* To the extent that any legal theories or opinions are expressed, such theories and opinions are those

of the author and

not those of the Perrigo Company. Nothing in this presentation constitutes the providing of legal advice or analysis.

1
á
 Trends in API / Pharma
Patent Filing
and Par. IV Activity
‡ Number of generic filings on the rise
‡ Number of generic filers on the rise
‡ Increased number of Par. IV filers
‡ Larger proportion of Par. IV challenges
‡ Intensification of the brand-generic patent litigations
‡ Earlier generic filing
‡ Inter-generic litigations
‡ Brands seem to deal less with true inventions and more with
generics blocking
3
 Number of Brand Patent Families
in á
Returned to the 199
Values

  

GSK
Pfizer




No of atent Families

No of Patent families

No of atent families
   
AstraZeneca

Merck & Co
Merck & Co

AstraZeneca
AstraZeneca
Pfizer

 

Pfizer

Merck & Co

GSK
 
GSK




BMS

á á á

BMS

BMS
1 1 1

á 1 á

199
Publication Year
Publication Year Publication Year

Pfizer GSK AstraZeneca Merck & Co BMS

`. Pfizer search included the companies Warner Lambert, Pharmacia, Kabi Pharmacia, GD Searle, Calgene and Farmitalia
2. search included the companies Burroughs Wellcome, Corixa, SmithKline Beecham, Smith KlineFrench, and all Glaxo Smith Kline subsidiaries
3. AstraZeneca search included all AstraZeneca subsidiaries and Zeneca Group
4. Merc Co. search included all Merck & Co. subsidiaries and Merck Sharp & Dohme
5. BM search included all E R Squibb subsidiaries and all Bristol-Myers Squibb subsidiaries

h


   

 Brand Life-cycle Extension
trategies
‡ Also nown as ³total product strategies´, ³evergreening´ or ³lifecycle maximization´

‡ Brands stand to lose 70-80 % of their revenue on first generic¶s launch and up to 85-95 % on
multiple launch, so the incentive for LcE is very strong
‡ The generic penetration increases every year, with US penetration reaching 54% (or 6`%
including approved generics) and EU penetration varying according to country from 5-65%.
‡ LcE activities begin very early but become more aggressive towards the end of patent¶s life.
‡ Brand LcE tactics are improving all the time and adapt to changing legislation and generic
tactics
‡ Brands spend $50-400 mill dollars per product for LcE
‡ An important part of the LcE budget is used for lobbying for new legislation favoring brands,
placating generic legislation, patent law, etc
‡ Litigations and patenting activity are the largest LcE budget item
‡ Multiple strategies are employed for each product

h
  


   5
Brand IP and Regulatory Tactics
API
‡ Patenting the genus and disclosing the species in a later patent, several years later.
‡ Sketchy description of the NCE in the seminal patent (NMR, etc), with full characterization in
a later patent (e.g. oily to crystalline)
‡ New salts, new derivatives
‡ ³Next generation products´ (active enantiomer, etc)
‡ Increasingly complex, difficult to synthesize organics and new biological molecules

Final Dosage Forms

‡ New formulations, such as modified release (controlled, extended, fast-release, once-daily,
pulsatile, ODT)
‡ New indications
‡ New dosage forms (nasal, buccal, injectable, spray, patch, transdermal, foam, etc)
‡ New dosages, new dosage regimens, ³patient monitoring´, ³ database dispensing´
‡ Combination products (two or more drugs in one delivery form)
‡ Administration in conjunction with other drugs (pre-treatments, etc)
‡ Rx to OTC switch
‡ Pediatric studies, population change
‡ Legal action (litigations, motions) and regulatory action (citizen petitions, etc)
‡ Generic subsidiaries and Authorized Generics

(
 To file or not to file?
Pro Con
‡ May help evade future ‡ Disclosing your strategy
FtO problems to competitors
‡ Deter competition ‡ Providing ammunition
‡ Strengthen marketing to the brand in Par. IV
‡ Positioning ‡ Providing third parties
‡ Safeguard IP with litigation grounds

Defensive publication is a viable option but, as a fact,

it is not widely used
8
 Number of eneric Patent Families
Increased Dramatically over the Years
60 60 60

anba y
0 0 0
No of Patent families

No of atent families
20

eva
20

No of Patent families
20

un Pharmaceutical
00 00 00

un Pharmaceutical

un Pharmaceutical

0 0 0

eddy's
anba y
eva
60 60

eddy's
60

i la td
arr
eddy's

i la td
0 0 0
eva
anba y

i la td

Dr
arr
20

Dr
20 20
arr
Dr

0
0 0
200 2006
6
Publication Year Publication Year Publication Year

anba y eva Dr eddy¶s arr un Pharma i la

h


  

 Freedom-to-Operate vs.
Competitor Bloc ing
‡ Freedom-to-operate is a must, competitor blocking is desirable
‡ Multiple approvals are commonplace (recently `3 approvals for Ambien),
so competitor blocking is sometimes a life or death activity for the product
‡ The brand is in a better position to block generics than generics are to block
their generic competitors
‡ The timing of the application filing is paramount. FtO must be determined
very early, while the impact of patent applications on CB can vary
according to the timing of filing
‡ Can generic patents totally block competition? In principle, yes, but those
cases are rare. Generic tactics can help
‡ There are cases in which the generic competition is made particularly
difficult, although not always impossible
‡ Brand and generic blocking patent filing activity intensified lately

1
 API Filing trategies
for eneric Products
‡ Aggressive and massive patenting, to scare away would-be
competitors
‡ Potentially avoiding future FtO problems by early filing
‡ Filing competitor blocking patents
‡ Countering generic competitors' IP by defensive patenting
‡ Improved quality of the product
‡ API polymorphs and amorphous forms
‡ Various other properties related to solid state (particle size,
flow properties, morphology)

11
 Pharma eneric Filing trategies

‡ Limitations
‡ Product must be bio-equivalent in order to get AB-rating.
505(b)2 route presumes branding
‡ New formulations must include inactives that are approved for
the same route of administration for at least the required
concentration (IIG). New inactives must be approved by a
more complicated and expensive regulatory process and may
amount in 505(b)2 designation
‡ Devices, packings, bottles, canisters, coatings, valves, are
patented separately and must be designed around as well.
Designing around may amount in losing the look-alike effect
needed for marketing

1á
 þeneric
Competitor-Bloc ing trategies
‡ Processes
‡ Patenting all the practical synthetic processes for the API
‡ API properties
‡ Patenting the amorphous API when the crystalline API is already protected
(valganciclovir, candesartan cilexetil)
‡ Patenting all the practical stable polymorphs and processes for the seminal
polymorph, if any
‡ Patenting the API with low level of impurity and requesting
pharmacopoeial monograph update to the new purity
‡ Analytical methods
‡ Patenting a specific method of analysis and its marker, and requesting
pharmacopoeial monograph update to include this method
‡ Formulations
‡ Patenting the practical bioequivalent formulations
13
 Early þeneric Filing
How early?
‡ Onset of R&D activity for filing purposes should be
shortly after the identification of the API candidate
Ideally, this should start shortly after the brand
product takes off in the first country
‡ The CB may start somewhat later
‡ Generic R&D activity for filing `5 years before the
actual generic launch is not uncommon

14
 Early þeneric Filing
First þeneric alc late nset First U roval þeneric a nc ration f þeneric
om o n
atent f & * ate ate re aration (years)
W 070`6582 to r.
July 29, 2003 `2
eddy s
W 07044829 to r. pril `7, 20`5
prepitant ct. 06, 2003 ar 26,2007 `2
eddy s a
ter extension
W 07039883 To
ct. 05, 2003 `2
anbaxy
W 03070720 to
uloxetine eb `,2000 ug 8,2004 Jun ``,20`3 `3
egussa
W 04074502 to Jul 4,20`5 ter
Imatinib Fe 1,á 1 ay 1 ,á 1 `4
ipla
W 04099`32 to ct 25,20`6 a ter
zetimibe ay 1,á 1 ct á5, á á `5
anbaxy extension
W 040832`3 to pr 25,20`6
ter
lmesartan ar `,200` pr 25, 2002 `5
hanghai Institute extension

*- alc late as á years efore first filing ate

15
 ³Purity´ Patents
‡ Purity patents (high assay, low level of specific impurities and solvents).
‡ Brands do not always patent or otherwise make known the purity levels, so it may
be difficult to find prior art to challenge a purity patent. Analysis of the brand
product to challenge novelty of the generic patent is not easy, and old samples
(before the filing) are not easy to find. Buying and storing brand samples detailing
batch production dates as soon as you start a project may, in the future, serve as
useful evidence of prior art purity profiles
‡ The relevant ICH guideline is ³Impurities in New Drug Substances Q3A (R2),´
second revision, issued in October 2006. For any drug substance, this guideline
states that any impurity present at a level of 0.05% or above must be reported. The
structure of any impurity present at a level of 0.`0% or more must be determined.
For impurities present at a level of 0.`5% or more, a toxicological qualification to
assess its risk to humans is required
‡ The usefulness of such patents outside the US is questionable (see German Appeal
Board decision T 990/96 on non-novelty of high purity claims)

1

 holid htate API Patents
‡ New polymorphs
‡ Hydrates
‡ Solvates, clathrates
‡ Amorphous APIs
‡ APIs with specific particle size ranges, or other
supposedly advantageous properties
‡ Specific particle surface area ranges
‡ Specific particle morphology
1(
 Intermediates Patents
‡ Newly discovered intermediates, resulting
from new or known processes
‡ Processes using specific intermediates
‡ Polymorphic forms of intermediates
‡ APIs containing low level of specific intermediates
‡ The usefulness of such patents in the US and EP is
questionable if there are viable alternatives

18
 Patenting as a Mar eting Tool

‡ As the market situation stands today, the product's IP

standing is a heavy argument, sometimes making or
breaking the deal
‡ A secure IP standing for the finished drug form buys
the market entrance ticket, and sells the API. More
and more, Marketing Managers are talking patents
with the prospective clients, and every new
application published needs to be scrutinized and
given a clean bill of health before the deal goes
further
19
 Published þeneric Patent Families for
the period á á-á

e a
anba
r. edd s
un Pharmaceutical
ipla td.
upin td.
þeneric ompan

rchid
Watson/ ndr
arr
etero ru s
adila
Perri o
þlenmar Pharma.
lembic td.
urobindo Pharma
lan/ atri
Woc hardt
orrent Pharma.

  á á
h
 o. of Patent Families

  
  
     á
 Brea down by htrategy
of Published þeneric Patent Families
á á-á


P Pharma nno ati e

  

á á á


o of atent families

á á á

Process holid htate Purity ntermediate   

Formulation odified elease e ice P Pharma

anbaxy Te a r eddy¶s Barr hun Pharma Ci la

h


      

á
 þeneric Patent Filing htrategies of helected þenerics
á á-á
Filings
76& &

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Table

       áá

 Is there a Correlation between the
þeneric Patent Filing Activity and the
Number of ANDA Approvals?
:e;eric
<otal To. of :e;eric
Uate;t 9amilies
G
ar. I
S á
-88rovals
<otal 8er ‡ There is some parallelism
filiAgs 88roval 9irst :e;eric <e;tative Vom8a;y
=
á á-á
between the patent filing activities
eva/Iva>/ ?icor
@ AB >
a a y
C @ DD
354
338
9(
á

á9


1á
3
á3
á

4
11 and ANDA approvals, but there
GH
r. e y Es
8FA armaceFtical
á35
11

á

1
13
(
4 5
9
áá
1

are exceptions as well (e.g.
IJ KD
i la t .
KFJ A K D
i t .
99
( ( 5 3


á


1
Mylan/Matrix). Mylan has a small
L H D IH
rc i
M A AD >
GH
em & arma
9 á 8 8 number of filings but it has a large
atso / r
N
arr

8



á8
33
1
4
4
á
5
4
19
1
number of Par. IV filings, which
O C
etero rFgs

might explain its success
I D
a ila
3 3 4 1 5 1
G
P A
le mar
errigo
Q GH
arma.


55
4
á
(
4
3
1
á
1
1á


‡ Steep increase in the Indian
B D GH
Fro iA o arma 45 3 9 ( 1
patent filings (see table) and
R AR >
yla / atri 38 á
9 ( 9 á5
M QH D
oc ar t
P AD =
33 3 1 1 ANDA approvals from `2 Indian
ra otal 1((5 á( 115 4 81 á3

companies, led by Aurobindo,
Wockhardt, Ranbaxy, Dr. Reddy
and Sun. (Source FDA site and
The Business Standard, May 2007
by PB Jayakumar)
h


  h ! !"

# $
 
# 
á3
á4
 Intensification of the Brand-þeneric
Litigations
s with aragraph I ha enge

20
ha enges

00

0
er of ar& I

60
%6 % %2
0 

20  
u

0
200 2002 200 200 200 2006
ear
h
 
# 
2
 Larger Proportion
of Par. IV Challenges

h
"
!!%h&!
'
á

 Increased Number of Par. IV Filers
‡ After 2003, about 42 generic
0
companies had active Par IV
6
0 6 filings.
‡ The number of companies after
N & Pr& 9 er

60

0 2006 increased to 67
0
0 ‡ Thus, new players have entered
0 this market.
 20
20 ‡ The average number of filers per
0 case has increased from `.5 to 2.0.
0
High volume products (>500 $
200 2002 200 200 200 2006 mill) have 6.` filers and AGs and
Yer
lower volume have 3.` filers
‡ Some cases have a much larger
number of challengers (Claritin ±
h
 "
# 
`5 filers)
! !
á(
 Patents and the þeneric Competition
The Impact of the Indian Penetration into
Regulated Mar ets
‡ Zestril (Lisinopril) ± `7 companies received FDA approval
‡ Ambien (Zolpidem) ± `3 companies obtained FDA approval
‡ India has now over `00 FDA-approved production facilities
‡ Over 40% of the total DMF files applications are filed by
Indian companies
‡ Over 33% of the new ANDAs are filed by Indian companies
‡ The growth of the US generic drug market has slowed from
double digits to single digit (from `7% in 2000 to 8.3% in
2006)
‡ The market environment has become very crowded

h

h!(
)!'( *+ *


á8
 þeneric vs. þeneric Litigations

‡ The number of generics offering the same API or

formulation on patent¶s expiry is on the rise
‡ The net result is price erosion, as many companies are
building large inventories with high hopes of
unloading at launch, only to find out that everybody
did the same
‡ As the generic landscape becomes more and more
crowded, G vs. G litigations might become the rule
rather than the exception
á9
 þeneric vs. þeneric Litigations
hertraline (Zoloft)
‡ Teva, the holder of `80 days exclusivity, filed several patent
applications reciting Sertraline polymorphs. Evidently, Teva
plans to market both the API and the FDF of sertraline
‡ Numerous API suppliers and their pharma clients are involved
in the same sertraline business
‡ Teva sued `2 different companies close to the expiry of its
exclusivity, asserting four of its polymorph patents.
‡ All the generics went ahead and launched their products on
day `8`.
‡ Teva admitted it did not know whether these companies
infringe on its patents or not.
3
 þeneric vs. þeneric Litigations
Other Cases
‡ Teva vs. nine generics over carvedilol process and
polymorph patents
‡ Apotex vs. Eon Labs over a cyclosporin formulation
patent
‡ LEK vs. Watson over a polymorph patent of
pravastatin. Watson is the AG for Pravachol.
Watson¶s API is probably supplied by the brand
(Sankyo)
‡ Teva vs. Apotex over a polymorph patent and a purity
patent related to pravastatin
31
 þenerics vs. Brand Litigations

‡ LEK sued BMS over Pravastatin, asserting its

rights to a crystalline form. BMS apparently
did not describe the crystalline form in the
seminal patent, but used spray drying,
probably obtaining amorphous form
‡ Synthon sued Pfizer over a amlodipine process
patent. Court decided in Pfizer¶s favor

3á
33
 Pro-generic h Legislation
and Court Decisions
‡ Biosimilars, rebranding (authorized generics) frivolous citizen petitions and
early resolution of patent disputes ± Waxman ± Feb. 2007 ³Access to Life
Saving Medicines´
‡ Two bills on authorized generics ± Rockefeller and Schumer ± ³Fair
Prescription Drug Competition Act of 2007´ (Senate) and Emerson and
Wamp (House)
‡ Reverse payments ± Kohl ±January 2007 ³Preserve Access to Affordable
Generics Act´
‡ The positive Court of Appeals declaratory judgment decision in Teva vs.
Novartis on Famvir (Famciclovir)
‡ Norvasc (Amlodipine) decision in Apotex vs. Pfizer
‡ A U.S. Supreme Court decision that recently rejected rigid application of
the teaching-suggestion-motivation (TSM) standard in the KSR vs.
Teleflex case and the Norvasc Apotex vs. Pfizer Court decision may
weaken patent positions on new salts, enantiomers and crystal structures
34
 Pro-generic EP Legislation
and Court Decisions
‡ Directive 2004/27/EC and its provisions (³the European Bolar´)
‡ Teva/Arrow/Generics UK vs. Lundbeck decision over narrowing of the
escitalopram (Cipralex) patent
‡ Actavis vs. Merck UK decision on revocation of the finasteride (Proscar)
patent µ444
‡ Egis Gyogyszergyar and Neolab vs. Ely Lilly German decision on
revocation of the olanzapine (Zyprexa) patent µ436
‡ Ivax, Cipla, Neolab, Generics, Arrow vs. GSK decision on Seretide
(fluticasone and salmeterol) patent revocation
‡ German Federal Supreme Court decision on carvedilol dosing regimens
‡ Clinical studies in Germany for registration purposes are not infringing
(Clinical Trials II ± German Constitutional Court)
h

h  ,' -.

#  /
-. 35

  h Patent Reform Act of á (
‡ First-to-file rights and elimination of interference proceedings
‡ Reform to make it easier to file a patent application without
the inventor's cooperation
‡ Limitation of damages to only the economic value of the
improvement as compared to the prior-art;
‡ Specific limitations on when damages may be trebled for
willfulness
‡ Post-grant opposition proceedings with a reduction in the
litigation estoppel effect
‡ Limitations on patent venue
‡ Authority to the PTO director to create further regulations

3

3(
 Conclusions
‡ The event horizon of the patenting activity onset
becomes longer every year
‡ The regulatory environment is a moving target
‡ The patent law and its interpretation are changing
‡ The generic landscape has become very crowded, and
this is and will cause quantum leaps in the behavior
of the players
‡ Generic patenting has morphed from a scientific
activity to an art form
38
0'
1
 Total No. of Pharmaceutical Patents
Over the Years

60,000

0,000
‡ The number of patent
families in the broad
er ent families

0,000

Y
Z
0,000
pharmaceutical
classification has more
No. of patent

20,000

than doubled in the last

W0,000
decade.
0
W%%6 W%% W%%X W%%% 2000 200W 2002 200 200 200 2006

Publication ear $Basic patent'

h


  
** 2
 B- Derwent Classification Definition
‡ Derwent Classification hystem: Pharmaceuticals
(http //scientific.thomson.com/support/patents/dwpiref/reftools/classification)
‡ All patents stated to be of pharmaceutical or veterinary interest, as well as those relating to compounds for use as
intermediates in the manufacture of pharmaceutical or veterinary products. Compositions used for diagnosis and analysis in
the pharmaceutical and veterinary fields (eg stains for bacterial pathogens) are also included.
‡ Artificial sweeteners, chemical warfare agents and plaque disclosing compositions are also included.
‡ Patents dealing with the production of tablets, pills, capsules, suppositories etc. are included, as are devices for dispensing
pharmaceuticals such as - syringes, child-proof closures, calendar pill boxes, aerosols etc.
‡ For each compound where more than one of the classifications given below could be assigned, then the order of priority is B`
before B2, B2 before B3.
‡ B 1 Steroids - including systems containing carbocyclic and/or heterocyclic rings fused onto the basic steroidal ring
structure.
‡ B á Fused ring heterocyclics.
‡ B 3 Other heterocyclics.
‡ B 4 Natural products and polymers. Including testing of body fluids (other than blood typing or cell counting),
pharmaceuticals or veterinary compounds of unknown structure, testing of microorganisms for pathogenicity, testing of
chemicals for mutagenicity or human toxicity and fermentative production of DNA or RNA. General compositions.

‡ B 5 Other organics - aromatics, aliphatic, organo-metallics, compounds whose substituents vary such that they would be
classified in several of B0` - B05.
‡ B
Inorganics - including fluorides for toothpastes etc.
‡ B ( General - tablets, dispensers, catheters (excluding drainage and angioplasty), encapsulation etc, but not systems for
administration of blood or saline or IV feeding etc.
 hertraline Patents and Applications


   
 
 
m
 
    
     
 
   




   
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    `
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h

  h 
 Teva¶s hertraline Patents
‡ Teva¶s Patents in Litigation
‡  h
495(á1 - hertraline hydrochloride Form II and methods for the preparation thereof
‡  h
5 98(- hertraline hydrochloride polymorphs
‡  h

(3- Methods for preparation of sertraline hydrochloride polymorphs
‡  h
89(34 - Processes for preparation of polymorphic form II of sertraline hydrochloride
‡ Patents/ application belonging to the litigated family
‡  h( áá881 - hertraline hydrochloride polymorphs (Reissue of 1 /á18,8
3 ±abandoned which is a
continuation of 98( above)
‡  há
/ á41189 - hertraline hydrochloride polymorphs (continuation of 1 /á18,8
3 ±abandoned
which is a continuation of 98( above)
‡  há (/ 38 5 -hertraline hydrochloride Form II and methods for the preparation thereof
‡  há (/ 9355( -hertraline hydrochloride Form II and methods for the preparation thereof
‡ Other Teva Patents applications
‡  h
45á 54 - Novel sertraline hydrochloride polymorphs, processes for preparing them, compositions
containing them and methods of using them
‡  h
858
5á - Novel sertraline hydrochloride polymorphs, processes for preparing them, compositions
containing them and methods of using them
‡  há 5/ 85

9 - Process for the preparation of sertraline
‡  há (/ 1
94 - Processes for the preparation of sertraline
‡ Oá (/ 831(- Process for preparation of sertraline hydrochloride form I
‡  há ( 1 1
5- Process for preparation of sertraline hydrochloride form I
Number of Brand Patent Families
in the Last Decade

P .B 199
á 1 á 4 á 5 á

Pfizer 326 567 6`2 440 297
8: 2`2 607 277 287 252
erc 235 222 2`8 204 225
strazeneca `42 232 245 22` 240
B 8 `22 `00 `59 `02 8`