Timeline Analysis

5.3.2.1 R&D Timeline vs. Chemical Claims

The process of research and development of Gleevec is organized in a timeline diagram. Accordingly, application dates of the chemical compound patents which claim scopes encompassed at least Imatinib are aligned together in time order. The order of the application is based on the earliest priority date instead of the filing date in the United States.

Function in Body vs Filing Date

Application Date

66

The reason of using the earliest priority date is because such invention had already been mentioned or at least partially disclosed in a previous US or foreign patent application. In order to understand the exact

relationships between patent applications and R&D events, the very first disclosure of invention is used. By matching and comparing the time order of R&D events and patent application dates, Figure 12 shows the relationships between the two.

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Figure 12: R&D Timeline vs. Chemical Claims Source: Compiled by the study

Research & Development Events Chemical Patent Application

1990 2-Phenylaminopyrimidine derivative Program

started The compound that became Gleevec was

synthesized in lab 1992

Began first STI571/Gleevec laboratory studies and found its inhibition of Bcr-Abl

1993 US5728708, US5705502, US5521184(+)

Began functional tests of STI571 in animal model 1996

US6894051(+ *), US7544799(+ *), USRE43932(+ *)

1998 IND filed; Phase I started

1997 FDA filed supplementary NDA under #21-335 for

kit+ GIST patients sNDA for GIST indication approved sNDA for untreated CML filed sNDA for untreated CML approved

#21-588 NDA (capsule to tablet) filed 2002

#21-588 NDA approved sNDA for pediatric CML who failed first-line

treatment filed sNDA for pediatric CML approved

2003

+ : patents listed in Orange Book

* : patents claiming crystal forms of Imatinib

Solid Line Box : patent scope encompassing

Imatinib

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5.3.2.2 R&D Timeline vs. Functional Claims

Figure 13: R&D Timeline vs. Functional Claims Source: Compiled by the study

Research & Development Events

1990 2-Phenylaminopyrimidine derivative Program

started The compound that became Gleevec was

synthesized in lab 1992

Began first STI571/Gleevec laboratory studies and found its inhibition of Bcr-Abl

1993

Began functional tests of STI571 in animal model 1996

1998 IND filed; Phase I started

1997

Phase II started 1999 Phase III started 2000

#21-355 NDA was filed 2001 FDA approved #21-335 NDA FDA filed supplementary NDA under #21-335 for

kit+ GIST patients sNDA for GIST indication approved sNDA for untreated CML filed sNDA for untreated CML approved

#21-588 NDA (capsule to tablet) filed 2002

#21-588 NDA approved sNDA for pediatric CML who failed first-line

treatment filed sNDA for pediatric CML approved

2003

· Gastrointestinal stromal tumours

US8653093

· Leukemia

US8653093

· Gastrointestinal stromal tumors (Gleevec is used in combination with other drug)

2008 _US8697702

· Ph+ Leukemia

· Chronic lymphocytic leukemia

· Ph+ Acute lymphoblastic leukemia

(optimization of treatment)

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Figure 13 illustrates R&D events and the patent applications which claimed medical uses in time series. As shown in the figure, upon the first synthesis Imatinib, US Pat. No. 5,521,184 (US '184) claiming the use of 2-phenyaminopyrimidine to treat "tumoral disease." The term

"tumoral disease" is rather blur since it encompasses all types of tumor and/or cancers. In 1997, US Pat. No. 6,894,051 (US '051) was filed to protect the use Imatinib to treat "tumoral disease." Both US '051 and US '184 protects the "tumoral disease" indication. The difference is that in US '184, a larger scope of chemical compounds

(2-phenyaminopyrimidine) are claimed while US '051 only claims the exact Imatinib compound.

As the phase III clinical trial of Imatinib on chronic myeloid leukemia started in 2000, a narrower indication is claimed in US '355.

The disease GIST is a kind of tumoral disease. The GIST clinical trial started in July 2000 while US '355 was first filed as a provisional application (US 60/243,810) in October 2000, and then a

non-provisional was filed and claimed the provisional benefit. The two events, clinical trials over GIST and the patent application protecting GIST, pretty much started at the same time. All following indications claimed in patent applications have much narrower and a clearer scopes compared to US ' 184, US '051 and US '355. For example, leukemia, Ph+ leukemia, and chronic lymphocytic leukemia are all very well defined by either physiological and/or genetic and are narrower than tumoral disease in terms of protection scope.

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5.3.2.3 R&D Timeline vs. Orange Book Patent Filing Date

Figure 14: R&D Timeline vs. Orange Book Patent Filing Date Source: Compiled by the study

Figure 14 illustrated the research and development events and the filing dates of the patents listed in the orange book. An NDA applicant is required to list certain relevant patents (mainly three types, drug

substance, formulation and use patent) that protect the drugs in the

Research & Development Events Orange Book Patent Filing Date

1990 2-Phenylaminopyrimidine derivative Program

started The compound that became Gleevec was

synthesized in lab 1992

Began first STI571/Gleevec laboratory studies and found its inhibition of Bcr-Abl

1993

Began functional tests of STI571 in animal model 1996

1998 IND filed; Phase I started

1997 FDA filed supplementary NDA under #21-335 for

kit+ GIST patients sNDA for GIST indication approved sNDA for untreated CML filed sNDA for untreated CML approved

#21-588 NDA (capsule to tablet) filed 2002

#21-588 NDA approved sNDA for pediatric CML who failed first-line

treatment filed sNDA for pediatric CML approved

2003

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orange book while filing NDA. There are five patents listed in the orange book as shown in Figure 14. Before the first NDA (#21-335) was filed, three patents were filed, namely US' 184, US' 051 and US' 335.

The three patents covered key aspects of the drugs, respectively

chemical structure, crystalline form and the indication. Another different crystalline form patent was filed after the NDA submission.

There might be some reasons that at least the chemical compound patent and use patent were filed before an NDA submission. First, before an NDA submission, multiple publications that disclose the details of the drug might be published, which would endanger the patentability of the key patents. Second, the chemical compound and use patent for the first indication are of the most importance in protecting the drug, while other types of patents, for example, formulation and crystalline form come second. Before the market potential is confirmed by the actual sales number, it is reasonable to file only the minimum necessary patents before NDA submission to control the resources. Third, the phenomenon also reflects the actual research process. In general, chemical compound is the first to be identified and its main biological function is tested right after. Not until some time after the research of the drug does the

crystalline form and formulation are further studied. The patents are also filed in alignment with this timeline.

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5.3.2.4 Patent Family Analysis

Figure 15: Patent Family Application Timeline Source: Compiled by the study

CH19970001764

1997/07/18

WO9903854A1 1998/07/16

US6894051B1 2000/01/18

US7151106B2 2001/11/16

US2006030568A1 2005/09/29

US7544799B2 2006/09/05 CH19920001083

1992/04/03

US19930042322 1993/04/02

US20000243810P 2000/10/27

US6958335B2 2003/08/11 US5521184A

1994/04/28

WO0234727A3 2001/10/26

USRE43932 2011/09/21 1992

1993

1994

1998 1997

2000

2001

2003

2005

2006

2011

Bold Solid Line Box: patents listed in the orange book

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Figure 15 illustrates an abbreviated patent family in application time series. The figure only shows the United States patents and their parents. Patents of other countries are not shown. As can be seen in the figure, all five patents that are listed in the orange book are not the first applications in its own patent family. Every listed patents claim priority to prior applications, and is a continuation, a divisional, a reissue patent or a non-provisional application of previous applications.

Figure 15, together with Figure 14 which shows that there are two patents filed long after the first NDA submission, also shows that Novartis leveraged the United States patent system and the international patent cooperation treaty and kept filing patents for around 20 years (from 1992 to 2011).

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Chaper 6： Discussions on the Patenting Strategies of Gleevec

As previously mentioned, patents are one of the most important measure to secure commercial rights of selling approved drugs and therefore to secure profits.

This study analyzed the patents and applications in the United States that are relevant to the drug Gleevec. All patents and applications are categorized and analyzed by matrix analysis. In order to understand the relationship between the patent

applications and the research and development of the drug, the study surveyed the time of R&D event and the date of the patent applications, and matched the time in several timeline diagrams. Based on the matrices and timeline diagrams, the study tries to delineate the drug patent development in the United States of America and the corresponding R&D and regulatory activities by employing Gleevec as an example.

6.1 Patent Types in Protecting the Drug

In Section 5.3.1.1 Figure 7, Figure 8 and Figure 9, it is clear that in order to protect Gleevec in every aspects, Novartis has filed applications claiming several different aspects of the drug Gleevec, including the compound (Imatinib

structure), salt form, crystalline form, drug composition, Imatinib derivatives, method of use and process of drug preparation. These aspects encompass most features of Gleevec. The following discussion focuses on how different patent types contribute to protect Gleevec.

Compound Patents

The study showed that compound patents and crystalline form patents are the most abundant in the analysis scope. The focus of claiming compound and different crystalline forms is in good agreement with previous study

¹⁰⁷

, which

107

Richard B. Smith, Repositioned drugs: Integrating Intellectual Property and Regulatory Strategies,

Drug Discovery Today: Therapeutic Strategies, 8: 3-4: 131-137 (2011)

75

suggested that a compound claim provides stronger protections of the drug product and protects the drug products in a more comprehensive way. By claiming the compound itself, no matter what indication, formulation, salt form, synthesis method and compositions are used in an alleged drug product, there would be infringement if the compound is used, made, offered to sell or sell within the United States. Therefore, it is preferable to protect the compound by compound patents than by claiming a method of using the compound or a method of producing the compound.

The study also showed that the compound patents (US '184 and US '051) covering Imatinib were filed between 1993 to 1997, while all patents in the scope of analysis were filed between 1993 to 2013. Compound patents are usually the first filed patent applications among all other patent types, therefore they are also the first few to expire. There are several measures to prolong the patent term.

First, request for adjustment of patent term under 35 U.S. Code § 154(b) in USPTO. The extension is a compensation due to delays in patent examination and prosecution. US '051 patent documents shows that the patent term was adjusted for 311 days. Second, request for patent term restoration under 35 U.S. Code § 156. This extension is maximum 3 years and is given to only one patent listed in the orange book and is a compensation for the NDA reviewing period. US '184 patent documents shows that the patent term was extended for 586 days. Third, request for pediatric exclusivity. Under 21 U.S. Code § 355, if pediatric studies of drugs are submitted and approved, the sponsor may obtain a 6-month exclusivity attaches to all the applicant's formulations, dosage forms, and indications for products with existing marketing exclusivity or patent life that contain the same active moiety. According to the Orange Book information, Novartis is granted with pediatric exclusivity for all patents in the listed patents.

In addition to the Imatinib compound itself is claimed, the derivatives of Imatinib are also of crucial role in patenting and protecting Imatinib. It is a

76

common practice to design around the original drug compound by, for example, changing functional groups or stereoisomeric arrangements. By protecting other derivatives of Imatinib, the patentee may preempt the possibility of any similar compound becoming a drug, thereby avoiding competition and keep the rights to develop a new but similar drug.

Crystalline Form Patents

Except for compound structure, different crystalline forms of Imatinib are also largely claimed, for example, crystalline form H, G and I. Generally, different crystalline forms are found and studied in a later stage of development or even after the approval of the drug. Different crystalline forms of the same chemical may have different characteristics such as better stability or solubility. If the researchers identifies a specific crystalline form in the approved drug which is previously unknown and exerts unpredictable advantages over the known, by patenting the specific crystalline the company can prolong the patent protection of the drug.

As the study showed, Novartis has many crystalline form patents and one of them covers Imatinib and helps to prolong the patent protection. US '184 is the original compound patent which protects the chemical structure of Imatinib and some of its derivatives. The official estimated expiration date of the US '184 patent according to USPTO is July 4

^th

, 2015

¹⁰⁸

. US '051 is a later -filed

compound patent protecting the β-crystal form of Imatinib. The β-crystal form has a better properties, namely a) more beneficial flow properties, b) better

thermodynamic stability, and c) lower hygroscopicity. These features make it easy to process Imatinib, to store and to manufacture the drug. The estimated

expiration date of US '051 is November 23

^rd

, 2019, about four years after US

108

The patent term has been extended under 35 U.S.C. §156 and Section 505 A (Pediatric exclusivity).

77

'184

¹⁰⁹

. Therefore, patenting crystalline form of a drug might provide longer protection and result in higher generic drug entry barrier because the generic companies will have to wait until the patent expired or will have to challenge the validity of more patents which increases the cost burden.

Paxil is another example which uses different crystalline form patents to protect the drug. SmithKline filed a patent protecting a hemihydrate crystalline form of paroxetine hydrochloride after almost 10 years of its original anhydrate form patent was filed. By claiming different crystalline form, SmithKline

prolonged the patent protection of Paxil until the later-filed patent was invalidated in a federal court.

¹¹⁰

Method of Use Patents

Figure 10 shows that Novartis also holds a lot of method of use claims. A method of use claim usually recites a class of compounds or a certain compound and specifies the use of the compound. As shown in Figure 10 and Figure 11, Novartis has claimed more indications than Gleevec is approved for. Some of the uses are for Imatinib derivatives and some are for Imatinib itself. The patents that cover Imatinib itself claims indications including tumoral disease, GIST,

leukemia, CML, Ph+ leukemia and Ph+ ALL, while the rest including lung cancer, and breast cancers are directed to Imatinib derivatives. Since the tumoral disease encompasses almost all other disease as seen in Figure 10 and Figure 11, any indications that fall in the "tumoral disease" classification would infringe the patent.

Gleevec is currently approved for kit+ GIST and Ph+ CML, both of these approved indications are covered by a broad claim that covers many different

109

The patent term has been extended under Section 505 A (Pediatric exclusivity).

110

SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331 (Fed. Cir. 2005).

78

kinds of diseases other than the approved indications. The fact that both approved indications are covered by broader claims is in agreement with previous studies.

In a 2011 Law360 article

¹¹¹

and a 2012 CRA Charles River Associates Report

¹¹²

, it is important to have patents protect broad indications. This patenting strategy might help to avoid skinny label. If there is one approved indication that is not protected by patents, a generic drug company may file an ANDA seeking the indication that is not protected by patents. If the generic drug treating the patent-unprotected indication is approved, the generic drug may be used in the market by doctors for protected indications under off-label prescription. By filing many different method of use claims, the brand name company may reduce potential loss incurred by generic companies' skinny label strategy. In addition, patenting indications that are not approved may also block or at least increase cost for any other drug company who wishes to seek indication that is not yet approved but protected by patents.

Compound patents, crystalline form patents and method of use patents are the three major types of patents in Gleevec case. But there are still other patents filed by Novartis that are relevant to Gleevec, namely salt form, metabolite, composition ratio, process of preparation and combination therapy. These types of patents does not seem to be currently active in protecting Gleevec itself but may also help in blocking competitive derivative compounds.

Salt Form Patents

Organic compounds may exist in many different salt forms and each salt form may exert an unique features. In the study, there are three salt form claims that protect Gleevec. The claim uses a broad term such as "a pharmaceutcally acceptable salt" to encompass all possible salt forms. The study finds that a broad

111

Sandra Lee and Anna Volftsun, THE SKINNY ON SKINNY LABELS, Law360 (2011)

112

CRA Insights, Skinny labeling, CRA Charles River Associates (2012)

79

scope of salt forms are recited in early patent applications and specific salt form is described in a later-filed patents. In Gleevec case, a specified salt form, a methanesulfonic acid addition salt, was described in US '799 which is filed at least 12 years after the first application US '184. Methanesulfonic acid addition salt (also called myselate) is the salt form currently used in Gleevec. Other patents describes different salt forms but does not cover Imatinib itself. For example, US Pat. No. 8,163,904 recites an Imatinib derivative with a specific monohydrochloride form. Overall, in Gleevec patent deployment strategy, salt form patents have the least number. This is in good agreement with previous literature

¹¹³

which suggests that it is generally not easy to obtain patents on different salt forms of a same drug since there are limited numbers of suitable salts and thus may lead to lack of inventive steps.

Metabolite Patents

Metabolite patents claim a specific metabolite of a drug. In Gleevec case, there are 3 patents (See Figure 7) with claims reciting metabolites of Imatinib and they all belong to one patent family. The claimed metabolites, N-desmethyl Imatinib, are the major metabolites of Imatinib formed predominantly via CYP3A4

¹¹⁴

, an human liver enzyme. The three metabolite patents are mostly filed several years after the original Imatinib patent. The three patents seem to play a role in the patent protection of Imatinib. However, it is unclear how the metabolite patents will act in protecting Gleevec from competition since these three patents are not listed in the orange book and there is no litigation based on the three patents yet.

If a metabolite of a drug is novel and inventive, it can be patented. However, the United States cases

^{115 116}

, reports

¹¹⁷

and a literature

¹¹⁸

all discussed on

113

Supra note 36, at 243.

114

Novartis, Clinical Pharmacology and Biopharmaceutics Review, at 12, (2001).

115

Marion Merrell Dow, Inc. v. Baker Norton Pharm., Inc., 152 F.3d 941 (Fed. Cir.1998).

80

whether taking an original drug which is naturally metabolized in human body would infringe a metabolite claim. Two renown United States cases

¹¹⁹

both held that taking an original drug did not infringe a metabolite claim but based on different reasoning. However, the cases were only brought to Federal Circuits and may still change with time if the same issue is brought to the Supreme Court.

Overall, given the fact of the non-infringement decisions in both Federal cases, metabolite patents do not seem to protect a drug product currently. Yet,

pharmaceutical companies might consider to keep applying or maintaining metabolite patents, at least before an unfavorable decision is issued by the Supreme Court.

Crystalline Form Composition Patents

There are two composition ratio patents in Gleevec case, both of which are filed many years later after the first Imatinib compound patent. Specifically, US Pat. No. 8,633,213 claims a composition of drug where a certain amount of a specific crystalline form of Imatinib is in a drug. The study is unable to determine whether Gleevec contains the claimed amount of the claimed crystalline and thus is unable to analyze whether the patent is active in protecting Gleevec.

However, if the composition shows unexpected superadditive effect than the single use of each crystalline form, then one may obtain a composition patent.

Composition patents also show strong legal protection if the approved pharmaceutical composition falls in the claim scope.

Process of Preparation Patents

116

Schering Corp. v. Geneva Pharm., Inc., 339 F.3d 1373 (Fed. Cir.2003).

117

Richard Li-dar Wang and Pei-Chen Huang, Patent Protection of Pharmacologically Active Metabolites: Theoretical and Technologica Analysis on the Jurisprudence of Four Regions, 29 Santa Clara High Tech. L.J. 489 (2012).

118

Supra note 36, at 253.

119

Supra notes 115, 116.

81

Among the 6 patents that claim process of preparation, only one covers the preparation of Imatinib itself, US '051. Generally, if the preparation process or the synthesis process of a compound or a drug cannot be deduced, it should be

subject to trade secret protection rather than patents. Revealing the synthesis process in a patent may lower the entry barrier of generic companies since patents are public accessible documents. Patents can protect the process for only 20 years but it can be kept in secret for as many years as it can be (protected by trade secret). However, in the United States, the discovery system in litigation may affect the way the synthesis process is protected. Through discovery, a party may request the other party to reveal the synthesis process of the alleged infringing product under certain criteria. The discovery system is particularly useful when a process or a method patent is at issue, since it is usually difficult for a plaintiff to collect evidence of a defendant's manufacturing process. If the claimed synthesis process is broad enough to cover most possible ways to synthesize a drug or there are only limited ways to synthesize the compound, the protection would be strong.

However, this is generally not the case since designing around the patented synthesis process is not as difficult as designing around a compound structure.

Other strategic patenting is to keep the actual process of drug preparation in secret in early times (protected by trade secret) and in a later time file patents protecting the process. Through the strategy, the later-filed process of preparation patents might prolong the patent protection. Last but not least, a pharmaceutical company may consider to file patents protection processes of preparation that are not used currently. These patents may help to reduce competitors who seek to produce the drugs in other process so as to avoid infringing the actual process patents.

In this study, however, only one patent covers the synthesis process of Imatinib is found, and since the actual synthesis of Imatinib is not disclosed, the study was unable to determine whether the patent covers the synthesis process.

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Combination Therapy Patents

In this study, there are five patents protecting combination therapies. A combination therapy usually combine at least two active drug substances in a single drug product. In the five patents analyzed, all of them recites Imatinib as one of the drug substances in the therapy even though Gleevec is not approved

In this study, there are five patents protecting combination therapies. A combination therapy usually combine at least two active drug substances in a single drug product. In the five patents analyzed, all of them recites Imatinib as one of the drug substances in the therapy even though Gleevec is not approved

在文檔中 美國藥物專利布局與其相應之研究開發與法規活動 - 以諾華藥廠之Gleevec®為例 - 政大學術集成 (頁 74-91)