decision 293mumnp2008

8/10/2019 Decision 293mumnp2008

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Patents Act 1970

(Section 77 and Section 15)

In the matter of the Patents Act 1970

In the matter of Patents Rule 2003

In the matter of an application for a patent 293/mumnp/2008

Date of Hearing: initially fixed on 08 th October 2012, later adjourned to and heard on 24 th January2013; held before Dr Amitava Chakraborti, Deputy Controller Of Patents and Designs

Present: Saima Ansari for the applicant

Dr S kulkarniExaminer Of Patents and Designs

Decision

1. The subject application carrying the title ISOTOPICALLY SUBSTITUTED PANTOPRAZOLE wasfiled by NYCOMED GMBH (later changed to Takeda GMBH ) of Germany on 18/02/2008 as anational phase application of PCT application PCT/EP2006/064669 with the priority date of

26/07/2005 of an EP application. The application was filed with 25 claims. The applicationwas duly published and subsequent to the request for examination filed by the agent of theapplicant, was referred for examination. First Examination Report was issued on 14 th July2011. The agent of the applicant M/s Krisna and Saurastri responded to the FER on05.07.2012 and made certain amendments to the claims. The application was re-examined,and a hearing notice was sent to the applicants agent on 11.09.2012.

2. As communicated in the letter of the unresolved issues on the date of hearing, were,Agents observations were carefully considered, however Paras 2,3 & 5 of this office letterare not met properly i.e.

a. The isotopically substituted pantoprazole & its enaniomers as claimed in theclaims 1-11, falls under section 3(d) of the Patents Act, 1970 as amended by thePatents (Amendment) Act 2005, therefore not allowable.Claim 12 &13 do not clearly define the pharmaceutical composition; all thenovel inventive % or proportion of components used for the preparation ofpharmaceutical composition should be defined clearly.

The invention as claimed in the claims 1-20 lack Inventive step for instance seecited documents

D1: EP-A-0 005 129 (HAESSLE AB) (1979-10-31)D2: US-B2-6 818 200 (FOSTER ROBERT T ET AL) (2004-11-16)


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The closest prior art D1 discloses the corresponding non-deuterated derivativeswith the same use. The presently claimed deuterated compounds exhibit adecreased metabolization rate over the H-derivatives which mean a longerduration of action (half-life) of these compounds. The technical problem that theapplication intends to solve is to provide derivatives of pantoprazole with alonger half-life. This is apparently solved in the application (see table 1, p.19).However such a solution has already been used in D2, which discloses that bydeuterating known drugs, an enhanced, efficiency is provided, which accordingto the inventor of D2, can be linked to the fact that the deuterated compoundsare less susceptible to usual metabolic pathways thus increasing the half-life(see col.26, 1.45-58). Although D2 focuses more particularly on deuterateddihydropyridine, it also cites other antibiotics and also omeprazole with aspecific pathway to get the corresponding deuterated derivative (see col.24,1.50 to col.25, 1.18). D2 constitutes a clear indication that deuteration modifies

the metabolization of drugs and in particular that such a method is applicable toderivatives of omeprazole. Therefore the subject-matter of claims 1-13 cannotbe considered as inventive over D1 in combination with D2.The process for making these compounds is a mere adaptation of the process-known from D1 to the preparation of deuterated compounds, which is notenough to justify an inventive step. The subject-matter of claims 14-20 isconsequently not inventive.

b. The isotopically substituted pantoprazole & its enaniomers as claimed in theclaims 1-11, & 17-20 falls under section 3(d) of the Patents Act, 1970 as

amended by the Patents (Amendment) Act 2005, therefore not allowable.

3. After the hearing, the learned agent submitted a written note of arguments on 18 th February, 2013

Alleged invention and claims

4. The invention as described in the specification relates to the compounds of the generalformula I:


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5. The compound of the alleged invention is an already known substance, whose generic name isPantoprazole. The present invention, as was described in the complete specification, as submitted,contained deuterated pantoprazole compounds as indicated above. The alleged invention lies in theproposed replacement of the H-atoms with deuterium. With respect to the use of the compoundsthe specification states that the (deuterated) compounds significantly influences acid secretioninhibition properties of these compounds.

6. Claims 1 and 2, as on the date of the hearing read as:

7. Claims 3 to 9 are different variants of compound of formula I and are dependent either onclaim 1 or on claim 2


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8. Claims 10 and 11 were recited as:

9. Claims 12 and 13 were related to pharmaceutical compositions containing compounds offormula 1 or 3 to 11.

10. Claims 14 to 20 relate to the process of making of the compounds.

Submission of the agent of the applicant after the hearing:

11. The agent of the applicant submitted a fresh set of claims.

Claim I is amended. Claim 3 is incorporated in claim 1.

Claim 2 is amended. Claim 3 is incorporated in claim 1. Claim 3 is cancelled

Claim 4 is cancelled

Claims 5-20 are renumbered as claims 3-18 respectively and their dependencies

are changed accordingly.

12. Main aspect of the amendment is the deletion of deuterium substitution in R1 group. As anexample I would like to reproduce marked up copies of the revised claims 1 as given below:


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13. Similarly, claim 2 and other claims have been revised to delete the reference of deuteratedR1 group.

Issues related to Section 3(d)

14. The law:

Section 3

What are not inventions

The following are not inventions within the meaning of this Act,

..

Section 3(d): the mere discovery of a new form of a known substance which does not result in theenhancement of the known efficacy of that substance or the mere discovery of any new property ornew use for a known substance or of the mere use of a known process, machine or apparatus unlesssuch known process results in a new product or employs at least one new reactant.Explanation. For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pureform, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives ofknown substance shall be considered to be the same substance, unless they differ significantly inproperties with regard to efficacy;

While discussing the issue of efficacy, the honourable Supreme Court in Novartis v Union Of Indiaobserved:

What is efficacy? Efficacy means the ability to produce a desired or intended result. Hence, thetest of efficacy in the context of section 3(d) would be different, depending upon the result theproduct under consideration is desired or intended to produce. In other words, the test of efficacywould depend upon the function, utility or the purpose of the product under consideration.Therefore, in the case of a medicine that claims to cure a disease, the test of efficacy can only betherapeutic efficacy. The question then arises, what would be the parameter of therapeut icefficacy and what are the advantages and benefits that may be taken into account for determiningthe enhancement of therapeutic efficacy? With regard to the genesis of section 3(d), and moreparticularly the circumstances in which section 3(d) was amended to make it even more constrictivethan before, we have no doubt that the therapeutic efficacy of a medicine must be judged strictlyand narrowly. Our inference that the test of enhanced efficacy in case of chemical substances,especially medicine, should receive a narrow and strict interpretation is based not only on externalfactors but there are sufficient internal evidence that leads to the same view. It may be noted thatthe text added to section 3(d) by the 2005 amendment lays down the condition o f enhancement ofthe known efficacy. Further, the explanation requires the derivative to differ significantly in

properties with regard to efficacy. What is evident, therefore, is that not all advantageous orbeneficial properties are relevant, but only such properties that directly relate to efficacy, which incase of medicine, as seen above, is its therapeutic efficacy . [Paragraph 180] MIPR2013(1)313,2013(5)SCALE12. Therefore, the efficacy as referred in Section 3(d) is therapeutic efficacy.

15. With respect to the objection under Section 3(d), the learned agent referred to Table 1:


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[Page 31 of the specification].

16. According to the learned agent, Table I shows comparative results of metabolizedpantoprazole (non-deuterium substituted) and deuterium substituted compounds of example 1and example 2 after 90 minutes. Various animal and human models were used for the exposureof the compounds whose comparison was meant to be done under same conditions. Theefficacy of the compounds claimed is achieved by higher exposure of the compound toinhibit the target protein. A higher exposure of the compound is achieved by a lower removal ofthe compound from the body. The percentage of pantoprazole metabolized after 90 min ofexposure in rat was 61 % meaning that 39 % of pantoprazole was remaining after 90 min ofincubation. For example 1 and example 2, the amount of the deuterated compound metabolisedafter 90 min was reduced to 35 %, and 17% respectively that means 65% and 83 % of thedeuterated compound were remaining after 90 min of incubation. This means that thedeuterated compound under same conditions and same time as that of the non-deuteratedcompound is metabolized to a much lower extent, thereby indicating a higher stability andexposure of the deuterated compound. This higher exposure results in the enhancement of theefficacy of the deuterated compounds.

17. She further, referred to Table II:


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[Page 33 of the specification].

18. Explaining the results of Table II, she submitted the higher the intrinsic clearance values, thelower is the metabolic stability and lower is the exposure of the compound resulting in a lowerefficacy. The intrinsic clearance describes the metabolic capacity of an organ. Thus from Table Iand Table II, it is evident that Examples 1,2,5, 6, 30 have higher metabolic stability and higherexposure allegedly resulting in a higher efficacy.

The compounds of the examples 5,6 and 30 are as extracted in the table below:

Example Compound

Example 1 (R/S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole

Example 2 (S)(-)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole

Example 5 Sodium (S)-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1 H-benzimidazolide} hydrate

Example 6 Sodium (R/S)-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1 H-benzimidazolide}hydrate

Example 30 (R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole sodium salt trihydrate

If we see these compounds, a single pattern evolves, i.e., R1 and R2 are non- deuterated and R3is tri- deuterated Methoxy.


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19. On the basis of these two tables, she concludes that from table I and table II, it is clear thatthe deuterated compounds of the invention have higher metabolic stability and also concludesthat higher exposure of the compounds results in an enhanced efficacy.

20. The examiner identifies D1 as the closest prior art. D1 as I find, discloses compounds of the

same structures with H-substitutions instead of D-substitutions. In fact it discloses a class ofproton pump inhibitors similar to pantoprazole. The present application relates to D-substitutedpantoprazole derivatives. And the applicant has provided comparative data with pantoprazole.Further to that, the examiner insisted that D2 involves preparation of deuterated compoundsincluding omeprazole, a structurally close compound having similar proton pump inhibitoractivity. However, it seems to me that these arguments are all directed to the findings ofinventive step. The question of Section 3(d), vis--vis the significantly improved therapeuticefficacy is to be adjudicated against the closest compound known, in this case, pantoprazole andnot omeprazole. Therefore, the question to be answered is, whether the applicants counterargument and experimental details meet the requirement of significantly improved therapeuticefficacy against pantoprazole.

21. In the present case I find that the only experimental details provided are those related tothe metabolic stability and intrinsic clearance value. Improved metabolic stability and intrinsicclearance value show how the system acts on the drug. However, the therapeutic efficacy can beunderstood from the way how the drug acts upon the system. In the instant case, however, thisis missing. I do not find anything from which how the drug in question shows a better result or iscapable to show a better result, is established.

22. Therefore, in my opinion the present invention as claimed in the amended claims is not

allowable under Section 3(d) of the Patents Act 1970.

Inventive step

23. The other objection maintained by the examiner is of lacking of inventive step.

The law:

Section 2: Definitions and interpretation

(1) In this Act, unless the context otherwise requires,-

....

(j) "invention" means a new product or process involving an inventive step and capable ofindustrial application;

(ja) "inventive step" means a feature of an invention that involves technical advance ascompared to the existing knowledge or having economic significance or both and that makes theinvention not obvious to a person skilled in the art;

24. As I have said D1 discloses a class of proton pump inhibitors similar to one which was later

known as pantoprazole. Examiner observed that D2 focuses more particularly on deuterateddihydropyridine, it also cites other antibiotics and also omeprazole with a specific pathway to get


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the corresponding deuterated derivative (see col.24, 1.50 to col.25, 1.18). D2 constitutes a clearindication that deuteration modifies the metabolization of drugs and in particular that such amethod is applicable to derivatives of omeprazole. Therefore the subject-matter of claims 1-13cannot be considered as inventive over D1 in combination with D2 .

25. With respect to D1, the applicant submitted that the compounds of D1 differs from thepresent compounds with respect to R1, in that R1 for Pantoprazole is difluoro-methoxy and isnot connected to D1. Although I do not find this argument as not tenable, despite that for adifferent reason I think that D1 is not relevant at all. As I said, D1 relates to similarly structuredcompounds but it does not cover D-substituted pantoprazole. It is meaningless to cite D1, whenalready we know that the invention begins from Pantoprazole itself, and subsequently bymaking deuterium substitution of the same. But again when the invention admittedly is animprovement over pantoprazole, I think that the issue of the inventive step needs reformulation.

26. In my opinion the question may be asked whether D2 would motivate any person skilled in

the art for making modifications by way of D-substitution to Pantoprazole molecule. I referredthat the concern of the examiner was that D2 focuses more particularly on deuterated

dihydropyridine, it also cites other antibiotics and also omeprazole. As far as strucr ual similarityis concerned, the nearest compound mentioned in D2 is Omeprazole, a Benzimidazole derivativelike Pantoprazole. I like to quote the two compounds side by side, also I like to :

Omeprazole Pantoprazole

Omeprazole was mentioned, along with other compounds in D2. As it belong to the same classof compounds, it was my major concern and I enquired specially about that to the agent also.The learned agent of the applicant observed that:

The main concern of the Controller was the disclosure of the deuteration of the drug`omeprazole' in column 25 of D2. The Controller's contention was that as pantoprazoleand omeprazole both belong to the class of proton pump inhibitors, it would be obviousfor a person skilled in the art to deuterate pantoprazole as deuteration of omeprazole ismentioned in D2.

It was explained to the Controller that D2 is silent with respect to the deuterationpattern especially omeprazole. There is no disclosure in D2 about the replacementpattern of H atom with that of deuterium, which is the case with the present inventionthat is specifically the H atoms of the methoxy groups is replaced with that ofdeuterium .

27. The agent further observed that The deuterated compounds, specifically at


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positions 3 and 4 (R2 and R3) of the present invention demonstrate efficacy asexplained above. The advantageous effect of deuteration mentioned in D2 is withrespect to penicillin V, which is completely different than the compound disclosed in thepresent invention. Also, D2 is silent about the deuteration pattern that is which H atomof penicillin is replaced by deuterium.

I find that the compounds shown to have improved metabolic stability are those inwhich R3 is tri-D substituted (as against the assertion of the R2 and R3). However, Iagree that D2 is silent about the D-pattern of Omeprazole. Also, I did not see anyreference of increased efficacy of omeprazole in D2.

28. It therefore seems to me that omeprazole containing D substitution as referred inD2 cannot be considered as a point of motivation to the applicant of the presentapplication. For the other compounds of D2 also, the D-substitution is shown either directly tothe ring or to the N-atom and not in the methoxy groups. The agent concluded by saying that inthe case of the present application t he D-patterns of the D2 is that Deuterium is notattached to ring and H atoms of the methoxy group is replaced as opposed to the citedcompounds.

29. I find that there is enough force in the arguments of the applicant and the reply to thequestion of inventive step is satisfactory. Additionally, I would like to say that the deuteratedcompounds of the present invention shows much improved results with respect to themetabolic stability and intrinsic clearance value. Therefore, I conclude that the claims of thepresent application do not offend Section 2.1.(j) in not meeting the criterion of inventive step.

30. However, as I said before, the claims are not allowable on the ground of Section 3(d), Itherefore refuse the application.

Dated 25 th day of June 2013 Dr. Amitava Chakraborti;

Deputy Controller of Patents and Designs;

decision 293mumnp2008

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