Kyle Bass, Celgene IPR Petition, Patent '720

Paper No. ______ Filed: April 23, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE ____________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD ___________________

COALITION FOR AFFORDABLE DRUGS VI LLC

PETITIONER

V.

CELGENE

PATENT OWNER

___________________

CASE NO.: UNASSIGNED PATENT NO. 6,315,720

FILED: OCTOBER 23, 2000 ISSUED: NOVEMBER 13, 2001

INVENTORS: BRUCE A. WILLIAMS AND JOSEPH K. KAMINSKI

TITLE: METHODS FOR DELIVERING A DRUG TO A PATIENT WHILE AVOIDING THE OCCURRENCE OF AN ADVERSE SIDE EFFECT KNOWN

OR SUSPECTED OF BEING CAUSED BY THE DRUG ___________________

PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 6,315,720

Patent No. 6,315,720

TABLE OF CONTENTS

I. INTRODUCTION ..................................................................................................... 1

II. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ........................................ 1

III. MANDATORY NOTICES (37 C.F.R. § 42.8) ........................................................ 1

A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................................................... 1

B. Related Judicial and Administrative Matters (37 C.F.R. § 42.8(b)(2)) ................. 2

C. Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)) and Service Information (37 C.F.R. § 42.8(b)(4)) ....................................................................... 3

IV. PAYMENT OF FEES (37 C.F.R. § 42.15(a) and § 42.103) ................................... 3

V. IDENTIFICATION OF CHALLENGE ................................................................ 3

A. Overview of U.S. Patent No. 6,315,720 ................................................................. 3

The ’720 Patent Specification ............................................................................. 4 1.

The ’720 Claims .................................................................................................... 5 2.

The ’720 Prosecution History ............................................................................. 6 3.

B. Claim Construction of Challenged Claims ............................................................. 9

“Consulted” ......................................................................................................... 10 1.

“Teratogenic effect” ........................................................................................... 10 2.

“Adverse side effect” ......................................................................................... 11 3.

C. Statement of Precise Relief Requested for Each Claim Challenged ................. 11

Claims for Which Review is Requested ........................................................... 11 1.

Statutory Grounds of Challenge ....................................................................... 11 2.

D. Overview of the State of the Art ........................................................................... 12

VI. DETAILED EXPLANATION OF THE CHALLENGE ................................. 14

A. Ground 1: THALOMID™ (thalidomide) Capsules Revised Package Insert anticipates Claims 1–32 of U.S. Patent No. 6,315,720 under 35 U.S.C. § 102(b). ...................................................................... 14

Thalomid PI anticipates Claim 1. ........................................................................ 17 1.

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Thalomid PI anticipates Claims 2–6. .................................................................. 22 2.

Thalomid PI anticipates Claims 7–10. ................................................................ 25 3.

Thalomid PI anticipates Claims 11–14 and 20–25. ........................................... 28 4.

Thalomid PI anticipates Claim 15. ...................................................................... 30 5.

Thalomid PI anticipates Claims 16–17. .............................................................. 31 6.

Thalomid PI anticipates Claims 18–19 and 26–27. ........................................... 33 7.

Thalomid PI anticipates Claims 28–32. .............................................................. 34 8.

Claim chart for Ground 1 showing exemplary citations in 9.Thalomid PI. ......................................................................................................... 36

B. Ground 2: Claims 1–32 of U.S. Patent No. 6,315,720 are obvious under 35 U.S.C. § 103(a) over Thalomid PI in view of Cunningham, and in further view of the knowledge of one of ordinary skill in the art. ........ 51

Claims 1(e) and 28(e) are obvious over Thalomid PI in view 1.of Cunningham. .................................................................................................... 52

Claims 5 and 6 are obvious over Thalomid PI in view of the 2.knowledge of one of ordinary skill in the art. ................................................ 54

Claims 9 and 10 are obvious over Thalomid PI in view of the 3.knowledge of one of ordinary skill in the art. ................................................ 57

Claim 17 is obvious over Thalomid PI in view of the knowledge 4.of one of ordinary skill in the art. .................................................................... 59

Claim Chart for Ground 2 showing exemplary citations in 5.Cunningham. ......................................................................................................... 59

VII. CONCLUSION ......................................................................................................... 60

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TABLE OF AUTHORITIES Cases Abbott Labs v. Andrx Pharms., Inc.,

452 F.3d 1331 (Fed. Cir. 2006) ....................................................................................... 54 Atlas Powder Co. v. IRECO, Inc.,

190 F.3d 1342 (Fed. Cir. 1999) ....................................................................................... 16 Bayer Schering Pharma AG v. Barr Labs., Inc.,

575 F.3d 1341 (Fed. Cir. 2009) ....................................................................................... 56 Continental Can Co. USA, Inc. v. Monsanto Co.,

948 F.2d 1264 (Fed. Cir. 1991) ................................................................................. 17, 21 Dow Chem. Co. v. Sumitomo Chem. Co.,

257 F.3d 1364 (Fed. Cir. 2001) ....................................................................................... 17 Dystar Textilfarben GmbH v. C.H. Patrick Co.,

464 F.3d 1356 (Fed. Cir. 2006) ....................................................................................... 54 In re Am. Acad. of Sci. Tech. Ctr.,

367 F.3d 1359 (Fed. Cir. 2004) ....................................................................................... 10 In re Baxter Travenol Labs,

952 F.2d 388 (Fed. Cir. 1991) ......................................................................................... 17 In re Cruciferous Sprout Litigation,

301 F.3d 1343 (Fed. Cir. 2002) ....................................................................................... 27 In re Cuozzo Speed Techs., LLC,

778 F.3d 1271 (Fed. Cir. 2015) ......................................................................................... 9 In re Glatt Air Techniques, Inc.,

630 F.3d 1026 (Fed. Cir. 2011) ....................................................................................... 18 In re Graves,

69 F.3d 1147 (Fed. Cir. 1995) ............................................................................. 21, 25, 27 In re LeGrice,

301 F.2d 929 (CCPA 1962) ....................................................................................... 21, 27 In re Venner,

262 F.2d 91 (C.C.P.A. 1958) ........................................................................................... 59 KSR Int'l Co. v. Teleflex Inc.,

550 U.S. 398 (2007) .......................................................................................................... 53 Pacing Techs., LLC v. Garmin Int’l, Inc.,

778 F.3d 1021 (Fed. Cir. 2015) ....................................................................................... 10

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Pentec, Inc. v. Graphic Controls Corp., 776 F.2d 309 (Fed. Cir. 1985) ......................................................................................... 18

Perfect Web Techs., Inc. v. InfoUSA, Inc., 587 F.3d 1324 (Fed. Cir. 2009) ....................................................................................... 56

Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373 (Fed. Cir. 2003) .............................................................. 21, 24, 31, 27, 33

SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331 (Fed. Cir. 2005) ....................................................................................... 33

Titanium Metals Corp. v. Banner, 778 F.2d 775 (Fed. Cir. 1985) ......................................................................................... 16

Tyco Healthcare Grp. LP v. Ethicon Endo-Surgery, Inc., 774 F.3d 968 (Fed. Cir. 2014) ......................................................................................... 58

Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352 (Fed. Cir. 2011) ....................................................................................... 58

Verdegaal Bros. v. Union Oil Co. of California, 814 F.2d 628 (Fed. Cir. 1987) ......................................................................................... 16

Rules 37 C.F.R. § 42.103 .................................................................................................................. 3 37 C.F.R. § 42.15(a) ................................................................................................................ 3 37 C.F.R. § 42.8(b)(1) ............................................................................................................. 1

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TABLE OF EXHIBITS

Exhibit No. Description Exhibit 1001 U.S. Patent No. 6,315,720 to Bruce A. Williams and Joseph K.

Kaminski, filed on Oct. 23, 2003, and issued on Nov. 13, 2001 (the “’720 Patent”)

Exhibit 1002 U.S. Patent No. 6,315,720 Prosecution History (“’720 prosecution history”)

Exhibit 1003 U.S. Patent No. 6,045,501 to Marc Elsayed and Bruce Williams, filed on Aug. 28, 1998, and issued on Apr. 4, 2000 (“Elsayed”)

Exhibit 1004 U.S. Patent No. 6,063,026 to Mark A. Schauss and Patricia Kane, filed on Mar. 22, 1996, and issued on May 16, 2000 (“Schauss”)

Exhibit 1005 U.S. Patent No. 6,202,923 to Joseph H. Boyer et al., filed on Aug. 23, 1999, and issued on Mar. 20, 2001 (“Boyer”)

Exhibit 1006 “THALOMID™ (thalidomide) Capsules Revised Package Insert” (Jul. 15, 1998) (“Thalomid PI”)

Exhibit 1007 “Guideline for the clinical use and dispensing of thalidomide,” R.J. Powell and J.M.M Gardner-Medwin, Postgrad Med. J. (1994) 79, 901–904 (“Powell”)

Exhibit 1008 “Pharmacists’ role in clozapine therapy at a Veterans Affairs medical center,” Benjamin R. Dishman et al., Am. J. Hosp. Pharm. (Apr. 1, 1994) 51, 899–901 (“Dishman”)

Exhibit 1009 U.S. Patent No. 5,832,449 to David W. Cunningham, filed on Nov. 13, 1995, and issued on Nov. 3, 1998 (“Cunningham”)

Exhibit 1010 U.S. Patent No. 6,055,507 to David W. Cunningham, filed on Aug. 20, 1998, and issued on Apr. 25, 2000 (“Cunningham Divisional”)

Exhibit 1011 “A Pregnancy-Prevention Program in Women of Childbearing Age Receiving Isotretinoin,” Allen A. Mitchell et al., New Eng. J. Med. (Jul. 13, 1995) 333:2, 101–06 (“Mitchell”)

Exhibit 1012 “S.T.E.P.S.TM: A Comprehensive Program for Controlling and Monitoring Access to Thalidomide,” Jerome B. Zeldis et al., Clinical Therapeutics (1999) 21:2, 319–30 (“Zeldis”)

Exhibit 1013 Transcript of the FDA’s “Forty-Seventh Meeting of the Dermatologic and Opthalmic Drugs Advisory Committee,” Sept. 4, 1997 (“FDA Meeting Part 1”)

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Exhibit No. Description Exhibit 1014 Transcript of the FDA’s “Forty-Seventh Meeting of the

Dermatologic and Opthalmic Drugs Advisory Committee,” Sept. 5, 1997 (“FDA Meeting Part 2”)

Exhibit 1015 “CDC Meeting: 03/26/1997 Minutes and Agenda Regarding Thalidomide” (“CDC Meeting”)

Exhibit 1016 “Assessing the Effectiveness of a Computerized Pharmacy System,” Reed M. Gardner et al., Decision Support Systems in Critical Care, 1994, M.M. Schabot et al., eds. (“Gardner”)

Exhibit 1017 “Review of computer applications in institutional pharmacy—1975–1981,” Ken W. Burleson, Am. J. Hosp. Pharm. (1982) 39:53–70 (“Burleson”)

Exhibit 1018 “Challenges of thalidomide distribution in a hospital setting,” Daniel P. Keravich and Charles E. Daniels, Am. J. Health-Syst. Pharm. (Sept. 1, 1999) 56:1721–75 (“Keravich”)

Exhibit 1019 “The Assessment of Refill Compliance Using Pharmacy Records: Methods, Validity, and Applications,” John F. Steiner and Allan V. Prochazka, J. Clin. Epidemiol. (1997) 50:1, 105–16 (“Steiner”)

Exhibit 1020 “Therapeutic Antibiotic Monitoring: Surveillance Using a Computerized Expert System,” Stanley L. Pestotnik et al., Am. J. Med. (Jan. 1990) 88:43–48 (“Pestotnik”)

Exhibit 1021 Declaration of Jeffrey Fudin, R.Ph., B.S., Pharm.D., DAAPM, FCCP, FASHP (“Fudin Decl.”)

Exhibit 1022 Curriculum Vitae for Jeffrey Fudin, R.Ph., B.S., Pharm.D., DAAPM, FCCP, FASHP (“Fudin CV”)

Exhibit 1023 “Joint Claim Construction and Prehearing Statement,” Celgene Corp. v. Natco Pharma Ltd., NJD-2-10-cv-05197, Jul. 18, 2011 (“Celgene Claim Construction Brief”)

Exhibit 1024 “Interactive Voice Response Systems in Clinical Research and Treatment,” James C. Mundt, Psychiatric Services (May 1997) 48:5, 611–12, 623 (“Mundt”)

Exhibit 1025 “Center for Drug Evaluation and Research Approval Package for: Application Number NDA 20-785 Approval Letter(s),” Sept. 19, 1997, and Jul. 16, 1998 (“FDA Thalomid Approval Letters”)

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I. INTRODUCTION

Petitioner Coalition For Affordable Drugs VI LLC (“CFAD”), requests an Inter

Partes Review (“IPR”) of Claims 1–32 (collectively, the “Challenged Claims”) of U.S.

Patent No. 6,315,720 (the “’720 Patent”) (Ex. 1001) in accordance with 35 U.S.C.

§§ 311–19 and 37 C.F.R. §§ 42.100 et seq.

II. GROUNDS FOR STANDING (37 C.F.R. § 42.104(A))

Pursuant to 37 C.F.R. § 42.104(a), Petitioner certifies that the ’720 patent is

available for IPR and that Petitioner is not barred or estopped from requesting IPR

challenging the claims of the ’720 patent on the grounds identified in this Petition.

III. MANDATORY NOTICES (37 C.F.R. § 42.8)

A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))

Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Coalition For

Affordable Drugs VI LLC (“CFAD VI”), Hayman Credes Master Fund, L.P.

(“Credes”), Hayman Orange Fund SPC – Portfolio A (“HOF”), Hayman Capital

Master Fund, L.P. (“HCMF”), Hayman Capital Management, L.P. (“HCM”), Hayman

Offshore Management, Inc. (“HOM”), Hayman Investments, L.L.C. (“HI”), nXn

Partners, LLC (“nXnP”), IP Navigation Group, LLC (“IPNav”), J. Kyle Bass, and

Erich Spangenberg are the real parties in interest (collectively, “RPI”). The RPI

hereby certify the following information: CFAD VI is a wholly owned subsidiary of

Credes. Credes is a limited partnership. HOF is a segregated portfolio company.

HCMF is a limited partnership. HCM is the general partner and investment manager

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of Credes and HCMF. HCM is the investment manager of HOF. HOM is the

administrative general partner of Credes and HCMF. HI is the general partner of

HCM. J. Kyle Bass is the sole member of HI and sole shareholder of HOM. CFAD

VI, Credes, HOF and HCMF act, directly or indirectly, through HCM as the general

partner and/or investment manager of Credes, HOF and HCMF. nXnP is a paid

consultant to HCM. Erich Spangenberg is the 98.5% member of nXnP. IPNav is a

paid consultant to nXnP. Erich Spangenberg is the 98.5% member of IPNav. Other

than HCM and J. Kyle Bass in his capacity as the Chief Investment Officer of HCM

and nXnP and Erich Spangenberg in his capacity as the Manager/CEO of nXnP, no

other person (including any investor, limited partner, or member or any other person

in any of CFAD VI, Credes, HOF, HCMF, HCM, HOM, HI, nXnP or IPNav) has

authority to direct or control (i) the timing of, filing of, content of, or any decisions or

other activities relating to this Petition or (ii) any timing, future filings, content of, or

any decisions or other activities relating to the future proceedings related to this

Petition. All of the costs associated with this Petition will be borne by HCM, CFAD

VI, Credes, HOF and/or HCMF.

B. Related Judicial and Administrative Matters (37 C.F.R. § 42.8(b)(2))

Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner states that the ’720 Patent has

been the subject of the following lawsuits: Celgene Corp. et al. v. Lannett Holdings, Inc. et

al., NJD-2-15-00697 (filed Jan. 30, 2015); Celgene Corp. v. Natco Pharma Ltd., NJD-2-10-

cv-05197 (filed Oct. 8, 2010); Celgene Corp. et al. v. Barr Laboratories, Inc. et al., NJD-2-

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08-cv-03357 (filed July 3, 2008); Celgene Corp. et al. v. Barr Laboratories, Inc. et al., NJD-2-

07-cv-05485 (filed Nov. 14, 2007); Celgene Corp. et al. v. Barr Laboratories, Inc. et al., NJD-

2-07-cv-04050 (filed Aug. 23, 2007); Celgene Corp. et al. v. Barr Laboratories, Inc. et al.,

NJD-2-07-cv-00286 (filed Jan. 18, 2007).

C. Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)) and Service Information (37 C.F.R. § 42.8(b)(4))

Lead counsel is Sarah E. Spires, Reg. No. 61,501,

[email protected]. Back-up counsel are Ki O, Reg. No. 68,952,

[email protected]; Dr. Parvathi Kota, Reg. No. 65,122,

[email protected]; and Paul J. Skiermont (pro hac vice requested),

[email protected]—all of Skiermont Puckett LLP, 2200 Ross

Ave. Ste. 4800W, Dallas, Texas 75201, P: 214-978-6600/F: 214-978-6601. Petitioner

consents to electronic service.

IV. PAYMENT OF FEES (37 C.F.R. § 42.15(A) AND § 42.103)

The required fees are submitted herewith in accordance with 37 C.F.R.

§§ 42.103(a) and 42.15(a). If any additional fees are due during this proceeding, the

Office is authorized to charge such fees to Deposit Account No. 506293. Any

overpayment or refund of fees may also be deposited in this Deposit Account.

V. IDENTIFICATION OF CHALLENGE

A. Overview of U.S. Patent No. 6,315,720

The ’720 Patent is titled “Methods for Delivering a Drug To A Patient While

Avoiding The Occurrence Of An Adverse Side Effect Known Or Suspected Of Being 3


Caused By The Drug.” (Ex. 1001 at Front Cover.) The underlying application, U.S.

Patent Application Serial No. 09/694,217, was filed on October 23, 2000. The ’720

Patent issued to Bruce Williams and Joseph K. Kaminski on November 13, 2001. (Id.)

The ’720 Patent Specification 1.

The ’720 Patent claims methods for delivering a drug to a patient, while

avoiding the occurrence of adverse side effects. (Id. at Abstract.) The ’720 Patent

generally describes methods for “the distribution to patients of drugs, particularly

teratogenic drugs, in ways wherein such distribution can be carefully monitored and

controlled.” (Id. at 1:13–16.) A teratogenic drug can cause severe birth defects when

administered to a pregnant woman. (Id. at 1:27–29.) The ’720 specification

acknowledges that prior “[m]ethods for monitoring and educating patients to whom a

drug is distributed have been developed in connection with” a known teratogenic

drug (isotretinoin), including a “pregnancy prevention program.” (Id. at 2:13–20.)

The invention of the ’720 Patent was allegedly conceived in the context of the

FDA approval of thalidomide—a teratogenic drug effective in treating a variety of

diseases—when the inventors were seeking methods “to control the distribution of

[thalidomide] so as to preclude administration to foetuses.” (Id. at 1:46–64.)

The ’720 Patent’s invention can be summarized as: (1) filling prescriptions only

after consulting a computer readable storage medium to confirm that the prescribers,

pharmacies, and patients are registered in a computer database; (2) assigning patients

to risk groups based on the risk that the drug will cause adverse side effects and

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entering the risk group assignment in the storage medium; (3) determining the

acceptability of the likely adverse effect; and (4) “generating a prescription approval

code to … said pharmacy before said prescription is filled.” (Id. at 2:49–3:4.) The ’720

Patent specification also teaches that “[t]he invention is not limited to the distribution

of teratogenic drugs; other potentially hazardous drugs may also be distributed in

accordance with embodiments of this invention … in such a fashion that persons for

whom such drugs are contraindicated will not receive them.” (Id. at 3:21–26.)

The patent also discloses that when a patient is registered in the computer

readable storage medium, information probative of the risk of a drug’s side effects is

also collected from the patient. (Id. at 6:30–33.) This information can then be

compared with a defined set of risk parameters for the drug, allowing for assignment

of the patient to a particular risk group. (Id. at 6:33–36.) If the risk of adverse side

effects is deemed acceptable, the patient may receive the drug from a registered

pharmacy, subject to conditions such as a negative pregnancy test, but may not receive

refills without a renewal prescription from the prescriber. (Id. at 11:62–12:8.)

The ’720 Claims 2.

The ’720 Patent has two independent claims and 30 dependent claims. Claim 1

is representative and is reproduced below.

In a method for delivering a drug to a patient in need of the drug, while

avoiding the occurrence of an adverse side effect known or suspected of

being caused by said drug, wherein said method is of the type in which

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prescriptions for said drug are filled only after a computer readable

storage medium has been consulted to assure that the prescriber is

registered in said medium and qualified to prescribe said drug, that the

pharmacy is registered in said medium and qualified to fill the

prescription for said drug, and the patient is registered in said medium

and approved to receive said drug, the improvement comprising:

a. defining a plurality of patient risk groups based upon a

predefined set of risk parameters for said drug;

b. defining a set of information to be obtained from said patient,

which information is probative of the risk that said adverse side effect is

likely to occur if said drug is taken by said patient;

c. in response to said information set, assigning said patient to at

least one of said risk groups and entering said risk group assignment in

said medium;

d. based upon said information and said risk group assignment,

determining whether the risk that said adverse side effect is likely to

occur is acceptable; and

e. upon a determination that said risk is acceptable, generating a

prescription approval code to be retrieved by said pharmacy before said

prescription is filled.

(Ex. 1001 at 18:17–42.) All other claim limitations are listed within Ground 1 below.

The ’720 Prosecution History 3.

During prosecution of U.S. Patent Application No. 09/694,217 (filed October

23, 2000), which led to the ’720 Patent, the Examiner initially rejected Claims 1–27 as

obvious under 35 U.S.C. § 103(a) over U.S. Patent No. 6,045,501 (Ex. 1003, “Elsayed”)

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in view of U.S. Patent No. 6,063,026 (Ex. 1004, “Schauss”). (See Ex. 1002 at 57–58.1)

At this time, Claims 1–32 were pending. (Id. at 56.) Claim 1, the only independent

claim, recited “a method for delivering a drug to a patient in need of the drug while

avoiding the occurrence of an adverse side effect known or suspected of being caused

by said drug.” (Id. at 44.)

The Examiner rejected Claims 1–27, stating that Elsayed suggested the “use of

the information to evaluate risk levels,” while Schauss taught “a medical diagnostic

analysis system that evaluates patient data obtained from medical testing or patient

questioning for drugs contraindications.” (Id. at 58.) The Examiner concluded that “it

would have been obvious to one of ordinary skill in the art at the time of the invention

to implement the screening for drug contraindications suggested in Elsayed et al. with

the method of Schauss et al., since Schauss et al. teach the particular steps for

performing the analysis.” (Id. at 58.) Regarding Claim 6, the Examiner stated that

although Elsayed “does not specifically teach that data received by facsimile

transmission is entered by an OCR software, it is inherent that this data must be

entered into database.” (Id. at 58.) The Examiner objected to Claims 28–32 “as being

dependent upon a rejected base claim, but would be allowable if rewritten in

independent form.” (Id. at 59.)

1 Except for the prosecution history, exhibit cites herein are directed to the internal

page numbers of the exhibit, rather than to the Exhibit’s Bates numbers.

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In response, applicants amended Claim 1 by adding, among other limitations,

“upon a determination that said risk is acceptable, generating a prescription approval

code to be retrieved by said pharmacy before said prescription is filled.” (Id. at 87.)

Based on this amendment, applicants argued that “Elsayed, although teaching a

method which contains many of the steps of the present invention, contains no

disclosure of the generation of a prescription approval code as recited in amended

Claim 1.” (Id. at 85.) Applicants further argued that “[a]lthough Schauss may describe

a medical diagnostic analysis system that evaluates patient data obtained from

questioning a patient or medical testing, Schauss contains no disclosure remotely

related to the generation of a prescription approval code, this being the subject of

Applicants’ claims.” (Id. at 86.)

In response, the Examiner rejected the claims as obvious over Elsayed in view of

Schauss and Boyer, U.S. Patent No. 6,202,923 (Ex. 1005, “Boyer”), which “includes a step

for generating a prescription number or code associated with said prescription by a

computer workstation.” (Id. at 91–92.)

In response, applicants argued:

As amended on March 23, 2001, Claim 1 further requires an assessment,

based upon the risk group assignment and the information collected

from the patient, as to whether the risk of the side effect occurring is

acceptable. Upon a determination that the risk is acceptable, and only upon

such a determination, a prescription approval code is generated, which must

be retrieved by the pharmacy before the prescription may be filled. Thus,

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the prescription approval code is not merely a number that is associated

with the prescription, but instead represents the fact that a determination

has been made that the risk of the side effect occurring is acceptable, and

that approval—an affirmative decision—has been made for the

prescription to be filled. Boyer does not disclose or suggest such an

approval code.

(Id. at 106–07.) Applicants further argued that in Boyer, the prescription number “is

simply an identifier for the prescription, and is not an approval code, as recited in

Applicants’ claims,” and that Boyer provides “no indication that a prescription approval

code, as described and claimed in the instant application, must be generated and

retrieved by the pharmacist before the prescription may be filled.” (Id. at 107.)

The applicants amended Claim 28 to be an independent claim, and then argued

that because “[a]ny proper combination of the disclosure of Boyer with that of

Elsayed and Schauss does not teach or suggest the invention defined by Applicants’

claims,” the Examiner should withdraw the 103 rejection. (Id. at 106–07.)

After this response, all of the ’720 Patent claims were allowed. (Id. at 111.)

B. Claim Construction of Challenged Claims

A claim subject to IPR receives the “broadest reasonable construction in light

of the specification of the patent in which it appears.” 37 C.F.R. § 42.100(b); see In re

Cuozzo Speed Techs., LLC, 778 F.3d 1271, 1279 (Fed. Cir. 2015). In applying such a

standard, the broadest reasonable construction of claim language is not one that

permits any reading, but instead is one that must be made “in light of the specification

9


as it would be interpreted by one of ordinary skill in the art.” In re Am. Acad. of Sci.

Tech. Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004) (citation omitted).

Unless otherwise noted, Petitioner accepts, for purposes of IPR only, that the

claim terms of the ’720 Patent are presumed to take on the ordinary and customary

meaning that they would have to one of ordinary skill in the art.2

“Consulted” 1.

“Consulted” means “accessed and considered.” (Ex. 1023 at 3; Ex. 1021 ¶ 39.)

“Teratogenic effect” 2.

“Teratogenic effect” means “any effect that disturbs the normal growth and

development of an embryo or fetus.” (Ex. 1023 at 3; Ex. 1021 ¶ 40.)

2 Petitioner notes that, in some instances, the patentee has defined claim terms apart

from their plain meaning. See Pacing Techs., LLC v. Garmin Int’l, Inc., 778 F.3d 1021,

1024 (Fed. Cir. 2015). These terms include “drug,” “computer readable storage

medium,” “patient risk groups,” “risk parameters,” “risk group assignment,” “likely to

occur,” “prescription approval code,” “counseled,” “risk avoidance measures,” and

“informed consent.” (Ex. 1001 at 3:35–38, 3:45–48, 4:54–56, 5:29–33, 6:30–7:19,

8:45–57, 9:8–26, 10:41–46, 13:44–64.)

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“Adverse side effect” 3.

“Adverse side effect” means “any unfavorable abnormality, defect, mutation,

lesion, degeneration or injury which may be caused by taking the drug.” (Ex. 1023 at

6; Ex. 1021 ¶ 41; see Ex. 1001 at 3:38–44.)

C. Statement of Precise Relief Requested for Each Claim Challenged

Claims for Which Review is Requested 1.

Petitioner requests IPR under 35 U.S.C. § 311 of Claims 1–32 of the ’720

Patent, and cancellation of these 32 claims as unpatentable.

Statutory Grounds of Challenge 2.

Petitioner requests IPR of Claims 1–32 of the ’720 Patent in view of the

following references, each of which is prior art to the ’720 Patent under 35 U.S.C.

§§ 102(a) and (b) or 103. The Examiner did not reference any of the prior art listed in

the following chart in any Office Action. (See generally, Ex. 1002.) Claims 1–32 are

unpatentable under 35 U.S.C. §§ 102(b) and 103(a):

Ground Proposed Rejections for the ’720 Patent Exhibit Number(s) 1 Claims 1–32 are anticipated under 35 U.S.C. §

102(b) by the Thalidomide Package Insert (Ex. 1006,

“Thalomid PI”).

1006

2 Claims 1–32 are obvious under 35 U.S.C. § 103(a) in

view of Thalomid PI (Ex. 1006) and Cunningham (Ex.

1009).

1006 and 1009

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D. Overview of the State of the Art

By October of 2000, it was well recognized in the art that teratogenic drugs—

which can cause birth defects—needed to be regulated. (See, e.g., Ex. 1007 at 901–04;

Ex. 1011 at 101–05.) The central regulatory goal was to avoid pregnancy in patients

treated with the drug. (See, e.g., Ex. 1011 at 101.) One notable case of a drug marketed

through methods to prevent its use in pregnant patients is isotretinoin, marketed

under the trade name Accutane®. (See id. at 101.) Rather than remove this drug from

the market once its teratogenicity was realized, isotretinoin became part of a

manufacturer-sponsored Pregnancy Prevention Program (“PPP”). (Id. at 101.) The

program, among other features, included the distribution to physicians of a kit that

included informed consent documents and patient counseling information. (Id. at

101.) In particular, patients were warned against the teratogenic risk of isotretinoin

and the need to prevent pregnancy while taking the drug. (Id. at 105.) Patients were

also advised as to the proper methods of birth control available. (See id. at 103.)

Thalidomide is a drug that originated in Germany in 1957. (Ex. 1001 at 1:40–

41.) Doctors initially prescribed the drug as a sedative, but quickly noticed its

effectiveness in treating a form of leprosy, erythema nodosum leprosum (ENL), as

well. (Ex. 1012 at 320–21.) However, shortly after thalidomide came on the market,

doctors realized that the drug caused severe birth defects in infants whose mothers

took the drug while pregnant. (Ex. 1012 at 320.) As a result, thalidomide was generally

12


taken off of most markets by 1962. (Ex. 1001 at 1:44–45.) Due to thalidomide’s

therapeutic effects, the drug was reintroduced in the United States in the 1990s with

the understanding that it could be marketed only with strict controls, and gained FDA

approval for treatment of ENL in 1998. (See Ex. 1007 at 901; Ex. 1012 at 320.)

Doctors and pharmacists interested in bringing thalidomide to the market with

restrictions to protect from its teratogenic effects considered the Accutane PPP, with

its focus on counseling, as a starting point. (Ex. 1013 at 110–11; see Ex. 1015 at 1.)

They also considered modeling a thalidomide program on experiences with other

hazardous drugs, including clozapine (trade name Clozaril®). (Ex. 1013 at 111–12.)

As early as 1997, medical professionals observed that the prescription control

methods for clozapine, an anti-depressant with potential adverse effects indicated by

white blood cell counts (“WBCs”), could be copied for thalidomide. (Ex. 1013 at

112.) In particular, these prescription control methods included keeping records of

patients taking the drug, as well as physicians and pharmacists pre-approved to

prescribe and dispense the drug. (Ex. 1008 at 899–900; see Ex. 1013 at 115–19;

Ex. 1015 at 9, 24.) The clozapine patients were also required to submit to weekly

WBC testing and could only have a prescription for clozapine filled if the test results

fell within a pre-designated range. (Ex. 1008 at 899; see Ex. 1013 at 112; Ex. 1015 at 8.)

“It was also well known in the art prior to 2000 to keep prescription records in

a computerized system.” (See, e.g., Ex. 1016 at 174; Ex. 1017 at 56, 60–63, 68; Ex. 1021

¶ 56.) Such records would include information such as the patient’s sex, allergies,

13


height, weight, and other health-related measures. (See Ex. 1017 at 59; Ex. 1021 ¶ 56.)

Physicians and pharmacists had used computerized systems to track their patients

since at least 1975. (See, e.g., Ex. 1017 at 53; Ex. 1016 at 174, 182–83.) Practitioners

then used this data to determine (1) whether to prescribe a drug to a patient, and (2)

the duration of the prescription. (See Ex. 1017 at 53, 63–67.)

Thus, in the case of thalidomide or any other teratogenic drug, those of

ordinary skill in the art would have been—and indeed were—motivated to combine

the method for avoiding pregnancy with a computerized tracking system that only

permits filling prescriptions for the drug when certain conditions (e.g., non-pregnancy)

are met. (See Ex.1013 at 111–12; Ex. 1021, ¶ 59.) An example of this combination,

discussed in detail below, is the System for Thalidomide Education and Prescribing

Safety (S.T.E.P.S.)—“a comprehensive program to control prescribing, dispensing,

and use of” thalidomide to ensure that fetal exposure to thalidomide does not occur.

(Ex. 1006 at 1, 2, 3; Ex. 1012 at Abstract; see Ex. 1021 ¶ 59.)

VI. DETAILED EXPLANATION OF THE CHALLENGE

A. Ground 1: THALOMID™ (thalidomide) Capsules Revised Package Insert anticipates Claims 1–32 of U.S. Patent No. 6,315,720 under 35 U.S.C. § 102(b).

The ’720 Patent’s method for delivering a drug to a patient while avoiding the

occurrence of an adverse side effect was known before October 23, 2000—the earliest

possible priority date for the ’720 Patent—as evidenced by the THALOMID™

(thalidomide) Capsules Revised Package Insert (15 July 1998) (“Thalomid PI”). (See

14


Ex. 1006 at 1.) Thalomid PI was published on July 15, 1998, and is prior art under 35

U.S.C. § 102(b). (Ex. 1006 at 1.) Thalomid PI was not considered by the USPTO during

prosecution of the ’720 Patent. (Ex. 1001 at Cover.)

Thalomid PI describes a method for delivering thalidomide to a patient in need

of the drug, while avoiding the occurrence of severe, life-threatening birth defects.

(Ex. 1006 at 1.) Specifically, Thalomid PI recites:

BECAUSE OF THIS TOXICITY AND IN AN EFFORT TO MAKE

THE CHANCE OF FETAL EXPOSURE TO THALOMID AS

NEGLIGIBLE AS POSSIBLE, THALOMID IS APPROVED FOR

MARKETING ONLY UNDER A SPECIAL RESTRICTED

DISTRIBUTION PROGRAM APPROVED BY THE FOOD AND

DRUG ADMINISTRATION. THIS PROGRAM IS CALLED THE

“SYSTEM FOR THALIDOMIDE EDUCATION AND

PRESCRIBING SAFETY (S.T.E.P.S.).”

(Ex. 1006 at 1.) Thalomid PI also states:

UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY

PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE

PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE

THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED

OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS

OF THE S.T.E.P.S. PROGRAM IN ORDER TO RECEIVE

PRODUCT.

(Ex. 1006 at 1.)

15


Thalomid PI further teaches that “a prescription for thalidomide for a woman of

childbearing potential must not be issued by the prescriber until a written report of a

negative pregnancy test has been obtained by the prescriber.” (Id at 2.) Further,

Thalomid PI requires that, for these women to receive the drug, “[t]wo reliable forms

of contraception must be used simultaneously. … Women of childbearing potential

should be referred to a qualified provider of contraceptive methods, if needed.” (Id. at

2.) Thalomid PI further discloses that “[t]halidomide is contraindicated in sexually

mature MALES.…” (Id. at 4.) Based on these disclosures, Thalomid PI teaches the

subject matter claimed in the ’720 Patent – a method of delivering drug to a patient in

need of the drug while avoiding the occurrence of a known adverse side effect. (Id. at

1–4; Ex. 1021 ¶ 76.)

To anticipate a claim, a prior art reference must disclose each claim limitation,

either expressly or inherently. Verdegaal Bros. v. Union Oil Co. of California, 814 F.2d 628,

631 (Fed. Cir. 1987). “[I]f granting patent protection on the disputed claim would

allow the patentee to exclude the public from practicing the prior art, then that claim

is anticipated, regardless of whether [the claim] also covers subject matter not in the

prior art.” Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1349 (Fed. Cir. 1999) (citing

Titanium Metals Corp. v. Banner, 778 F.2d 775, 781 (Fed. Cir. 1985)). The patent

protection previously granted to Claims 1–32 of the ’720 Patent excludes the public

from practicing Thalomid PI, so the ’720 Patent claims should be canceled.

16


To explain the meaning of an anticipatory prior art reference or to describe the

technical knowledge available to persons skilled in the art, extrinsic evidence may be

used; however, extrinsic evidence may not be used to expand on, or fill in gaps in an

anticipation prior art reference. In re Baxter Travenol Labs, 952 F.2d 388, 390 (Fed. Cir.

1991); Continental Can Co. USA, Inc. v. Monsanto Co., 948 F.2d 1264 (Fed. Cir. 1991).

Here, the Keravich reference and the Fudin Declaration are used to explain the

meaning of Thalomid PI and to explain the technical facts known in the medical

community more than one year before the ’720 Patent filing, but they are not used to

expand on or fill in any gaps in Thalomid PI—which by itself, as understood by a

POSA—contains every claim limitation of the ’720 Patent. (See generally, Ex. 1018; Ex.

1021.)

Thalomid PI anticipates Claim 1. 1.

Claim 1 of the ’720 Patent “is written in Jepson format, meaning that the claim

first describes the scope of the prior art and then claims an improvement over the

prior art.” Dow Chem. Co. v. Sumitomo Chem. Co., 257 F.3d 1364, 1368 (Fed. Cir. 2001).

Specifically, the Claim 1 preamble recites:

In a method for delivering a drug to a patient in need of the drug, while

avoiding the occurrence of an adverse side effect known or suspected of

being caused by said drug, wherein said method is of the type in which

prescriptions for said drug are filled only after a computer readable

storage medium has been consulted to assure that the prescriber is

registered in said medium and qualified to prescribe said drug, that the

17


pharmacy is registered in said medium and qualified to fill the

prescription for said drug, and the patient is registered in said medium

and approved to receive said drug, the improvement comprising:

(Ex. 1001 at 18:17–27.) (emphasis added) Because “a preamble is impliedly admitted

to be prior art when a Jepson claim is used,” the patentee has admitted that the Claim

1 preamble is prior art, rather than a point of novelty. Pentec, Inc. v. Graphic Controls

Corp., 776 F.2d 309, 315 (Fed. Cir. 1985); see In re Glatt Air Techniques, Inc., 630 F.3d

1026, 1028 (Fed. Cir. 2011) (rejecting a claim “as obvious in view of the admitted

prior art from the claim preamble and a single cited reference”).

Thalomid PI teaches every element of Claim 1 of the ’720 Patent, including

“defining a plurality of patient risk groups based upon a predefined set of risk

parameters for said drug” as required by Claim 1(a), “defining a set of information to

be obtained from said patient, which information is probative of the risk that said

adverse side effect is likely to occur if said drug is taken by said patient” as required by

Claim 1(b), “in response to said information set, assigning said patient to at least one

of said risk groups” as required by the first portion of Claim 1(c), “based upon said

information and said risk group assignment, determining whether the risk that said

adverse side effect is likely to occur is acceptable” as required by Claim 1(d), and

“upon a determination that said risk is acceptable, generating a prescription approval

code to be retrieved by said pharmacy before said prescription is filled” as required by

Claim 1(e). (See Ex. 1001 at 28–42; Ex. 1006 at 1, 3–4, 18; Ex. 1021 ¶ 76.)

18


Specifically, Thalomid PI teaches the risk groups to which a drug with

teratogenic side effects, such as thalidomide, cannot be administered, as in Claim

1(a), because of an unacceptable risk of teratogenic side effects to a fetus, as in Claim

1(d). (See Ex. 1006 at 3–4; Ex. 1021 ¶¶ 83–84, 97–99.) Thalomid PI’s risk group list

includes, for example, “WOMEN of childbearing potential,” further differentiated by

those who do and do not meet a listed set of conditions, as well as “sexually mature

“MALES,” also further differentiated by those who do and do not meet a listed set of

conditions. (Ex. 1006 at 3–4.) One of ordinary skill in the art would understand that a

prescriber would assign a patient to these various risk groups, as in the first portion of

Claim 1(c), by obtaining information from the patient such as their gender,

“childbearing potential” and whether they meet the listed set of conditions for their

gender, which are “probative of the risk that said adverse side effect is likely to occur

if said drug is taken by said patient,” as in Claim 1(b). (Ex. 1006 at 3–4; Ex. 1021

¶¶ 85–90.)

With respect to the second portion of Claim 1(c)—“entering said risk group in

said medium”—Thalomid PI discloses entering the patient’s information in a computer

readable medium. (Ex. 1006 at 3–4.) For example, Thalomid PI requires that the patient

“is capable of complying with the mandatory contraceptive measures, pregnancy

testing, patient registration, and patient survey as described in the System for

Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program.” (Id. at 3–4.)

Thalomid PI further requires:

19








PRODUCT.

(Id. at 1.) An ordinarily skilled artisan would have understood from Thalomid PI “that

the S.T.E.P.S. program must include the patient’s risk group assignment data in a

computer database” for “prescribers and pharmacists to access the patient’s

information before they prescribe and fill prescriptions for thalidomide.” (Ex. 1021 ¶

95.)

The final portion of Claim 1—Claim 1(e)—requires that, “upon a

determination that said risk is acceptable, generating a prescription approval code to

be retrieved by said pharmacy before said prescription is filled.” (Ex. 1001 at 18:40–

42.) This mechanism would have been recognized by an ordinarily skilled artisan as

inherent in the system disclosed by Thalomid PI. (Ex. 1021 ¶¶ 105–06.) Specifically,

Thalomid PI discloses the following details about Celgene’s S.T.E.P.S. program:






20



PRODUCT.

(Ex. 1006 at 1.) Thalomid PI further explains:

THALOMID MUST ONLY BE ADMINISTERED IN

COMPLIANCE WITH ALL OF THE TERMS OUTLINED IN THE

S.T.E.P.S. PROGRAM. THALOMID MAY ONLY BE PRESCRIBED

BY PRESCRIBERS REGISTERED WITH THE S.T.E.P.S.

PROGRAM AND MAY ONLY BE DISPENSED BY

PHARMACISTS REGISTERED WITH THE S.T.E.P.S. PROGRAM.

(Ex. 1006 at 18.) One of ordinary skill in the art would have known that an approval

code system—such as that required by Claim 1(e)—was one of the mechanisms

“outlined in the S.T.E.P.S. program,” and inherent in Thalomid PI’s requirement that

“THALOMID MUST ONLY BE ADMINISTERED IN COMPLIANCE WITH

ALL OF THE TERMS OUTLINED IN THE S.T.E.P.S. PROGRAM.” (Ex. 1006 at

18; Ex. 1021 ¶¶ 104–05.) See Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373, 1377

(Fed. Cir. 2003) (“[A] prior art reference may anticipate without disclosing a feature of

the claimed invention if that missing characteristic is necessarily present, or inherent,

in the single anticipating reference (quoting Continental Can Co. U.S.A. Inc. v. Monsanto

Co., 948 F.2d 1264, 1268 (Fed. Cir. 1991))” (emphasis added).); see also In re Graves, 69

F.3d 1147, 1152 (Fed. Cir. 1995) (“A reference anticipates a claim if it discloses the

claimed invention ‘such that a skilled artisan could take its teachings in combination

with his own knowledge of the particular art and be in possession of the invention.’”)

(quoting In re LeGrice, 301 F.2d 929, 936 (CCPA 1962).

21


Thalomid PI anticipates Claims 2–6. 2.

Each of Claims 2 through 6 of the ’720 Patent directly or indirectly depends

from Claim 1, and merely add limitations anticipated by Thalomid PI. Claim 2 requires

that “in response to said risk group assignment, said patient is counseled as to the

risks of taking said drug and advised as to risk avoidance measures,” while Claim 3

requires that the Claim 2 “counseling comprises full disclosure of said risks,” Claim 4

requires that “said prescription is filled only following [the Claim 3] full disclosure and

informed consent of said patient,” Claim 5 requires that “said risk group assignment

and [Claim 4] informed consent is verified by said prescriber at the time that said

patient is registered in said computer readable storage medium,” and Claim 6 requires

that “said risk group assignment and said informed consent is transmitted to [the

Claim 5] computer readable storage medium by facsimile and interpreted by optical

character recognition software.” (Ex. 1001 at 18:43–58 (emphasis added).)

“Thalomid PI requires counseling patients regarding thalidomide risks and risk

avoidance measures.” (Ex. 1006 at 2, 9, 10, 13; Ex. 1021 ¶ 108.) For example, Thalomid

PI teaches that “Thalidomide is contraindicated in WOMEN of childbearing potential

unless” “she has received both oral and written warnings of the hazards of taking

thalidomide during pregnancy and of exposing a fetus to the drug,” and “she has

received both oral and written warnings of the risk of possible contraception failure

and of the need to use two reliable forms of contraception simultaneously.” (Ex. 1006

22


at 3.) Therefore, Thalomid PI’s disclosure anticipates the counseling requirements of

Claims 2 and 3. (Ex. 1021 ¶ 110.)

Further, the second portion of Claim 3 requires that “counseling comprises

full disclosure of said risks.” (Ex. 1001 at 18:46–47.) Thalomid PI requires that

“[p]atients should be instructed” of all thalidomide risks including, for example,

“potential teratogenicity,” “drowsiness and somnolence,” “peripheral neuropathies,”

and “orthostatic hypotension.” (Ex. 1006 at 11.) Thalomid PI further requires that the

physician has “fully explained to the patient the nature, purpose, and risks of the

treatment,” as required by the ’720 Patent’s Claim 3. (Ex. 1006 at 21.) Thus, Thalomid

PI anticipates the full disclosure requirement of Claim 3. (Ex. 1021 ¶ 113.)

With respect to Claims 4 and 5 of the ’720 Patent, Thalomid PI’s

“Authorization” form teaches that the physician has “fully explained to the patient the

nature, purpose, and risks of the treatment … [and] will ensure that the appropriate

components of the patient consent form are completed. In addition, I will comply

with all of my obligations and responsibilities as a prescriber registered under the

S.T.E.P.S. restricted distribution program.” (Ex. 1006 at 21.) These teachings

anticipate the disclosure and informed consent prerequisites of Claim 4, as well as the

consent verification of Claim 5. The Claim 5 consent and risk group verification at

the time of patient registration is inherently anticipated by Thalomid PI’s warning:

PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY

WITH THE REQUIREMENTS OF THE S.T.E.P.S. PROGRAM IN

23


ORDER TO RECEIVE PRODUCT. … THALOMID MUST ONLY

BE ADMINISTERED IN COMPLIANCE WITH ALL OF THE

TERMS OUTLINED IN THE S.T.E.P.S. PROGRAM.

(Id. at 1, 18.)

One of ordinary skill in the art would have known that, as part of the

physician’s requirements under “THE TERMS OUTLINED IN THE S.T.E.P.S.

PROGRAM” to ensure that the patient was “ADVISED OF, AGREE[S] TO, AND

COMPL[IES] WITH THE REQUIREMENTS OF THE S.T.E.P.S. PROGRAM,”

“the physician was required to verify the patient’s risk group and informed consent” at

the time of “registering the patient in the database,” as Claim 5 requires. (Ex. 1021 ¶ 119

(emphasis added.) See Schering Corp. v. Geneva Pharms., Inc., 339 F.3d at 1377. For

example, Keravich—published more than one year before the earliest priority date of

the ’720 Patent—explains that the S.T.E.P.S. program “patient database provides

critical patient-related information that is found on the consent form.” (Ex. 1018 at

1723.) Indeed, the prescriber must use information from the patient’s informed

consent form—which Thalomid PI discloses is a different form for male and female

patients and so indicative of the patient’s risk group—when registering the patient in

the database. (See Ex. 1006 at 20–21.) Therefore, Thalomid PI also anticipates Claim 5

of the ’720 Patent. (Ex. 1006 at 3, 4, 21; Ex. 1021 ¶ 120.)

Thalomid PI discloses that the informed consent and risk group assignment are

transmitted to the S.T.E.P.S. program database described above with respect to Claim

24


1(c), and as required by the first portion of Claim 6. (Ex. 1021 ¶ 121.) As with Claim

5, Thalomid PI’s disclosure that the S.T.E.P.S program must be followed would

inherently disclose to one of ordinary skill in the art that one way that a patient’s

informed consent and risk group assignment are transmitted to the S.T.E.P.S.

database is through fax, which is then interpreted by optical character recognition

(OCR) software. (Ex. 1021 ¶¶ 127–29.) For example, Keravich explains that “Celgene

provides telephone and fax services for patient registration, patient approval, and

prescriber verification.” (Ex. 1018 at 1723–24.) Keravich further explains that the

S.T.E.P.S. program “patient database provides critical patient-related information that

is found on the consent form,” thus making clear that the S.T.E.P.S. program

disclosed in Thalomid PI inherently requires that the faxed informed consent

information make it into the database, which one of ordinary skill in the art would

have known to be interpreted through OCR means as Claim 6 requires. (Ex. 1018 at

1723; Ex. 1021 ¶ 129.) See In re Graves, 69 F.3d 1147, 1152 (Fed. Cir. 1995) (“A

reference anticipates a claim if it discloses the claimed invention ‘such that a skilled

artisan could take its teachings in combination with his own knowledge of the

particular art and be in possession of the invention.’”) (quoting In re LeGrice, 301 F.2d

929, 936 (CCPA 1962)).


Claims 7–10 depend from Claim 1, and merely add limitations anticipated by

Thalomid PI. Claim 7 requires that the “information to be obtained from said patient,”

25


prior to treatment, “includes the results of diagnostic testing,” while Claims 8, 9, and

10 respectively require that the diagnostic testing “is probative of the onset of said

adverse side effect,” “is probative of the concentration of said drug in a tissue of said

patient,” and “comprises genetic testing.” (Ex. 1001 at 18:59–67.)

Thalomid PI discloses diagnostic testing, including testing “probative of the

onset of said adverse side effect,” anticipating the additional limitations of Claims 7

and 8. Specifically, Thalomid PI teaches that “[b]efore starting treatment, women of

childbearing potential should have a pregnancy test … within the 24 hours prior to

beginning therapy” because “IF THALIDOMIDE IS TAKEN DURING

PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO

AN UNBORN BABY.” (Ex. 1006 at 1–2.)

With respect to Claim 9, Thalomid PI teaches that “[d]ecreased white blood cell

counts, including neutropenia, have been reported in association with the clinical use

of thalidomide. … White blood cell count and differential should be monitored on an

on-going basis.” (Ex. 1006 at 10.) From this teaching, a person of ordinary skill in the

art “would have recognized the need to conduct diagnostic testing probative of the

concentration of the drug remaining in the patient’s body.” (Ex. 1021 ¶ 136.)

However, because many drugs do not generally distribute uniformly in the body, but

instead are preferentially absorbed by certain body tissues, one of ordinary skill in the

art would have further recognized the importance of performing diagnostic testing

that would be probative of the concentration of such a non-uniformly distributed

26


drug in the drug’s target tissues. (Ex. 1021 ¶ 138–39.) See In re Cruciferous Sprout

Litigation, 301 F.3d 1343, 1345 (Fed. Cir. 2002) (“The patent owners had not done

anything more than recognize properties inherent in certain prior art sprouts, and had

not invented anything new, and therefore, their claims were invalid.”).

With respect to Claim 10, a person of ordinary skill in the art “would have

recognized genetic testing as one of the tests” in “the extensive diagnostic testing

taught by Thalomid PI.” (Ex. 1021 ¶ 142.) Specifically, it was common in the art at the

time of the ’720 Patent “to conduct genetic testing at the same time as the pregnancy

testing taught in Thalomid PI.” (Ex. 1021 ¶ 141.) Because thalidomide was known to

cause birth defects at the time of the ’720 Patent, a person of ordinary skill in the art

would have recognized that the extensive diagnostic testing in Thalomid PI would

include genetic testing. (Ex. 1021 ¶ 143.) More generally, because genetic testing was a

well-known diagnostic procedure at the time of the ’720 Patent, one of ordinary skill

in the art would have included genetic testing as one of the methods in the diagnostic

testing for thalidomide therapy. (Ex. 1021 ¶ 141.) See Schering Corp., 339 F.3d at 1377;

see also In re Graves, 69 F.3d 1147, 1152 (Fed. Cir. 1995) (“A reference anticipates a

claim if it discloses the claimed invention ‘such that a skilled artisan could take its

teachings in combination with his own knowledge of the particular art and be in

possession of the invention.’”) (quoting In re LeGrice, 301 F.2d 929, 936 (CCPA 1962).

27


Thalomid PI anticipates Claims 11–14 and 20–25. 4.

Claims 11–14, and 21–25 depend from Claim 1, and merely add limitations

anticipated by Thalomid PI. Claims 11, 12, and 13 respectively require that the drug’s

associated side effect “is likely to arise in said patient,” “is likely to arise in a foetus

carried by said patient,” and “is likely to arise in a recipient or a foetus carried by a

recipient of the bodily fluid of said patient,” while Claim 14 requires that the Claim

12 “recipient is a sexual partner of said patient.” (Ex. 1001 at 19:1–9.) Claim 22

requires that the “drug is thalidomide.” (Ex. 1001 at 19:34–35.) Claim 21 requires that

the drug’s associated side effect “comprises a teratogenic effect,” while Claims 23

and 24 respectively require that the Claim 21 teratogenic effect “is likely to arise in a

foetus carried by said patient,” and “is likely to arise in a foetus carried by a recipient

of the bodily fluid of said patient.” Claim 25 requires that the Claim 24 “recipient of

the bodily fluid of said patient is a sexual partner of said patient.” (Ex. 1001 at 19:32–

33, 36–42.) Claim 20 requires “providing said patient with a contraceptive device or

formulation.” (Ex. 1001 at 19:30–31.)

“Thalomid PI explicitly discloses that thalidomide’s side effects arise in the

patient taking the drug”—in the case of “peripheral neuropathy,” “and also in a fetus

carried by the patient taking the drug”—in the case of “teratogenicity,” anticipating

Claims 11, 12, 21, 22 and 23. (Ex. 1006 at 1, 2, 8, 9, 10; Ex. 1021 ¶ 149–50.)

Thalomid PI also explicitly discloses that thalidomide side effects likely arise in a

sexual partner and recipient of bodily fluid of a male treated with the drug,

28


anticipating Claims 13, 14, and 25, or in the fetus of this sexual partner, anticipating

in Claims 13 and 24.For example, Thalomid PI discloses that “[b]ecause it is not

known whether or not thalidomide is present in the ejaculate of males receiving the

drug, males receiving thalidomide must always use a latex condom when engaging in

sexual activity with women of childbearing potential.” (Ex. 1006 at 9.) Thalomid PI

further discloses that “male patients should be instructed that they are not permitted

to donate sperm while taking thalidomide;” and that male patients “must NEVER

have unprotected sex with a woman because it is not known if the drug is present in

semen or sperm.” (Ex. 1006 at 11, 21.)

Finally, with respect to Claim 20, Thalomid PI teaches informing patients that

“[e]ffective contraception … must be used for at least 1 month before beginning

thalidomide therapy, during thalidomide therapy, and for 1 month following

discontinuation of thalidomide therapy. … Women of childbearing potential should

be referred to a qualified provider of contraceptive methods, if needed.” (Ex. 1006 at

2 (emphasis added).) Thalomid PI further teaches:

Women must commit either to abstain continuously from heterosexual

sexual intercourse or to use two methods of reliable birth control,

including at least one highly effective method (e.g., IUD, hormonal

contraception, tubal ligation, or partner’s vasectomy) and one additional

effective method (e.g., latex condom, diaphragm, or cervical cap),

beginning 4 weeks prior to initiating treatment with thalidomide, during

29


therapy with thalidomide, and continuing for 4 weeks following

discontinuation of thalidomide therapy.

(Id. at 8–9.) In light of Thalomid PI’s teachings, a person of ordinary skill in the art

would have inherently understood that when a potential patient for whom

contraception was a prerequisite for taking thalidomide was referred to a “qualified

provider of contraceptive methods,” that doctor would provide the “patient with a

contraceptive device or formulation” as in Claim 20, in order to accomplish Thalomid

PI’s objective of ensuring that “[w]omen of childbearing potential” taking thalidomide

took “reliable contraceptive precautions.” (Ex. 1006 at 2; Ex. 1021 ¶ 159.) See In re

Graves, 69 F.3d at 1152.

Thalomid PI anticipates Claim 15. 5.

Claim 15 depends from Claim 1, and merely adds limitations anticipated by

Thalomid PI. Claim 15 requires “f. defining for each said risk group a second set of

information to be collected from said patient on a period basis; g. obtaining said

second set of information from said patient; and h. entering said second set of

information in said medium before said patient is approved to receive said drug.”

(Ex. 1001 at 19:10–18.)

Thalomid PI explicitly discloses defining information to be collected and

periodically obtaining that information from the patient as in Claim 15(f) and (g).

For example, Thalomid PI discloses, “Once treatment has started, pregnancy testing

should occur weekly during the first month of use, then monthly thereafter,” and that

30


the patient consents that “I understand that I must participate in a survey and patient

registry while I am on THALOMIDTM.” (Id. at 2, 20–21.) Further, as previously

discussed above with respect to the second portion of Claim 1(c)—Thalomid PI

discloses that the patient’s periodic evaluations are stored in the S.T.E.P.S. program.

(Id. at 10.) Thalomid PI additionally discloses that “Drug prescribing to women of

childbearing potential should be contingent upon initial and continued

confirmed negative results of pregnancy testing.” (Id. at 18.) From these teachings

requiring periodic test results and computer approval before drug distribution, one of

ordinary skill in the art would have recognized that, to make use of the computerized

tracking, the periodic test results inherently must be entered in the “medium before

said patient is approved to receive said drug,” as required by Claim 15(h). (Id. at 10;

Ex. 1021 ¶ 168–69.) See Schering Corp., 339 F.3d at 1377.


Claims 16–17 depend from Claim 1, and merely add limitations anticipated by

Thalomid PI. Claim 16 requires that the Claim 15 second set of information

“comprises a survey regarding said patient’s behavior and compliance with said risk

avoidance measures,” while Claim 17 requires that the Claim 16 survey “is conducted

telephonically using an integrated voice response system.” (Ex. 1001 at 19:19–24.)

With respect to Claim 16’s requirement of “a survey regarding said patient’s

behavior and compliance with said risk avoidance measures,” Thalomid PI teaches the

importance of compliance with risk avoidance measures, as well as pre-treatment

31


interview surveys regarding the patient’s behavior and ability to comply with risk

avoidance measures. For example, Thalomid PI requires that the patient sign an

authorization stating “I understand that if I do not follow all of my doctor’s

instructions, I will not be able to receive THALOMIDTM” and “I understand that I

must participate in a survey and patient registry while I am on THALOMIDTM.”

(Ex. 1006 at 20–21.) Thalomid PI also requires that the patient “is capable of

complying with the mandatory contraceptive measures, pregnancy testing, patient

registration, and patient survey as described in the System for Thalidomide Education

and Prescribing Safety (S.T.E.P.S.) program.” (Id. at 3, 4.) Additionally, the required

survey for “continued confirmed negative results of pregnancy testing”—an

indicator of the patient’s behavior and compliance with the required risk avoidance

measures—anticipates the Claim 16 requirements. (Id. at 18; Ex. 1021 ¶ 176.)

Just as for Claims 5 and 6, Thalomid PI’s disclosure that the S.T.E.P.S program

must be followed would inherently disclose to one of ordinary skill in the art that one

way that a patient’s required survey may be conducted is via telephone, and

specifically utilizing a telephonic integrated voice response system as required by

Claim 17. (Ex. 1021 ¶ 178–79.) For example, Keravich explains that, under the

S.T.E.P.S. program, “[p]atients are eligible to continue to receive thalidomide if they

… [p]articipate in a mandatory and confidential patient survey every 30 days (women)

or every 90 days (men),” and that for subsequent prescriptions, “[o]nce patient

eligibility is confirmed, the prescription needs to be authorized through online

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adjudication, fax submission, or telephone contact with Celgene.” (Ex. 1018 at 1722–

23 (emphasis added).) See Schering Corp., 339 F.3d at 1377; see also SmithKline Beecham

Corp. v. Apotex Corp., 403 F.3d 1331, 1343 (Fed. Cir. 2005).

Thalomid PI anticipates Claims 18–19 and 26–27. 7.

Claims 18–19 and 26–27 ultimately depend from Claim 1, and merely add

limitations anticipated by Thalomid PI. Claim 18 requires that, where the “patient is a

female of childbearing potential,” the Claim 15 second set of information collected on

a periodic basis “comprises the results of a pregnancy test,” while Claim 19 requires

that the periodic interval for the Claim 18 pregnancy test “comprises about 28 days.”

(Ex. 1001 at 19:25–29.) Claim 26 similarly requires that, where the drug has a

teratogenic effect, the “information to be obtained from said patient” “includes the

results of a pregnancy test,” while Claim 27 adds to the requirements of Claim 26 that

“said prescription is filled for no more than about 28 days.” (Ex. 1001 at 19:43–20:2.)

Thalomid PI explicitly discloses that, in light of thalidomide’s “teratogenicity,”

“[b]efore starting treatment, women of childbearing potential should have a

pregnancy test … within the 24 hours prior to beginning therapy,” as required by

Claim 26. (Ex. 1006 at 2; see also Id. at 9, 11–12, 20.)

Thalomid PI further anticipates the Claim 18 and 19 requirements for obtaining

periodic pregnancy test results every about 28 days by requiring that the patient

acknowledge “I know that I must have a pregnancy test done every week during the

first 4 weeks of THALOMID therapy. I will then have a pregnancy test every 4 weeks

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if I have regular menstrual cycles, or every 2 weeks if my cycles are irregular while I

am taking THALOMID.” (Ex. 1006 at 20.)

Thalomid PI also explicitly discloses that prescriptions must be filled “for no

more than about 28 days,” as in Claim 27. For example, Thalomid PI discloses that

patients must “have a pregnancy test every 4 weeks … while I am taking

THALOMID,” that “[d]rug prescribing to women of childbearing potential

should be contingent upon initial and continued confirmed negative results of

pregnancy testing” occurring every 28 days, and that the “DRUG MUST ONLY

BE DISPENSED IN NO MORE THAN A 1-MONTH SUPPLY.” (Ex. 1006 at 18–

19 (emphasis added); Ex. 1021 ¶¶ 185–88.)


Claim 28, although an independent claim, merely repeats the language of Claim

1 with a single added limitation anticipated by Thalomid PI. Claims 29–32 depend from

Claim 28, and similarly add limitations already known in the field and anticipated by

Thalomid PI. In addition to the exact requirements of Claim 1, Claim 28 requires that

“said adverse side effect is likely to arise in patients who take said drug in combination

with at least one other drug.” (Ex. 1001 at 20:3–31.) Claims 29 and 30 respectively

require that the “information to be obtained from said patient” “is also probative of

the likelihood that said patient may take said drug and said other drug in

combination,” and “includes the results of diagnostic testing,” while Claims 31 and

32 respectively require that the Claim 30 diagnostic testing “comprises testing for

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evidence of the use of said other drug” and “comprises testing for evidence which is

indicative of the onset of said adverse event.” (Ex. 1001 at 20:32–42.)

Thalomid PI teaches that thalidomide in combination with other drugs would

cause adverse side effects in patients. (Ex. 1006 at 12.) For example, Thalomid PI

teaches, “Drug Interactions. Thalidomide has been reported to enhance the sedative

activity of barbiturates, alcohol, chlorpromazine, and reserpine.…” (Id. at 12.)

Thalomid PI further teaches that “[m]edications known to be associated with peripheral

neuropathy should be used with caution in patients receiving thalidomide.” (Id. at 12.)

Because these Thalomid PI teachings satisfy “adverse side effect is likely to arise in

patients who take said drug in combination with at least one other drug,” as required

by Claim 28, Thalomid PI anticipates Claim 28.

As previously discussed with respect to Claims 7 and 8, Thalomid PI discloses

extensive diagnostic testing, including testing “for evidence which is indicative of the

onset of said adverse side effect” prior to treatment, anticipating Claims 30 and 32.

Specifically, Thalomid PI teaches that “[b]efore starting treatment, women of

childbearing potential should have a pregnancy test. … The test should be performed

within the 24 hours prior to beginning therapy” because “IF THALIDOMIDE IS

TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS

OR DEATH TO AN UNBORN BABY.” (Ex. 1006 at 1–2.)

Thalomid PI teaches “Drug Interactions. Thalidomide has been reported to

enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine,”

35


which reports that patient data regarding taking Thalomid in combination with other

drugs has been collected, as required by Claim 29. (Id. at 12.) Thalomid PI further

teaches that “[m]edications known to be associated with peripheral neuropathy should

be used with caution in patients receiving thalidomide.” (Id. at 12.) In light of these

teachings, a person of ordinary skill in the art would have recognized that the

extensive patient consultations would have included questioning regarding other drugs

the patient may take along with Thalomid, as required by Claim 29. (Ex. 1021 ¶ 208.)

With respect to Claim 31, Thalomid PI discloses diagnostic “testing for evidence

of the use of said other drug.” For example, Thalomid PI discloses testing

pharmacokinetic profiles of patients on oral contraceptives—“[i]n 10 healthy women,

the pharmacokinetic profiles of norethindrone and ethinyl estradiol following

administration of a single dose containing 1.0 mg of norethindrone acetate and 75 μg

of ethinyl estradiol were studied. The results were similar with and without

coadministration of thalidomide 200 mg/day to steady-state levels.” (Id. at 12.)

Claim chart for Ground 1 showing exemplary citations in 9.Thalomid PI.

Element Prior Art 1pre. In a method for delivering a drug to a patient in need of the drug, while avoiding the occurrence of an adverse side effect known or suspected of being

Thalomid PI teaches a method for delivering thalidomide to a patient in need of the drug, while avoiding the occurrence of an adverse side effect: Ex. 1006 at 2 (“THALOMIDTM (thalidomide) may be prescribed only by licensed prescribers who are registered in the S.T.E.P.S. program and understand the risk of teratogenicity if thalidomide is used during pregnancy.”); Id. at 1 (“Thalidomide is contraindicated in WOMEN of

36


caused by said drug, wherein said method is of the type in which prescriptions for said drug are filled only after a computer readable storage medium has been consulted to assure that the prescriber is registered in said medium and qualified to prescribe said drug, that the pharmacy is registered in said medium and qualified to fill the prescription for said drug, and the patient is registered in said medium and approved to receive said drug, the improvement comprising:

childbearing potential unless alternative therapies are considered inappropriate AND the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant while on thalidomide therapy).”); Id. at 4 (“Thalidomide is contraindicated in sexually mature MALES unless the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS: … he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the S.T.E.P.S. program.”); Id. at 3 (see “Female Patients” chart); Id. at 18 (“THALOMID MUST ONLY BE ADMINISTERED IN COMPLIANCE WITH ALL OF THE TERMS OUTLINED IN THE S.T.E.P.S. PROGRAM. THALOMID MAY ONLY BE PRESCRIBED BY PRESCRIBERS REGISTERED WITH THE S.T.E.P.S. PROGRAM AND MAY ONLY BE DISPENSED BY PHARMACISTS REGISTERED WITH THE S.T.E.P.S. PROGRAM.”); Id. at 19 (“THIS PRODUCT IS ONLY SUPPLIED TO PHARMACISTS REGISTERED WITH THE S.T.E.P.S. PROGRAM. … SPECIFIC INFORMED CONSENT … AND COMPLIANCE WITH THE MANDATORY PATIENT REGISTRY AND SURVEY ARE REQUIRED FOR ALL PATIENTS (MALE AND FEMALE) PRIOR TO DISPENSING BY THE PHARMACIST.”). Ex. 1021, Fudin Decl. ¶¶ 78–82.

a. defining a plurality of patient risk groups based upon a predefined set of risk parameters for said drug;

Thalomid PI defines a plurality of patient risk groups based on a predefined set of risk parameters: Ex. 1006 at 3 (“Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative therapies are considered inappropriate.”); Id. at 4 (“Thalidomide is contraindicated in sexually mature MALES.”).

b. defining a set of information to be obtained from said patient, which

Thalomid PI provides guidelines on the information that is probative of the risk to the adverse side effect of the drug: Ex. 1006 at 20 (“WARNING: SERIOUS HUMAN BIRTH

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information is probative of the risk that said adverse side effect is likely to occur if said drug is taken by said patient;

DEFECTS IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. THALIDOMIDE SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD BECOME PREGNANT WHILE TAKING THE DRUG. EVEN A SINGLE DOSE [1 CAPSULE (50 mg)] TAKEN BY A PREGNANT WOMAN CAN CAUSE SEVERE BIRTH DEFECTS.”); Id.

; Id. at 21

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. c. in response to said information set, assigning said patient to at least one of said risk groups and entering said risk group assignment in said medium;

Thalomid PI discloses that the patient is assigned to one of the risk groups and this information is entered into the S.T.E.P.S. database: Ex. 1006 at 3 (“Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative therapies are considered inappropriate AND the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant while on thalidomide therapy).”); Id. at 4 (“Thalidomide is contraindicated in sexually mature MALES unless the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS: … he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the S.T.E.P.S. program.”); Id. at 1 (“UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS OF THE S.T.E.P.S. PROGRAM IN ORDER TO RECEIVE PRODUCT.”); Id. at 21

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.

Ex. 1021, Fudin Decl. ¶¶ 89–96. d. based upon said information and said risk group assignment, determining whether the risk that said adverse side effect is likely to occur is acceptable; and

Thalomid PI discloses that the patient is assigned to one of the risk groups and the adverse side effect is likely to occur is acceptable: Ex. 1006 at 3 (“Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative therapies are considered inappropriate AND the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant while on thalidomide therapy).”); Id. at 4 (“Thalidomide is contraindicated in sexually mature MALES unless the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS: … he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the S.T.E.P.S. program.”); Id. at 21 (see Authorization form copied at Claim 1c.). Ex. 1021, Fudin Decl. ¶¶ 97–99.

e. upon a determination that said risk is acceptable, generating a prescription approval code to be retrieved by said

Thalomid PI teaches that upon information that the risk is acceptable, the patient’s information is entered into the S.T.E.P.S. program to generate a prescription approval code : Ex. 1006 at 20, 21 (“I have read the THALOMIDTM patient brochure and/or viewed the videotape, ‘Important Information for Men and Women Taking THALOMIDTM (thalidomide)’. I understand the contents, including other possible health

40


pharmacy before said prescription is filled.

problems from THALOMIDTM, so-called ‘side effects’. I know that I cannot donate blood while taking THALOMIDTM.”); Id. at 1 (“UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS OF THE S.T.E.P.S. PROGRAM IN ORDER TO RECEIVE PRODUCT.”); Id. at 21 (see Authorization form copied at Claim 1c.); Id. at 19 (“Rx only and only able to be prescribed and dispensed under the terms of the S.T.E.P.S. Restricted Distribution Program.”). Ex. 1021, Fudin Decl. ¶¶ 101–06.

2. The method of claim 1 wherein, in response to said risk group assignment, said patient is counseled as to the risks of taking said drug and advised as to risk avoidance measures.

Thalomid PI teaches counseling for patients regarding the risks of taking thalidomide and the risk avoidance measures: Ex. 1006 at 2, 9, 13 (“Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding … [if a]ny suspected fetal exposure to THALOMID (thalidomide) … [t]he patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.”); Id. at 10 (“Patients should be regularly counseled, questioned, and evaluated for signs or symptoms of peripheral neuropathy.”).

3. The method of claim 2 wherein said counseling comprises full disclosure of said risks.

Thalomid PI teaches counseling comprising full disclosure of risks of thalidomide treatment: Ex. 1006 at 21 (see Authorization form copied at Claim 1c.).

4. The method of claim 3 wherein said prescription is filled only following said full disclosure and

Thalomid PI teaches that the prescription is filled only after full disclosure of risks is given and informed consent is obtained: Ex. 1006 at 20 (“SPECIFIC INFORMED CONSENT … AND COMPLIANCE WITH THE MANDATORY PATIENT REGISTRY AND SURVEY ARE REQUIRED FOR ALL PATIENTS (MALE AND FEMALE) PRIOR TO

41


informed consent of said patient.

DISPENSING BY THE PHARMACIST.”); Id. at 21 (see Authorization form copied at Claim 1c.).

5. The method of claim 4 wherein said risk group assignment and said informed consent is verified by said prescriber at the time that said patient is registered in said computer readable storage medium.

Thalomid PI teaches that the prescriber screens patient’s risk group assignment and informed consent at the time the patient is registered in the S.T.E.P.S. program: Ex. 1006 at 1 (“UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS OF THE S.T.E.P.S. PROGRAM IN ORDER TO RECEIVE PRODUCT.”); Id. at 21 (see Authorization form copied at Claim 1c.). Ex. 1021, Fudin Decl. ¶¶ 118–20.

6. The method of claim 5 wherein said risk group assignment and said informed consent is transmitted to said computer readable storage medium by facsimile and interpreted by optical character recognition software.

Thalomid PI teaches risk group assignment and informed consent are transmitted to S.T.E.P.S. program: Ex. 1006 at 3, 4 (See supra Claim 1(c)); Id. at 10 (“Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to enable the clinician to detect early signs of neuropathy. … Patients should be evaluated periodically thereafter during treatment. Patients should be regularly counseled, questioned, and evaluated for signs or symptoms.”). Keravich teaches patient registration by fax: Ex. 1018 at 1722 (“The pharmacy is responsible for registering the patient with Celgene by one of three methods: online adjudication, submission of a manual patient-registration form by fax … or telephone.”). Ex. 1021, Fudin Decl. ¶¶ 121–29.

7. The method of claim 1 wherein said set of information includes the results of diagnostic testing.

Thalomid PI teaches diagnostic testing prior to treatment: Ex. 1006 at 2 (“Before starting treatment, women of childbearing potential should have a pregnancy test. … The test should be performed within the 24 hours prior to beginning therapy.”); Id. at 3 (“[S]he has had a negative pregnancy test with a

42


sensitivity of at least 50 mIU/mL, within the 24 hours prior to beginning therapy.”); Id. at 20 (“I must have a pregnancy test done by my doctor within the 24 hours prior to starting THALOMID therapy.”).

8. The method of claim 7 wherein said diagnostic testing is probative of the onset of said adverse side effect.

Thalomid PI warns severe birth defects caused by thalidomide: Ex. 1006 at 1 (“IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY.”); Id. at 10 (“Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to enable the clinician to detect early signs of neuropathy. … Patients should be evaluated periodically thereafter during treatment. Patients should be regularly counseled, questioned, and evaluated for signs or symptoms.”).

9. The method of claim 7 wherein said diagnostic testing is probative of the concentration of said drug in a tissue of said patient.

Thalomid PI teaches that thalidomide treatment may cause neutropenia: Ex. 1006 at 10 (“Decreased white blood cell counts, including neutropenia, have been reported in association with the clinical use of thalidomide. … White blood cell count and differential should be monitored on an on-going basis.”). Ex. 1021, Fudin Decl. ¶¶ 135–39.

10. The method of claim 7 wherein said diagnostic testing comprises genetic testing.

Ex. 1021, Fudin Decl. ¶¶ 141–44.

11. The method of claim 1 wherein said side effect is likely to arise in said patient.

Thalomid PI teaches that thalidomide causes severe birth defects and peripheral neuropathy: Ex. 1006 at 1 (“IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY.”); Id. at 9 (“Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common, potentially severe, side effect of treatment with thalidomide that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months.”); Id. at 10 (“Patients should be evaluated periodically thereafter

43


during treatment. Patients should be regularly counseled, questioned, and evaluated for signs or symptoms of peripheral neuropathy.”).

12. The method of claim 1 wherein said side effect is likely to arise in a foetus carried by said patient.

Thalomid PI teaches thalidomide side effects in a foetus: Ex. 1006 at 1 (“IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY.”); Id. 9 (“Thalidomide can cause severe birth defects in humans.”).

13. The method of claim 1 wherein said side effect is likely to arise in a recipient or a foetus carried by a recipient of the bodily fluid of said patient.

Thalomid PI teaches thalidomide side effects in a recipient and a foetus carried by a recipient of the bodily fluid of said patient: Ex. 1006 at 3 (“Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative therapies are considered inappropriate AND the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant while on thalidomide therapy).”); Id. at 4 (“Thalidomide is contraindicated in sexually mature MALES unless the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS: … he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the S.T.E.P.S. program.”); Id. at 6 (“It is not known whether thalidomide is present in the ejaculate of males.”); Id. at 9 (“Because it is not known whether or not thalidomide is present in the ejaculate of males receiving the drug, males receiving thalidomide must always use a latex condom when engaging in sexual activity with women of childbearing potential.”); Id. at 11 (“male patients should be instructed that they are not permitted to donate sperm while taking thalidomide.”); Id. at 21 (“Male patient “must NEVER have unprotected sex with a woman because it is not known if the drug is present in semen or sperm.”); See supra Claim 12.

14. The method of claim 13 wherein said recipient is a

Thalomid PI teaches thalidomide side effects in a foetus: Ex. 1006 at 6 (“It is not known whether thalidomide is present

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sexual partner of said patient.

in the ejaculate of males.”); Id. at 9 (“Because it is not known whether or not thalidomide is present in the ejaculate of males receiving the drug, males receiving thalidomide must always use a latex condom when engaging in sexual activity with women of childbearing potential.”); Id. at 11 (“male patients should be instructed that they are not permitted to donate sperm while taking thalidomide.”); Id. at 21 (“Male patient “must NEVER have unprotected sex with a woman because it is not known if the drug is present in semen or sperm.”); See supra Claim 13.

15. The method of claim 1 further comprising:

See supra Claim 1pre.

f. defining for each said risk group a second set of information to be collected from said patient on a periodic basis;

Thalomid PI teaches periodic evaluation of patients during thalidomide treatment: Ex. 1006 at 10 (“Patients should be evaluated periodically thereafter during treatment.”); Id. at 20, 21 (“I understand that I must participate in a survey and patient registry while I am on THALOMIDTM.”); Id. at 10 (“Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to enable the clinician to detect early signs of neuropathy ... [, and p]atients should be evaluated periodically thereafter during treatment. … If symptoms of drug-induced neuropathy develop, thalidomide should be discontinued immediately.”).

g. obtaining said second set of information from said patient; and

Thalomid PI teaches periodic evaluation of patients during thalidomide treatment: Ex. 1006 at 10 (“Patients should be evaluated periodically thereafter during treatment.”); Id. at 20, 21 (“I understand that I must participate in a survey and patient registry while I am on THALOMIDTM.”).

h. entering said second set of information in said medium before

Thalomid PI teaches periodic evaluation of patients must be entered into the S.T.E.P.S. program: Ex. 1006 at 10 (“Patients should be evaluated periodically

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said patient is approved to receive said drug.

thereafter during treatment.”); Id. at 20, 21 (“I understand that I must participate in a survey and patient registry while I am on THALOMIDTM.”); Id. at 1 (“UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS OF THE S.T.E.P.S. PROGRAM IN ORDER TO RECEIVE PRODUCT.”).

16. The method of claim 15 wherein said second set of information comprises a survey regarding said patient’s behavior and compliance with said risk avoidance measures.

Thalomid PI teaches survey regarding patient’s compliance with risk avoidance measures: Ex. 1006 at 3, 4 (Patient “is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program.”); Id. at 20, 21 (“I understand that I must participate in a survey and patient registry while I am on THALOMIDTM, which will require completing additional forms.”); Id. at 21 (see Authorization form copied at Claim 1c.);

Id. at 10 (“Patients should be evaluated periodically … during treatment.”); Id. at 20 ( “I know that I must have a pregnancy test done every week during the first 4 weeks of THALOMID therapy. I will then have a pregnancy test every 4 weeks if I have regular menstrual cycles, or every 2 weeks if my cycles are irregular while I am taking THALOMID.”); Id. at 20, 21(“I understand that I must participate in a survey and patient registry while I am on THALOMIDTM.”).

17. The method of claim 16 wherein said survey is conducted telephonically using an integrated voice

Thalomid PI teaches survey regarding patient’s compliance with risk avoidance measures: See supra Claim 16. Keravich discloses telephone services provided by the S.T.E.P.S. program for patient registration and authorization:

46


response system. Ex. 1018 at 1723 (“A pharmacist who registers a patient by telephone can provide the information required for prescription authorization at the same time.”); Id. at 1724 (“The binders also contain blank patient registration forms and prescription verification forms for use when registration and verification by telephone are not possible.”) Ex. 1021, Fudin Decl. ¶¶ 177–79.

18. The method of claim 16 wherein said patient is a female of childbearing potential and said second set of information comprises the results of a pregnancy test.

Thalomid PI teaches periodic pregnancy tests for a woman of childbearing potential on Thalomid: Ex. 1006 at 2 (“Once treatment has started, pregnancy testing should occur weekly during the first month of use, then monthly thereafter in women with regular menstrual cycles.”); Id. at 18 (“Drug prescribing to women of childbearing potential should be contingent upon initial and continued confirmed negative results of pregnancy testing.”); Id. at 20 (“I know that I must have a pregnancy test done every week during the first 4 weeks of THALOMID therapy. I will then have a pregnancy test every 4 weeks if I have regular menstrual cycles, or every 2 weeks if my cycles are irregular while I am taking THALOMID.”).

19. The method of claim 18 wherein said periodic interval comprises about 28 days.

Thalomid PI teaches periodic (about 28 days) pregnancy tests for a woman of childbearing potential on Thalomid: Ex. 1006 at 20 (“I know that I must have a pregnancy test done every week during the first 4 weeks of THALOMID therapy. I will then have a pregnancy test every 4 weeks if I have regular menstrual cycles, or every 2 weeks if my cycles are irregular while I am taking THALOMID.”).

20. The method of claim 1 further comprising providing said patient with a contraceptive device or formulation.

Thalomid PI discloses types of contraception that can be used by women on Thalomid: Ex. 1006 at 2 (“Effective contraception … must be used for at least 1 month before beginning thalidomide therapy, during thalidomide therapy, and for 1 month following discontinuation of thalidomide therapy. … Women of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed.”) Ex. 1021, Fudin Decl. ¶¶ 156–60.

21. The method of Thalomid PI discloses teratogenic effect of Thalomid:

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claim 1 wherein said adverse side effect comprises a teratogenic effect.

Ex. 1006 at 1 (“IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY.”); Id. at 2 (“THALOMIDTM (thalidomide) may be prescribed only by licensed prescribers who are registered in the S.T.E.P.S. program and understand the risk of teratogenicity if thalidomide is used during pregnancy.”); Id. at 8 (“Due to its known human teratogenicity, even following a single dose, thalidomide is contraindicated in pregnant women and women capable of becoming pregnant.”); Id. at 9 (“Patient should be instructed about the potential teratogenicity of thalidomide.”).

22. The method of claim 1 wherein said drug is thalidomide.

Thalomid PI discloses the drug THALOMIDTM (thalidomide): Ex. 1006 at 1 (“IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY.”); Id. at 2 (“THALOMIDTM (thalidomide) may be prescribed only by licensed prescribers who are registered in the S.T.E.P.S. program and understand the risk of teratogenicity if thalidomide is used during pregnancy.”).

23. The method of claim 21 wherein said teratogenic effect is likely to arise in a foetus carried by said patient.

Thalomid PI discloses that teratogenic effect of Thalomid is likely to arise in a foetus: Ex. 1006 at 1 (“IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY.”); Id. at 2 (“THALOMIDTM (thalidomide) may be prescribed only by licensed prescribers who are registered in the S.T.E.P.S. program and understand the risk of teratogenicity if thalidomide is used during pregnancy.”); Id. at 8 (“Due to its known human teratogenicity, even following a single dose, thalidomide is contraindicated in pregnant women and women capable of becoming pregnant.”); Id. at 9 (“Patient should be instructed about the potential teratogenicity of thalidomide.”).

24. The method of claim 21 wherein said teratogenic

Thalomid PI discloses that teratogenic effect of Thalomid is likely to arise in a foetus:

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effect is likely to arise in a foetus carried by a recipient of the bodily fluid of said patient.

See supra Claims 12, 13, 14.

25. The method of claim 24 wherein said recipient of the bodily fluid of said patient is a sexual partner of said patient.

Thalomid PI explicitly discloses that thalidomide side effects likely arise in a sexual partner of a male treated with the drug: Ex. 1006 at 6 (“It is not known whether thalidomide is present in the ejaculate of males.”); Id. at 9 (“Because it is not known whether or not thalidomide is present in the ejaculate of males receiving the drug, males receiving thalidomide must always use a latex condom when engaging in sexual activity with women of childbearing potential.”); Id. at 11 (“male patients should be instructed that they are not permitted to donate sperm while taking thalidomide.”); Id. at 21 (“Male patient “must NEVER have unprotected sex with a woman because it is not known if the drug is present in semen or sperm.”).

26. The method of claim 21 wherein said set of information includes the results of a pregnancy test.

Thalomid PI teaches that information includes results of pregnancy tests: Ex. 1006 at 2 (“Before starting treatment, women of childbearing potential should have a pregnancy test … within the 24 hours prior to beginning therapy.”); Id. at 18 (“Drug prescribing to women of childbearing potential should be contingent upon initial and continued confirmed negative results of pregnancy testing.”); Id. at 20 (“I know that I must have a pregnancy test done every week during the first 4 weeks of THALOMID therapy. I will then have a pregnancy test every 4 weeks if I have regular menstrual cycles, or every 2 weeks if my cycles are irregular while I am taking THALOMID.”).

27. The method of claim 26 wherein said prescription is filled for no more than about 28 days.

Thalomid PI teaches that the prescription is filled for no more than about 28 days: Ex. 1006 at 19 (“DRUG MUST ONLY BE DISPENSED IN NO MORE THAN A 1-MONTH SUPPLY.”).

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Keravich teaches that the prescription is filled for no more than about 28 days: Ex. 1018 at 1722 (“Prescribe no more than 28 days of therapy and not authorize refills.”). Ex. 1021, Fudin Decl. ¶¶ 188–90.

28pre and (a)–(e). See supra Claim 1pre and (a)–(e).

28. wherein said adverse side effect is likely to arise in patients who take said drug in combination with at least one other drug.

Thalomid PI teaches thalidomide drug interactions: Ex. 1006 at 12 (“Drug Interactions. Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine.…”); Id. (“Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide.”). Ex. 1021, Fudin Decl. ¶¶ 191–96.

29. The method of claim 28, wherein said set of information is also probative of the likelihood that said patient may take said drug and said other drug in combination.

Thalomid PI teaches thalidomide drug interactions: Ex. 1006 at 12 (“Drug Interactions. Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine.…”); Id. (“Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide.”). Ex. 1021, Fudin Decl. ¶¶ 205–09.

30. The method of claim 28 wherein said set of information includes the results of diagnostic testing.

Thalomid PI teaches that the patient information includes diagnostic test results: Ex. 1006 at 3 (“[S]he has had a negative pregnancy test with a sensitivity of at least 50 mIU/mL, within the 24 hours prior to beginning therapy.”); Id. at 20 (“I know that I must have a pregnancy test done by my doctor within the 24 hours prior to starting THALOMID therapy, then every week during the first 4 weeks of THALOMID therapy. I will then have a pregnancy test every 4 weeks if I have regular menstrual cycles, or every 2 weeks if my cycles are irregular while I am taking THALOMID.”); Id. at 10 (“Patients should be evaluated periodically thereafter during treatment. Patients should be regularly counseled,

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questioned, and evaluated for signs or symptoms of peripheral neuropathy. Consideration should be given to electrophysiological testing.”). See also Ex. 1021, Fudin Decl. ¶¶ 197–204.

31. The method claim 30 wherein said diagnostic testing comprises testing for evidence of the use of said other drug.

Thalomid PI discloses testing women on other medications: Ex. 1006 at 12 (“In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 μg of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels.”). See also Ex. 1021, Fudin Decl. ¶¶ 210–12.

32. The method of claim 30 wherein said diagnostic testing comprises for evidence which is indicative of the onset of said adverse side effect.

Thalomid PI teaches adverse side effects and laboratory tests to determine the evidence of adverse side effects in patients on thalidomide therapy: Ex. 1006 at 9–11 (“Birth defects … Drowsiness and somnolence … Peripheral neuropathy … Dizziness and orthostatic hypotension … Neutropenia … Increased HIV-viral load … Hypersensitivity … [and] Bradycardia.…”); Id. at 11–12 (“Pregnancy Testing … Neutropenia … [and] HIV viral load.”). Ex. 1021, Fudin Decl. ¶¶ 197–204.

B. Ground 2: Claims 1–323 of U.S. Patent No. 6,315,720 are obvious under 35 U.S.C. § 103(a) over Thalomid PI in view of Cunningham, and in further view of the knowledge of one of ordinary skill in the art.

The Cunningham patent constitutes prior art under 35 U.S.C. § 102(b) because it

was filed in 1995 and granted in 1998. (Ex. 1009 at Cover.) During the prosecution of

the ’720 Patent, the examiner did not consider this reference. (See Ex. 1001 at Cover.)

3 For all claim elements not specifically discussed under Ground 2, those claim

element disclosures are the same as discussed under Ground 1.

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The examiner did consider, but did not cite, a divisional of this reference. (See id. at

Cover; Ex. 1010 at Cover.)

Cunningham discloses a method of dispensing pharmaceutical product samples

by linking prescribers and pharmacies to a central computing station. (Ex. 1009 at

Cover.) Specifically, before filling any prescription for a pharmaceutical trial product,

the pharmacy must upload defined information into the central computing station.

(See id. at 11:6–13.) Only if the central computing station establishes that the uploaded

information is valid can the central computing station issue a pharmacy approval code

for the pharmacy to then dispense the pharmaceutical product. (See id. at 11:13–23.)

Claims 1(e) and 28(e) are obvious over Thalomid PI in view of 1.Cunningham.

Claims 1(e) and 28(e)4 of the ’720 Patent require that, “upon a determination

that said risk is acceptable, generating a prescription approval code to be retrieved by

said pharmacy before said prescription is filled.” (Ex. 1001 at 18:40–42.) This

mechanism would have been obvious to a person of ordinary skill in the art, upon

reading Thalomid PI, which discloses that a prescription may not be filled until the

risks are deemed acceptable and the prescription has been approved:

THALOMIDTM (thalidomide) may be prescribed only by licensed

prescribers who … understand the risk of teratogenicity if thalidomide is

used during pregnancy. … A prescription for thalidomide for a woman

4 The other elements of Claims 1 and 28 are as described for Ground 1.

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of childbearing potential must not be issued by the prescriber until a

written report of a negative pregnancy test has been obtained by the

prescriber.

(Ex. 1006 at 2; Ex. 1021 ¶¶ 213–14.)

As the ’720 Patent correctly states, “[s]uitable computer readable storage media

… will be apparent to one of ordinary skill in the art, once armed with the teachings

of the present application.” (Ex. 1001 at 5:11–16.) Indeed, it would have been

apparent and obvious to one of ordinary skill in the art to utilize the Claim 1(e) and

28(e) approval codes to implement the drug restriction required by Thalomid PI, in

light of Cunningham’s disclosure of an approval code lockout system for a pharmacy:

If authenticity is not established, it follows that the participating

pharmacy cannot dispense corresponding pharmaceutical product. …

However, if authenticity is established then the pharmac[y’s] terminal

dials the central computing station and data and information from the

pharmac[y’s] authorization media and personal identification is uploaded

to the database of the central computing station 12. … Assuming full

validation, the central computing station issues a pharmacy

approval code and the pharmacy records that approval code on the

actual presented product trial media 18. … Once validation is established

the pharmacy then dispenses pharmaceutical trial product …

(Ex. 1009 at 11:6–8, 17–23 (emphasis added); Ex. 1021 ¶ 214.) See KSR Int'l Co. v.

Teleflex Inc., 550 U.S. 398, 416–17 (2007) (where a combination of references “[s]imply

arranges old elements with each performing the same function it had been known to

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perform and yields no more than one would expect from such an arrangement, the

combination is obvious.”) (internal quotations and citations omitted).

“In view of the guidelines for the avoidance of treating pregnant patients with

thalidomide taught by Thalomid PI, it would have been obvious to a” person of

ordinary skill in the art “to implement the methods disclosed in Cunningham to limit

dispensation of a drug associated with adverse effects to certain risk groups.” (Ex.

1021 ¶ 215.) See Abbott Labs v. Andrx Pharms., Inc., 452 F.3d 1331, 1345 (Fed. Cir.

2006) (finding substantial question of invalidity because the combination of references

for “the reduction of systemic side effects would not be surprising and would not be

unexpected.”). Therefore, an ordinarily skilled artisan “treating a patient with a

teratogenic or other risk-laden drug in accordance with Thalomid PI’s guidelines would

look to the approval code system taught by Cunningham—and would view Claims 1

and 28 of the ’720 Patent obvious in view of these references.” (Ex. 1021 ¶ 216.) See

Dystar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356, 1361 (Fed. Cir. 2006)

(“The motivation need not be found in the references sought to be combined, but

may be found in any number of sources, including common knowledge, the prior art

as a whole, or the nature of the problem itself.”).

Claims 5 and 6 are obvious over Thalomid PI in view of the 2.knowledge of one of ordinary skill in the art.

Claim 5 requires that “said risk group assignment and informed consent is

verified by said prescriber at the time that said patient is registered in said computer

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readable storage medium,” and Claim 6 requires that “said risk group assignment and

said informed consent is transmitted to [the Claim 5] computer readable storage

medium by facsimile and interpreted by optical character recognition software.”

(Ex. 1001 at 18:51–58.)

The Claim 5 consent and risk group verification at the time of patient

registration was obvious to one of ordinary skill in the art in light of Thalomid PI’s

requirement that the prescriber “ensure that the appropriate components of the

patient consent form are completed.” (Ex. 1006 at 21; Ex. 1021 ¶ 217.) Specifically,

“Thalomid PI sets forth different consent forms for male and female patients, thus

requiring that the prescriber verify the patient’s gender risk group by selecting the

consent form for completion.” (Id. at 20–21; Ex. 1021 ¶ 218.) Further, it was within

the knowledge of one of ordinary skill in the art “that, as part of the S.T.E.P.S.

Program, information from the consent form had to be entered into the patient

registration database.” (Ex. 1021 ¶ 219; see, e.g., Ex. 1018 at 1723 (“The patient

database provides critical patient-related information that is found on the consent

form”); Ex. 1012 at 325; Ex. 1015 at 8.) “Because Thalomid PI requires that the

prescriber is the one to ‘ensure that the appropriate components of the patient

consent form are completed,’ it would have been obvious to” one of ordinary skill in

the art “that, while verifying the patient consent and associated risk group assignment,

the prescriber could eliminate error and delay by also registering the patient into the

database at that time.” (Ex. 1006 at 21; Ex. 1021 ¶ 220.) See Bayer Schering Pharma AG

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v. Barr Labs., Inc., 575 F.3d 1341, 1347 (Fed. Cir. 2009) (“When there is a design need

or market pressure to solve a problem and there are a finite number of identified,

predictable solutions, a person of ordinary skill has good reason to pursue the known

options within his or her technical grasp. If this leads to the anticipated success, it is

likely the product not of innovation but of ordinary skill and common sense.”)

(quotation omitted).

The previous disclosure also teaches an ordinarily skilled artisan that the

informed consent and risk group assignment are transmitted to the patient database

described in Ground 1’s Claim 1(c), and as required by the first portion of Claim 6.

(Ex. 1021 ¶ 221.) One of ordinary skill in the art “would understand that a prescriber

would typically print Thalomid PI’s consent forms.” (Ex. 1006 at 20–21; Ex. 1021

¶ 222; see Ex. 1018 at 1722 (“A packet of materials is mailed to each interested or

registered prescriber for use with each patient undergoing thalidomide treatment. The

packet contains an FDA-approved informed-consent form, an initial confidential

patient survey”).) Because it was within the knowledge of one of ordinary skill in the

art “to transfer paper data into a computer database by fax, which is then ‘interpreted

by optical character recognition [OCR] software,’ it would have been obvious to” an

ordinarily skilled artisan “that paper risk group assignments and informed consents

could similarly be transferred to the patient database through fax and OCR,” as the

last portion of Claim 6 requires. (Ex. 1021 ¶ 223.) See Perfect Web Techs., Inc. v.

InfoUSA, Inc., 587 F.3d 1324, 1329 (Fed. Cir. 2009) (“KSR expanded the sources of

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information for a properly flexible obviousness inquiry to include … the background

knowledge, creativity, and common sense of the person of ordinary skill.”).

Claims 9 and 10 are obvious over Thalomid PI in view of the 3.knowledge of one of ordinary skill in the art.

Claims 9 and 10 include the Claim 7 requirement that the “information to be

obtained from said patient” prior to treatment “includes the results of diagnostic

testing,” with the further respective limitations that this diagnostic testing “is

probative of the concentration of said drug in a tissue of said patient,” and “comprises

genetic testing.” (Ex. 1001 at 18:59–60, 66–67.)

As explained in Ground 1, Thalomid PI anticipates the Claim 7 diagnostic

testing. (Ex. 1006 at 2 (“Before starting treatment, women of childbearing potential

should have a pregnancy test”).) With respect to Claim 9, it would have been obvious

to an ordinarily skilled artisan “to include, within the extensive diagnostic testing

taught by Thalomid PI, testing for the drug concentration in patient tissue.” (Ex. 1021

¶ 226.) Specifically, “[f]or a patient previously treated with the drug, it would have

been obvious to” one of ordinary skill in the art “to conduct diagnostic testing

probative of the concentration of the drug remaining in the patient’s body.” (Ex. 1021

¶ 227.) However, “[b]ecause many drugs do not generally distribute uniformly in the

body, but instead are preferentially absorbed by certain body tissues,” one of ordinary

skill in the art “would have further recognized the importance of performing

diagnostic testing that would be probative of the concentration of such a non-

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uniformly distributing drug in the drug’s target tissues.” (Ex. 1021 ¶ 228.) See Tyco

Healthcare Grp. LP v. Ethicon Endo-Surgery, Inc., 774 F.3d 968, 977 (Fed. Cir. 2014)

(“Claims would have been obvious if they are nothing more than a combination of

familiar elements that yield predictable results.”).

With respect to Claim 10, it would have been further obvious to an ordinarily

skilled artisan “to include genetic testing in the extensive diagnostic testing taught by

Thalomid PI.” (Ex. 1021 ¶ 229.) Specifically, “[i]t was common in the art at the time of

the ’720 Patent to conduct genetic testing at the same time as the pregnancy testing

taught in Thalomid PI.” (Ex. 1021 ¶ 230.) More generally, “because genetic testing was

a well-known diagnostic procedure at the time of the ’720 Patent, it would have been

obvious” to one of ordinary skill in the art “to include genetic testing in the diagnostic

testing that preceded such last-resort treatments as that disclosed in Thalomid PI.” (Ex.

1021 ¶ 231.) See Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352, 1361 (Fed. Cir. 2011)

(“This court has observed that teachings from prior art, suggestions beyond the literal

teachings of those art references, or even motivations from the store of common

knowledge of one of ordinary skill in the art field (‘TSM’)—flexibly viewed and

applied—provide the sources of evidence that an ordinary skilled artisan might have

found and combined at the time of the invention.”).

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Claim 17 is obvious over Thalomid PI in view of the knowledge of 4.one of ordinary skill in the art.

Claim 17 requires that the Claim 16 survey “is conducted telephonically using

an integrated voice response system.” (Ex. 1001 at 19:22–24.) As explained in Ground

1, Thalomid PI anticipates the Claim 16 patient survey requirement. Further, “[b]ecause

one method of conducting surveys well known” to those of ordinary skill in the art

“at the time of the ’720 Patent was via the telephone, using an integrated voice

response system—which was well known” to those of ordinary skill in the art at the

time—as required by Claim 17, “would have been obvious” to one of ordinary skill in

the art. (Ex. 1021 ¶ 233; see, e.g., Ex. 1024 at 611–12, 623.) See In re Venner, 262 F.2d

91, 95 (C.C.P.A. 1958) (“Furthermore, it is well settled that it is not ‘invention’ to

broadly provide a mechanical or automatic means to replace manual activity which has

accomplished the same result.”).

Claim Chart for Ground 2 showing exemplary citations in 5.Cunningham.

All Thalomid PI disclosures are listed in the Ground 1 claim chart above.

Element Prior Art 1e./28e. upon a determination that said risk is acceptable, generating a prescription approval code to be retrieved by said pharmacy before said prescription is

Cunningham discloses an approval code lockout system for a pharmacy: Ex. 1009 at 11:6–8, 17–23 (“If authenticity is not established, it follows that the participating pharmacy cannot dispense corresponding pharmaceutical product. … However, if authenticity is established then the pharmac[y’s] terminal dials the central computing station and data and information from the pharmac[y’s] authorization media and personal identification is uploaded to the database of the central computing station 12. … Assuming full validation, the central computing station

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filled. issues a pharmacy approval code and the pharmacy records that approval code on the actual presented product trial media 18. … Once validation is established the pharmacy then dispenses pharmaceutical trial product….”). Ex. 1021, Fudin Decl. ¶¶ 214–16.

VII. CONCLUSION

Thus, Petitioners respectfully request inter partes review of Claims 1–32 of U.S.

Patent No. 6,315,720.

Respectfully Submitted, /Sarah E. Spires/ Sarah E. Spires (Reg. No. 61,501) SKIERMONT PUCKETT LLP 2200 Ross Ave. Ste. 4800W Dallas, Texas 75201 P: 214-978-6600/F: 214-978-6601 Lead Counsel for Petitioner

April 23, 2015 Ki O (Reg. No. 68,952) Dr. Parvathi Kota (Reg. No. 65,122) Paul J. Skiermont (pro hac vice requested) SKIERMONT PUCKETT LLP 2200 Ross Ave. Ste. 4800W Dallas, Texas 75201 P: 214-978-6600/F: 214-978-6621 Back-Up Counsel for Petitioner

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CERTIFICATE OF SERVICE

I hereby certify that on April 23, 2015, a copy of this Petition for Inter Partes

Review of U.S. Patent No. 6,315,720, including all exhibits, was served via FedEx,

overnight delivery, upon the following:

Celgene Corporation 86 Morris Avenue Summit, New Jersey 07901 S. Maurice Valla BakerHostetler Cira Centre, 12th Floor 2929 Arch Street Philadelphia, Pennsylvania 19104-2891

Date: April 23, 2015 /Sarah E. Spires/

Documents

Kyle Bass, Celgene IPR Petition, Patent '720