Gene patents in plant biotechnology: model organisms

v. major commercial crops Koen Jonkers*

European Commission, JRC IPTS

Catalina Martinez CSIC-IPP, Madrid, Spain

STI 2014 Conference, Leiden, The Netherlands 3-5 September 2014

Disclaimer: The information and views set out in this publication do not necessarily reflect the opinion of the European Commission. The EC does not guarantee the accuracy of the data included in this study. Neither the EC nor any person

acting on its behalf may be held responsible for the use which may be made of the information contained herein.

Background

• Genetic patenting: scientific, legal and economic importance (e.g. Louwaars et al 2009).

• Global seed market has grown from 18 billion USD in 1985 to 34 billion USD in 2006. Seeds form the basis for a product market which is many times this size and they are of central importance to global food security (Louwaars, 2007).

• The market for genetically modified seeds is growing at a high rate too, from 2.7 billion USD in 2000 to 6.2 billion in 2006 (Le Buanec 2007).

• The past decade has seen a process of concentration of the plant seed sector (Howard 2009).

• Two types of IPR: plant breeders’rights and patents (Louwaars et al 2009).

The focus of the present study is gene patents in plant biotechnology, defined as ‘patent applications including gene sequences of plants’

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Previous research on gene patents

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Large literature, growing fast, especially on human DNA, but not only, by economic, legal and science scholars (e.g. medicine, biotech):

• Human DNA: e.g. Thomas et al (2002); Hopkins et al (2007); Rosenfeld and Mason (2013)

• Marine genetic resources: e.g. Arrieta et al (2010); Arnaud-Haond et al (2011)

• GM crops: e.g. Regibeau and Rockett (2003); Conti, Regibeau and Rockett (2003); Regibeau and Rockett (2005); Schneider (2011), CAMBIA reports (www.cambia.org)

Main issues: Owmership of patents claiming gene sequences; subject matter of patents with gene sequences; competition issues; effect on follow-on research, access to resources; diffusion, etc.

Our data

EPO filings with plant gene sequences from GBPAT files in GENBANK • We downloaded all the patent sequences files

(GBPAT) from NCBI GENBANK flat file release 183.0 (April 2011) which were used to create a relational database and linked those files to patent information from PATSTAT (Sep. 2010). Patent information has been updated for sample using PATSTAT April 2014 and OECD patent quality data July 2014.

• EPO and WIPO sequence information in GBPAT contains information on the source organism.

• Source not provided in the USPTO: BLAST searches for sequence homology is an option.

• We have coded by EPO patent filings by source organism and top plant categories, and EPO granted patents by subject matter (using Derwent family summaries)

• Analysis presented here is at the patent level, but we are doing similar analysis at the family level.

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EPO filings from GENBANK April 2011

Gene sequences

% Total Patent

applications % Total

Unclassified 47664 1% 1823 12%

Synthetic 570022 17% 6969 44%

Mammalia 2231844 68% 3316 21%

Bacteria 227932 7% 1352 9%

Plantae 133995 4% 581 4%

Virus 9849 0% 562 4%

Fungi 18344 1% 385 2%

Arthropoda 10201 0% 126 1%

Archae 4590 0% 94 1%

Other 8530 0% 532 3%

Total 3262971 100% 15740 100%

Most filings from firms, Public Research Organisations growing fast. Top 5 firms control more than 60% of filings from the private sector (high share of Basf)

0

20

40

60

80

100

120

140

160

1980-2000 2001-2005 2006-2009

Private

Public

Public/Private

0

10

20

30

40

50

60

70

1980-2000 2001-2005 2006-2009

Basf

Bayer

Dupont

Monsanto

Syngenta

Other firms

5

Basf and ‘other firms’ (not top 5) peak in 2001-2006

arabidopsis

ricemaize

wheat soybean

tobacco

tomato barley

pea

0.1

.2.3

.4

35% of all plant genetic sequence patents filed at EPO between 1981 and 2009 are associated with Arabidopsis thaliana genetic sequences. Rice with 23% and maize with 21% follow. Some patents contain DNA sequences of more than one type of organism

Distribution of EPO filings by top plants Genbank (plus some coding) allows to classify by the organism of the gene sequence included in the patent filing, advantage over using patent classes or keyword search

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Arabidopsis

• No commercial use, except as a research tool

• Arabidopsis DNA sequences in patent claims as an indicator of science relatedness?

• Potentiallly: patent filings with arabidopsis sequences may be used to claim protection for homologous sequences in related plant species (including the dicots tomato and soybean)

• Arabidopsis DNA sequences appear often together with DNA sequences from other organisms in patent filings

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Research questions

• Does the presence of genetic sequences of model organisms such as Arabidopsis indicate more basic/exploratory inventions (science-related) or is it instead a sign of the strategic use of broad claims and homology?

• How could both patterns be disentangled?

• Are patents with Arabidopsis alone more ‘basic’ than patent filings with Arabidopsis listed together with major crops?

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To study the effect of Arabidopsis, with and without major crops, we build four mutually exclusive categories of patents in our sample:

0

20

40

60

80

100

120

140

160

arabidopsiswithout major

crops

arabidopsisand major

crops

major cropswithout

arabidopsis

Other

0

10

20

30

40

50

60

70

Major cropswithoutArabidopsis

Arabidopsiswith majorcrops

Arabidopsiswithoutmajor crops

Other

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Patent filings with Arabidopsis are less likely withdrawn than patent filings without Arabidopsis

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

major cropswithout

arabidopsis

arabidopsiswithout

major crops

arabidopsisand major

crops

other

withdrawn

refused

pending

granted

unknown

0

10

20

30

40

50

60

70

19

81

19

84

19

87

19

90

19

93

19

96

19

99

20

02

20

05

20

08

withdrawn

refused

pending

granted

unknown

But need to control for filing year (more recent filings have had less time to be withdrawn), as we will do later in regressions

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With Arabidopsis

Different business models of the Top 5 firms

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0

5

10

15

20

25

30

35

Basf Bayer Dupont Monsanto Syngenta

arabidopsis without major crops

arabidopsis and major crops

major crops without arabidopsis

other

Howard, Philip H. 2009.Visualizing Consolidation in the Global Seed Industry: 1996–2008. Sustainability, 1(4), 1266-1287.

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Subject matter of granted EPO patents

improved method

pathogen production

stress yield

"There are two major types of products from plant biotechnology: methods and traits. traits such as disease and stress resistance, improved yield, product quality [or the production of new compounds] can improve the [direct] value in the [product] chain. Methods such as molecular marker techniques, transformation techniques [and in our definition also vectors and regulatory elements] create value in the process of breeding." (Louwaars, 2009)

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0

5

10

15

20

25

arabidopsiswithout majorcrops

arabidopsis andmajor crops

major cropswithoutarabidopsis

other

We manually coded the 130 patent applications which had been granted by July 2014, to analyse what use was patented - explain. We also considered coding for patents that were more or less science based, but this proved challenging.

PROBIT ANALYS

Statistically significant differences in the characteristics of patents with and without arabidopsis?

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Mean Std. Dev. Min Max Mean Std. Dev. Min Max Without-With e(t)

bulk100 0.14 0.35 0 1 0.08 0.28 0 1 -0.0619* (-2.05)

invnbr 1.33 0.57 0 3 1.26 0.55 0 4 -0.0719 (-1.31)

patent_scope 2.58 1.24 1 7 2.76 1.57 1 8 0.174 (1.20)

claims 16.86 8.22 1 42 18.70 12.83 1 85 1.842 (1.64)

pct 0.23 0.42 0 1 0.19 0.39 0 1 -0.0465 (-1.17)

family_size 8.55 4.17 1 18 8.54 5.29 1 38 -0.0121 (-0.02)

npl_cits 31.50 39.93 0 109 20.30 31.04 0 116 -11.20** (-3.29)

bwd_cits 17.48 26.12 0 120 10.57 21.12 0 122 -6.912** (-3.04)

onefwdcits5 0.04 0.21 0 1 0.12 0.33 0 1 0.0801** (2.78)

largefirmonly 0.41 0.49 0 1 0.51 0.50 0 1 0.102* (2.07)

proonly 0.19 0.40 0 1 0.23 0.42 0 1 0.0395 (0.96)

firmpro 0.03 0.16 0 1 0.05 0.22 0 1 0.0266 (1.34)

smallfirmonly 0.31 0.46 0 1 0.18 0.39 0 1 -0.125** (-3.06)

otheronly 0.06 0.24 0 1 0.02 0.14 0 1 -0.0422* (-2.32)

monsanto 0.06 0.24 0 1 0.11 0.31 0 1 0.0475 (1.65)

bayer 0.05 0.22 0 1 0.08 0.27 0 1 0.0255 (1.04)

basf 0.35 0.48 0 1 0.14 0.35 0 1 -0.214*** (-5.46)

syngenta 0.02 0.14 0 1 0.07 0.26 0 1 0.0535* (2.42)

dupont 0.01 0.08 0 1 0.08 0.27 0 1 0.0696** (3.23)

otherfirms 0.25 0.44 0 1 0.27 0.45 0 1 0.0208 (0.48)

granted 0.27 0.45 0 1 0.30 0.46 0 1 0.0330 (0.73)

withdrawn 0.41 0.49 0 1 0.48 0.50 0 1 0.0671 (1.37)

refused 0.03 0.18 0 1 0.03 0.16 0 1 -0.00386 (-0.23)

pending 0.28 0.45 0 1 0.18 0.39 0 1 -0.100* (-2.47)

With Arabidopsis (N=159) Without Arabidopsis (N=290) Student's T test

Descriptive statistics for first probit analysis

(1) (2) (3) (4) (5)

VARIABLES arabidopsis arabidopsis arabidopsis arabidopsis arabidopsis

bulk100 0.0913 0.0562 0.0654 0.0460 0.0621

(0.0889) (0.0914) (0.0938) (0.0901) (0.0922)

linvnbr 0.0309 0.0390 0.0163 -0.115 -0.120

(0.115) (0.118) (0.121) (0.125) (0.127)

lscope 0.0160 0.0170 0.0185 0.0498 0.0582

(0.0516) (0.0524) (0.0529) (0.0541) (0.0550)

pct -0.0105 -0.0372 -0.0553 0.0697 0.0639

(0.0714) (0.0725) (0.0736) (0.0784) (0.0805)

lfamsize 0.0501 0.0580 0.0445 0.0397 0.0388

(0.0457) (0.0476) (0.0492) (0.0482) (0.0497)

lnplcits 0.00369 0.00217 0.00409 -0.0165 -0.0163

(0.0262) (0.0271) (0.0272) (0.0277) (0.0279)

lpatcits 0.0361 0.0518 0.0479 0.0667** 0.0666**

(0.0301) (0.0321) (0.0324) (0.0333) (0.0335)

onefwdcits5 -0.194** -0.189** -0.188** -0.185** -0.182**

(0.0781) (0.0801) (0.0805) (0.0799) (0.0804)

proonly 0.0869 0.0882

(0.0778) (0.0781)

firmpro -0.121 -0.115

(0.122) (0.123)

smallfirmonly 0.187*** 0.199***

(0.0692) (0.0699)

otheronly 0.340*** 0.352***

(0.124) (0.123)

granted -0.0266 0.0187

(0.0736) (0.0763)

withdrawn -0.0634 0.0256

(0.0710) (0.0746)

refused -0.160 -0.132

(0.138) (0.140)

monsanto -0.230*** -0.227***

(0.0734) (0.0739)

bayer 0.00134 -0.00160

(0.134) (0.134)

basf 0.156 0.173*

(0.0950) (0.0976)

syngenta -0.194* -0.197*

(0.114) (0.113)

dupont -0.385*** -0.384***

(0.0360) (0.0361)

otherfirms -0.0587 -0.0585

(0.0701) (0.0704)

fi l ing years yes yes yes yes yes

Log likelihood -254.7344 -247.52309 -246.75343 -237.53659 -237.0001

Pseudo R2 0.0628 0.0893 0.0922 0.1261 0.1281

Observations 406 406 406 406 406

Standard errors in parentheses

*** p<0.01, ** p<0.05, * p<0.1

FIRST PROBIT arabidopsis or not Dependent variable is ‘including gene sequences of Arabidopsis in the claims’ Full sample Marginal effects

Patent filings with arabidopsis in the claims are less likely to be cited, more likely to be filed by small firms or other (neither firm nor PRO), than by large firms. When we distinguish among firms controlled by the top five firms and other (instead of small and large) we find that patent filings with arabidopsis in the claims are positively associated with Basf, and negatively with Monsanto, Syngenta and Dupont reflecting their different business models. A significant positive association between having arabidopsis in the claims and the number of citations to patent prior art emerges when this distinction among the top 5 is made (probably because these firms build on previous patents of themselves and each other, indicating R&D competition on research using arabidopsis, something we should look at in further research). Neither legal status, scope, nbr of inventors, nbr of claims, filing route (PCT or not) or family size are significantly associated with having arabidopsis or not in the claims

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Mean Std. Dev. Min Max Mean Std. Dev. Min Max Alone - With Top e(t)

bulk100 0.35 0.48 0 1 0.02 0.14 0 1 -0.330*** (-6.39)

invnbr 1.45 0.62 1 3 1.25 0.52 0 3 -0.197* (-2.15)

patent_scope 2.42 1.14 1 7 2.69 1.30 1 7 0.270 (1.33)

claims 18.90 7.85 1 41 15.63 8.22 2 42 -3.274* (-2.47)

pct 0.37 0.49 0 1 0.15 0.36 0 1 -0.215** (-3.19)

family_size 8.30 3.86 2 16 8.71 4.36 1 18 0.407 (0.60)

npl_cits 27.38 39.50 0 105 33.99 40.19 0 109 6.607 (1.01)

bwd_cits 17.07 26.54 0 106 17.74 25.99 0 120 0.671 (0.16)

onefwdcits5 0.05 0.22 0 1 0.04 0.20 0 1 -0.00960 (-0.28)

largefirmonly 0.32 0.47 0 1 0.46 0.50 0 1 0.148 (1.85)

proonly 0.18 0.39 0 1 0.20 0.40 0 1 0.0187 (0.29)

firmpro 0.02 0.13 0 1 0.03 0.17 0 1 0.0136 (0.53)

smallfirmonly 0.45 0.50 0 1 0.22 0.42 0 1 -0.228** (-3.09)

otheronly 0.03 0.18 0 1 0.08 0.27 0 1 0.0475 (1.19)

monsanto 0.10 0.30 0 1 0.04 0.20 0 1 -0.0596 (-1.50)

bayer 0.05 0.22 0 1 0.05 0.22 0 1 0.000505 (0.01)

basf 0.40 0.49 0 1 0.32 0.47 0 1 -0.0768 (-0.98)

syngenta 0.03 0.18 0 1 0.01 0.10 0 1 -0.0232 (-1.04)

dupont 0.02 0.13 0 1 0.00 0.00 0 0 -0.0167 (-1.29)

otherfirms 0.18 0.39 0 1 0.29 0.46 0 1 0.110 (1.55)

granted 0.13 0.34 0 1 0.35 0.48 0 1 0.220** (3.10)

withdrawn 0.38 0.49 0 1 0.42 0.50 0 1 0.0409 (0.51)

refused 0.07 0.25 0 1 0.01 0.10 0 1 -0.0566* (-1.99)

pending 0.42 0.50 0 1 0.20 0.40 0 1 -0.215** (-2.97)

Student's T testArabidopsis with Top crops (N=60) Arabidopsis alone (N=99)

Descriptive statistics for second probit analysis

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(1) (2) (3) (4) (5)

VARIABLES top top top top top

bulk100 0.587*** 0.558*** 0.551*** 0.603*** 0.589***

(0.101) (0.119) (0.131) (0.111) (0.125)

linvnbr 0.309 0.307 0.301 0.440 0.450

(0.253) (0.254) (0.266) (0.292) (0.297)

lscope 0.104 0.137 0.147 0.147 0.141

(0.109) (0.112) (0.115) (0.123) (0.124)

pct 0.102 0.0957 0.0949 0.0692 0.0515

(0.135) (0.139) (0.142) (0.155) (0.155)

lfamsize -0.0201 -0.0626 -0.0484 -0.0387 0.0285

(0.0962) (0.1000) (0.103) (0.117) (0.123)

lnplcits -0.0986* -0.0841 -0.0805 -0.0684 -0.0733

(0.0551) (0.0569) (0.0575) (0.0570) (0.0574)

lpatcits 0.0277 -0.0126 -0.0138 -0.0272 -0.0157

(0.0604) (0.0669) (0.0693) (0.0657) (0.0678)

onefwdcits5 -0.105 -0.0988 -0.0617 -0.0346 -0.00101

(0.216) (0.216) (0.238) (0.242) (0.273)

proonly -0.180 -0.226*

(0.134) (0.128)

firmpro -0.157 -0.223

(0.252) (0.217)

smallfirmonly 0.0794 0.0365

(0.125) (0.127)

otheronly -0.168 -0.217

(0.201) (0.179)

granted -0.183 -0.174

(0.132) (0.138)

withdrawn 0.0987 0.189

(0.151) (0.164)

refused 0.0662 0.0862

(0.399) (0.446)

monsanto 0.574*** 0.644***

(0.128) (0.0984)

bayer 0.474** 0.458**

(0.189) (0.206)

basf 0.152 0.198

(0.173) (0.178)

syngenta 0.600*** 0.633***

(0.111) (0.0833)

otherfirms 0.0481 0.0602

(0.161) (0.166)

fi l ing years yes yes yes yes yes

Log likelihood -75.595764 -73.997626 -71.488517 -67.428357 -63.945154

Pseudo R2 0.2586 0.2743 0.2989 0.3326 0.3671

Observations 152 152 152 151 151

Standard errors in parentheses

*** p<0.01, ** p<0.05, * p<0.1

SECOND PROBIT Arabidopsis with top crops or alone Dependent variable is ‘including genetic sequences of top crops in the claims’ Subsample, only patents with gene sequences of Arabidopsis in the claims Marginal effects

Patent filings with arabidopsis and top crops in the claims are more likely to contain bulk genetic sequences (more than 100) and include less NPL references than patent filings with arabidopsis alone. When the types of applicants is included, the significance of NPL references disappears and is replaced by having public research organisations as applicants than large firms, which also reflects science-relatedness of patents including only Arabidopsis, without top crops. When we distinguish among firms controlled by the top five firms and other (instead of small and large) we find that patent filings with arabidopsis and top crops are positively associated with Monsanto, Bayer and Syngenta. No other variable is significantly associated to having gene sequences of arabidopsis with top crops or of arabidopsis alone in the claims.

FURTHER DESCRIPTIVE ANALYSIS (ONLY GRANTED)

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Arabidopsis with crops is more likely to be associated to traits 'pathogen' and 'yield' (immediately useful for breeders), bulk sequence patents (broad coverage) and PCT (seeking worldwide protection and time to prospect market potential) . They are also more likely to be filed by Syngenta Arabidopsis alone is therefore less likely to be associated to these variables Both arabidopsis alone and arabidopsis with crops are equally likely to be associated with methods and other traits, and the rest of variables that have non significant differences of means according to the t-test There are only very few observations. We may try to extend this sample in further research

Comparison of granted patents of Arabidopsis alone and Arabidopsis with top crops

Mean Std. Dev. Min Max Mean Std. Dev. Min Max Alone - With Top e(t)

method 0,25 0,46 0 1 0,43 0,50 0 1 0.179 (0.92)

trait_improved 0,25 0,46 0 1 0,17 0,38 0 1 -0.0786 (-0.50)

trait_pathogen 0,25 0,46 0 1 0,00 0,00 0 0 -0.250** (-3.34)

trait_production 0,38 0,52 0 1 0,31 0,47 0 1 -0.0607 (-0.32)

trait_stress 0,25 0,46 0 1 0,17 0,38 0 1 -0.0786 (-0.50)

trait_yield 0,38 0,52 0 1 0,09 0,28 0 1 -0.289* (-2.20)

bulk100 0,13 0,35 0 1 0,00 0,00 0 0 -0.125* (-2.18)

Granted with Arabidopsis alone (N=35)Granted with Arabidopsis and Top crops (N=8) Student's T test