In the Gleevec case, it is clear that Novartis has dedicated a lot of resources into obtaining the patents. That includes human resources which includes patent agents, patent attorneys, inventors and other managers involved in clinical trials, and capital resources. In an estimation, for a relatively complex invention, an US patent filing cost around $10,000 to $15,000
122
. To calculate the cost of 40 US patent filings as analyzed in the study, it takes at least $400,000 (using a conservative estimation, $10,000 per patent) not to mention the cost of patent strategy planning service and the cost of patent families in all different countries.Despite the stunning figure of the cost, compared to the revenue of Gleevec, it is a necessary, unavoidable and yet very profitable investment.
This amount of money may seem small to an international pharmaceutical company like Novartis, but it is almost unbearable for a biotech company, especially those in the start-up stage. However, looking back at the timeline analysis of this study, the cost of patents is not paid at once, but instead paid within a very long period of time. From the result of this study, the most
important patent application, which usually has the broadest scope of protection, is the first one to be filed. Not all types of patents protecting the drug are filed at the same time. Even for the most important patents, the compound patents in this case, not all compound patents in different countries are filed at once. By using the flexibility of the United States patent system and other international patent systems like PCT and EPO, Novartis was able to defer most of the cost of the same compound patents in different countries to at most around two years. If carefully planned, a start-up company can actually establish its patent
deployments without dedicating all its capital resources in IP.
122
Gene Quinn, The Cost of Obtaining a Patent in the US, IP Watchdog,
http://www.ipwatchdog.com/2011/01/28/the-cost-of-obtaining-patent/id=14668/ (last visited Feb. 5,
2015).
88
Chaper 7： Conclusion
Gleevec is a blockbuster for Novartis. In 2014, it generates $ 4.7 billion dollars globally and is still ranked the 14th based on the sales figure
123
even after around 13 years on the market. An important part of Gleevec's commercial success is due to its patent protection. Patents have been an important strategy to secure profits of a drug and prevent potential competition. A detailed strategic planning of patent deployment is needed in order to generate a comprehensive patent protection over a drug. This patent deployment considers at least patent types, patent filing timing, invention scope, and patent family. All these elements are in dynamic relationships with the R&D and regulatory events of a drug. This study analyzed the patent strategy of Gleevec in the United States and its correspondence with R&D and regulatory events.In terms of the patent types, it is preferable to patent many features of a drug without disclosing too much know how which should be kept in secret. In Gleevec case, these patentable features are within three types, physical, chemical and biological properties of the drug. These features include at least compounds, salt forms, crystalline forms, drug composition, metabolites, Imatinib derivatives, methods of use, processes of drug preparation and combination therapies. Through literature research, formulation, drug delivery systems and prodrugs may also contribute to protect the drug though they are not found in the Gleevec case. In order to protect Gleevec, patents claiming features of Imatinib derivatives are also filed and issued.
This is to avoid a designed-around version of Gleevec which might exert the same or even better drug response than Gleevec itself. In addition, this also retains the rights to develop any derivatives in Novartis. Among all patent types, the ones that claim compounds and composition are considered to be the strongest in terms of protection.
The study presents results similar to the notion, where compound and composition
123
PMLives, Top 50 pharmaceutical products by global sales,
http://www.pmlive.com/top_pharma_list/Top_50_pharmaceutical_products_by_global_sales (last
visited Feb. 25, 2015).
89
patents are the most in number.
Different patent types may have a different filing timing. The study shows that the filing time of patents are in correspondence with R&D and regulatory events.
Generally, upon a certain event, such as a laboratory research result and a clinical accomplishment, patents were filed immediate after or filed within one to two years after the event. The study also shows that patents claiming physical properties, specifically the chemical structure, and drug composition are among the first to be filed. With the advancement of R&D, derivatives, crystalline forms, salt forms,
processes of preparation, and combination therapies are filed continuously and later in time. Method of use patents are filed at the beginning of the first patent and till the most current filings. The difference in the continuous filing of method of use patents is that the early filed method of use patents usually claim a broader scope of a disease while later filed patents claim the use of the drug in a more specific population of patients. The dynamic relationships between patent filing time and R&D and
regulatory events suggest a close communication between R&D team and intellectual property right team.
In the United States, patent application is more flexible than in other countries.
Mainly, the United States patent law allows several different filing types including continuation application, divisional applications, reissue patents or non-provisional applications of previous applications. These types allow strategic patent application based on the results of R&D and provide an early priority to at least partial
applications. In spite that claiming priority could lead to a shorter patent term, the drawbacks can be overcome by filing different patent types. The different patent types are usually filed at different time and a later filed patent would prolong the protection of a drug. Therefore, utilizing the United States patent system flexibility takes careful planning and may need to combine with different patent type applications to optimize the overall patent protection. As previously mentioned, the study shows that Gleevec R&D and regulatory events were in close communication with patent applications. It
90
is reasonable to infer from the result that the R&D and regulatory team collaborated with the intellectual property right team closely. Information between two teams has to be constantly exchanged so that the intellectual property right team could identify what can be patented and file the patent in time.
The data of this study has shown the patent strategy of a blockbuster drug of a global pharmaceutical company. The strategy is no difference from what a small biotech or a small pharmaceutical company should employ. Base on the result of the study, the following paragraphs provides key patent strategies for a Taiwanese biotechnology companies at relatively early stages.
First, dedicate capital resources in applying for key patents. Key patents in biotech/pharma cases are the compound patents and crystalline form patents. The compound patents usually claims a large group of compounds with same backbone, which corresponded with the development of the drug since at discovery stage the researchers were still testing a large number of potential drug candidates and were unable to determine the best choice. The second most important patent types would probably be the crystalline form patent of the drug. Crystalline form patents, in this case, claims a specific compound structure selected from previous compound library patent and describes its specific crystalline features.
Second, in general, file patents around one to two years after the first laboratory results and/or preliminary animal study results. Compound and crystalline form patents should be filed once some supportive laboratory results and/or preliminary animal experiments are studied. The timing of filing a patent is a crucial decision because if the invention is patented too early, it would lead to a shortened sales protection period. If the patent is filed too late, there might be prior arts published before the patent filing and would lead to invalidity of the patent. It is also important to not publish the laboratory result too early by the research team. R&D team should regularly consult IP team regarding the current development, study results and the
91
patent filing issue.
Third, key patents are filed globally. Though global patent strategy is not the focus of this study, a preliminary search (See Appendix III) has shown that the key patents were filed globally. As in this case, Gleevec compound patents can be found in 32 countries and were all filed in very early research stages. Obtaining global key patents are crucial for a small or start-up biotech companies. In most of the cases, a small biotech companies might not have the resources to develop a drug from the beginning to the marketing in all countries. Instead, the drug candidates are usually licensed out or in partnering with other big pharmaceutical companies in early stages including discovery, preclinical phase I and phase II.
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With early global patents, the biotech companies can selectively license out different rights in different patents in different countries to different partners in early stages. Therefore, patents are not just a way to protect the drug, it can be an alternative source of capital.Fourth, take advantage of the flexibility of US patent regulations. As previously discussed, the flexibility gives a biotech company a choice to file provisional
application, claim priority, add new matter to old applications, defer patent filing time to a certain extent and filing continuation-in-part application and continuation
applications. Again, a resources-limited company can take the advantage to generate more R&D results, evaluate the potential of the candidate, defer patent timing and costs and make the final decision.
In conclusion, from the study of patent deployment of Gleevec in the United States, it is clear that drug patent deployment is a very well-organized plan. The plan aligns with the R&D and regulatory events, and is dynamic and adjustable with time.
Patent deployment isn't just applying patents in the patent office. It require a detailed and comprehensive plan. A patent deployment plan needs various professionals who have deep knowledge in drug research, clinical development, regulatory activities and
124
Heather Cartwright, A Review of Deal Making in 2012, PharmaDeals Review, (2013).
92
global patent regulations and who are very experienced in utilizing the knowledge. It also requires these professionals to complement their knowledge with other
professionals and to work closely. Despite such resources might require a lot of capital resources, these resources are not a lump sum cost, instead, the cost are dispersed throughout the whole product life cycle. If a biotechnology company with limited resources could employ the aforementioned suggestion, it might optimize the cost benefit of patent deployment plan and generate a patent deployment with
effectiveness and efficiency.
93
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Appendix Appendix I
Event Time
Indication NDA # Stage
Particpants EventSources
1960/6 CML
Pre-Discovery
Peter Nowell and David Hungerford
Abnormal chromosome 22 (Philadelphia Chromosome) observed in CML patients
http://www.cancer.gov/PublishedContent/Images/images/d
ocuments/6ac3a026-8c6c-4a0f-97b0-df63d9f8ef92/poster_timeline.gif
1973/6/1 CML
Pre-Discovery Rowley, J.D. Chromosome 22 and 9 translocation observed by new staining techniques
http://www.cancer.gov/PublishedContent/Images/images/d
ocuments/6ac3a026-8c6c-4a0f-97b0-df63d9f8ef92/poster_timeline.gif
1982/12/23 CML
Pre-Discovery de Klein, A. Cellular oncogene identified in chromosome 22 translocation
http://www.cancer.gov/PublishedContent/Images/images/d
ocuments/6ac3a026-8c6c-4a0f-97b0-df63d9f8ef92/poster_timeline.gif
1983/11/17 CML
Pre-Discovery Heisterkamp N. Cellular oncogene is identified to be c-ab1 oncogene
1984/1/1 CML
Pre-Discovery Groffen, J.
found the transallocation region on Chromosome 22 and identified the tranallocated bcr gene
1984/7 CML
Pre-Discovery Konopka, J.B.
identify potential protein (tyrosine kinase activity) of c-ab1 altered protein ；(BCR-ABL protein identified as possible cause of CML)
http://www.cancer.gov/PublishedContent/Images/images/d
ocuments/6ac3a026-8c6c-4a0f-97b0-df63d9f8ef92/poster_timeline.gif
1985/6/13 CML
Pre-Discovery Shtivelman, E. transcript of ab1 and bcr genes are detected in CML
1985/12/5 CML
Pre-Discovery Stam, K. mRNA of ab1 and bcr fusion was identified clinically
1986 CML
Pre-Discovery
CIBA-Geigy, Nick Lydon
establish tyrosine kinase inhibitor research program
1986/7/11 CML
Pre-Discovery
Bcr-Abl protein identified to be tyrosine kinase (P210) which regulate cell growth and division
http://www.cancer.gov/PublishedContent/Images/images/d
ocuments/6ac3a026-8c6c-4a0f-97b0-df63d9f8ef92/poster_timeline.gif
99
1990 CML Pre-Clinical
bcr-abl Gene identified as cause of leukemia in mice (including cell tranplantation, trangenic mouse)
http://www.cancer.gov/PublishedContent/Images/images/d
ocuments/6ac3a026-8c6c-4a0f-97b0-df63d9f8ef92/poster_timeline.gif
1992 CML the compound that would become gleevec
was synthesized
http://www.innovation.org/index.cfm/StoriesofInnovation/In novatorStories/The_Story_of_Gleevec
不確定1993 CML Drug
Discovery First STI571/Gleevec laboratory studies begin
http://www.cancer.gov/PublishedContent/Images/images/d
ocuments/6ac3a026-8c6c-4a0f-97b0-df63d9f8ef92/poster_timeline.gif
1995/1 Pre-Clinical
TEST of CPG53716 (not gleevec); Preclinical models test (just a paper identified in Buchdunger's other paper)
Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest. 2000 Jan;105(1):3-7.
1996/1/1
1996/5/2 CML Pre-Clinical Functional Test of STI571 in animal model
1996/7 CML Drug
tested 400 molecules to find the target EX: CGP53716; identify lead coumpounds and gave it to Dr. Druker to test the function
http://www.innovation.org/index.cfm/StoriesofInnovation/In novatorStories/The_Story_of_Gleevec
1998/4/9 CML IND
IND for imatinib mesylate was received by the depratment of health and human services on april 9, 1998. IND number is 55666.
USPTO FILE WRAPPER: 2001-07-03 Patent Term Extension Application Under 35 USC 156
1998/6 CML Phase I
STARTED
Brian Druker First human test begin; clinical paper cannot be found in any website
http://www.cancer.gov/PublishedContent/Images/images/d
ocuments/6ac3a026-8c6c-4a0f-97b0-df63d9f8ef92/poster_timeline.gif
http://www.jci.org/articles/view/9083#B23
1999/1 Pre-Clinical CGP57148B tested in mice (not the first study
of animal model)
100
1999 CML Preliminary Result of 31 patients reported
http://www.cancer.gov/PublishedContent/Images/images/d
First patient enrolled. A phase II open-label study to determine the safety and anti-leukemic effects in patients
1999/12 started first of three phase II trials and completed 532 patients in May2000
Gleevec FDA DATA: Medical Review P3 Study 0102 (Page 118)
The accelerated-phase CML Trial (2nd of three phase II) started
2nd Phase II recruited 235 patients and ended.
1999/12 started first of three phase II trials and completed 532 patients in May2000
http://www.medscape.org/viewarticle/418676
http://www.cptech.org/ip/health/gleevec/drucker.html
101
2000/5 CML Phase I
ENDED
From June 1998 to May 2000, 83 patients (interim study) in whom treatment with interferon alfa had failed, or who could not tolerate the drug, were enrolled at three participating study centers.
Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia
http://www.nejm.org/doi/full/10.1056/NEJM2001040534414
completed enrollment of 260 (or some said 262) patients with CML blast crisis
2000/6 CML Phase III
STARTED
The study was conducted in 177 hospitals in 16 countries, and 1106 patients (553 in each group) were enrolled between June 2000 and January 2001.
http://clinicaltrials.gov/ct2/show/record/NCT00006343?term
=imatinib&phase=23&rcv_s=01%2F01%2F1992&rcv_e=01
%2F01%2F2004&rank=5
2000/7 kit+ GIST Phase II
STARTED B2222 phase II trial began
2001/1 CML Phase III
ENDED
The study was conducted in 177 hospitals in 16 countries, and 1106 patients (553 in each group) were enrolled between June 2000 and January 2001.
http://www.nejm.org/doi/full/10.1056/NEJMoa022457#t=art icleMethods
2001/2/27 2nd CML #21-335 NDA Applicant Novartis Pharmaceuticals
NDA received (#21-335)
indication: CML in three stages after failure of IFN alpha
2001/3 FDA granted an expedited review of
Gleevec；Also called fast track
1998/6~2000/5: primary end point of this phase 1, dose-escalation trial was the safety and tolerability of STI571
83 patients included
Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia. N Engl J Med 2001; 344:1031-1037April 5, 2001DOI:
10.1056/NEJM200104053441401
102
2001/4/5
2002 CML Phase II
REPORTED
1999/4~2000/3 Phase II study
; larger study confirms earlier findings 58 patients included
Treatment for chronic myelogenous leukemia PAPER http://bloodjournal.hematologylibrary.org/content/105/7/2
FDA approves STI571/Gleevec for treatment for CML; The approval was based on results of three large Phase 2 studies
http://www.cancer.gov/PublishedContent/Images/images/d
ocuments/6ac3a026-8c6c-4a0f-97b0-df63d9f8ef92/poster_timeline.gif
http://www.fda.gov/drugs/resourcesforyou/consumers/ucm 289601.htm
2001/10/16 kit+ GIST #21-335 sNDA Novartis filed sNDA
2002/1/31 Phase III data submitted to the authoriteis
Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia. N Engl J Med 2003; 348:994-1004March 13, 2003 DOI: 10.1056/NEJMoa022457
2002/2/1 kit+ GIST Approval
Phase III data submitted to the authoriteis approved for the treatment of unresectable and/or metastatic malignant kit+ GIST
2002/6/28 First Line
CML #21-335 sNDA
Novartis submits sNDA June 28 seeking approval of Gleevec for first-line use in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid
This new drug application (#21-588) provides for the use of Gleevec (imatinib mesylate) Tablets, 100 mg and 400 mg.
Please note that this approval is considered
an accelerated approval (21 CFR 314 subpart
H) because all of the indications being
approved for Gleevec (imatinib mesylate)
Tablets are accelerated approval indications
from NDA 21-335 Gleevec (imatinib mesylate)
Capsules.
103 2002/12/20 First Line
CML #21-335 Approval
Gleevec was approved to be the first line treatment of CML
Gleevec is now approved for the treatment of patients with all three stages of CML -- CML myeloid blast crisis, CML accelerated phase, and CML in chronic phase, either before or after use of other therapy. The only known cure for CML is still by a stem cell (bone marrow) transplant.
177 hospitals in 16 countries, and 1106 patients (553 in each group)
http://www.cancer.gov/cancertopics/pdq/treatment/CML/H
Change from capsule to tablet
This supplemental new drug application provides for the use of for Gleevec (imatinib mesylate)
Tablets for the treatment of pediatric patients with Ph+ chronic phase CML whose disease has recurred
after stem cell transplant or who are resistant to interferon alpha therapy.
Revision #21-588 sNDA 2nd CML in all three stages by using tablets
2003/11/3 1st
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1 A method of treatment of warm-blooded animals suffering from a protein kinase C dependent tumoral disease, which
comprises treating warm-blooded animals in need of such treatment with an effective tumor-inhibiting amount of a compound of formula I ##STR7##
wherein R1 is hydrogen or C1 -C3 alkyl, R2 is hydrogen or C1 -C3 alkyl, R3 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methyl-3-pyridyl, 4-methyl-3-pyridyl, 2-furyl, 5-methyl-2-furyl, 2,5-dimethyl-3-furyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-phenothiazinyl, 4-pyrazinyl, 2-benzofuryl, oxido-2-pyridyl, oxido-3-pyridyl, N-oxido-4-pyridyl, 1H-indol-2-yl, 1H-indol-3-yl, 1-methyl-1H-pyrrol-2-yl, 4-quinolinyl, 1-methyl-pyridinium-4-yliodide, dimethylaminophenyl or N-acetyl-N-methylaminophenyl, R4 is hydrogen, C1 -C3 alkyl, --CO--CO--O--C2 H5 or N,N-dimethylaminoethyl, at least one of R5, R6, R7 and R8 is C1 -C6 alkyl, C1 -C3 alkoxy, chloro, bromo, iodo, trifluoromethyl, hydroxy, phenyl, amino, mono-(C1 -C3 -alkyl)amino, di(C1 -C3 alkyl)amino, C2 -C4 alkanoyl, propenyloxy, carboxy, carboxymethoxy, ethoxycarbonylmethoxy, sulfanilamido, N,N-di(C1 -C3 alkyl)sulfanilamido, N-methylpiperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethylbenzyl or a radical of one of the formulae:
--CO2 R, --NH--C(═O)--R, --N(R)--C(═O)--R, --O--(CH2)n --N(R)--R, --C(═O)--NH--(CH2)n --N(R)--R, --CH(CH3)--NH--CHO, --C(CH3)═N--OH, --C(CH3)
═N--O--CH3, --C(CH3)--NH2, --NH--CH2 --C(═O)--N(R)--R, ##STR8## --(CH2)m --R10, --X--(CH2)m --R10 or ##STR9## wherein R is C1 -C3 alkyl, X is oxygen or sulfur, m is 1, 2 or 3, n is 2 or 3, R9 is hydrogen, C1 -C3 alkyl, C1 -C3 alkoxy, chloro, bromo, iodo or trifluoromethyl, R10 is 1H-imidazol-1-yl or morpholinyl, and R11 is C1 -C3 alkyl or unsubstituted phenyl or phenyl which is monosubstituted by C1 -C3 alkyl, halogen or trifluoromethyl, and the other substituents R5, R6, R7 and R8 are hydrogen, or a pharmaceutically acceptable salt thereof.
1 An N-phenyl-2-pyrimidine-amine compound
of formula I ##STR9## wherein R1 is 4-pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each case is free, alkylated or acylated, 1H-indolyl or 1H-imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen,
R2 and R3 are each independently of the other hydrogen or lower alkyl, one or two of the radicals R4, R5, R6, R7 and R8 are each nitro, fluoro-substituted lower alkoxy or a radical of formula II
--N(R9)--C(═X)--(Y)n --R10 (II) wherein
R9 is hydrogen or lower alkyl,
X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino, Y is oxygen or the group NH,
n is 0 or 1 and
R10 is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or hetero-cyclicaliphatic radical,
and the remaining radicals R4, R5, R6, R7 and R8 are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy,
21 A pharmaceutical composition for the treatment of tumours in warm-blooded animals including humans,
comprising, in a dose effective against tumours, a compound of formula I according to claim 1, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, together with a pharmaceutical carrier.
22 A method of treating warm-blooded animals including humans, which
comprises administering to such a warm-blooded animal suffering from a tumoral disease a dose, effective against tumours, of a compound of formula I according to claim 1 or of a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.
US5521184
Pyrimidine derivatives and processes for the preparation thereof
105
of formula I ##STR9## wherein R1 is a substituted cyclic radical, the cyclic radical being bonded at a ring carbon atom in each case and being selected from pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl and imidazolyl, and the substituents of the above-mentioned cyclic radical being selected from one or more of the groups
of formula I ##STR9## wherein R1 is a substituted cyclic radical, the cyclic radical being bonded at a ring carbon atom in each case and being selected from pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl and imidazolyl, and the substituents of the above-mentioned cyclic radical being selected from one or more of the groups