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The Hatch Waxman Act (1984) simplified the approval process for generic drugs
Started the generic drug industry Provided for ANDAs (cheaper, faster)
Generic Drugs can be manufactured even while originals are still under patent
FDA Orange Book Purpose: To make generic pharmaceutical firms aware of patents protecting brand-name
drugs
All patents that claim a new drug, or some method of using this drug are listed in the Orange
Book
ALL new patent-protected drugs since Hatch-Waxman are listed in the
Orange Book
Our analysis focused on linking data from the FDA Orange Book with data from European Patent Office Orange Book: Focus on patent-protected, RLD NDAs
Reference Listed Drugs (RLDs): Designated by FDA to be imitated by generics To prevent biochemical differences between brand-name drug and generic versions
The “core” drug
Patent-protected NDAs: NDAs that list patents (appear in PATENT.TXT – see Appendix)
Data processing automated via Python and GNU text processing
Open Patent Services (OPS) Online European Patent Office database containing patent info
Data from European Patent Office, US Patent Office, Japanese Patent Office
Patent family data, legal data, and bibliographic data For example: Classification Symbols (International or European), Abstract, Inventor Name
Python code accesses OPS via SOAPpy (Python SOAP implementation) Given patent number, can retrieve assignee name(s)
The number of RLD NDAs approved per year is slowly increasing Since 1982, approximately 20% of all NDAs are RLD NDAs
The number of RLD NDAs approved is less variable than the number of total NDAs approved
NDAs Approved Per Year
0
100
200
300
400
500
600
700
800
900
NDAs
Yea
r Total NDAs
RLD NDAs
Most drugs (RLD NDAs) are protected by very few patents
Average RLD NDA lists 2.69 patents
269
169
118
48 45
20 168 7 4 4 7 2 0
0
50
100
150
200
250
300
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Patents Listed in NDA
ND
As
There appears to be little evidence of “platform technologies”
Average patent is listed in 1.40 RLD NDAs
1036
225
6930 15 6 1 0
0
200
400
600
800
1000
1200
1 2 3 4 5 6 7 8
Drugs Covered by Patent
Pa
ten
ts
* There are 22 patents that cover 5 or more drugs each. Half of these patents concern two areas: 5 are related to treatment of the HIV or AIDS virus and 6 cover methods of production of microcapsules.
The companies with the most drugs (RLD NDAs) tend to be “big pharma” firms
152 (29.5%)516284Total By Top 10:
21 (87.5%)2416Eli Lilly
1 (2.8%)3618Aventis
41 (78.8%)5223Merck
28 (56.0%) 5023Abbott Laboratories
4 (8.7%)4624Pharmacia and Upjohn Co.
8 (12.9%)6225AstraZeneca
23 (50.0%)4629Pfizer
6 (17.1%)3530Bristol Myers Squibb
19 (28.4%)6738Novartis
1 (1.0%)9858GlaxoSmithKline
Number (Percentage) of Those Patents that is Owned by Company
Total Number of Patents Covering all of Company’s
RLD NDAs
Total RLD NDAs by Company
Company Name
* Subsidiaries and mergers ARE NOT considered
Subsidiary companies and mergers play an important role in the pharmaceutical industry
413 (64.0%)645351Total By Top 10:
18 (64.3%)2819Roche
41 (78.8%)5223Merck
32 (64.0%)5023Abbott Laboratories
32 (62.7%) 5126Sanofi-Aventis
38 (60.3%)6326AstraZeneca
13 (34.2%)3833Bristol Myers Squibb
35 (52.2%)6738Novartis
51 (71.8%)7139Johnson and Johnson
75 (72.8%)10360GlaxoSmithKline
78 (63.9%)12264Pfizer
Number (Percentage) of Those Patents that is Owned by Company
Total Number of Patents Covering all of Company’s
RLD NDAs
Total RLD NDAs by Company
Company Name
* Subsidiaries and mergers ARE considered
61.0%326199Total by Top 10
47.8%2311Abbott Laboratories
63.2%1912Roche
52.2%2312Merck
81.3%1613Eli Lilly
53.8%2614Sanofi-Aventis
83.3%1815Schering Plough
55.3%3821Novartis
59.0%3923Johnson and Johnson
60.0%6036GlaxoSmithKline
65.6%6442Pfizer
Percentage of Total NDAs by Firm:Total RLD NDAs by firm:NDAs filed:Name:
“In-licensing” plays a significant role for more than 50% of drugs
* Firms with the most drugs (RLD NDAs) where the drug maker owns all the patents protecting the drug
“Out-licensing” varies significantly by firm
451 (76.7%)588Total by Top 10:
18 (52.9%)34Roche
32 (94.1%)34Abbott Laboratories
38 (90.5%)42AstraZeneca
11 (25.6%)43Takeda Chemical Industries
35 (77.8%)45Novartis
32 (65.3%)49Sanofi-Aventis
41 (65.1%)63Merck
71 (85.5%)83Johnson and Johnson
78 (90.7%)86Pfizer
75 (68.8%)109GlaxoSmithKline
Patents owned by firm in Orange Book that cover firm’s own drugs (RLD NDAs)
(% of total patents owned)
Total patents owned by firm in Orange Book (cover RLD NDAs):
Name:
* Firms by most patents owned on RLD NDAs in the Orange Book
Close-up view of a sample “patent-thicket”
Oval – patent
Line – shared NDA
* 13 of the 16 patents in this thicket belong to Merck and Co, Inc. The three patents that do not belong to Merck are highlighted. There are a total of 4 NDAs “shared” between the patents in this thicket. Three of these are different NDAs for Merck’s drug Fosamax, and the other is an NDA for Procter and Gamble’s drug Actonel. Both of these drugs are used to treat osteoporosis.
Oral liquid alendronate formulations
Method for inhibiting bone resorption
Research Institutions are active in filing joint-patent Applications
2Acad. Of Science Czech Republic
2Brigham and Women’s Hospital
2Ceskoslovenska Akademie Ved.
2Gen. Hospital Corp.
2Takeda Chemical Industries Ltd
2University of Texas
2University of Houston
2University of California
2Schering AG
2Novartis
4REGA Stichting
4Merck
4Kaiser Permanente
5GlaxoSmithKline
6Alkermes, Inc.
8Johnson and Johnson
Joint Patent Applications Filed:Organization:
Research institutions are HIGHLIGHTED
*46 out of 1382 (3.3%) patents on RLD NDAs in the Orange Book have multiple applicants. A sample of 1744 random patents was found to have a slightly higher percentage (4.4%) of patents with joint applicants. The difference in ratios was statistically significant at a 90% confidence level, but not at a 95% confidence level.
The relationship between patenting, drugs (RLD NDAs) and R&D is very complex
Shading: R&D expense, not including subsidiaries (lighter = more spent)
Size: proportional to number of RLD NDAs (also in parenthesis)
Distance to diagonal: dependency of licensing
* There seems to be a general correlation between greater R&D spending, more RLD NDAs and more parents covering those NDAs. However, this pattern does not apply to Sanofi-Aventis and Roche (high R&D expense, few NDAs) and Bristol Myers Squibb (many NDAs, few self-owned patents).
Conclusions / Summary
There are only 2491 drugs (RLD NDAs) listed in the FDA Orange Book 717 are patent protected
Fewer than 1382 patents cover all drugs (RLD NDAs) approved since 1984
Firms try to be self sufficient For close to 60% of their RLD NDAs, own all the patents listed in the NDA
One-fourth of patents in the Orange Book are out-licensed
But collaboration still necessary Acquisition of subsidiaries plays major role
Joint-patent applications show small, but important effect of non-profits
Licensing, joint-ventures needed also Own R&D and subsidiaries not enough to provide firms with the patents they need to protect all of
their drugs (RLD NDAs)
Conclusions / Summary
Effects of the Hatch-Waxman Act Generic vs. brand-name drug competition
Benefits: Forces collaboration and more research by big pharma firms
Stimulates innovation: Pharmaceutical companies need to keep developing new drugs, because older
drugs replaced by cheaper generics
Format:Column 1: NDA NumberColumn 2: Patent Number Column 3: Patent Applicant Name Column 4: Country of Patent Applicant Column 5: NDA Applicant Name
Sample Data:
004782 5210081 AMERICAN HOME PROD (US) WYETH PHARMACEUTICALS INC010971 5210081 AMERICAN HOME PROD (US) WYETH AYERST LABORATORIES011522 6384020 SHIRE LAB INC (US) SHIRE DEVELOPMENT INC013217 6407128 ELAN PHARM INC (US) JONES PHARMA INC013718 5872147 BIO TECHNOLOGY GENERAL CORP (US) SAVIENT PHARMACEUTICALS INC013718 6090799 BTG PHARMA CORP (US) SAVIENT PHARMACEUTICALS INC013718 6576659 BIO TECHNOLOGY GENERAL CORP (US) SAVIENT PHARMACEUTICALS INC013718 6670351 BIO TECHNOLOGY GENERAL CORP (US) SAVIENT PHARMACEUTICALS INC013718 6828313 BIO TECHNOLOGY GENERAL CORP (US) SAVIENT PHARMACEUTICALS INC017922 5482931 FERRING AB (SE) AVENTIS PHARMACEUTICAL PRODUCTS INC
Appendix: Data File Structure
NDA No.: Pat. No.: Patent Applicant: Country: NDA Applicant:
Appendix: Orange Book Data Details
Data available online (http://www.fda.gov/cder/orange/obreadme.htm) PRODUCTS.TXT: Information about FDA approved Drugs
PATENT.TXT: List of patents and the NDAs they site
“NDA Number” is a common field
All fields delimited by tilde (‘~’)
Sample Sizes 13,500 NDAs total in PRODUCTS.TXT
2,491 RLD NDAs
737 Patent-Protected RLD NDAs (5.5%) Our data file incorporates 717 (97.3%) of them because OPS query failed for some patents. This
means the NDAs listing only those patents were not included in the data file because the entry was
not complete (patent assignee was missing)