasonable interpretation in light of the specification In an inter partes review, claim terms in an unexpired patent are interpreted according to their broadest reasonable interpretation ( BRI ) in view of the specification in which they appear. 37 C.F.R (b). The USPTO uses BRI because, among other reasons, the patentee has the opportunity to amend its claims in this proceeding. See, e.g., Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,764, 48,766 (Aug. 14, 2012). The BRI of claim terms here may be different from the construction that those same terms may receive following claim construction proceedings in district court. See, e.g., In re Trans Tex. Holdings Corp., 498 F.3d 1290, 1297 (Fed. Cir. 2007). For purposes of IPR of the 358 patent, Petitioner respectfully requests that the Board construe, under the BRI standard, the following claim terms in the 358 patent. Furthermore, where they are not specifically interpreted, the individual biomarkers recited in claims 1 and 2 should be given the meanings described in 10

19 specification of the 358 patent. See, e.g., Ex at Tables 1-3, beginning at approximately column 44. All other terms in claims 1-10 of the 358 patent are given their ordinary and customary meaning under a broadest reasonable construction as understood by a person of ordinary skill as of the filing date and need not be further construed for this Petition. Biological Sample Samples of a biological origin are defined in the 358 patent to include whole blood, serum, plasma, blood cells, endothelial cells, tissue biopsies, lymphatic fluid, ascites fluid, interstitial fluid, extracellular fluid, bone marrow, cerebrospinal fluid (CSF), saliva, mucous, sputum, sweat, urine, or any other secretion, excretion, or other bodily fluids. Ex at 24:4-13. RDMARKERS RDMARKERS are defined in the 358 patent as biomarkers selected from the group consisting of adiponectin (ADIPOQ), C- reactive protein (CRP); glucose (GLUCOSE); glutamic-pyruvate transaminase (GPT or ALT); glycosylated hemoglobin (HBA1C); heat shock 70 kda protein 1B (HSPA1B); insulin-like growth factor binding protein 1 (IGFBP1); insulin-like growth factor binding protein 2 (IGFBP2); insulin (INS, INSULIN-M, pro-insulin and SCp), leptin (LEP) and triglycerides (TRIG). Ex at 18:23-26 and 24:66-25:14. ALLDBRISKS ALLDBRISKS are defined in the 358 patent as biomarkers selected from Table 1 of the 358 patent. Ex at Table 1 11

20 (beginning at approximately column 44). ALLDBRISKS includes 271 biomarkers, some of which are redundant with RDMARKERS. CPs Clinical Parameters ( CPs ) are defined in the 358 patent as biomarkers selected from Table 2 of the 358 patent. Ex at Table 2 (beginning at approximately column 69). CPs includes body-mass index (BMI). Id. TLRFs Traditional Laboratory Risk Factors ( TLRFs ) are defined in the 358 patent as biomarkers selected from Table 3 of the 358 patent. Ex at Table 3 (beginning at approximately column 69). TLRFs include glucose (GLU) and glycosylated hemoglobin (HbA1c). Id. Core Biomarkers I Core Biomarkers I is a set of biomarkers listed in column 3 of Table 4 of the 358 patent. Ex at Table 4 (starting at approximately column 73). Core Biomarkers I includes C-reactive protein (CRP) and insulin (INS). Core Biomarkers II Core Biomarkers II is a set of biomarkers listed in column 4 of Table 4 of the 358 patent. Ex at Table 4 (starting at approximately column 73). Index Value As used in the 358 patent, an index value covers any calculated value that can be used to enumerate a risk of developing diabetes. Ex at 8:

21 Said index value is a Diabetes risk score; the Diabetes risk score can be calculated according to any of the methods described herein. The means for collecting and tracking test results for one or more individuals can comprise a data structure or database. The means for calculating a Diabetes risk score can comprise a computer, microprocessor, programmable calculator, dedicated device, or any other device capable of calculating the Diabetes risk score. Ex at 8: Model As used in the 358 patent, a model is any mathematical technique or algorithm that is used to calculate an index value. Ex at 19:9-25. The terms formula, algorithm, and model are used interchangeably for any mathematical equation, algorithmic, analytical or programmed process, or statistical technique that takes one or more continuous or categorical inputs (herein called parameters ) and calculates an output value, sometimes referred to as an index or index value. Ex at 19:9-14. Longitudinal study of a selected population of individuals A longitudinal study is a study involving observations of a selected population over a period of time. Ex at 79: As used in the 358 patent, longitudinal study and prospective study are interchangeable. Id. The biomarker data may be initially derived through a variety of means, including prospective (longitudinal) studies to [sic] involving observations of the representative population over a 13

22 period of time. Ex at 79: In Example 1 of the 358 patent, a longitudinal study is described wherein a study population was later divided into two different populations; one that had not developed diabetes and one that had developed diabetes. Ex at 88: Diabetes-modulating drug Includes any agent for reducing the risk of diabetes, pre-diabetes, pre-diabetic conditions, or diabetic complications. Ex at 30: These agents include insulin, hypoglycemic agents, antiinflammatory agents, lipid reducing agents, anti-hypertensives such as calcium channel blockers, beta-adrenergic receptor blockers, cyclooxygenase-2 inhibitors, angiotensin system inhibitors, ACE inhibitors, rennin inhibitors, together with other common risk factor modifying agents. Ex at 30: Frank Diabetes Frank diabetes is not specifically defined in the 358 patent. Lacking a specific definition, frank diabetes should be given its ordinary meaning in the art, i.e., clinically obvious diabetes mellitus, as opposed to a prediabetic condition. See also Ex at 22: End point is risk for developing a diabetic condition A portion of the study population was diagnosed as being at risk for developing a diabetic condition. See Ex at 82:

23 End point is diagnosis of a diabetic condition A portion of the study population was diagnosed as having a diabetic condition. See Ex at 82: End point is response to a Diabetes-modulating drug A portion of the study population was diagnosed as being likely to benefit from administration of a Diabetes-modulating drug. See Ex at 81: Prior to filing the 358 patent, it was known in the art that diabetes-modulating drugs could be used to control diabetes, and that such drugs would influence measured levels of the some of the biomarkers recited in the claims. See Id. C. File history of the 358 patent U.S. Patent Application No. 12/106,070 (the 070 application), now U.S. Patent No. 8,119,358 was filed on April 18, Ex 1008 at 83. The 070 application (now 358 patent) claims priority to U.S. 61/002,609, filed November 8, Id. The 070 application (now 358 patent) was also filed as a continuation-in-part of U.S. 11/788,260, filed April 18, 2007, and expressly abandoned on November 21, Id. U.S. 11/788,260 (parent to 358 patent), itself, was a continuation-in-part of U.S. 11/546,874, filed October 11, 2006 and expressly abandoned on November 21, U.S. 11/546,874 (grandparent to 358 patent), was a non-provisional application claiming priority to U.S. 60/725,462 (Ex. 1009), filed October 11,

24 October 11, 2005 is the earliest priority date claimed for the 358 patent. However, Petitioners do not concede that any of the claims of the 358 patent are entitled to that priority date. In particular, the earliest application in the priority chain (U.S. 60/725,462) does not disclose all of the biomarkers recited in claims 1 and 2 of the 358 patent. See Ex For example, U.S. 60/725,462 does not disclose heat shock 70 kda protein 1B (HSPA1B) or insulin-like growth factor binding protein 2 (IGFBP2), each of which is recited in several of the alternative biomarker sets of claims 1 and 2 of the 358 patent. Accordingly, claims 1-10 of the 358 patent may not be entitled to the October 11, 2005 priority date. Petitioners note that the 358 patent received little substantive examination. The only Office action on the merits was issued on June 24, Ex at In the non-final Office action, claims 190 and were rejected only for non-statutory obviousness-type double patenting over claims 1-20 of U.S. 7,723,050 (child of 358 patent), detailed below. Ex at After the Applicants filed a terminal disclaimer against U.S. 7,723,050 (child of 358 patent) on October 24, 2011, a Notice of Allowance was issued on December 20, Ex at 24. While both the BWH application and Krakoff were submitted in an information disclosure statement during prosecution of the 358 patent, there is no indication in the file history that either reference was given substantial consideration during prosecution. Ex at

25 Patent number 7,723,050 ( the 050 patent ; Ex. 1010), over which the 358 patent is terminally disclaimed, is a child of the 358 patent. The 050 patent was filed as U.S. Patent Application No. 12/501,385 on July 10, 2009 under the Revised Accelerated Examination Program detailed in the June 26, 2006 Federal Register. 71. Fed. Reg (2006). Because it was filed under the prior accelerated examination program, U.S. Application 12/501,385 was accompanied by an Accelerated Examination Support Document detailing reasons that the Applicant deemed the claims patentable. The Accelerated Examination Support Document briefly discussed both the BWH application and Krakoff in relation to the claims in U.S. Application 12/501,385; however those claims have claim elements that are not recited in the 358 patent, such as displaying a risk of diabetes. Additionally, all of the claims in U.S. Application 12/501,385 (now the 050 patent) required a biomarker panel including adiponectin (ADIPOQ), GLUCOSE, and C-reactive protein (CRP). See Ex The claims of the 358 patent are not subject to the same limitations. V. Explanation of Grounds for Invalidity under 37 C.F.R (b) A. Overview of grounds for invalidity Generically, the 358 patent recites a) obtaining measurements of biomarkers for diabetes, b) using the measurements to calculate a diabetes risk 17

26 score using a model based upon a diabetes population study, and c) administering a drug. Ex at claims 1 and 2. As explained below, WO/ ( the BWH application ) identically discloses each element as claimed in claims 1-9 of the 358 patent, and therefore anticipates claims 1-9 of the 358 patent. For at least that reason, claims 1-9 of the 358 patent should be found invalid and should be canceled. Claim 10 recites the elements of claim 1 with the addition of administering liraglutide. That claim is unpatentable over the BWH application and Harder. Harder discloses the use of liraglutide to treat diabetes. For at least that reason, claim 10 of the 358 patent should be found invalid and should be canceled. Claims 1-8 of the 358 patent are obvious over Krakoff in view of the ADA position statement, while claims 9 and 10 are obvious over Krakoff in view of the ADA position statement and Harder. Claims 1-8 of the 358 patent are also obvious over Spranger in view of the ADA position statement, while claims 9 and 10 are also obvious over Spranger in view of the ADA position statement and Harder. For any or all of the forgoing reasons, claims 1-10 of the 358 patent should be found invalid and should be canceled. 18

27 B. Ground 1: Claims 1-9 are anticipated by the BWH application 1. Overview of the BWH application The BWH application (Ex. 1003) discloses methods for assessing diabetes or diabetes risk by screening individuals for levels of various biomarker associated with diabetes or pre-diabetes that are identical to those claimed in the 358 patent. The BWH application also uses a model and index value identical to that claimed in the 358 patent, and teaches the benefits of administering diabetes-modulating drugs. The BWH application touts the benefits of screening individuals for diabetes risk using a biomarker panel identical to the biomarker panel claimed in the 358 patent. Ex at 2: Specifically, the BWH application teaches that traditional diabetes markers, such as GLUCOSE, INSULIN, HBA1C, and BMI should be combined with biomarkers of inflammation, such as C-reactive protein ( CRP ), and interluken-6 ( IL-6) to provide a more complete picture of diabetes risk. Ex at 2:21-24; 2:29-32; 5:3-21. In some instances, elevated levels of CRP are indicative of diabetes risk in healthy individuals, i.e., when the traditional diabetes biomarkers are within normal ranges, i.e., having a body-mass index ( BMI ) less than 30, having a glycosylated hemoglobin ( HBA1C ) within a normal range, having a blood glucose level ( GLUCOSE ) within a normal 19

28 range, and/or having an insulin level ( INS ) within a normal range. Ex at 2:25-34; 5:3-9; 24:9-25:8. The BWH application was based upon a longitudinal study known as the Women s Health Study. Ex at 6: The Women s Health Study was a randomized study of cardiovascular disease in 28,000 apparently healthy women. Id. Study participants who self-identified as having developed diabetic complications within four years of the start of the study were independently assessed for diabetes by measuring GLUCOSE levels. Ex at 24:9-20. Because the study participants had provided whole blood samples at the beginning of the study, and because the samples were kept in storage, it was possible to measure CRP, IL-6, INS, HBA1C, and GLUCOSE levels corresponding to the beginning of the study for those participants that developed diabetes after the study began. Ex at 6:26-28; 24:4-8. A selected group of non-diabetic study participants were also assayed for biomarkers, and used as controls. For each participant that developed diabetes, two different study participants (who did not develop diabetes) were chosen from the study to act as controls. Ex at 24: The case and control subjects were matched based upon age and fasting GLUCOSE measurements at the start of the study. Ex at 24:26-31; 24:32-25:8. HBA1C, BMI, hypertension, hyperlipidemia, and hormone replacement therapies were also considered in 20

29 matching case and control subjects. Ex at 24:32-25:6. Like the diabetic participants, the control participants also had their CRP, IL-6, INS, HBA1C, and GLUCOSE levels retrospectively measured. Ex at 25: In total, there were 188 subject cases (diabetic) and 362 controls (non-diabetic). Ex at 25:5-6. In a subset of cases, insulin levels (INS) were also factored into the risk assessment. Ex at 25:6-8; 27:5-14. Using the measured biomarker levels and the diabetes outcomes for the study participants, the BWH application developed a diabetes risk model. Ex at 25:23-26:14. Using the Student s t-test, the collected body of statistical data was evaluated, after which the biomarker distributions were adjusted using a rank-sum test. Ex at 25: The authors next correlated each biomarker range with a diabetes risk score based upon longitudinal outcome, i.e., development of diabetes within the first four years of the study. Ex at 25: Conditional logistic regressions, adjusting for BMI, were then used to assign a diabetes risk score to weighted combinations of biomarkers. Ex at 25:28-26:14 and Table 5 (page 38). Table 4 of the BWH application shows adjusted relative risks of developing diabetes based upon baseline biomarker measurements. Ex at Table 4 (page 37). 21

30 2. Overview of claims 1 and 2 Generically, independent claim 1 of the 358 patent includes the steps of: a) obtaining measurements of specific biomarkers for diabetes, b) calculating a risk score based on those measurements using a model based upon a population study, and c) administering a drug to an individual deemed to be at risk. Ex at claim 1. Claim 2 is very similar, but recites the administering step in the preamble. Ex at claim 2. The BWH application likewise discloses: a) obtaining measurements of those specific biomarkers for diabetes, b) calculating a risk score based on those measurements using a model based upon a population study, and c) administering a drug to an individual deemed to be at risk. Ex Accordingly, the BWH Application anticipates claims 1 and 2 of the 358 patent. Specific details of the overlap between the BWH application and the 358 patent are provided below for each step in the 358 patent. 3. The BWH application discloses step a) of claims 1 and 2 (obtaining measurements of specific biomarkers for diabetes) The BWH application discloses obtaining at least one biological sample (blood) and obtaining measurements of biomarkers from that sample. Ex at 25:10-14; supra p The BWH application also discloses that subjects can be evaluated for diabetes risk using a biomarker set including CRP, IL-6, INS, and 22

31 HbA1c, along with known diabetic markers, such as GLUCOSE. Ex at 5:3-8; 24:9-25. Ex at 29:9-20. The diabetes risk scores based upon those biomarkers were further adjusted for BMI, which is based upon an individual s height and weight. Ex at 27:20-24; FIG. 2; supra p. 20. As discussed in section IV, claims 1 and 2 of the 358 patent recite six alternative biomarker sets [(i)-(vi)] for calculating a risk for developing diabetes. Ex at claims 1 and 2, supra Because the six alternative sets are written as a Markush group, the BWH application only needs to disclose one of the biomarker sets to anticipate claims 1 and 2. See supra 7-8, citing In re Slayter. Nonetheless, the collective BWH biomarker set of CRP, GLUCOSE, INS, HbA1c, and BMI anticipates five of the six alternative biomarker sets, i.e., (i)-(v), as shown in the claim chart at the end of this section. Ex. 1003, infra The BWH application discloses step b) of claims 1 and 2 (calculating a risk score based on those measurements using a model based upon a population study) The biomarkers used in the BWH application were evaluated and then used to determine a risk score based upon measurements obtained in a longitudinal heath study, i.e., the Women s Health Study. Ex at 6: As described, supra, statistical methods were used to determine an overall diabetes risk score 23

32 based upon the measured biomarkers. See supra 21. In particular, the goals of the BWH application were: New diagnostic tests for assessing the risk for future development of diabetes or diabetic complications in an individual. These new tests broadly include (1) the prediction of risk of developing clinically apparent diabetes; and (2) the determination of the likelihood that certain individuals will benefit to a greater or lesser extent from the use of certain treatments designed to prevent and/or treat diabetes. Ex at 2: Furthermore, the BWH application used study data of the same nature as recited in the 358 patent, i.e., using a longitudinal study: We designed a prospective, nested case-control study involving participants in the Women's Health Study (WHS)... Case subjects were WHS participants providing blood specimens who were free of reported diabetes at enrollment and subsequently developed newly diagnosed diabetes during a four-year observation period. Ex at 24:1-2, Using statistical analysis, including conditional regression, the BWH application produced a model that correlated the measured biomarker levels to a diabetes risk score (a.k.a. an index value). Ex at 25:23-26:14. Accordingly, the BWH application identically discloses step b) of claims 1 and 2 of the 358 patent. 24

33 5. The BWH application discloses step c) of claim 1 and the preamble of claim 2 (administering a drug to an individual deemed to be at risk of diabetes) The BWH application additionally discloses step c) of claim 1 of the 358 patent because the BWH application describes treating individuals who have been identified as being at risk of developing diabetes with an agent for reducing the risk of developing diabetes. Ex at 3: The agent can be selected from the group consisting of insulin, a hypoglycemic agent, an anti-inflammatory agent, a lipid lowering agent, a calcium channel blocker, a beta-adrenergic receptor blocker, a cyclooxygenase-2 inhibitor, and an angiotensin system. Ex at 3: It also follows that the BWH application s disclosure of treatment anticipates the preamble of claim 2 of the 358 patent, i.e., In a method of treating an individual with a Diabetes-modulating drug. Accordingly, the BWH application anticipates every element of independent claims 1 and 2 of the 358 patent, and the Board should cancel those claims. 6. The BWH application identically discloses claim 3 (type II diabetes) The BWH application teaches that its biomarker panel can be used to identify patients at risk for diabetes mellitus, including both Type I and Type II. Ex at 8: Accordingly, the BWH application discloses A method 25

34 according to claim 2 wherein said diabetes is Type II, as recited in claim 3 of the 358 patent. Ex at claim The BWH application discloses claim 4 (individual has not converted to frank diabetes) The BWH application teaches that the disclosed biomarker panels can be used to identify individuals who are at risk for developing diabetes, although they do not currently show signs of diabetes. Ex at 8:3-5. Accordingly, the BWH application discloses A method according to claim 3 wherein said individual has not converted to frank diabetes, as recited in claim 4 of the 358 patent. Ex at claim The BWH application discloses claim 5 (endpoint is risk for developing a diabetic condition) The BWH application teaches that an endpoint that was used in determining a model for diabetes risk was whether the study participant had developed diabetes. Ex at 24:9-25. It is self-evident that individuals that developed diabetes were at risk for developing a diabetic condition. Accordingly, the BWH application discloses A method according to claim 4 wherein said end point is risk for developing a diabetic condition, as recited in claim 5 of the 358 patent. Ex at claim 5. 26

35 9. The BWH application discloses claim 6 (endpoint is diagnosis of a diabetic condition) The BWH application teaches that an endpoint that was used in determining a model for diabetes risk was whether the study participant had developed diabetes. Ex at 24:9-25. Accordingly, the BWH application discloses A method according to claim 4 wherein said end point is diagnosis of a diabetic condition, as recited in claim 6 of the 358 patent. Ex at claim The BWH application discloses claim 7 (endpoint is response to a Diabetes-modulating drug) The BWH application teaches that the biomarker panels of the BWH application can be used to evaluate whether certain individuals will benefit more or less from the use of treatments to prevent and/or treat diabetes. Ex at 2: Thus, the BWH application teaches that an endpoint could be a positive or negative response to a treatment to prevent and/or treat diabetes (e.g., a diabetesmodulating drug). Accordingly, the BWH application discloses A method according to claim 3 wherein said end point is response to a Diabetes-modulating drug, as recited in claim 7 of the 358 patent. Ex at claim The BWH application discloses claim 8 (individual has not converted to frank diabetes; drug is for prophylaxis) 27

36 The BWH application describes that the disclosed tests can be used to identify individuals who are not currently diabetic, but who are at risk for developing diabetes, and may benefit from a treatment to avoid developing diabetes. Ex at 3: Accordingly, the BWH application discloses A method according to claim 7 wherein said individual has not converted to frank diabetes and said drug administration is for diabetes prophylaxis, as recited in claim 8 of the 358 patent. Ex at claim The BWH application discloses claim 9 (individual has converted to frank diabetes; drug is for treatment) The BWH application discloses that the tests can be used to determine the likelihood that diabetic individuals will benefit from the use of certain treatments. Ex at 2: As discussed supra, frank diabetes is clinically-evident diabetes. See supra 14. Accordingly, the BWH application discloses A method according to claim 7 wherein said individual has converted to frank diabetes and said drug administration is for diabetes treatment., as recited in claim 9 of the 358 patent. Ex at claim Claim chart summarizing the anticipation of claims 1-9 by the BWH application For the convenience of the Board, Petitioner additionally submits a claim chart summarizing where each element of each of claim 1-9 is found in the BWH 28

37 Application. Because claims 1 and 2 are presented in a Markush format, it is only necessary for the BWH application to disclose one of biomarker sets (i)-(vi). (Nonetheless, the BWH application discloses biomarker sets (i)-(v).) When necessary, italicized parentheticals are used to reflect the selection of specific biomarkers from a larger list. Claim 1 of 358 patent The BWH Application (Ex. 1003) 1. A method comprising: Blood samples were collected from (a) obtaining measurements of study subjects at enrollment. Ex biomarkers from at least one biological at 24:5. Glucose levels were determined sample isolated from an individual, from blood serum in subjects identified wherein said biomarkers comprise: as having diabetes. Ex at 24: (i) at least three biomarkers, where three Study subjects were evaluated for CRP, of the biomarkers are selected from the GLUCOSE, HBA1C. Ex at 24:5- RDMARKER sets listed in FIG. 6A; 20. Oral glucose testing can be used in [Panel 3.3 of FIG. 6A is CRP, addition to blood panel. Ex at GLUCOSE, HBA1C] 5:3-8. or (ii) at least four biomarkers selected Study subjects were evaluated for CRP, from RDMARKERS; GLUCOSE, HBA1C, and INS. Ex [CRP, GLUCOSE, HBA1C, and INS are at 24:5-20. listed in RDMARKERS] or (iii) at least three biomarkers, where Study subjects were evaluated for CRP two biomarkers are selected from and HBA1C. Ex at 24:5-20. BMI ADIPOQ; CRP; GLUCOSE; GPT; values were used to establish 29

38 HBA1C; HSPA1B; IGFBP1; IGFBP2; INS, LEP; and TRIG; and one biomarker is selected from the ALLDBRISKS, CPs, and TLRFs of Table 1, Table 2, and Table 3; [BMI is a CP listed in Table 2] or (iv) at least three biomarkers, where at least one biomarker is selected from GLUCOSE and HBA1C; at least one biomarker is selected from ADIPOQ, CRP, GPT, HSPA1B, IGFBP1, IGFBP2, INS, LEP, and TRIG; and at least one biomarker is selected from the ALLDBRISKS, CPs, and TLRFs of Table 1, Table 2, and Table 3; [BMI is a CP listed in Table 2] or (v) at least three biomarkers, where at least two biomarkers are selected from the biomarkers within the group consisting of Core Biomarkers I and Core Biomarkers II and at least a third biomarker is selected from any of the biomarkers listed in Table 4; [CRP and INS are both Core Biomarkers I and BMI is a biomarker listed in Table 4] distributions of biomarker values. Ex at 25: Study subjects were evaluated for HBA1C and CRP. Ex at 24:5-20. BMI values were used to establish distributions of biomarker values. Ex at 25: Study subjects were evaluated for CRP and INS. Ex at 24:5-20. BMI values were used to establish distributions of biomarker values. Ex at 25:

39 or (vi) ADIPOQ, GLUCOSE, CRP and one biomarker selected from the group consisting of HBA1C, IGFBP1, IGFBP2, Insulin, LEP and TRIG; (b) calculating an index value from the output of a model, wherein the inputs to said model comprise said measurements, and further wherein said model was developed by fitting data from a longitudinal study of a selected population of individuals and said fitted data comprises levels of said biomarkers and an end point in said selected population of individuals, wherein said end point is selected from risk for developing a diabetic condition, the diagnosis of a diabetic condition, response to a Diabetes-modulating drugs, a surrogate diabetes endpoint, glucose class, a complication of a diabetic condition; and (c) administering to said individual a Diabetes-modulating drug. An index value (a.k.a. diabetes risk score) was developed by using statistical analysis on biomarker measurements obtained from two study cohorts identified from the Women s Health Study, a longitudinal study of cardiovascular health. Ex at 6:26-28; 24:1-25; 25:23-26:14. Both cohorts were diabetes-free at the start of the Women s Health Study, however, the members of one cohort were diagnosed with diabetes during the course of the study. Ex at 24:9-25:8. Individuals at risk may be administered an agent to reduce the risk of diabetes. Ex at 3: The BWH application provides a list of agents similar to the list of diabetes-modulating 31

40 drugs in the 358 patent. Ex at 3: Claim 2 of 358 patent The BWH Application (Ex. 1003) 2. In a method of treating an individual Individuals at risk may be administered with a Diabetes-modulating drug, the an agent to reduce the risk of diabetes. improvement comprising: Ex at 3: The BWH application provides a list of agents similar to the list of diabetes-modulating drugs in the 358 patent. Ex at 3: (a) obtaining measurements of Blood samples were collected from biomarkers from at least one biological study subjects at enrollment. Ex sample isolated from siad [sic] at 24:5. Glucose levels were determined individual, wherein said biomarkers from blood serum in subjects identified comprise: as having diabetes. Ex at 24: (i) at least three biomarkers, where three Study subjects were evaluated for CRP, of the biomarkers are selected from the GLUCOSE, HBA1C. Ex at 24:5- RDMARKER sets listed in FIG. 6A; 20. Oral glucose testing can be used in [Panel 3.3 of FIG. 6A is CRP, addition to blood panel. Ex at GLUCOSE, HBA1C] 5:3-8. or (ii) at least four biomarkers selected Study subjects were evaluated for CRP, from RDMARKERS; GLUCOSE, HBA1C, and INS. Ex [CRP, GLUCOSE, HBA1C, and INS are at 24:5-20. listed in RDMARKERS] or (iii) at least three biomarkers, where Study subjects were evaluated for CRP 32

41 two biomarkers are selected from ADIPOQ; CRP; GLUCOSE; GPT; HBA1C; HSPA1B; IGFBP1; IGFBP2; INS, LEP; and TRIG; and one biomarker is selected from the ALLDBRISKS, CPs, and TLRFs of Table 1, Table 2, and Table 3; [BMI is a CP listed in Table 2] or (iv) at least three biomarkers, where at least one biomarker is selected from GLUCOSE and HBA1C; at least one biomarker is selected from ADIPOQ, CRP, GPT, HSPA1B, IGFBP1, IGFBP2, INS, LEP, and TRIG; and at least one biomarker is selected from the ALLDBRISKS, CPs, and TLRFs of Table 1, Table 2, and Table 3; [BMI is a CP listed in Table 2] or (v) at least three biomarkers, where at least two biomarkers are selected from the biomarkers within the group consisting of Core Biomarkers I and Core Biomarkers II and at least a third biomarker is selected from any of the biomarkers listed in Table 4; [CRP and INS are both Core and HBA1C. Ex at 24:5-20. BMI values were used to establish distributions of biomarker values. Ex at 25: Study subjects were evaluated for HBA1C and CRP. Ex at 24:5-20. BMI values were used to establish distributions of biomarker values. Ex at 25: Study subjects were evaluated for CRP and INS. Ex at 24:5-20. BMI values were used to establish distributions of biomarker values. Ex at 25: