Patentability of Chemical and. Pharmaceutical Inventions

Transcription

1 Patentability of Chemical and Pharmaceutical Inventions (Enantiomer Invention, Crystalline Invention, and Selection Invention) October 22, 2013 Keum Nang Park, Partner

2 Contents I. Drug Development and Patent Application II. III. General Theory of Selection Invention Case of Enantiomer IV. Case of Crystalline Invention V. Conclusion 1 / 24

3 I. Drug Development and Patent Application

4 Cost and Time for Drug Development Cost for Drug Development According to Grabowski, the total cost for launching new drugs in the market is US $800 million in (J., R.W. Hansen and H.G. Grabowski, The Price of Innovation: New Estimates of Drug Development Costs, Journal of Health Economics, 22 (2003), pp ) <Table 1> Time for Drug Development by Year Year Phase of research 1960 s 1970 s 1980 s 1990~1996 and development Preclinical Phase 3.2 years 5.1 years 5.9 years 6.0 years Clinical Phase 2.5 years 4.4 years 5.5 years 6.7 years Approval Phase 2.4 years 2.1 years 2.8 years 2.2 years Total 8.1 years 11.6 years 14.2 years 14.9 years <Table 1> Time for Drug Development by Year Source : New Drug R&D of Korea 1999, Korea Drug Research Association, 1999, p. 14. See Yoon-taek Chung, FTA Research and Patent Strategy for the Evergreening of Pharmaceutical Industry, Vol. 6-2 Research on Intellectual Property (2011). 3 / 24

5 Process of Drug Development and Patent Application Research Phase Details of Research Patent Application Basic research and fundamental technology research Development phase Approval & sale Basic research and original technology research (synthesizing the new substance and extracting natural substance) selecting substance for development Preclinical Phase (toxicity and pharmacokinetics test) clinical test and conditional permission Phase 1 clinical trial : a few healthy volunteers, safety Phase 2 clinical trial : a few patients, dose, usage Phase 3 clinical trial : many patients, safety, effectiveness New drug approval Post-market surveillance (PMS),: phase 4 clinical trial (adverse drug reaction, indication), reexamination Substance patent Patent for the formulation and dosage form administration method, pharmacokinetics data salt, hydrate, crystal polymorphism and enantiomer Second use See Yoon-taek Chung, FTA Research and Patent Strategy for the Evergreening of Pharmaceutical Industry, Vol. 6-2 Research on Intellectual Property (2011). 4 / 24

6 Case Study Atorvastatin (Warner-Lambert Company) Criteria State South Korea Foreign Patent Patent No. Expiry date Patent No. Remarks Substance KR announced B May 29, 2007 US 4,681,893 First patent (South Korea, process) Raw material Purpose of use Enantiomer substance Intermediate Polymorphism Polymorphism Polymorphism Second-use KR registered B KR registered B KR registered B KR registered 39518B KR registered B KR registered B KR registered B Sep. 26, 2013 US 5,273,995 R-Form Enantiomer Feb. 24, 2014 WO/94/20492A Intermediate, intermediate process Jul. 8, 2016 WO/97/3958A Crystal form III Jul. 8, 2016 WO/97/3959A Crystal form I, II and IV Jul. 8, 2016 WO/97/395960A Amorphousness Nov. 4, 2018 WO 99/026583A Lipoprotein antioxidant Second-use - - US 02/169134A Sitosterolaemia Medicine Combination Combination KR registered B KR A Oct. 2, 2016 WO 97/016184A Mar. 30, 2007 Final Rejection for Patent US 6,455,574 Composition with Atorvastatin ACTC Combination of Atorvastatin- Amlodipine Hyperlipidemia drug, global sales of US $ 14 billion for 2007 (No.1 product), sales of KRW 78 billion in South Korea. 5 / 24

7 II. General Theory of Selection Invention

8 Definition of Selection Invention Definition of Selection Invention Selection invention refers to an invention in which the component in the genus invention is described in a superordinate concept and which selects only the subordinate concept contained in the genus invention as all or part of its components (Supreme Court, 2008Hu1935, Oct. 24, 2003 (S. Kor); Supreme Court, 2008Hu3469, Mar. 25, 2010 (S. Kor)). Selection invention is an invention which is described in a superordinate concept of the cited invention and in a subordinate concept of the requirement, and an invention selected the requirement not in description of the cited invention as the requisite for invention (Examination Guideline for Patent and Industrial New Design, 2012, p.3311 (S. Kor)). 7 / 24

9 Characteristics of Chemical/Pharmaceutical Invention The fruit of experiments It is hard to anticipate the effect without actual experiment. It is hard to predict the effect in chemical pharmaceutical invention even if the component parts of compound is known. If the applicant recognized the effect required for patentability, it is not a heavy burden to describe it in the written description. Markush-type claim is allowed. Selection Invention is basically a duplicative invention. Selection invention is granted a patent right exceptionally because of its outstanding effect that prior invention did not recognize. Selection invention should satisfy the disclosure requirement that distinguishes itself from the general chemical material invention. 8 / 24

10 Cases in each country Korea U.S. German Canada olanzapine Valid Valid Valid Invalid Korea Australian Canada U.S. clopidogrel Invalid Invalid Invalid Valid differences in level of technology, patent system differences in attorney s advocacy and level of proof differences in registered final description through patent examination process 9 / 24

11 Patentability of the Selection Invention - Requirement for Novelty Patentability Requirements for Novelty In order to deny the novelty of selection invention, there needs to be a detailed disclosure about the subordinate concept that selection invention shall be composed of in the prior genus invention; such cases include those prior arts which have literary mention regarding the selection invention, and also from the description of which the person having ordinary skill in the art could directly recognize the existence of the selection invention based on his technical knowledge at the time of the application (Supreme Court, 2008Hu736, Oct. 15, 2009 (S. Kor); Supreme Court, 2008Hu3469, Mar. 25, 2010 (S. Kor)). 10 / 24

12 Patentability of the Selection Invention - Requirement for Novelty (the Olanzapine case) Supreme Court, 2010Hu3424, Aug. 23, 2012 (S. Kor) (effective) Olanzapine fell under the subordinate concept disclosed by prior inventions. The ethyl olanzapine was disclosed specifically in the prior inventions but it was just one of about 100 chemicals in the prior invention 1 and about 59 chemical in another prior invention 2 and there wasn t a noteworthy mention about ethyl olanzapine. The Court accepted novelty since a person of ordinary skill in the art could not recognize directly that the olanzapine substituted methyl for ethyl of ethyl olanzapine in prior arts. 11 / 24

13 Patentability of Selection Invention Requirement for Inventive Step Requirement for Inventive Step In order to prevent inventive step being denied, every subordinate concept comprised in selection invention should have qualitatively different effect from the effect of the prior invention or, if not, quantitatively significant difference for inventive step of the selection invention. In this case, existence of the effect in comparison with prior invention should be stated clearly in the specification of the selection invention, and to be accepted as being stated clearly the above effect, there should be a detailed description to be able to confirm the difference in quality or a quantitative data description to be able to verify the significant difference from the prior arts in quantity (Supreme Court, 2008Hu736, Oct. 15, 2009 (S. Kor), Supreme Court, 2008Hu3469, Mar. 25, 2010 (S. Kor)). 12 / 24

14 Case of Selection Invention Olanzapine (Korea) Supreme Court, 2010Hu3424, Aug. 23, 2012 (S. Kor) (Effective) In case there are numerous effects of selection invention, in order to reach a decision about whether there are qualitative or quantitatively significant differences, it is sufficient if some of the effects of the selection invention were determined to exhibit noticeable effects when compared to an antecedent invention. The invention where olanzapine is the scope of patent claim, even though it is difficult to conclude olanzapine has substantially outstanding results in its effectiveness regarding psychiatric treatment in comparison to ethyl olanzapine which has a similar chemical structure. However, since it is acknowledged that olanzapine shows distinctive effects in reducing the side effect of cholesterol level increase, inventive step is not denied. 13 / 24

15 Case of Selection Invention - Olanzapine (Germany) Fluoran Decision (Federal Court of Justice) Supreme Court held that novelty is denied as a result of general formula disclosure. Olanzapine Decision (Federal Court of Justice) The Patent Court s decision that patent was null and void for lack of novelty was dismissed. The decision stated that merely because the chemical compound falls under a general formula in patent involving chemicals, patentability is not denied. The novelty of selection invention will be denied only when the following criteria are met: prior art has written specific chemical compound of subject selection invention in individualized form; and a person having ordinary skill in the art could read between the lines of the prior literature and could give attention to the chemical compound. 14 / 24

16 III. Cases of Enantiomer Invention

17 Enantiomer and Racemate Enantiomer Since same atoms are connected with each other in a same way, it seems as a same material. However, in the three dimensioned space, it means a mutual-complete enantiomer, among stereomers, different from each other. In other words, it means a material in which structure is same, but left and right side are exchanged as if it mirrors. An enantiomer generally compares to relationship of left and right hands. The molecular formula is completely same, so it is impossible to separate them with nomenclature, based on the molecular formula. Therefore, enantiomer is generally divided into two parts, being built up into S (or -) or R (or +), based on the stereosequence. An enantiomer includes asymmetric carbon atom in the core. An asymmetric carbon atom combines with four different atoms or atom group (A,B,C,D). 16 / 24

18 Enantiomer and Racemate Racemate Where a plane polarized light is passed through an enantiomer, the plane of polarization is rotated. It is called as the optical activity. At this time, where it is clockwise rotated, it is indicated as (+). And where it is counterclockwise rotated, it is shown as (-). (+) or (R) is dextrorotatory and (-) or (S) is levorotatory. Where (-), (S)- enantiomer and (+), (R)-enantiomer are combined in same amount, an optically inactive material is called as racemate and it is indicated as (±). Combined in the ratio of 1:1 17 / 24

19 Enantiomer Cases Novelty Considering that the prior art specifically described the invention does not signify only it explicitly disclosed the invention; rather, it takes into consideration the technical standard at the time of application and the specification of prior invention, etc, it is reasonable to conclude that an enantiomer invention lacks the novelty when racemate having one asymmetric carbon is disclosed in the prior art. An enantiomer invention itself lacks the novelty when racemate having one asymmetric carbon is disclosed, in Supreme Court [S. Ct.], 2001Hu2740, April.25, 2003 (S. Kor). 18 / 24

20 Cases of Enantiomers Japan and Europe Japanese Case A decision of Japan Tokyo High Court, case number 2008 case in litigation No , announced on June 30 th 2008: Japanese Court also held that the novelty is denied where racemate is disclosed in prior invention. European Case European Patent Office decided that even if the racemate is disclosed in the prior arts, the novelty of the enantiomer invention would not be denied. [Korean Patent law considers addition, change, deletion, or conversion of simple customary method and substitution of equivalental subject matters in a level of substantially same practical identity / the EPO considers the same in a level of inventive step. ] 19 / 24

21 IV. Case of Crystalline Invention

22 The Meaning of Crystalline Invention in Pharmaceutical Product Development It is unable to estimate the existence of specific form of crystal. Each crystal form has different physical and chemical properties (stability, absorbability, solubility, etc.). - Pharmacological effects could possibly differ. In many cases, the method of manufacturing crystal form has been publicly disclosed. 21 / 24

23 Patent Requirements The Supreme Court s Decision on Novelty and Inventive Step The Supreme Court, 2010Hu2865, July 14, 2011 It is widely known in the technical field of medicine compound that an identical compound may have various forms of crystal and pharmacological characteristics, such as solubility, stability, etc. Also, the Court held that reviewing and checking crystal polymorphism s existence for drug design of medicine compound is commonly conducted. The inventive step of crystalline invention is not denied, only when the crystalline invention has a different effect in quality from effect of the publicly known compound in prior invention or when the crystalline invention does not have quality difference, but has a. significant different effect in quantity. In written description of the crystalline invention, in order to consider the inventive steps of the invention, comparative data with the prior invention is not required, but at least there should be a clear mention as to the effects stated above. In a case of that effect, mentioned in the description, is ambiguous, the applicant or the patentee is required to prove claim more specifically by, for example, providing detailed comparative data after application date. 22 / 24

24 Case of Crystalline Patent Lercanidipine Hydrochloric Acid (South Korea) * The Supreme Court, 2010Hu2865, July 14, 2011 Applicant Recordati Ireland Purpose Hypertension drug Claim 24(Patent 667,687) Crystal form of lercanidipine hydrochloric acid that has X-ray diffraction pattern at a wavelength of Kα and DSC fusion point of 197~201 Prior invention Lercanidipine hydrochloric acid (commercially available Zanidip Tab.) Crystal form of lercanidipine hydrochloric acid (fusion point of )(US 5,912,351) Description of effects on the specification The easier production of the dosage form of lercanidipine can be attributed to a higher rate of consistency regarding the size of particles and reproducible solubility, and more accurate range of chemicophysical properties The separation of each crystal polymorphism could result in a reduced possibility of variation between batches. Quantitative data on water solubility (table 2) is described on the specification. Summary of judgment A five-fold difference in solubility is in the range that could be estimated by persons of ordinary skill (No data regarding the specific utility caused by the solubility difference) The variation reduction between batches is only the effect that single crystals have in contrast to mixed crystals, and is not recognized as the effect brought by the property of a crystal form itself (I) 23 / 24

25 V. Conclusion

26 Conclusion Korean courts recognize the (i) value of the selection invention, (ii) status of the chemical/pharmaceutical industry in Korea, (iii) propriety when compared to global standards as patentability requirements for chemical/pharmaceutical and selection patents. It would be necessary to address each of these patentability requirements reasonably and fairly for each individual cases. When a selection invention does not satisfy the patentability requirements, it would be necessary to receive compensation for the significant time and investment made to develop the selection invention through alternative legal mechanisms, such as data exclusivity and market exclusivity. 25 / 24

27 Thank you Keum Nang Park Partner