Experimental Data – Biological Pharmaceuticals /JP

1. HIRAKI & ASSOCIATES Experimental Data –Biological Pharmaceuticals /JP Takashi FUJITA Hiraki & Associates

2. Experimental Data • Why experimental data is required? -To meet Enablement requirements/Industrial Applicability -To meet Support requirements -To show Inventive Step: superior effects • Note: - Pharmaceutical use claims/Pharmaceutical composition claims: Pharmacological data is required. (Examination guidelines: medicinal inventions) - Composition claims comprising too many species lack utility.

3. Pharmacological Test Enablement

4. Examination Guideline (Medicine)(Enablement/Pharmacological test) • (1) Description of the Result of the Pharmacological Test • Since results of pharmacological tests are to confirm the pharmacological effect of the claimed medicinal invention, the following should be made sufficiently clear: • (i) which compound, • (ii) is applied to what sort of pharmacological test system, • (iii) what result is obtained, and • (iv) what is the relationship between the pharmacological test system and the medicinal use of the claimed medicinal invention. • Note that results of pharmacological tests should be described with numerical data. When results cannot be described with numerical data due to the nature of the pharmacological test system, an acceptable objective description equivalent to numerical data may be provided, for example, a description of objective observation results by a doctor is acceptable. The Guideline lists the following as pharmacological test systems that can be employed: clinical tests, animal experiments, and in-vitro tests.

5. Examination Guideline (Medicine) (Enablements/Pharmacological test) • (2) Example of a Case where Reasons for Refusal are Notified • (a) Where the result of the pharmacological test is not described • Generally, since it is difficult to predict whether a compound can actually be used for a specific medicinal use from only the name and chemical structure of the compound, it remains difficult for a person skilled in the art to predict whether the compound can actually be used for the specific medicinal use where an effective quantity, dosing method, and formulation method are described in the detailed description, but results of a pharmacological test are not described. Accordingly, in such a case, in principle, reasons for refusal are notified. • Note that the reasons for refusal will not be overcome by later submission of the results of the pharmacological test.

6. Enablement(Tokyo High Court 1996 (Gyoke) No. 201 (10 Oct 1998)(Ginko) Claims: Medicament against nausea or emesis comprising pharmacological ginger roots (Rhizoma Zingiberis) and bilobed and half-folded dried ginkgo (Extr.Ginkgo bilobae e fol.sicc.) Specification: It is described that the medicament is effective against sea sickness, nausea during pregnancy, and migraine. It is also disclosed that one dosage of the powdered medicine may contain 500mg ginger roots and 30mmg bilobed and half-folded dried ginko, and this is to be taken three times a day.

7. Enablement(Tokyo High Court 1996 (Gyo ke) No. 201 (10 Oct. 1998)(Ginko) Tokyo High Court: (1)In the specification, given its character as a technical publication, there is a requirement that the purpose, construction and particular effect is to be specifically described to an extent sufficient for a skilled person to easily carry out the invention (Art 36 (3)). Thus, in a use invention concerning a pharmaceutical, since it is generally difficult to predict its efficacy from only the name of the substance and the chemical formula, even where the effective amount, method of administration and formulation thereof has been described to some extent in the specification, it is not possible for a skilled person with only this information to know whether the pharmaceutical has efficacy in respect of this use or not. Consequently, it is necessary to provide support for the efficacy of this use with a description in the specification of pharmacological data or equivalent. Detailed descriptions of the invention which do not contain such descriptions must be said to contravene Article 36(3) of the Patent Law. • DE3626128, FR2602144

8. EnablementTokyo High Court 2001 (Gyoke) 99(Equivalent to pharmacological test) • Claim: Dietary supplement for treatment of an individual exhibiting insulin-resistance, or prevention of a clinical symptom in an individual predisposed to the development of a clinical symptom of insulin-resistant diabetes, comprising D-chiro-inositol in an amount sufficient to provide a treatment level to the individual exhibiting insulin-resistance… Tokyo High Court: “Equivalent to pharmacological test data” means a description that enables a person in the art to understand what pharmacological effect is provided by the chemical compound allegedly having a medicinal use, and how to use the compound to produce the desired pharmacological effect. A person skilled in the art may utilize the general common knowledge in the art at the time of filing to understand the specification.

9. EnablementTokyo High Court 2001 (Gyoke) 99(Equivalent to pharmacological test) • Specification: (Type II diabetes and inability of synthesis of DCI) • (1) As disclosed in co-pending U.S. Patent application ----, successful purification, to essential homogeneity, of at least two substances appearing to mediate the activity of insulin, particularly in terms of activation of PDH and the inhibition of other enzyme systems, • (2) Structural analysis of the insulin mediator possessing the biological activity of activating (PDH) has identified this mediator to be comprised of -- D-chiro-inositol. • (3) Further research as disclosed in U.S. Patent application --, inventors --- have demonstrated that D-chiro-inositol is either absent, or present in extremely low levels, in type II, insulin-resistant diabetics, in contrast to the levels observed in non-diabetic control individuals. • (4) Further research has indicated that insulin-resistant diabetes may in fact be due to a genetic inability to synthesize, in vivo, D-chiro-inositol, an essential carbohydrate of the insulin mediator responsible for activation of PDH. • (5) This inability prevents the formation of an insulin mediator responsible for the activation of PDH. Thus, individuals exhibiting diabetic symptoms as a result of this deficiency, will not respond to treatment with insulin. • Exhibit 4-8 relating to insulin mediator. (To show common general knowledge)

10. EnablementTokyo High Court 2001 (Gyoke) 99(Equivalent to pharmacological test) Tokyo High Court: - In points (1)-(3) above, there is no concrete description on isolation method or details of analysis results regarding insulin mediator, and as to point (4), there is no data supporting the hypothesis. • - Earlier US application may not be relied on because they are not laid open to the public at the time of filing. • - Exhibit 4-8 does not indicate the insulin mediator has PHD activation ability. - Thus, a person in the art may not be able to scientifically understand how DCI produces therapeutic or preventive effects against diabetes.

11. EnablementTokyo High Court 2001 (Gyoke) 99(Equivalent to pharmacological test) Specification (administration of DCI and solving the problem of lack of synthesis of DCI): (1) D-chiro-inositol, related to myoinositol, is available from non-dietary sources, in forms not readily assimilated by the body. The methylester of D-chiro-inositol (DCI) is found---in pines, and legumes. --But the assimilable sugar itself does not appear, in sufficient quantities, in normal dietary foods, to make up for a lack of the ability to synthesize the sugar. (2) When administered as a vitamin, in appropriate therapeutic amounts, the carbohydrate is absorbed directly through the lining of the gastrointestinal system, and available for utilization in the preparation of the insulin mediator.

12. EnablementTokyo High Court 2001 (Gyoke) 99(Equivalent to pharmacological test) Tokyo High Court: - Regarding points (1)-(2), there is no experimental data. • - Exhibits 9 and 10 indicate myo-inositol and DCI show different activity because a diabetic’s urine contains more myo-inositol than a non-diabetic’s. • - Exhibit 11-12 is a rapid communication or research report and is thus not considered as reflecting general common knowledge as of filing. • - Later filed experimental data

13. IP High Court 2006 (Gyoke) 10442 Stimulation of fertilityDecided on June 28, 2007 (EP0751782B1) Claim 1: An agent for stimulating fertility in mammals by reducing glycoprotein hormone activity having luteinizing hormone activity in circulation and thereby stimulating the production of follicle stimulating hormone characterized in that administration to mammals of a non-neutralizing antibody reduces biological activity of luteinizing hormone.

14. IP High Court 2006 (Gyoke) 10442 Stimulation of fertility Description 1: For example, B105 would reduce the effective hLH levels by a factor of approximately 4 whereas B110 will reduce the effective hLH levels by a factor of approximately 2. Reducing LH levels will permit FSH levels to rise. As FSH levels rise, they will cause follicular development and the production of estrogens. When these levels have reached the physiological concentrations characteristic of appropriate follicle development, they will negatively inhibit the secretion of more FSH.

15. IP High Court 2006 (Gyoke) 10442 Stimulation of fertility IP High Court: The terms “by a factor of approximately 4” or “by a factor of approximately 2” found in Description 1 are not considered to be pharmacological data obtained through some experiment in view of nature of the numeric.

16. IP High Court 2006 (Gyoke) 10442 Stimulation of fertility Description 2: (Example1) Administration of 10g-10 mg of high affinity antibody (i. e., Ka > 5 x 107M-1) will be sufficient to induce fertility in women having polycystic ovarian disease.

17. IP High Court 2006 (Gyoke) 10442 Stimulation of fertility IP High Court: The above description describes that use of a certain amount (10g-10 mg) of high affinity antibody (i. e., Ka > 5 x 107M-1) actually causes stimulation of fertility, but the enhancement is not quantitatively disclosed, and the subject of administration is limited to a patient having polycystic ovarian disease, among mammals recited in claim 1.

18. IP High Court 2006 (Gyoke) 10442 Stimulation of fertility Description 3: ( Example 4) Administration of 10 yg-10 mg of a non-neutralizing antibody to LH that causes a transient and self-limiting rise in FSH secretion will induce ovulation with less risk of hyper-stimulation than treatment with gonadotropin. The effect is transient because the antibody will be metabolized or otherwise cleared from the circulation and its effectiveness will be lost within 1-2 weeks after administration.The treatment is self-limiting because the negative feedback effect of estradiol on FSH secretion will not be eliminated. Thus, as FSH levels rise and stimulate follicle development, estradiol secretion will rise and inhibit further increases in FSH secretion.

19. IP High Court 2006 (Gyoke) 10442 Stimulation of fertility IP High Court: Above description (3) mentions administration amount quantitatively, but does not mention its effect quantitatively, namely, to what extent the danger is reduced and to what extent ovulation is induced quantitatively. Furthermore, the specific binding agent (a non-neutralizing antibody) to be used is not concretely described.

20. IP High Court 2006 (Gyoke) 10442 Stimulation of fertility Thus, the above descriptions (1)-(3) are not considered to disclose concrete data showing what amount of administration of specific binding agent reducing LH activity would provide what extent of reduction of LH activity, and thus what level of stimulation of fertility would be obtained thereby. Thus, the instant description does not enable a person in the art to work claim 1, which is not limited by the animal (subject) in which fertility is to be stimulated.

21. Pharmacological Test Support requirements

22. Examination Guideline MedicineSupport RequirementsTypical examples of violation (1) • An antiemetic drug having an active ingredient A is claimed, but neither the pharmacological test method nor pharmacological data are described in the detailed description of the invention. Furthermore, it would not be possible to presume that the ingredient A was effective as an antiemetic drug in the light of the common general technical knowledge as of the filing.

23. Examination Guideline MedicineSupport RequirementsTypical examples of violation (2) • Therapeutic agents for a specified purpose whose active ingredients are compounds defined by desired properties are comprehensibly claimed, but usefulness as therapeutic agents for the specified purpose can only be verified from the detailed description of the invention in respect of only a small fraction of the compounds included in the claim. A person skilled in the art could not generally presume the usefulness as therapeutic agents of chemical substances included in the claim in the light of the common general technical knowledge as of the filing .

24. Support Requirements IP High Court 2009 (Gyoke)10033 flibanserin • The Board found that the instant specification does not contain any pharmacological data supporting the efficacy of flibanserin as a medicament for treatment of disorders of sexual desire. Furthermore, the board found that the descriptions in the detailed description could not be deemed equivalent to pharmacological data. Therefore, the detailed description of the invention does not include any pharmacological data or equivalent, and thus it fails to meet the requirement set forth in section 36(6)1.

25. Support Requirements IP High Court 2009 (Gyoke)10033 flibanserin • IP High Court: • When interpreting the detailed description of the invention to assess support requirements by comparing the breadth of claims with detailed description, it would be sufficient to understand formally the technical matters described and disclosed through examples and the like in the detailed description. In the absence of extraordinary circumstances, it cannot be said that a description of pharmacological data or its equivalent is an indispensable requirement.

26. Enablement

27. From Examination Guideline (Enablement)(Rejection under Enablement Requirements) • Against the notice of reason for refusal, an applicant may argue or clarify by putting forth written arguments or experimental results, etc. Where the applicant's argument is confirmed to be adequate by examining the submitted evidence, the reason for refusal shall be deemed overcome. • However, it must be noted that the evidence, etc. that has been submitted later cannot be used to assert matters not described in the specification.

28. Examination Guideline (Specification)(Enablement) • In a technical field where it is difficult to predict the structure of a product from the function or characteristic of the product (e.g. chemical substances), the detailed description of the invention will be in violation of the enablement requirement if a person skilled in the art cannot understand how to make products defined by the function or characteristic, other than those for which there is a concrete description of the manufacturing method (or those which can be made from these products taking into consideration common general knowledge)

29. Examination Guideline (Biology)(Enablement, how to use) • Where genes are claimed in a generic form and the function is not specified in the • claim (genes specified only by "substituted, deleted or added," "hybridized" or "having more • than X% identity," etc.), the claim will include genes which do not have the stated function and a fraction of the claimed genes will not be able to be used. Therefore, the invention is not described in manner enabling a • person skilled in the art to use the product.

30. TOKYO HIGH COURT 1998 (Gyoke) No. 95 Enablement (22 Feb. 2000) • Claim 1 • A part of a mammal T-cell antigen receptor beta subunit which is an isolated polypeptide or peptide consisting of at least 8 amino acids, wherein said T-cell receptor beta subunit is characterized by: • (i) being expressed by T-cell specific mRNA, • (ii) being coded by a nucleic acid subject to T cell specific rearrangement, and • (iii) being coded by a nucleic acid that hybridize with a probe consisting of a sequence shown below or its complimentary sequence. • [Formula 1]

31. TOKYO HIGH COURT 1998 (Gyoke) No. 95 Enablement (22 Feb. 2000) • Detailed Description: • - A library of 5000 selected clones was screened and rescreened by standard procedures-- using the membrane-bound T-helper cell cDNA probes from the T-hybridoma 2B4 from which sequences common to B-cell messenger from the B-cell L10A had been subtracted (MBT2B4-BL10A). Thirty-five definite positives resulted-- fell into one of the 10 distinct patterns of mRNA size and expression shown in the following Table.

32. TOKYO HIGH COURT 1998 (Gyoke) No. 95 Enablement (22 Feb. 2000) • Detailed Description: • - In order to obtain other cDNA clones which arose independently in different T-lymphocytes, a thymocyte cDNA library was prepared------ • - Three thymus-derived clones were obtained designated 86T1, 86T3 and 86T5. A partial restriction map is shown in Figure 1.

33. TOKYO HIGH COURT 1998 (Gyoke) No. 95 Enablement (22 Feb. 2000) • Detailed Description: • - In conclusion, the structure of 86T1 is that of a 19 amino acid leader polypeptide, a 98 amino acid variable region, a 16 amino acid J region and a single globular constant region domain followed by transmembrane and cytoplasmic portions. By analogy to immunoglobulins, the two outermost cysteines in each globular domain would be linked and the last cysteine at position 260 would be bound to the other chain of the receptor heterodimer. .

34. TOKYO HIGH COURT 1998 (Gyoke) No. 95 Enablement (22 Feb. 2000) • Detailed Description: • - It was further found that antisera raised against synthetic peptide fragments of 86T1 can significantly inhibit the antigen-dependent release of IL-2 by T-helper hybridomas. It is therefore concluded that the locus described above represents a type of immunoglobulin gene specifically rearranged and expressed in at least some subsets of T-lymphocytes and that it plays a role in the recognition of antigen by T-cells

35. TOKYO HIGH COURT 1998 (Gyoke) No. 95 Enablement (22 Feb. 2000) Tokyo High Court: As described above, the present invention relates to a chemical substance being a “peptide or polypeptide”. Further, as each of the peptides encompassed in claim 1 are independent chemical substance inventions, and since the essence of a chemical substance invention is the creation of a useful chemical substance, it is a requirement that all of the numerous peptides to which the application relates, be useful. • Therefore, regarding utility, for the present application to fulfill the requirement of Art 36(3) of the patent law, the utility of all the peptides encompassed in the scope of the claim must either be described in the specification, or clear to a skilled person from common technical knowledge.

36. TOKYO HIGH COURT 1998 (Gyoke) No. 95 Enablement (22 Feb. 2000) • Consequently, cases where the present application would contravene Article 36(3) of the Patent Law are cases (1) where it cannot be said that the utility of all of the peptides etc., within the scope of the claims are described in the specification; nor that this utility would be clear to a skilled person on the basis of common technical knowledge; and (2) where there is no description in the specification allowing a skilled person to easily select from among the peptides, etc. included in the scope of the claims, only those having utility. • (EP174366, EP0570027)

37. 2008 (Gyoke) 10274Decided on September 2, 2009 • Claim 1 • A polypeptide comprising a sequence of at least 8 consecutive amino acids,and having following characteristics: • (1) the said sequence of at least 8 consecutive amino acids contains a part wherein the said part in the said sequence of at least 8 consecutive amino acids or in the said polypeptide (a) can combine with antibody against HCV, and • (2) the said sequence of at least 8 consecutive amino acids is obtained from a sequence having one or several deletions, insertions or substitutions to the following amino acid sequence • (Omitted: an amino acid sequence of 1-2436 ), provided that the polypeptide does not contain a sequence of at least 8 consecutive amino acids obtained from the following amino acid sequence (Omitted: same amino acid sequence of 1-2436 as above )

38. 2008 (Gyoke) 10274Decided on September 2, 2009 • Court: • - Indeed in the field of biotechnology，there are cases where it is allowed that a claim may be written to include a sequence having one or several deletions, insertions, or substitutions to a specifically recited sequence. • - In technical fields relating to a novel gene having a useful activity, from the viewpoint of promoting invention, and the viewpoint of preventing the imitation by third parties and inability to preserve a monopoly that would result from not allowing such claims, there should be cases where a claim may be written to include a sequence having one or several deletions, insertions, or substitutions to a specifically recited sequence.

39. 2008 (Gyoke) 10274Decided on September 2, 2009 • Court: • - In other words, regarding a case where an amino acid sequence constituting a novel polypetide having a useful activity may be generically described in a claim (in a way allowing a variation in a part of the sequence), it may be considered that enablement requirement is met when it is considered that a modified polypetide having same active as original polypetide may be easily obtained. • - However, the enablement requirement is not met when it would require excessive trial-and-error or an innovation beyond that which can be expected from person skilled in the art.

40. 2008 (Gyoke) 10274Decided on September 2, 2009 • Court: • In the instant case, the claimed polypetide of the present invention has an amino acid sequence of "at least 8 amino acids", and includes those having one or several deletions, insertions, or substitutions in the sequence, but the description of the application does not disclose a mode to obtain modified polypetides, based on the polypeptide defined with such a small number of amino acids, that have a similar activity as the polypetide so as to enable a person in the art to easily carry out the invention.

41. Reference for 2008 (Gyoke) 10274Decided on September 2, 2009 Granted Claim 1 of parent application : A polypeptide comprising a sequence of at least 8 consecutive amino acids,and having following characteristics: (1) the said sequence of at least 8 consecutive amino acids contains a part wherein the said part in the said sequence of at least 8 consecutive amino acids or in the said polypeptide (a) can combine with antibody against HCV, and (b) does not combine with antibody against other Flavi virus,and (2) the said sequence of at least 8 consecutive amino acids is obtained from the following amino acid sequence (Omitted: an amino acid sequence of 1-2436)

42. Inventive Step

43. From Examination Guideline (Inventive Step) (Effects to be considered, asserted in a written argument) • Where advantageous effects compared to cited inventions are described in a specification, or where advantageous effects are not explicitly described but can be inferred from the statements in the specification or the drawings by a person skilled in the art, effects asserted or verified (e.g., experimental results) in a written argument, etc. should be considered. • However, effects asserted in a written argument, which are not described in the specification and that a person skilled in the art couldn’t deduce from the description of the specification or the drawings, should not be taken into consideration

44. Soluble TNF-R 2007 (Gyoke) 10105 • Claim 1 • Multimer of soluble TNF-R having capability of blocking the binding of TNF to its receptor and preventing function of TNF-R or its salt, wherein the multimer consists of TBP-I, or mixture of TBP-I and TBP-II.

45. Soluble TNF-R (Yeda)2007 (Gyoke) 10105 • Applicant: • Inventors discovered: • (1) aggregation of TNF-R is essential for activation of its function, • (2) involvement of non-functional TNF-R in the aggregation efficiently blocks the function of TNF.

46. Soluble TNF-R (Yeda)2007 (Gyoke) 10105 • Prior art: • - D1 discloses multimer of soluble TNF-R comprising TBP-II. D1 also mentions that soluble TNF-R may be administrated to prevent TNF dependent reaction. • - D5 discloses TBP-I protect cells against TNF’s cell damaging activity, and made it clear that TBP-I specifically binds to TNF, and blocks its function.

47. Soluble TNF-R 2007 (Gyoke) 10105 • Applicant argued that the inventors discovered that: • (1) aggregation of TNF-R1 is essential for activation of its function, • (2) involvement of non-functional TNF-R1 in the aggregation efficiently block the function of TNF. • Claimed inventions are based on (2) above.

48. Soluble TNF-R 2007 (Gyoke) 10105 • Applicant: • - Exhibit 18 (later published document) shows that fusion protein of Ig and dimer of TBP-I(TNF-R1) completely neutralizes the function of TNF-alpha, while a fusion protein of Ig and dimer of TBP-II(TNF-R2) cannot. • - D1 discloses binding of TBP-II to TNF, but does not mention the maintenance of binding capability as a monomer nor mentions capability to bind as a multimer.

49. Soluble TNF-R 2007 (Gyoke) 10105 • Court: • - Both TBP-I and TBP-II had been known as having a ability to protect against TNF having an ability to damage cells before priority date. • - Thus, it would be obvious to a person in the art to extend knowledge of TBP-II to TBP-I.

50. Soluble TNF-R 2007 (Gyoke) 10105 • Court: • - Exhibit 18 was published after thus priority date, and thus cannot be considered. • - Furthermore, it does not deny the function of fusion protein comprising TNF-R1(TBP-I). • - The present specification does not contain any experimental data supporting the effect of claim 1.