preliminary response

Paper No. __ Filed: July 28, 2015

04841.00006/7042670.1

UNITED STATES PATENT AND TRADEMARK OFFICE ________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD ________________

COALITION FOR AFFORDABLE DRUGS VI LLC Petitioner,

v.

CELGENE CORPORATION Patent Owner

________________

Case IPR2015-01092 Patent 6,045,501

________________

PATENT OWNER PRELIMINARY RESPONSE PURSUANT TO 35 U.S.C. 313 AND 37 C.F.R. 42.107

Patent Owner Preliminary Response IPR2015-01092 Patent 6,045,501

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TABLE OF CONTENTS

Page

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

II. BACKGROUND ............................................................................................. 4

A. The Challenge of Protecting A Fetus From A Teratogenic Drug While Allowing A Patient Access to Its Efficacy........................ 6

B. Previous Attempts To Control Access To Other Drugs Were Unsuccessful ..................................................... 8

C. The 501 Patent ................................................................................... 11

III. ARGUMENT ................................................................................................. 12

A. Ground 2 Should Be Denied Because The NIH Reference Is Not Prior Art ................................................... 13

1. CFAD Has Not Proven That The NIH Reference Was Publicly Available ........................................... 15

2. CFAD Has Not Offered Any Evidence of Dissemination ........ 19

B. The Petition Should Be Denied Because CFAD Has Failed To Show A Reasonable Likelihood That The Claims Would Have Been Obvious .................. 20

1. CFADs Expert Declaration Is Entitled To little or no weight ........................................... 20

(a) Dr. Fudin Is Not A POSA ............................................... 20 (b) Dr. Fudins Opinions Are

Unsupported, Verbatim Recitations Of CFADs Conclusory Arguments .................................... 22

2. Ground 1: The Claimed Inventions Would Not Have Been Obvious Over Powell, Mitchell, and Dishman ................ 23

(a) CFAD Fails To Address Both The Claims And The Prior Art As A Whole ...................... 23


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(b) CFAD Has Not Provided A Motivation To Combine Powell With Dishman Or Mitchell ................. 24

(c) The Ground 1 References Fail To Disclose, Teach, Or Suggest Key Elements Of The Claimed Inventions ..................... 29

i. Independent Claim 1 Would Not Have Been Obvious Over Powell, Mitchell, And Dishman ........................... 29

1) Elements 1(a), 1(b), and 1(c) ..................... 29 2) Element 1(d) ............................................... 32

ii. Dependent Claims 2-10 Would Not Have Been Obvious Over Powell, Mitchell, And Dishman ........................... 34

3. Ground 2: The Claimed Inventions Would Not Have Been Obvious Over the NIH Reference And Honigfeld .......... 36

(a) CFAD Fails To Address Both the Claims and the Prior Art As a Whole ......................... 36

(b) CFAD Has Not Provided A Motivation To Combine The NIH Reference And Honigfeld ................ 37

(c) The Cited References Fail To Disclose, Teach, Or Suggest Key Elements Of The Claimed Inventions ..................... 40

i. Claim 1 Would Not Have Been Obvious Over The NIH Reference and Honigfeld ............. 40

1) Element 1(c) ............................................... 40 2) Element 1(d) ............................................... 41

ii. Dependent Claims 2-10 Would Not Have Been Obvious Over The NIH Reference And Honigfeld ..................... 43


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4. CFAD Fails To Address The Objective Evidence Of Nonobviousness Regarding The 501 Patent ............................ 44

(a) Long-Felt Need Further Supports The Nonobviousness Of The Claimed Inventions ................. 45

(b) Commercial Success Further Supports The Nonobviousness Of The Claimed Inventions ................. 46

(c) Third-Party Praise And Awards Further Supports The Nonobviousness Of The Claimed Inventions ......... 47

(d) Licensing by Others Further Supports The Nonobviousness Of The Claimed Inventions ................. 47

(e) Unexpected Results Further Supports The Nonobviousness Of The Claimed Inventions ................. 48

C. The Petition Should Be Denied Under 35 U.S.C. 314(a) And 316(b) .............................................. 49

D. The Petition Should Be Denied For Failing To Name All Real Parties-In-Interest .............................. 52

IV. CONCLUSION .............................................................................................. 55


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I. INTRODUCTION

Pursuant to 35 U.S.C. 313 and 37 C.F.R. 42.107(a), Patent Owner

Celgene Corporation (Celgene) submits this Preliminary Response to Coalition

For Affordable Drugs VI LLCs (CFAD ) Petition for Inter Partes Review (the

Petition) of U.S. Patent No. 6,045,501 (the 501 patent).

The 501 patent describes and claims methods for delivering a teratogenic

drug, such as thalidomide, to a patient while preventing fetal exposure and related

birth defects. The inventions were conceived as part of Celgenes efforts to obtain

approval from the U.S. Food and Drug Administration (FDA) to market a

thalidomide drug product in the United States. In the 1950s and 1960s,

thalidomide was responsible for more than 10,000 severe birth defects worldwide.

The United States refused approval of the drug in the early 1960s, and it remained

unlawful in the United States for decades. But after discovery of important new

uses for thalidomide, the methods developed at Celgene and claimed in the 501

patent convinced the FDA to lift its nearly 40-year ban on marketing the drug in

the United States.

No other prior-art method for controlling access to pharmaceutical drug

products was able to accomplish what the invention embodied in the 501 patent

(and other of Celgenes patents) dida 100% success rate in preventing drug-

related birth defects. In fact, the inventions of the 501 patent were so successful


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and innovative that the FDA required other drug manufacturers to copy Celgenes

patented methods if they wanted to keep their products on the market, resulting in

licenses to several of Celgenes patents, including the 501 patent.

Notwithstanding Celgenes significant innovations, CFAD has filed the

present Petition as part of a hedge fund investment strategy developed by the real

parties-in-interest (RPI). CFADs Petition has several fatal defects.

First, CFADs petition fails to establish that all of its Ground 2 references

are prior-art printed publications upon which an inter partes review (IPR) may

be instituted. Specifically, CFAD has failed to show that the NIH reference

constitutes prior art to the 501 patent, and there is strong evidence that the NIH

reference was first made public after the patents priority date. CFAD has

therefore failed to show that Ground 2 justifies review.

Second, CFAD relies heavily on an expert declaration that is entitled to little

or no weight because the declarant is not a person of ordinary skill in the art

(POSA), and because the declaration merely reiterates CFADs conclusory

arguments.

Third, CFADs Grounds 1 and 2 both fail on the merits, as they do not

demonstrate a reasonable likelihood that the challenged claims are unpatentable.

Specifically, even if the NIH reference is prior art, all references asserted in both

Grounds 1 and 2 fail to disclose, teach, or suggest key elements of the challenged


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claims. CFADs proposed modifications to, and combinations of, the prior-art

disclosures are driven entirely by hindsight and supported only by conclusory

assertions by CFADs declarant, who merely parrots the arguments in the Petition.

Moreover, CFAD ignores disclosures in the prior art teaching away from the

claimed inventions, including disclosures teaching that prior methods did not

prevent drug-related birth defects. CFADs arguments do not warrant an IPR trial

of the 501 patent.

Fourth, CFADs petition is an improper use of the IPR proceedings.

Specifically, CFAD and the RPI are abusing and misusing the IPR process in an

attempt to effectuate changes in the stock prices of the targeted innovator

pharmaceutical companies. The self-serving actions of the RPI create unwarranted

burdens on both patent owners and the Board. The Board should exercise its

discretion under 35 U.S.C. 314(a) and 316(b) and deny the Petition.1

Fifth and finally, the Petition should also be denied because it fails to name

all RPIa threshold requirement for an IPR. Specifically omitted from the RPI

identification are the investors in the Hayman funds responsible for filing the

Petition. Having failed to name all RPI, the Petition cannot be considered.

1 With the Boards permission, Celgene has separately moved to dismiss the

Petition pursuant to 37 C.F.R. 42.12.


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II. BACKGROUND

Celgene is a biopharmaceutical company that is committed to improving the

lives of patients through research and development of drug products that treat

cancers and other devastating conditions. Three drug products developed by

Celgene are relevant to this IPR: Thalomid, Revlimid, and Pomalyst.

Thalomid is approved for the treatment of (1) erythema nodosum leprosum

(ENL)an inflammatory condition associated with leprosy; and (2) newly

diagnosed multiple myeloma (MM) (in combination with dexamethasone). Ex.

2001 at 1. The active ingredient in Thalomid is thalidomide, which is well known

for its teratogenicity (or ability to cause severe birth defects). Unfortunately, as

described in more detail below, the devastating effects of thalidomide were felt

worldwide during the thalidomide tragedy of the 1950s and 1960s, and continue

today for the surviving victims. Ex. 1001 at 1:19-24; Ex. 2002 at 1.

Revlimid is approved for the treatment of (1) transfusion-dependent anemia

due to low- or intermediate-1-risk myelodysplastic syndromes associated with a

deletion 5q abnormality, with or without additional cytogenetic abnormalities;

(2) MM (in combination with dexamethasone); and (3) mantle cell lymphoma in

certain patients whose disease has relapsed or progressed after two prior therapies.

Ex. 2003 at 1. Pomalyst (in combination with dexamethasone) is approved for

the treatment of MM in patients who have received at least two prior therapies and


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whose disease has progressed. Ex. 2004 at 1. The active ingredient in Revlimid

is lenalidomide, and the active ingredient in Pomalyst is pomalidomide. Ex. 2003

at 1; Ex. 2004 at 1. According to the FDA-approved package inserts, lenalidomide

and pomalidomide are thalidomide analogue[s], and if these drugs are used

during pregnancy, [they] may cause birth defects or embryo-fetal death. Ex. 2003

at 1,3, 7, 22-23; Ex. 2004 at 1, 2, 4, 14 and 24. As described herein, due in large

measure to the inventions claimed in the 501 patent (and other of Celgenes

patents), Celgenes FDA-approved systems for preventing fetal exposure to the

active ingredients in Thalomid, Revlimid, and Pomalyst have been 100%

successful in preventing drug-related birth defects.

Because of the known teratogenicity of thalidomide, Celgene realized that if

it were to market Thalomid, a system would need to be developed for safely

controlling patient access to the drug. Celgene was thus faced with a great

challengefind a way to effectively avoid the teratogenic side effects of

thalidomide while still making the drug available to patients in need. Indeed,

Celgene recognized that it would need to create a system that was so effective at

preventing birth defects of the type associated with teratogenic drugs that it would

convince skeptical FDA regulators, and understandably vocal and concerned

thalidomide victims around the world, that Thalomid could be safely marketed.


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In other words, the new system would need to convince the FDA to lift its nearly

40-year ban on thalidomide.

That is precisely what the inventors of the 501 patent did. Their innovative

solution to the problemoriginally known as the System for Thalidomide

Education and Prescribing Safety, or S.T.E.P.S., and what has now become the

FDA-approved Thalomid Risk Evaluation and Mitigation Strategy (REMS)is

claimed in the 501 patent (with later iterations claimed in other Celgene patents,

including U.S. Patent No. 6,315,720, at issue in IPR2015-01096, -01102, and

01103). Thalomid was first approved by the FDA in 1998, in large measure due

to S.T.E.P.S. Revlimid and Pomalyst were later approved by the FDA, again in

large measure due to the inventions of the 501 patent and later patents (including

the 720 patent). Had Celgene not developed the claimed methods for preventing

fetal exposure to teratogenic drugs, Thalomid, Revlimid, and Pomalyst would

not be available to patients today.

A. The Challenge of Protecting A Fetus From A Teratogenic Drug While Allowing A Patient Access to Its Efficacy

Beginning in 1958, thalidomide was marketed in Europe as a sedative and a

treatment for pregnant women with morning sickness. See Ex. 1001 at 1:19-24;

Ex. 2002 at 1. Shortly after entering the European market, it was discovered that

thalidomide caused deformities in children born to mothers who had taken the drug

during pregnancy. Id. As a result, by 1962, thalidomide had been withdrawn from


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all markets. Id. By then, the damage had been done. Thalidomide had been

linked to more than 10,000 birth defects in at least 46 countries. Id. The birth

defects were severe. Some children were born with missing or abnormal limbs,

feet, or hands, a condition known as phocomelia (from the Greek for seal

limb). Id. Many other deformities and complications were linked to

thalidomide, including abnormal or absent ears, and heart and kidney problems.

Id. As a result of this tragedy, drug regulatory authorities worldwide, including the

FDA, revised their regulations to ensure that new drugs were screened for safety in

addition to efficacy, and were specifically investigated for their potential to cause

harm to a developing fetus. Id; Ex. 2005.

Years later, it became clear that despite its teratogenicity, thalidomide had

the power to benefit certain patient populations. Ex. 1001 at 1:25-36.

Accordingly, Celgene believed it would be beneficial if the drug were made

available to those patient populations. Due to its known teratogenicity, however,

Celgene realized that to market thalidomide, it needed to develop a system that

would allow patients in need of thalidomide to access it while ensuring that no

thalidomide-related birth defects would occur. Ex. 1001 at 1:39-47.

In response to this realization, Celgene developed the methods claimed in

the 501 patent (described below). When the FDA approved Thalomid for the

treatment of ENL in July 1998, the approval letter stated that Thalomid was being


04841.00006/7042670.1 - 8 -

approved under a special regulation, 21 CFR 314.520 (Subpart H), which

allowed the FDA to approve drugs that were shown to be effective, but that could

only be used safely under restricted conditions. Ex. 1016 at 0002. Specifically,

the approval letter stated that Thalomid was being approved because Celgene had

presented adequate information to demonstrate that the drug would be safe and

effective for use when marketed under S.T.E.P.S., which is claimed in the 501

patent. Id. When Thalomid was approved for the treatment of newly diagnosed

MM in 2006, the FDA maintained the same restrictions on distribution of the drug.

Ex. 2006 at 1. Similarly, the FDA conditioned its approval of both Revlimid and

Pomalyst (for all indications), on Celgenes use of the same restrictions applied to

Thalomid. Ex. 2006 at 1; Ex. 2007 at 7-10.

Those restrictions are reflected in the 501 patents claims. They include

various checks and controls to ensure that patients who need the drug receive it,

and that no child is born with a drug-related birth defect as a result. See generally

Ex. 1001.

B. Previous Attempts To Control Access To Other Drugs Were Unsuccessful

Others attmpted to control access to the drugs Accutane (isotretinoin) and

Clozaril (clozapine) before Celgene invented S.T.E.P.S., but as described below,

those attempts failed to meet their goals. Both failed to provide a workable


04841.00006/7042670.1 - 9 -

solution for dealing with a drug like thalidomide, where even a single drug-related

birth defect was unacceptable.

Accutane contains isotretinoin, a form of vitamin A (a vitamin A analogue)

that has been used as a treatment for severe cystic acne since 1982. Ex. 1006 at

101. Isotretinoin can and has caused birth defects in children whose mothers are

taking the drug. Id. Because of the teratogenic effects of isotretinoin, and instead

of removing the drug from the market, the manufacturer of isotretinoin

implemented the Pregnancy Prevention Program (PPP).

The PPP, however, was not effective in preventing women who were taking

Accutane from becoming pregnant or preventing birth defects. In fact, the

Mitchell reference that CFAD relies upon discloses that there were more than 400

pregnancies that occurred during isotretinoin treatment, at least six of which

resulted in live born infants with at least minor anomalies, and at least one with

major anomalies. Id. at 103-04. Mitchell further reports that in the first several

months of the PPP, there was incomplete compliance with several parts of the

program, such as failures to ensure negative pregnancy tests before beginning

treatment, failures to wait until menses begins before treatment, and failures to use

effective birth control before, during, and after treatment. Id. at 104. Compliance

remained incomplete even after the manufacturer changed the packaging to

highlight the most important parts of the PPP. Id.


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Publications in prominent scientific journals also disparaged the PPP. For

instance, an article in the New England Journal of Medicine reported that [s]ince

the [PPP] program was implemented in 1989, a substantial number of fetuses have

been exposed to the drug. As many as 30 percent of the women with exposed

fetuses did not use any mode of contraception, even though they were cognizant of

the high fetal risk. Ex. 2009 at 1130.

Clozaril contains clozapine, and is used to treat schizophrenia. Ex. 1007 at

899. Its release into the market was permitted only with certain prescribing and

distribution restrictions implemented by the manufacturer. Id. These restrictions

were put in place because the use of clozapine is associated with a high frequency

of agranulocytosis, a potentially fatal blood disorder. Ex. 1009 at 52. Clozapine is

not a teratogenic drugit does not cause birth defectsand the system employed

to monitor its use was not tailored to restrict or prevent birth defects. Instead, the

manufacturer developed a program called the Clozaril National Registry to

enhance patient safety by facilitating early detection of potentially dangerous

white blood cell suppression. Id. at 52-53. But like the PPP, the clozapine system

was also a failure. Specifically, during its first five years, 382 patients developed

agranulocytosis, and 12 of those patients died as a result. Id. at 55.

When Celgene invented S.T.E.P.S. and the methods claimed in the 501

patent, the programs in place for both the Accutane and Clozaril were


04841.00006/7042670.1 - 11 -

ineffective. The 501 patent was a significant innovation over those systems. To

date, Celgenes FDA-approved systems for preventing fetal exposure to the active

ingredients in Thalomid, Revlimid, or Pomalystall of which are covered by

the claims of the 501 patenthave been 100% successful in preventing birth

defects of the type associated with thalidomide. Celgenes patented methods were

so successful that, in 2006, it became clear that the PPP (and later attempts at

managing the distribution of isotretinoin) were ineffective by comparison.

Consequently, the FDA required the manufacturers of isotretinoin to use Celgenes

patented methods if they wanted to keep their products on the market. This

resulted in licenses to several of Celgenes patents, including the 501 patent, in

connection with the distribution of isotretinoin under a program known as iPledge.

See Ex. 2010; Ex. 2011; Ex. 2012.

C. The 501 Patent

As described above, the 501 patent describes and claims methods for

delivering a teratogenic drug to a patient while preventing fetal exposure to the

drug. The claims all require various steps including checks and controls that

ensure safe methods of treatment, thereby avoiding birth defects that may result

from exposure to the drug. See Ex. 1001 at 2:10-3:9; see also id. at Abstract. For

example, independent Claim 1 of the 501 patent recites:

A method for delivering a teratogenic drug to patients in need of the drug while avoiding the delivery of said drug to a foetus comprising:


04841.00006/7042670.1 - 12 -

a. registering in a computer readable storage medium prescribers who are qualified to prescribe said drug;

b. registering in said medium pharmacies to fill prescriptions for said drug;

c. registering said patients in said medium, including information concerning the ability of female patients to become pregnant and the ability of male patients to impregnate females;

d. retrieving from said medium information identifying a subpopulation of said female patients who are capable of becoming pregnant and male patients who are capable of impregnating females;

e. providing to the subpopulation, counseling information concerning the risks attendant to fetal exposure to said drug;

f. determining whether patients comprising said subpopulation are pregnant; and

g. in response to a determination of non-pregnancy for said patients, authorizing said registered pharmacies to fill prescriptions from said registered prescribers for said non-pregnant registered patients.

See id. at Claim 1. The dependent claims further limit and define the controls to

avoid delivery of a teratogenic drug to a fetus. See id. at Claims 2-10.

III. ARGUMENT

The Petition should be denied due to several fatal defects. First, CFAD has

failed to establish that the NIH reference that it relies on for Ground 2 is a prior-art

printed publication upon which an IPR petition may be based. Second, CFAD


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relies heavily on an expert declaration that is entitled to little or no weight because

the declarant is not a POSA, and because the declaration merely parrots CFADs

conclusory arguments. Third, CFAD has not shown that any combination of

references set forth in Ground 1 or 2 establishes a reasonable likelihood that the

challenged claims are unpatentable. Fourth, CFADs petition is an improper use

of the IPR process, and should be denied under 35 U.S.C. 314 and 316. Fifth,

pursuant to 35 U.S.C. 312(a)(2), CFADs petition fails to name all RPI.

A. Ground 2 Should Be Denied Because The NIH Reference Is Not Prior Art

A threshold issue for all patentability inquiries in an IPR is that a claim may

be challenged only on the basis of prior art consisting of patents or printed

publications. 35 U.S.C. 311(b); see also Boehringer Ingelheim Intl v. Biogen

Inc., IPR2015-00418, Paper 14 at 7,14 (July 13, 2015) (holding that the Board will

not institute review of an asserted ground of unpatentability that relies on a

reference that the petitioner has not established is a prior-art patent or printed

publication). Here, the Board should decline to institute review of Ground 2

because it relies on the NIH reference (Ex. 1015), and CFAD has not established

that the NIH reference is a prior-art printed publication to the 501 patent.

CFAD bears the burden of proving that each of its references are printed

publications. See Cisco Sys., Inc. v. Constellation Techs. LLC, IPR2014-00871,

Paper 12 at 11(Dec. 19, 2014). The Federal Circuit has held that public


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accessibility is the touchstone in determining whether a reference is a printed

publication. See In re Hall, 781 F.2d 897, 899 (Fed. Cir. 1986). To establish that a

reference was publicly accessible, CFAD must make a satisfactory showing that

[the reference] has been disseminated or otherwise made available to the extent

that persons interested and ordinarily skilled in the subject matter or art exercising

reasonable diligence, can locate it. A.R.M., Inc. v. Cottingham Agencies Ltd.,

IPR2014-00671, Paper 10 at 7 (Oct. 3, 2014) (citing Bruckelmyer v. Ground

Heaters, Inc., 445 F.3d 1374, 1378 (Fed. Cir. 2006)). Further, when the reference

in question is [a] reference prepared for a conference, as CFAD alleges it is here,

CFAD must demonstrate that it was actually disseminated at [the] conference

without restriction. Ciena Corp. v. Cirrix Sys., Appeal 2011-013123, 2012 WL

946543, at *4 (B.P.A.I. Mar. 16, 2012) (citing Mass. Inst. of Tech. v. AB Fortia,

774 F.2d 1104, 1109 (Fed. Cir. 1985)).

As discussed below, CFAD has not met its burden of proving that the NIH

reference was either made available or disseminated to a POSA, and thus, has not

proven that the NIH reference is a prior-art printed publication to the 501 patent.

Because at least one reference in the combination of references relied on by CFAD

in Ground 2 is not prior art, Ground 2 should be denied. See Actavis, Inc. v.

Research Corp. Techs. Inc., IPR2014-01126, Paper 22 at 13-14 (Jan. 9, 2015)

(denying institution of IPR where one reference in a combination of several


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references asserted to prove obviousness was not prior art); L-3 Commcn

Holdings, Inc. v. Power Survey, LLC, IPR2014-00832, Paper 9 at 18 (Nov. 14,

2014) (same); A.R.M., IPR2014-00671, Paper 10 at 6-8 (same).

1. CFAD Has Not Proven That The NIH Reference Was Publicly Available

CFAD makes two arguments to support its contention that the NIH reference

was publicly available prior to the 501 patents August 28, 1998 priority date.

Both lack merit.

First, CFAD relies on an NIH press release (the Press Release) that directs

viewers to a link for the website http://rarediseases.info.nih.gov/ord/ (the Link),

where [a] complete agenda and background information on the meeting, along

with an extensive bibliography on thalidomide research is available. Pet. at 17-

18; Ex. 1017. Based on the date of the Press Release, CFAD concludes that the

NIH reference was available no later than September 5, 1997. Pet. at 17.

CFAD, however, has not provided any evidence that any documents were

available through the Link, let alone that the NIH reference was available at that

location at any time prior to the August 28, 1998 priority date of the 501 patent.

Instead, CFAD merely assumes that the NIH reference was available at that

location. But evidence of a document being a printed publication must rest on

facts, not assumptions. See AT&T Corp. v. Microsoft Corp., No. 01-4872, 2004

WL 292321, at *6-7 (S.D.N.Y. Feb. 17, 2004); Cisco Sys., IPR2014-00871, Paper


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12 at 11 (finding Petitioner lacked evidence of publication where there was no

evidence to back up the naked assertion that it was published).

The facts demonstrate that the NIH reference was not available at the Link

prior to the 501 patents priority date. Evidence from the Internet Archive

Wayback Machine confirms this fact. The Wayback Machine collects archived

versions of web pages as they exist as of their date of capture by web crawlers.

The accessibility of a particular web page cannot be established before its earliest

archived date. The Wayback Machine takes a person to the closest available

date for the Link. Ex. 2013 at 10.

Exhibit 2014 depicts the Wayback Machine archive record associated with

the Link. The archive record excerpt, shown below, states the address of the

webpage archived, and most importantly, the range of dates during which the

webpage was archived. Here, the excerpt, with annotations, shows that the Link in

the Press Release was archived 260 times, with the first archive occurring on

December 2, 1998months after the 501 patents priority date.2

2 Notably, the Wayback Machines archives of the main NIH website go back

until at least December of 1997 (see http://web.archive.org/web/*/http://nih.gov),

and archives of rarediseases.info.nih.gov go back until at least January of 1998

(see http://web.archive.org/web/*/http://rarediseases.info.nih.gov).


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The Wayback Machine does not have an image of the webpage associated

with the Link in December 1998, but the first image of that webpage from

February 1999 shows that the Link did not go to the NIH reference at that time.

Rather, it went to the Office of Rare Diseases home page:

Ex. 2015.


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Further, and independent of the Wayback Machine, the Press Release itself

does not establish that the NIH reference could be accessed at the Link at any time

because the Press Releases description does not match the NIH references

content. Specifically, the Press Release describes a document that includes an

extensive bibliography of thalidomide research. Ex. 1017. But the NIH reference

does not contain a bibliography of thalidomide research, let alone an extensive

one. See Ex. 1015. The Press Release also describes the document found at the

Link as having [a] complete agenda and background information on the meeting.

Ex. 1017. But the NIH Reference does not have background information on the

meeting. Rather, it is composed of abstracts for each speaker, further

distinguishing its content from the unidentified document (if it even exists) that is

described in the Press Release. As such, the evidence demonstrates that the NIH

reference was not available at the Link referenced in the Press Release.

Second, CFAD relies on the following disclosure within the NIH reference:

This book is designed for the use of participants in the workshop and as a pertinent reference document for anyone interested in the workshop subject. We are grateful to the authors who have summarized their materials and made them available in a timely fashion.

See Pet. at 18; Ex. 1015 at 15. The content of the NIH reference, however, is

irrelevant to whether it was publicly available before the 501 patents priority


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date. Indeed, CFAD does not provide any explanation as to how this disclosure

relates to the references public availability as of the 501 patents priority date.

Notably, CFAD does not provide any evidence concerning when the NIH

reference was published, or when, if at all, the reference was actually made

available to any person who attended the workshop. Rather, CFAD again assumes

that the excerpt it relies on means that the NIH reference was published before the

workshop, as opposed to after. But there is nothing in the disclosure that evidences

CFADs assumption. Accordingly, CFAD has not established that the NIH

reference was publicly available prior to the 501 patents priority date.

2. CFAD Has Not Offered Any Evidence of Dissemination

Even assuming that CFAD had alleged sufficient facts to show that the NIH

reference was made available in some fashionit has notCFAD still has not met

its burden of showing that the NIH reference was disseminated to a POSA at the

conference without restriction. See Ciena, 2012 WL 946543, at *4. In fact, CFAD

has not offered any proof that the NIH reference was distributed to a single person

at the conference. Nor has CFAD offered any evidence that anyone at the

conference actually downloaded the NIH reference from the Link in the Press

Release, or, as discussed above, that it was ever possible to do so.

In addition, CFAD has not put forth any information regarding the details of

the workshop. CFAD has not even provided information regarding the number of


04841.00006/7042670.1 - 20 -

attendees and whether the attendees were POSAs. All of this information is

necessary to establish that the NIH reference is a printed publication. See Mass.

Inst., 774 F.2d at 1109 (finding a scientific paper was prior art only where it was

presented to between 50 and 500 persons having ordinary skill in the art, and the

paper itself was actually distributed to at least six persons).

For this additional reason, CFAD has not demonstrated that the NIH

reference is a printed publication and, as a result, Ground 2 should be denied.

B. The Petition Should Be Denied Because CFAD Has Failed To Show A Reasonable Likelihood That The Claims Would Have Been Obvious

1. CFADs Expert Declaration Is Entitled To little or no weight

As discussed below, CFADs Petition relies heavily on the declaration of Dr.

Jeffrey Fudin. See generally Pet. (citing Ex. 1002). Dr. Fudins opinions,

however, are entitled to little or no weight, including because: (1) Dr. Fudins

experience does not qualify him as a POSA; and (2) his opinions are unsupported,

verbatim recitations of CFADs conclusory arguments.

(a) Dr. Fudin Is Not A POSA Dr. Fudin does not have the knowledge of a POSA or any experience with

the problem that is solved by the 501 patent. CFAD defines a POSA as a

pharmacist. Pet. at 20. In particular, a POSA under CFADs definition would

typically have either a Pharm.D. or a BS in pharmacy with approximately 5-10


04841.00006/7042670.1 - 21 -

years of related experience and a license to practice as a registered pharmacist in

any one or more of the United States. Id. This definition improperly ignores the

true field of the claimed inventions, which is avoidance of adverse events

associated with drug products (i.e., pharmaceutical drug product risk management).

As such, Celgene disagrees with CFADs definition of a POSA, and proposes that

a POSA would have had at least a bachelors degree and at least 2 years of

experience in risk management relating to pharmaceutical drug products, or a B.S.

or M.S. in pharmaceutical drug product risk management or a related field.

Celgenes definition of a POSA is supported by the claims and specification

of the 501 patent. See generally Ex. 1001. CFADs POSA, on the other hand, is

intentionally shaped to mirror the skills of Dr. Fudin and the alleged prior-art

references on which CFAD relies. While Dr. Fudin work[ed] in close

collaboration with medical staff members in the management of various acute and

chronic pain disease states, and has experience with . . . computerized billing and

patient record systems through his work as a pharmacist (Ex. 1002 at 5, 8), he

does not have the knowledge of a POSA or any experience with the problem that is

solved by the 501 patent. For example, a POSA would have experience in

designing and implementing systems for controlling access to pharmaceutical drug

products that have the potential for life threatening adverse eventsthe subject

matter of the 501 patent.


04841.00006/7042670.1 - 22 -

Because Dr. Fudins opinions regarding the patentability of the 501 patent

claims are not from the view of a POSA, they are entitled to no weight.

(b) Dr. Fudins Opinions Are Unsupported, Verbatim Recitations Of CFADs Conclusory Arguments

Dr. Fudins opinions are also entitled to little or no weight because they are

unsupported and largely verbatim recitations of CFADs conclusory arguments.

See infra. To the extent that Dr. Fudin fails to cite any underlying factual bases for

his opinions, they are entitled to little or no weight. See 37 C.F.R. 42.65(a);

Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 294 (Fed. Cir.

1985) (stating a lack of factual support for expert opinion may render the

testimony of little probative value in a validity determination).

Indeed, the Board has been clear that it will exercise its well-established

discretion to give little weight to conclusory, unsupported expert testimony, such

as testimony that d[oes] not elaborate on [the Petitioners] position because it

simply repeat[s the Petitioners] conclusory statements verbatim. TRW

Automotive US LLC v. Magna Elecs., Inc., IPR2014-00258, Paper 18 at 10-11

(Aug. 27, 2014); see also Apple Inc. v. Smartflash LLC, CBM2014-00111, Paper 7

at 21 (Sept. 30, 2014) (denying institution where the expert declaration simply

reiterates [the Petitioners] contentions and conclusory reasoning). Celgene

submits that the Board should do the same here.


04841.00006/7042670.1 - 23 -

2. Ground 1: The Claimed Inventions Would Not Have Been Obvious Over Powell, Mitchell, and Dishman

CFADs Ground 1 lacks merit because CFAD: (1) fails to address both the

claims and the prior art as a whole; (2) does not identify a colorable motivation to

combine or modify the cited art; and (3) cannot show that the prior art disclosed,

taught, or suggested each and every element of the claims.

(a) CFAD Fails To Address Both The Claims And The Prior Art As A Whole

CFADs obviousness analysis is improper because it fails to address both the

claims and the prior art as a whole. [A] patent composed of several elements is

not proved obvious merely by demonstrating that each of its elements was,

independently, known in the prior art. KSR Intl Co. v. Teleflex Inc., 550 U.S.

398, 418 (2007). Indeed, [i]f identification of each claimed element in the prior

art were sufficient to negate patentability, very few patents would ever issue. In

re Rouffet, 149 F.3d 1350, 1357 (Fed. Cir. 1998). CFAD ignores this well settled

principal of patent law. Instead, with hindsight, CFAD parses each individual

element of the challenged claims for the purpose of identifying corresponding

portions of the prior art that allegedly suggest that element to a POSA. Not once

does CFAD address the combination of claim elements as a whole. For this reason

alone, its obviousness ground should be denied.


04841.00006/7042670.1 - 24 -

The law also requires CFAD to consider the prior art as a whole, including

teachings that point away from the claimed invention. Leo Pharm. Prods. v. Rea,

726 F.3d 1346, 1353-56 (Fed. Cir. 2013). As described below, CFAD also fails to

conduct this critical analysis. Instead, it picks and chooses only those portions of

the prior art that allegedly support its obviousness position. For this additional

reason, CFADs obviousness analysis is legally flawed and should be rejected.

(b) CFAD Has Not Provided A Motivation To Combine Powell With Dishman Or Mitchell

CFADs Petition should also be denied because it does not explain how the

teachings of the references would be arranged or combined by a POSA, or why a

POSA would have made such a combination without the benefit of hindsight. A

Petitioner must show some reason why a [POSA] would have thought to combine

particular available elements of knowledge, as evidenced by the prior art, to reach

the claimed invention. Heart Failure Techs., LLC v. Cardiokinetix, Inc.,

IPR2013-00183, Paper No. 12 at 9 (July 31, 2013). Indeed, obviousness cannot

be sustained by mere conclusory statements; instead, there must be some

articulated reasoning with some rational underpinning to support the legal

conclusion of obviousness. In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006).

The Board has repeatedly denied institution where a petitioner fails to

demonstrate that it would have been obvious to combine or modify references,

holding that conclusory or general statements regarding alleged reasons to combine


04841.00006/7042670.1 - 25 -

or modify references are insufficient. See, e.g., TRW Auto. US LLC v. Magna

Elecs., IPR2014-00293, Paper 19 at 17 (July 1, 2014); Moses Lake Indus. v.

Enthone, Inc., IPR2014-00243, Paper 6 at 20 (June 18, 2014); Biodelivery Sci. Intl

v. Monosol Rx, LLC, IPR2015-00167, Paper 6 at 26-27 (May 20, 2015). Absent an

articulated reasoning with a rational underpinning to support the legal conclusion

of obviousness, CFAD fails to establish a prima facie case of obviousness. See

TRW Auto. US LLC v. Magna Elecs., IPR2014-00257, Paper 16 at 7, 12 (June 26,

2014) (denying petition where Petitioner failed to set forth motivation to combine).

Here, CFAD has not provided any analysis that supports a motivation to

combine Powell, Mitchell, and Dishman. Its arguments should be rejected because

they: (1) are rooted in hindsight, using the 501 patents disclosures as a basis to

combine the references; (2) are based on unsupported conclusory statements;

(3) fail to account for the fact that the references are directed to different endeavors

and also teach away from the claimed inventions; and (4) ignore that there can be

no motivation to combine because the prior art does not disclose each and every

element of the claimed inventions.

First, CFAD improperly uses the 501 patents disclosures as its basis to

combine the references. Specifically, CFAD contends that a POSA would look to

Powell for guidance on the clinical use and dispensing of thalidomide, and

would garner from it recommendations for delivering a teratogenic drug to


04841.00006/7042670.1 - 26 -

patients in need of the drug while avoiding the delivery of said drug to a foetus.

Pet. at 21 (emphasis added). CFAD admits, however, that the emphasized

language is from the 501 patents preamble. Id.; Ex. 1001 at 10:44-46. CFAD

thus defin[es] the nature of the problem to be solved as the specific problem

solved by the invention . . . [CFAD] has relied on impermissible hindsight to

supply the reason to combine. Purdue Pharma L.P. v. Depomed, Inc., IPR2014-

00379, Paper 72 at 28 (July 8, 2015); see also Texas Instruments Inc. v. Vantage

Point Tech. Inc., IPR2014-01105, Paper 8 at 17 (Jan. 5, 2015) (finding it

impermissible to use the challenged patents description of the invention as a

roadmap to piece together the prior art). As such, its argument lacks merit.

Second, CFAD improperly basis its motivation argument on only its experts

unsupported and conclusory opinions. Specifically, CFAD alleges that a POSA

would: (1) implement Powells teachings in clinical and pharmacy settings in

view of the Accutane and Clozaril programs disclosed in Mitchell and

Dishman, respectively; and (2) recognize that Powell and Dishman address the

shortcomings of the Accutane program . . . disclosed in Mitchellnamely, that the

use of the registry was not mandatory for all patients, and that the system did not

involve verification by pharmacists that a patient was authorized to receive the

drug. Pet. at 21-22.


04841.00006/7042670.1 - 27 -

The only support that CFAD offers for this conclusory argument, however,

is its experts opinion at 89, which recites the exact same conclusory statement

without the rational underpinning required to establish obviousness. Dr. Fudins

opinion should, therefore, be given little to no weight since it d[oes] not elaborate

on [CFADs] position because it simply repeat[s CFADs] conclusory statements

verbatim. TRW Auto., IPR2014-00258, Paper 18 at 10. CFADs alleged

motivation argument should be rejected for this additional reason.

Third, CFAD fails to account for the fact that the prior art references are

directed to completely different endeavors and also teach away from the claimed

inventions. Specifically, CFAD ignores that, at the very least, a POSA would not

have been motivated to combine Dishman with Powell or Mitchell because

Dishman is not directed to a system designed to prevent exposure of a drug to a

fetus and, thus, fetal birth defects. Further, a POSA looking to develop a system

for universal use would not find a distribution system isolated to the Department of

Veteran Affairs (as Dishman is) to be particularly instructive. In that regard, the

risks associated with commercial pharmacy distribution of a teratogenic drug are

far more complex, and require different management, than distribution to a small

group of individuals at the Department of Veterans Affairs.

Furthermore, even if a POSA would look to the system disclosed in

Dishman, they would not ignore the prior art as a whole, which teaches away from


04841.00006/7042670.1 - 28 -

the Clozaril system discussed in Dishman because that system, as a whole, was a

failure. See supra at II.B. As such, a POSA would have been taught away from

combining Dishman with any reference, including Powell or Mitchell. A reference

that teaches away cannot serve as a basis for obviousness. See, e.g., In re Gurley,

27 F.3d 551, 553 (Fed. Cir. 1994). A reference may be said to teach away when a

[POSA], upon reading the reference, would be discouraged from following the

path set out in the reference, or would be led in a direction divergent from the path

that was taken by the applicant. Id. That is exactly what Dishman does here.

Similarly, a POSA would not have relied on the Accutane system described

in Mitchell because it was also a failure. As discussed above, Mitchell discloses

that compliance with the program was not complete and, as a result, there were

hundreds of pregnancies during isotretinoin treatment, at least six of which resulted

in fetal birth defects. See supra at II.B. CFAD ignores this additional reason that a

POSA would not have been motivated to combine Powell, Mitchell, and Dishman.

Fourth, CFAD ignores that there can be no motivation to combine the

references because the prior art does not disclose each and every element of the

claimed inventions. Specifically, the Federal Circuit has instructed that motivation

to combine is only a consideration if all the elements of an invention are found in

a combination of prior art references. Medichem, S.A. v. Rolabo, S.L., 437 F.3d

1157, 1164 (Fed. Cir. 2006). As discussed below, the prior art does not disclose all


04841.00006/7042670.1 - 29 -

of the elements of the challenged claims. CFAD has failed to meet its burden of

showing a motivation to combine for this additional reason.

For the foregoing reasons, CFAD has failed to set forth a motivation to

combine the prior art as set forth in Ground 1. This ground should be denied.

(c) The Ground 1 References Fail To Disclose, Teach, Or Suggest Key Elements Of The Claimed Inventions

CFAD relies on Powell, Dishman, and Mitchell as teaching the elements of

the 501 patent. None of these references, however, teach all of the elements of the

claimed subject matter, and certain elements are missing from every reference.

Attempting to fill in the missing elements, CFAD relies only on attorney argument,

its experts unsupported and conclusory statements, and impermissible hindsight.

CFAD falls far short of showing a reasonable likelihood that the challenged claims

would have been obvious.

i. Independent Claim 1 Would Not Have Been Obvious Over Powell, Mitchell, And Dishman

1) Elements 1(a), 1(b), and 1(c) In Ground 1, CFAD alleges that Powell and Dishman teach (a) registering

in a computer readable storage medium prescribers who are qualified to prescribe

said drug; (b) registering in said medium pharmacies to fill prescriptions for said

drug; and (c) registering said patients in said medium, including information

concerning the ability of female patients to become pregnant and the ability of


04841.00006/7042670.1 - 30 -

male patients who are capable of impregnating females. Pet. at 25-29. CFAD is

incorrect.

As an initial matter, CFAD admits that Powell does not disclose the use of a

computer readable storage medium. Id. at 26; Ex. 1002 at 113. Rather, CFAD

cites to In re Venner, 262 F.2d 91, 96 (CCPA 1955) for the proposition that

automation of known manual processes is obvious, and argues that it would be

routine optimization to have electronic records of the information disclosed in

Powell. Pet. at 26. But in Venner, unlike here, all of the limitations in the claims

were disclosed in the alleged prior-art references. Thus, CFADs reliance on

Venner is inapplicable to the present facts, where the art does not disclose all

elements of claim 1. See In re Ralf Wollenhaupt, Matthias Pietsch, & Matthias

Michanicki, Appeal No. 2007-3142, 2008 WL 685165, at *3 (P.T.A.B. Mar. 13,

2008) (distinguishing Venner on the same grounds).

CFAD then cites to its expert, who merely parrots the same conclusory

assertion that an advantage of having computer records is ease in sharing and

storing information . . . for purposes such as communicating with managed care

organizations. Pet. at 26; Ex. 1002 at 114. The alleged advantage proffered

by Dr. Fudin is irrelevant here. No aspect of the claimed invention relates to

communication with managed care organizations, and CFAD has not even


04841.00006/7042670.1 - 31 -

attempted to explain why a POSA would have been motivated to focus on such

communications at the time of the 501 patents invention.

Recognizing the deficiency in its obviousness argument, CFAD next argues

that [a]rmed with these disclosures from Powell and Mitchell, a POSA would

look to Dishman to further implement a computerized registry for avoiding birth

defects from a teratogenic drug. Pet. at 26-27.3 CFAD alleges that a POSA

would have looked to Dishman because the clozapine program described therein

was allegedly proven successful. Pet. at 27. Of course, CFAD does not cite

anything to support the alleged proven success[] of the Dishman system, nor

could it. Instead, CFAD relies solely on its experts say-so. Id. (citing Ex. 1002 at

117). CFADs unsupported declarant testimony is entitled to little or no weight.

See 37 C.F.R. 42.65(a). Further, as described above, the clozapine program was

recognized to be a failure, as evidenced by the dozen deaths that occurred on its

watch. A POSA would not have looked to Dishman and would not have been

motivated to combine Dishman with Powell or Mitchell.

Moreover, CFAD admits that Dishman does not disclose registering

pharmacies with the Clozaril National Registry. Pet. at 28. Yet, CFAD argues

3 CFAD has not pointed to any disclosure in Mitchell for support that these claim

elements are met. See Pet. at 25-29. Its argument is baseless for this reason alone.


04841.00006/7042670.1 - 32 -

that a POSA would have understood that pharmacist information would need to

be collected and stored as part of the registry. Id. As alleged support for its

argument, CFAD cites Dr. Fudins quotation of a statement in Dishman indicating

that cooperation between patients, physicians, laboratories, and pharmacies is

required for the process. Id. (citing Ex. 1002 at 121). This statement, however,

does not disclose, teach, or suggest that the registry collects pharmacy information

or that this information would need to be collected. A POSA would only come

to such a conclusion by using the 501 patent as a roadmap to navigate the prior

art. This is the epitome of hindsight and cannot be used to render the claim

obvious. See Texas Instruments, IPR2014-01105, Paper 8 at 16-17 (finding it

impermissible to use the challenged patents description of the invention as a

roadmap to piece together the prior art). CFAD has failed to show that its cited

references disclose, teach, or suggest Elements 1(a), 1(b), and 1(c).

2) Element 1(d) CFAD asserts that Powell and Mitchell disclose the element retrieving from

said medium information identifying a subpopulation of said female patients who

are capable of becoming pregnant and male patients who are capable of

impregnating females. Pet. at 22. Again, CFAD is incorrect.

First, CFAD has failed to put forth any argument regarding whether Powell

or Mitchell disclose the beginning portion of this claim element: retrieving from


04841.00006/7042670.1 - 33 -

said medium. Instead, CFAD and its declarant completely ignore this portion of

the claim, arguing only that a POSA would have understood the desirability of

identifying the subpopulations of female and male patients required by this claim

element. Id.; Ex. 1002 at 91. For this reason alone, CFADs argument fails.

Second, CFAD does not argue that either Powell or Mitchell disclose, teach,

or suggest anything regarding male patients who are capable of impregnating

females. Pet. at 23. Instead, CFAD relies on only Dr. Fudins declaration, in

which he asserts that a POSA would have included in the subpopulation any

individual that could be affected by the teratogenic nature of the drug. Id. (citing

Ex. 1002 at 95.) For support for this assertion, Dr. Fudin cites Mann 1982s

disclosure that thalidomide was known to be present in male sperm. Pet. at 23; Ex.

1002 at 96 (citing Ex. 1018 at 7-8).

Mann 1982, however, is not asserted in any ground of unpatentability or

even discussed generally in the Petition. CFADs argument should be disregarded

for this reason alone. See Boehringer Ingelheim Intl v. Biogen, Inc., IPR2015-

00418, Paper 14 at 17 (July 13, 2015) (citing 37 C.F.R. 42.104(b)(2)) (holding

that its impermissible to rely on external references to establish obviousness); see

also 37 C.F.R. 42.6(a)(3) (arguments may not be incorporated from other

documents into the Petition). The Board should also disregard this argument

because CFAD has not alleged, let alone made a sufficient showing, of any


04841.00006/7042670.1 - 34 -

motivation to combine Mann with Powell or Mitchell to arrive at the claimed

inventions. See Norman Intl, Inc. v. Hunter Douglas Inc., IPR2014-00276, Paper

No. 11 at 20 (June 20, 2014) (denying institution and stating that the motivation to

combine analysis should be made explicit).

Further, Mann 1982 does not show the state of the art at the time of the 501

patents invention. Specifically, CFAD fails to analyze the prior art as a whole.

Despite relying on Powell elsewhere in its Petition, here CFAD ignores Powells

later published disclosure that states, with respect to thalidomide, no effects on

male sperm are recognized. Ex. 1005 at 903. Thus, a POSA would not have

been motivated to include males in any subpopulation, as Powell teaches away

from doing so. [R]eferences that teach away cannot serve to create a prima facie

case of obviousness. McGinley v. Franklin Sports, Inc., 262 F.3d 1339, 1354

(Fed. Cir. 2001).

For the foregoing reasons, CFAD has failed to show that there is a

reasonable likelihood that claim 1 is obvious.

ii. Dependent Claims 2-10 Would Not Have Been Obvious Over Powell, Mitchell, And Dishman

Because CFAD has failed to show that there is a reasonable likelihood that

claim 1 is obvious, it also has failed to show that there is a reasonable likelihood

that any of claims 2-10, which depend from claim 1, are obvious. See In re Fine,


04841.00006/7042670.1 - 35 -

837 F.2d 1071, 1076 (Fed. Cir. 1988) (holding that a dependent claim that depends

from a non-obvious independent claim is also nonobvious).

CFAD has also failed to demonstrate a reasonable likelihood that claim 7 is

obvious for additional reasons. Claim 7 depends from claim 1 and adds the

limitation that said prescriptions are filled for no more than about 28 days. Ex.

1001 at Claim 7. CFAD argues that claim 7 would have been obvious over Powell

and the general knowledge of the field. Pet. at 33. CFAD does not argue,

however, that Powell discloses the 28-day-prescription limitation. Id. In fact,

CFAD acknowledges that the only temporal limitation put on prescriptions in

Powell is 3 months. Id.; Ex. 1005 at 904. Claim 7s additional limitation is not

disclosed in the prior art, and CFAD cannot prove obviousness. See 37 C.F.R.

42.104(b)(4) (The petition must specify where each element of the claim is found

in the prior-art patents or printed publications relied upon.); see also Toshiba

Corp. v. Optical Devices, LLC, IPR2014-01446, Paper 7 at 16 (Mar. 10, 2015) (A

prior art reference demonstrating the feature of claim 3 was not provided.

Petitioner, therefore, has not shown a reasonable likelihood that it would prevail in

showing that claim 3 is obvious over the applied references.).

Further, CFAD does not argue that anything in Powell or in the other cited

references would have motivated a POSA to modify Powells teaching to use a 3-

month supply to arrive at the claimed 28-day limtiation. Without any reason or


04841.00006/7042670.1 - 36 -

explanation as to why a POSA would have modified the prior art based on the

general knowledge of the field, CFADs argument fails. CFAD has failed to show

there is a reasonable likelihood that claim 7 is obvious for this additional reason.

3. Ground 2: The Claimed Inventions Would Not Have Been Obvious Over the NIH Reference And Honigfeld

CFADs argument that Claims 1-10 are obvious over the NIH reference in

view of Honigfeld (Pet. at 45) also fails on the merits. As already discussed, the

NIH reference is not prior art, would not have been available to a POSA and,

therefore, cannot render the claimed inventions obvious. See supra at III.A. As

discussed below, even if the NIH reference is prior art, CFAD has not shown a

reasonable likelihood of prevailing on the challenged claims because CFAD:

(1) fails to address both the claims and the prior art as a whole; (2) does not

identify any colorable motivation to combine or modify the cited art; and

(3) cannot show that the prior art disclosed, taught, or suggested each and every

element of the claims.

(a) CFAD Fails To Address Both the Claims and the Prior Art As a Whole

CFADs obviousness analysis is improper because it fails to address both the

claims and prior art as a whole. [A] patent composed of several elements is not

proved obvious merely by demonstrating that each of its elements was,

independently, known in the prior art. KSR, 550 U.S. at 418. Indeed, "[i]f


04841.00006/7042670.1 - 37 -

identification of each claimed element in the prior art were sufficient to negate

patentability, very few patents would ever issue. Rouffet, 149 F.3d at 1357.

CFAD ignores this well settled principal of patent law. Rather, with hindsight,

CFAD parses each individual element of the challenged claims for the purpose of

identifying corresponding portions of the prior art that allegedly suggest that

element to a POSA. Not once did the CFAD address the combination of claim

elements as whole. For this reason alone, its obviousness argument fails.

The law also requires CFAD to consider the prior art as a whole, including

teachings that point away from the claimed invention. Leo, 726 F.3d at 1353-56.

As described below, CFAD also fails to conduct this critical analysis. Instead, it

picks and chooses only those portions of the prior art that allegedly support its

obviousness contentions. For this additional reason, Ground 2 should be denied.

(b) CFAD Has Not Provided A Motivation To Combine The NIH Reference And Honigfeld

CFAD argues that a POSA would have been motivated to combine the NIH

References alleged disclosures regarding the PPP with Honigfelds alleged

disclosures regarding clozapine because those programs were recognized methods

to avoid the delivery of drugs to contraindicated individuals. Pet. at 46. In other

words, CFAD argues that a POSA would have combined the references because

they are both allegedly directed to the same endeavor. CFAD is incorrect.


04841.00006/7042670.1 - 38 -

As an initial matter, CFADs alleged motivation is insufficient to carry its

burden because it is general and conclusory.4 The Board has consistently denied

institution where the only alleged motivation to combine is that all references were

directed to the same field or endeavor. See, e.g., Cisco Sys., Inc. v. C-Cation

Techs. LLC, IPR2014-00454, Paper 12 at 13-15 (Aug. 29, 2014); Norman Intl,

IPR2014-00276, Paper 11 at 19-20; Microsoft Corp. v. Enfish, LLC, IPR2013-

00561, Paper 13 at 23-24 (Mar. 4, 2014); OpenTV, Inc. v. Cisco Tech., Inc.,

IPR2013-00329, Paper 9 at 28-30 (Nov. 29, 2013); Heart Failure, IPR2013-00183,

Paper 12 at 9.

In any event, the NIH reference and Honigfeld are not directed to the same

endeavor. In particular, Honigfeld is not directed to preventing fetal birth

abnormalities. A POSA looking to design a system to prevent drug-related birth

defects would not look to the Honigfeld system because it was designed for a

completely different purpose. Moreover, as discussed above (see supra at II.B), a

POSA would have been aware that, based on Honigfeld itself, the clozapine system

was a failure and, thus, taught away from adopting its alleged disclosures. Indeed,

a reference that teaches away cannot serve as a basis for obviousness. See, e.g., In

4 Dr. Fudin likewise offers the same insufficient general motivation to combine in

his declaration. (Ex. 1002 at 176.)


04841.00006/7042670.1 - 39 -

re Gurley, 27 F.3d at 553. A reference may be said to teach away when a

[POSA], upon reading the reference, would be discouraged from following the

path set out in the reference, or would be led in a direction divergent from the path

that was taken by the applicant. Id. That is exactly what Honigfeld does.

CFADs motivation argument fails for this additional reason.

Recognizing the failure of prior-art systems, CFAD alleges that a POSA

would have sought to implement the methods described in NIH and Honigfeld in

order to improve upon the non-mandatory registration and unrestricted pharmacy

methods of the Accutane program. Pet. at 46. For this argument, CFAD relies

solely on Dr. Fudins conclusory opinion, verbatim. See Pet. at 46 (citing Ex.

1002 177.). Dr. Fudin does not provided any explanation as to why a POSA

would seek to improve upon the Accutane program, let alone why a POSA would

seek to specifically improve the non-mandatory registration and unrestricted

pharmacy methods of the program. CFADs alleged motivation to combine is not

supported by the factual record, and Dr. Fudins opinion is entitled to little or no

weight. See TRW Auto., IPR2014-00258, Paper 18 at 10; see also 37 C.F.R.

42.65(a). CFADs argument should be rejected for this additional reason.

Finally, the Federal Circuit has instructed that motivation to combine is only

a consideration if all the elements of an invention are found in a combination of

prior art references. Medichem, 437 F.3d at 1164. As discussed below, the prior


04841.00006/7042670.1 - 40 -

art does not disclose all of the elements of the challenged claims. Thus, CFAD has

failed to meet its burden of showing a motivation to combine.

(c) The Cited References Fail To Disclose, Teach, Or Suggest Key Elements Of The Claimed Inventions

In Ground 2, CFAD relies on the NIH reference and Honigfeld as teaching

the elements of the 501 patents claims. Neither of these references, however,

disclose, teach, or suggest all of the elements of the claimed subject matter, and

certain elements are missing from each reference as discussed below. Attempting

to fill in the missing elements, CFAD relies only on attorney argument, its experts

unsupported and conclusory statements, and impermissible hindsight. CFAD falls

far short of showing a reasonable likelihood that the challenged claims are obvious.

i. Claim 1 Would Not Have Been Obvious Over The NIH Reference and Honigfeld

1) Element 1(c) CFAD argues that Element 1(c), registering said patients in said medium,

including information concerning the ability of female patients to become pregnant

and the ability of male patients who are capable of impregnating females, would

have been obvious over Honigfeld. Pet. at 49. CFAD is incorrect.

As an initial matter, CFAD does not argue that Honigfeld discloses the

portion of Element 1(c) reciting including information concerning the ability of

female patients to become pregnant and the ability of male patients to impregnate

females. Pet. at 49. Rather, as CFAD acknowledges, Honigfeld discloses


04841.00006/7042670.1 - 41 -

recording information regarding white blood cell counts. Id.; see also Ex. 1009 at

53. Recognizing this deficiency, CFAD turns to Dr. Fudins conclusory and

unsupported assertion that a POSA would have known to modify this teaching and

record information concerning pregnancy in the case of a teratogenic drug as part

of the records entered into the computer database. Id. at 50 (citing Ex. 1002 at

207.) Dr. Fudins unsupported statement is entitled to little or no weight. See 37

C.F.R. 42.65(a). Indeed, only with hindsight and the claimed invention in mind

would a POSA take such an action. CFAD has not pointed to any teaching in the

prior art to support this position. It has, therefore, failed to show there is a

reasonable likelihood that this element would have been obvious. See 37 C.F.R.

42.104(b)(4) (The petition must specify where each element of the claim is

found in the prior art patents or printed publications relied upon.); see also

Toshiba, IPR2014-01446, Paper 7 at 16 (denying petition where a prior-art

reference demonstrating the feature of a claim was not provided).

2) Element 1(d) CFAD alleges that Element 1(d), retrieving from said medium information

identifying a subpopulation of said female patients who are capable of becoming

pregnant and male patients who are capable of impregnating females, is taught by

the NIH reference. Pet. at 46; Ex. 1002 at 175-182. CFAD is wrong.


04841.00006/7042670.1 - 42 -

As an initial matter, CFAD has failed to put forth any argument regarding

whether the NIH reference discloses the first portion of this claim element,

retrieving from said medium. Indeed, CFAD has completely ignored this

language, instead arguing only that the NIH reference teaches the identification of

a subpopulation of patients who are capable of becoming pregnant or capable

of impregnating females. Pet. at 46. From this, CFAD concludes that the NIH

reference teaches retrieving information, without providing any specific

evidence or explanation directed towards this language. Id. at 47. CFADs expert,

Dr. Fudin, similarly fails to provide any support for this portion of the claim

element and instead, mimicking CFAD, provides a conclusory assertion that the

NIH reference teaches retrieving information about patients to identify the

subpopulation described in claim 1. Ex. 1002 at 175-182. Conclusory

assertions, without more, cannot establish obviousness. See 37 C.F.R. 42.65(a).

For this reason alone, CFADs argument fails.

CFAD also cites to select portions of several abstracts in the NIH reference

to conclude that a POSA would have understood that information about the ability

to become pregnant or impregnate would also be included in a database of

individual patients taking thalidomide. Pet. at 46. In so arguing, CFAD concedes

that this element is not explicitly taught by the NIH reference. There is no

indication or teaching by the NIH reference, or any other reference, that the


04841.00006/7042670.1 - 43 -

database of individual patients to track regulatory documentation and assess

safety-related trends cited to by CFAD would include information regarding a

womans ability to become pregnant or a males ability to impregnate a female.

Indeed, CFAD has not pointed to any such teaching. Only with hindsight and the

claimed invention in mind would a POSA reach the conclusion that CFAD relies

upon. This is improper and CFADs argument should be rejected.

Accordingly, for the foregoing reasons, CFAD has failed to show there is a

reasonable likelihood that claim 1 is obvious.

ii. Dependent Claims 2-10 Would Not Have Been Obvious Over The NIH Reference And Honigfeld

Because CFAD has failed to show that there is a reasonable likelihood that

claim 1 is obvious, it also has failed to show that there is a reasonable likelihood

that any of claims 2-10, which depend from claim 1, are obvious. See In re Fine,

837 F.2d 1071 (holding that a dependent claim that depends from a non-obvious

independent claim is also nonobvious).

CFAD has also failed to show that there is a reasonable likelihood that claim

7 is obvious for additional reasons. Claim 7 depends from claim 1 and adds the

limitation that the prescriptions are filled for no more than about 28 days. Ex.

1001 at Claim 7. CFAD argues that claim 7 would have been obvious over

Honigfeld and the general knowledge of the field. Pet. at 53. CFAD admits,


04841.00006/7042670.1 - 44 -

however, that Honigfeld does not disclose a 28-day-prescription limitation. Id.

Rather, CFAD acknowledges that the only temporal limitation put on prescriptions

in Honigfeld is 7 days. Id. Recognizing this deficiency in the prior art, CFAD

then relies on Dr. Fudins declaration for his unsupported conclusion that a POSA

would have understood to limit the drugs supply to a short period of time and

particularly a 28-day period since it aligns with the menstrual cycle. Id.; Ex. 1002

at 230. Neither CFAD nor Dr. Fudin have explained, however, why a POSA

would have been motivated to limit the drugs supply to a short time period and

both have ignored the prior art as a whole. For example, Powell, a reference

CFAD relies on in Ground 1 of its argument, discloses a 3-month temporal

limitation on prescriptions of thalidomide. Ex. 1005 at 904. Only with hindsight

and the claimed invention in hand would a POSA reach the same conclusions

reached by CFAD and Dr. Fudin. This is improper. CFAD has failed to show that

there is a reasonable likelihood that claim 7 is obvious for this additional reason.

4. CFAD Fails To Address The Objective Evidence Of Nonobviousness Regarding The 501 Patent

Objective indicia of nonobvious are not just cumulative or confirmatory

part of the obviousness calculus but constitute[] independent evidence of

nonobviousness. Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358,

1365 (Fed. Cir. 2008). In fact, the Federal Circuit has observed that objective

indicia can be the most probative evidence of nonobviousness in the record, and


04841.00006/7042670.1 - 45 -

enable[] the . . . court to avert the trap of hindsight. Crocs, Inc. v. Intl Trade

Commn, 598 F.3d 1294, 1310 (Fed. Cir. 2010). Here, CFAD does not address or

challenge the merits of Patent Owners secondary consideration evidence, and

thus its petition fails for this additional reason. Omron Oilfield & Marine, Inc. v.

MD/Totco, IPR2013-00265, Paper 11 at 16 (Oct. 31, 2013).

(a) Long-Felt Need Further Supports The Nonobviousness Of The Claimed Inventions

The existence of a long-felt and unsolved need for the patented invention

supports a finding of nonobviousness. See Georgia-Pacific Corp. v. U.S. Gypsum,

195 F.3d 1322, 1330 (Fed. Cir. 1999). Before the development of the patented

inventions, there was a long-felt and unsolved need for a system that would protect

the public from the horrors associated with teratogenic drugs like thalidomide.

Celgene developed S.T.E.P.S., which is covered by the methods claimed in the

501 patent, to address that need. Without the inventions of the 501 patent,

Thalomid, Revlimid, and Pomalyst would not be on the market today.

Accordingly, the inventions claimed in the 501 patent provided a way for patients

in need to receive valuable, life-altering treatments, including cancer treatments.

The need for the therapies provided by Thalomid, Revlimid, and

Pomalyst is evidenced by the fact that the FDA granted Orphan Drug Exclusivity

to each product for meeting an unmet need felt by relatively small, untreated

patient populations. Ex. 2016; Ex. 2017; Ex. 2018. Moreover, all three drugs were


04841.00006/7042670.1 - 46 -

approved under accelerated approval regulations during the FDA approval process

so that they could reach patients in need faster. See, e.g., Ex. 2006-2008.

Of course, as noted above, none of these approvals would have been

possible without the inventions claimed in the 501 patent, which ultimately were

required as conditions for approval by the FDA. See Ex. 1016 at 0002; Ex. 2006 at

1; Ex. 2007 at 1; Ex. 2008 at 7-10 (discussing the drugs approvals subject to

Subpart H). The problems associated with safe access to teratogenic drugs

addressed by the claimed inventions were not solved by the prior-art Clozaril and

Accutane systems. The FDAs grant of ODE and accelerated approval for these

drugs, which contain actual or potential teratogens, also demonstrates the faith that

the FDA placed in the inventions claimed in the 501 patent, which represent the

gold standards in pharmaceutical risk management.

(b) Commercial Success Further Supports The Nonobviousness Of The Claimed Inventions

Commercial success is usually shown by significant sales in a relevant

market. J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d 1563, 1571 (Fed.

Cir. 1997); see also Neupak, Inc. v. Ideal Mfg. & Sales Corp., 41 F. Appx 435,

440 (Fed. Cir. 2002) ([S]ales figures alone can provide satisfactory evidence of

commercial success.).

Here, commercial success of the patented inventions is evidenced by the

sales of Thalomid, Revlimid, and Pomalyst, which together have annual U.S.


04841.00006/7042670.1 - 47 -

revenues of billions of dollars. See Ex. 2019 at 62. Each sale of these drugs is

made pursuant to, and is only possible as a result of, a restricted distribution or

REMS program that is covered by one or more claims of the 501 patent. See Ex.

1016 at 0002; Ex. 2006 at 1; Ex. 2007 at 1; Ex. 2008 at 7-10 (discussing the drugs

approvals subject to Subpart H). In other words, nexus is present because, but for

the methods claimed in the 501 patent, no sales of Thalomid, Revlimid, and

Pomalyst would have occurred.

(c) Third-Party Praise And Awards Further Supports The Nonobviousness Of The Claimed Inventions

Praise in the industry tends to indicate that the invention [is] not obvious.

Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d 1342, 1370 (Fed. Cir.

2012). Here, awards and industry recognition for the patented inventions also

support a finding of nonobviousness. Industry recognition is evidenced by the fact

that the National Organization for Rare Disorders (NORD) honored Celgene for

its development of Thalomid, including the development of S.T.E.P.S., which is

covered by the 501 patent. Ex. 2020. It is also evidenced by praise for those

systems in the published literature. See, e.g., Ex. 2021.

(d) Licensing by Others Further Supports The Nonobviousness Of The Claimed Inventions

Objective evidence of nonobviousness may also include licenses showing

industry respect. WMS Gaming, Inc. v. Int'l Game Tech., 184 F.3d 1339, 1359


04841.00006/7042670.1 - 48 -

(Fed. Cir. 1999). Here, licensing by others is evidenced by the fact that third

parties have licensed the 501 patent. For example, at the FDAs urging, several

manufacturers of isotretinoin (the active ingredient in Accutane) licensed several

patents, including the 501 patent, in connection with the restricted-distribution

program known as iPledge after it became clear that the PPP (and later attempts at

managing the distribution of isotretinoin) were ineffective. See Ex. 2010; Ex.

2011; Ex. 2012.

(e) Unexpected Results Further Supports The Nonobviousness Of The Claimed Inventions

Unexpected results are important indicia of nonobviousness. See United

States v. Adams, 383 U.S. 39, 51-52 (1966). [T]hat which would have been

surprising to a person of ordinary skill in a particular art would not have been

obvious. In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995).

Here, evidence of unexpected results is demonstrated by the fact that the

inventions claimed in the 501 patent have enabled the unexpected benefit of safely

administering teratogenic and potentially teratogenic drugs to patients who might

not otherwise have had access to them. Unexpected results are also demonstrated

by the fact that S.T.E.P.S.which is covered by the claims of the 501 patent

has been 100% successful in preventing birth defects of the type associated with

thalidomide. This stands in stark contrast to the birth defects associated with the

PPP and deaths associated with the Clozaril National Registry.


04841.00006/7042670.1 - 49 -

Celgenes results are especially unexpected in the face of skepticism

regarding the alleged impossibility of zero risk of drug-related birth defects before

the patented inventions were marketed. See, e.g., Ex. 2022 at 235 (We know that

when this drug is used by women of childbearing potential, the risk for causing

serious birth defects can never be lowered to zero.); id. at 241 (Unfortunately,

even with a stronger program for thalidomide, some affected infants will also be

born.); Ex. 2023 at 28 (Its important to remember that a zero risk is not

achievable. There is no system that will prevent the single birth of a child with

phocomelia.); Ex. 2024 at 33 ([N]o matter how exemplary the conduct of the

manufacturers is, no matter how good a job of warning the physicians and the

pharmacists do, there will be children born with birth defects as a result of

thalidomide. Its a fact. There will be.); Ex. 2025 at 2 (It is the view of the

Thalidomide Victims Association of Canada that babies will be born disabled. No

system is foolproof.). These unexpected results further support a finding of

nonobviousness.

For the foregoing reasons, CFAD has failed to show a reasonable likelihood

that any of claims 1-10 of the 501 patent would have been obvious.

C. The Petition Should Be Denied Under 35 U.S.C. 314(a) And 316(b)

As explained above, CFADs petition should be denied because it fails on

the merits. The Petition should also be denied because it is being used for an


04841.00006/7042670.1 - 50 -

improper purpose. Specifically, the RPI are non-practicing entities who are

abusing and misusing the IPR process as part of an investment strategy aimed at

causing changes in the stock prices of targeted innovator pharmaceutical

companies. The law gives the Board discretion over which petitions to accept, and

permits the Board to reject petitions that hinder the ability of the Office to timely

complete [IPR] proceedings. 35 U.S.C. 314(a) and 316(b). The Board should

use its discretion and deny this Petition.

The Petitioner, CFAD, is one of fifteen Coalition For Affordable Drugs

companies set up by one or more of the RPI. Ex. 2026 at 1; Ex.

preliminary response

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