THE PATENTS ACT, 1970 (AMENDED BY THE PATENTS ACT 2005) AND THE PATENT RULES, 2003 (AMENDED BY THE PATENTS RULES 2006) In the matter of patent Application no. 4805/DELNP/2007, filed on 21/06/2007(Divisional out of Application No. 263/DELNP/2005 dated 24/01/2005) AND In the matter of representation by way of opposition U/s 25 (1) on said application No. 4805/DELNP/2007
JANSSEN PHARMACEUTICA N.V, TURNHOUTSEWEG 30, 2340 BEERSE, BELGIUM ……… The Applicant CIPLA LIMITED, 289 BELASIS ROAD, MUMBAI CENTRAL, MUMBAI-400008 INDIA.……..The Opponent
Hearing held on 24th January, 2014 Present: Sh. Jitesh Kumar of M/s Remfry & Sagar……………………………………Attorneys for the Applicant Sh. S. Majumdar of M/s Majumdar & Co., Mumbai………… Attorney for the Opponent
DECISION An application titled as "PROCESSES FOR THE PREPARATION OF 4-[[4-(2CYANOETHENYL)-2,6-DIMETHYLPHENYL]-AMINO]-2-PYRIMIDINYL]AMINO] BENZONITRILE" was filed on 21st June 2007 by Janssen Pharmaceutica N.V, BELGIUM for grant of the patent and claims the priority of PCT/EP/2003/050366 dated 07/08/2003, which in turn derives a European priority of August 09, 2002. The impugned patent application is divisional to application no: 263/DELNP/2005 granted as IN242945. The said application was published in the patent office journal dated 24th August 2007. The said application was examined according to the provisions in force of the Patents Act, 1970 (as amended) and First Examination Report was issued to the Applicant's Agent on 23/01/2012. The applicant filed reply to FER on 18/12/2012 with amended set of claims and the number of claims were reduced to 7. Presently the claims 1-7 relate to the process for the preparation of an intermediate of formula (II), an appropriate acid addition salt, a quaternary amine or a stereochemically isomeric form thereof. 1
A pre grant opposition by way of representation was filed by CIPLA LIMITED u/s 25(1) of the th
Patents (Amended) Act, 2005 on 12 Dec. 2012. The said pre-grant opposition was forwarded to the applicant on 11th June, 2013 & the applicant filed reply statement & evidence on 11th September, 2013 within three months from the date of notice. GROUNDS OF OPPOSITION The opponent opposed the Grant of patents under section 25 (1), on the following grounds:• Section 25(1)(e) - that the invention so far as claimed in any claim of the complete specification is obvious and clearly does not involve any inventive step, having regard to the matter published as mentioned in clause (a) or having regard to what was used in India before the priority date of the claim; • Section 25(1)(f) - that the subject of any claim of the complete specification is not an invention within the meaning of this Act, or is not patentable under this Act; • Section 25 (1)(g) - that the complete specification does not sufficiently and clearly describe the invention or the method by which it is to be performed; • Section 25(1)(h) - the patentee has failed to disclose to the Controller the information required by Section 8 or has furnished the information which in any material particular was false to his knowledge . However, during the hearing the opponent only opposed the grounds of:I. 25(1)(e): Obviousness/Lack Of Inventive Step II. 25(1)(f): Not An Invention/Not Patentable III. 25(1)(g): Insufficiency Therefore, I will confine my considered view on the contested grounds only.
Opponent relied upon following prior art: WO01/85699 published on November 15, 2001, referred herein as Dl and annexed hereto as Exhibit 1 WO 99/50250 published on October 7, 1999, referred herein as D2 and annexed hereto as Exhibit 2 Nobel lecture entitled "The Logic of Chemical Synthesis: Multistep Synthesis of Complex Carbogenic Molecules" dated December 8, 1990 by E.J. Corey, referred herein as D3 and annexed hereto as Exhibit 3 Acrylamide (HSG 45, 1991) downloaded from the site www.inchem.org/documents/hsg/hsg/hsg045.htm, referred herein as D4 and annexed hereto as Exhibit 4 WO 03/016306 published on February 27, 2003, referred herein as D5 and annexed hereto as Exhibit 5 and Annexure C, Annexure D, Annexure E and Annexure F 2
The Opponent's attorney dropped the prior art citations D5 and Annexure C during hearing. Accordingly, the Opponent's mainly relied upon the cited documents Dl to D4, Annexure D, Annexure E and Annexure F.
The finally amended Claims (submitted on 18/12/2012) are reproduced below (Total 7): 1. A process for the preparation of an intermediate of formula (II), an appropriate acid addition salt, a quaternary amine or a stereochemically isomeric form thereof
(II) which comprises reacting an intermediate of formula (V), an appropriate acid addition salt or a quaternary amine thereof
(V) wherein W3 represents a suitable leaving group, with acrylonitrile in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent, optionally followed, if desired, by converting the free base into an acid addition salt by treatment with an acid, or conversely, by converting the acid addition salt form into the free base by treatment with alkali; and optionally followed, if desired, by preparing stereochemically isomeric forms, N-oxide forms or quaternary amines thereof. 2. A process for the preparation of an intermediate of formula (II), an appropriate acid addition salt, a quaternary amine or a stereochemically isomeric form thereof
(II) which comprises reacting an intermediate of formula (V), an appropriate acid addition salt or a quaternary amine thereof 3
(V) wherein W3 represents a suitable leaving group, with acrylamide in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent, followed by dehydration of the thus obtained intermediate of formula (VI), an appropriate acid addition salt, a quaternary amine or a stereochemically isomeric form thereof,
(VI) optionally followed, if desired, by converting the free base into an acid addition salt by treatment with an acid, or conversely, by converting the acid addition salt form into the free base by treatment with alkali; and optionally followed, if desired, by preparing stereochemically isomeric forms, TV-oxide forms or quaternary amines thereof. 3. The process as claimed in claim 1 or 2 wherein the palladium catalyst is a heterogeneous palladium catalyst. 4. The process as claimed in claim 3 wherein the heterogeneous palladium catalyst is palladium on charcoal. 5. The process as claimed in claim 1 or 2 wherein W3 is halo. 6. The process as claimed in claim 5 wherein W3 is iodo. 7. The process as claimed in claim 1 or 2 wherein the intermediate of formula (II), an appropriate acid addition salt, a quaternary amine or a stereochemically isomeric form thereof is
4
As the claims were amended by the applicant in response to the FER, the opposition will be examined in the light of the amended claims only. Both the parties opponents and applicants were heard at length on 24th January, 2014. The amended claims are directed to a process for the preparation of an intermediate of formula (II), an appropriate acid addition salt, a quaternary amine or addition salt, a quaternary amine or a stereochemically isomeric form thereof.
For the sake of brevity and to avoid repetition and conciseness of the decision, the detailed contentions taken in the written statement of the opponent and reply statement of the patentee has not been reproduced here. The main contentions raised by both the parties during hearing have been noted below.
Arguments of the opponents and hearing submission The Opponent submitted that the amended claims though related to process for the preparation of Rilpivirine intermediates and no longer claimed process for the preparation of rilpivirine, the process mentioned in the amended claim 1 and 2 were similar to those claimed in the as filed claims 1 and 3 and basically involved a well known name reaction i.e. Heck reaction. The Opponent further referred to point 4.13 on page 7 of the representation which provided a schematic representation of the process claimed in claim 1 and claim 2 which is as reproduced below:
5
Opponent submitted that the applicant has only contended that there is no motivation to prepare Rilpivirine or its intermediates but has failed to substantiate as to why the chemical reaction claimed in the application is non-obvious or possesses inventive merit. The opponent further submitted that Annexure D, Annexure E and Annexure F cited in the representation relates to the chemical reaction claimed in the impugned patent application, yet the Applicant has failed to provide any comments in relation to any of those documents. The invention claimed in the impugned application is directed towards a well known chemical process and the applicant has admitted in page 15 that well known processes can be performed according to methodologies well known to a person skilled in art. Annexure D-F provides a brief overview of the chemical reaction involved in the claimed processes which allegedly forms the background of the inventive merit of the invention. The opponent therefore submitted that the comments provided by the applicant in para 7.8-7.47 of the reply statement failed to provide any pleadings on the documents cited with regards to inventive step and hence failed to provide any pleadings to show as to why the claimed process should be held to be non-obvious or possessing inventive merit. Opponent argued that the representation (filed by the Opponent) and Reply statement (filed by the Applicant) forms a part of the pleadings which will help the adjudicating authority to frame the issues on which the parties differ with regards to the pregrant opposition. Failure on the part of the applicant to provide any response to the documents cited in the representation amounts to non-completion of pleadings on the part of the applicant. Even if the applicant was under an impression that the documents cited in the representation were non-relevant, the applicant’s reply statement should have provided pleadings to that effect. In the absence of applicant’s clear pleadings and its stand on the cited documents, the case made out by the applicant is unclear. Legal implications of not filing a reply statement/filing partial response to the objections raised in a Civil matter are also well settled as may be noted from the case laws cited hereafter. The Opponent placed the following cases to support their argument:- MANU/SC/0066/2011 (Kalyan Singh Chouhan Vs. C. P. Joshi), Ram Sarup Gupta (dead) by L. Rs. V. Bishun Narain Inter College and Ors. MANU/SC/0043/1987: AIR 1987 SC1242, Bachhaj Nahar v. Nilima Mandal and Ors. MANU/SC/8199/2008: AIR 2009 SC 1103, In MANU/SC/0045/1970 (Writ Petition No. 212 of 1969 and C.A. Nos. 1802 to 1805 6
Opponent further argued that in a pregrant opposition the Opponent’s pleadings are the representation while the Applicant’s pleadings are the Reply statement. If there is no representation, the Opponent does not have any right to interfere in the grant of patent as also there will be no dispute, but if there is no reply statement or partial response in the reply statement, than the Adjudicating authority (Controller) has to decide the case on the basis of partial pleadings of the Applicant case. I.
OBVIOUSNESS AND LACK OF INVENTIVE STEP [Section 25(1)(e)]:
On the ground of obviousness/lack of inventive step, Opponent submitted that Page 1of D2 states: The present invention is concerned with pyrimidine derivatives having HIV replication inhibition properties. The invention further relates to methods for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds in the manufacture of a medicament useful for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection. Page 2 of the impugned patent application states: 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile,------- thereof are novel, very potent HIV, especially HIV-1, replication inhibiting compounds. They have a high ability to inhibit the replication of the wild type Human Immunodeficiency Virus as well as resistant mutant strains thereof. Thus the compound disclosed in the impugned application as well as in D2 are pyrimidine derivatives and have HIV replication inhibiting properties. Further D2 is acknowledged prior art which admits that method of preparation of diaminopyridine compounds is disclosed therein. The opponent submitted that a skilled person while analysing any document which provides a general Markush structure and exemplifies few of them, is inclined to look out for those which appears to be most promising. The most promising compound is identified on the basis of which compound exhibits better pharmacological effect particularly better IC50 values. Table 7 on page 37 of D2 provides pharmacological data, particularly IC 50 , CC 50 and SI values for few compounds which have been exemplified in D2. It is well known that lower the IC50 values, better is the compound. Table 7 indicates that compound 69 with the
has the best IC50 values (0.0004). structure Analysis of the structure of compound 69 indicates that one of the phenyl group attached to the amino pyrimidine group has cyano at the para position and another phenyl group attached to the aminopyrimidine has cyano at the para position and methyl at the 2, 6 position. The Markush structure of the compounds disclosed in Table 7 are provided in Table 5 and table 6.
7
Markush structure of the compounds disclosed in Table 5 is as follows: Markush structure of the compounds disclosed in Table 6 is as follows:
Analysis of the Markush structure in Table 6 indicates that the phenyl group bearing cyano substituent which is attached to the amino pyrimidine group is a common factor in all the compounds of Table 6 and bearing a few compounds (82-89 and 63) all the other compounds have H as the substituent on the R5 position. So the structure
forms the background of the majority of the molecules in Table 6. Further analysis indicates that except for compound no.78 in Table 6, all the other compounds have H at the R6b position. Further analysis indicated that there were 4 compounds which differed only at the R6c position, all the other substituents being same. Those were
Compound no. 69
IC50
52
0.001
Structure
0.0004
8
80
0.011
75
0.0021
Thus when the cyano substituent was present at the R6c position, the compound showed the best IC50 value. 3 more compounds in the salt form also with substitution pattern similar to compound 69 is as provided below: 53 0.0006
.HCl 57
0.0007
.HCl 56
0.0023
.HCl Compounds 53 and 57 have IC50 values in the vicinity of compound 69 but they are in salt form and the IC50 value of those compounds perse is much more as compared to compound 69. The opponent further submitted that Compound 69 differs from other compounds basically at the R6c position with the cyano substituent as the driving force as may be noted from the above table. A skilled person is aware that a compound produces the best effect when the substituent pattern of that compound is such that they can bind effectively in the binding pockets available at that site in the body. Now since the above table indicates that when all the other substituents are same and only the substituent at the R6c position is changed to cyano, than the best IC50 value is obtained, a skilled person will deduce that Compound 69 is the best compound and to prepare any alternate compound with similar/better activity, compound 69 should be taken as the starting point and further variation needs to be done only in the cyano group present at the R6c position. 9
Now the question that arises is why a new compound is chosen when compound with the best IC50 value is already available. It may be noted that the arena of technology pertaining to HIV drugs is a complicated and fluctuating one in the sense that the virus is ever changing by means of developing resistant strains. Thus one compound or a class of compounds is never sufficient in treating an individual infected by HIV. Hence the field of study revolves around modification of compounds; such that the factor of motivation to modify a given compound is persistently present. It is stated that once a person skilled in the art and working in the field of HIV inhibitors identifies a promising compound from any document, the first step is to subject the promising compound to further carry out clinical studies, to ascertain the quantum of probability of resistant strains that would develop. Alternately the skilled person will attempt further modifications in the most promising compound starting with the modification of the substituents. Another step is to identify how the compound functions in the body especially how it binds to the available binding sites and then start making modifications so as to further improve the activity of the most promising compound. Further if a compound is protected by a patent a skilled person will have to look out at other compounds which will show similar/higher activity as compared to compound 69 so as not to infringe that patent. As discussed above a skilled person will note that compound 69 differs from the other compounds in activity due to the presence of the cyano group in the R6c position especially when comparison is made with other compounds wherein the substitution differs only at R6c position. A skilled person will therefore be inclined to maintain the cyano substituent at the R6c position under the impression that cyano substituent is one of the substituent which can accurately fit into the specific binding pockets and provide the desired activity. Opponent further submitted that D1 (for which the applicant is Janssen Pharmaceutica i.e. same as the applicant of the impugned application) provides compounds which possesses HIV inhibition activity and discloses the Markush structure of formula
Page 13 specifically states: Another special group of compounds contains those compounds of formula (I) wherein one or more, preferably all, of the following restrictions apply in the covalently bonded form of the pyrimidine compound of formula (II): i)-a'=a2-a3=a4-is a radical of formula (a-1); ii) n is 1; iii) R2 is cyano, preferably in the para position relative to the-NH-group; iv) Y is hydrogen, cyano,-C (=O) NH2 or a halogen, preferably a halogen; v) Q is hydrogen or-NR4R5 wherein R4 and R5 are preferably hydrogen; vi) L is-X-R3 ; preferably wherein X is NR7, O or S, most preferably wherein X is NH, and preferably wherein R3 is substituted phenyl, most preferably phenyl substituted with one, two or three substituents each independently selected from C1-6alkyl, halo and cyano. 10
Opponent argued that it may be noted that D1 indicates one of the preferred compounds to be compound 69 from D2. When a skilled person combines the teachings of D2 with D1, than they will specifically look out for such substituents which when substituted would provide cyano substituent at the R6c position as also provide a new compound. So when a skilled person looks out further for such substituents in D1, the skilled person will immediately identify that the substituents which are to be selected for R3 group in D1 is selected from R2 and R2 mentions a long list of substituents which includes C1-6 alkyl optionally substituted with one or more halogen atoms or cyano, C2-6 alkenyl optionally substituted with one or more halogen atoms or cyano, C2-6 alkynyl optionally substituted with one or more halogen atoms or cyano. Thus a skilled person will narrow down his routine experimentation to the above three substituents of R2 by which he can arrive at a new HIV inhibiting compound yet maintain the consistency of having a cyano group at the R6c position. The first group that may be selected from C1-6 alkyl optionally substituted with cyano will be CH3CN (acetonitrile). The first group that may be selected from C2-6 alkenyl optionally substituted with cyano is CH2=CH-CN i.e. acrylonitrile. The first group that may be selected from C2-6 alkynyl optionally substituted with cyano is HC≡CH-CN. The opponent submitted that in view of the teachings provided in D2 in the form of compound 69, a skilled person will combine the teachings of D1 with D2 and arrive at the conclusion that at the most only 3 compounds having the substituents (-CH2CN; -CH=CHCN) and -C≡C-CN) at the R6c position needs to be tested with the presumption that those compounds will show similar/better activity as compared to compound 69. Thus a skilled person in view of the combined teachings of D1 and D2 will be motivated to arrive at the Rilpivirine compound having the structure
The reaction scheme disclosed in D2 for compounds similar to compound 69 is provided on page 15 which is as follows:
11
wherein X1 is NR3 and R3 refers to H group and R6 is phenyl trisubstituted with two
methyl groups and a cyano group i.e. the HX1R6 intermediate is and W1 will be a suitable leaving group. Page 15 of D2 further states: Depending on the nature of X1 a suitable base or acid may be used to improve the reaction rate. For instance in case X1 is –O-, sodium hydride may be used as suitable base; or in case X1 is NR3, HCl may be used as suitable acid. Page 18 of D1 further states: The HIV replication inhibiting pyrimidine intermediates of formula (II), wherein L is a radical of formula -NR7R3, said intermediates being represented by formula (II-a), can be prepared by reacting an intermediate of formula (VIII) wherein W4 is a suitable leaving group such as, for example, a halogen or a triflate, with an intermediate of formula (IX) under solvent-free conditions or in an appropriate solvent such as, for example, ethanol, 1-methyl-2-pyrrolidinone, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, tetraline, sulfolane, acetonitrile and the like, under a reaction-inert atmosphere such as, for example, oxygen free argon or nitrogen, and optionally in the presence of an acid such as, for example, 1 N hydrochloric acid in diethyl ether. This reaction can be performed at a temperature ranging between 50 C and 250 C.
Thus D1 indicates that for the preparation of compound 69 of D2, the intermediate to be used is NHR7R3 wherein R7 is Hydrogen and R3 substituent is phenyl trisubstituted with two methyl groups and cyano group i.e. the intermediate will have the
structure
.
A skilled person from the combined reading of the teachings of D2 with D1 will note that for the preparation of compounds having a slightly different cyano substituent (i.e. C alkyl with cyano (CH3CN) at R6c position of compound 69 of D2, the intermediate to be used is NHR7R3 wherein R7 is Hydrogen and R3 substituent is phenyl trisubstituted with two
12
methyl groups and one substituents on phenyl will be –CH2CN so as to give an
intermediate of formula
.
A skilled person from the combined reading of the teachings of D2 with D1 will note that for the preparation of compounds having a slightly different cyano substituent (i.e. C2 alkenyl with cyano (CH=CHCN) at R6c position of compound 69 of D2, the intermediate to be used is NHR7R3 wherein R7 is Hydrogen and R3 substituent is phenyl trisubstituted with two methyl groups and one substituent on phenyl will be –CH=CHCN so as to give an
.
intermediate of the formula
A skilled person from the combined reading of the teachings of D2 with D1 will note that for the preparation of compounds having a slightly different cyano substituent (i.e. C2 alkynyl with cyano (-C≡CHCN) at R6c position of compound 69 of D2, the intermediate to be used is NHR7R3 wherein R7 is Hydrogen and R3 substituent is phenyl trisubstituted with two methyl groups and one substituent on phenyl will be –C≡CHCN so as to give an
intermediate of the formula
.
The opponent therefore submits that from the reaction schemes disclosed on page 18 in D1 and page 15 in D2, a skilled person will be able to identify that for the prpearation of compounds similar to compound 69 from D2 but with slight variation only at the R6c position, the intermediates required would have the formula
The opponent submits that it is well known in prior art that when a compound is identified, than the preparation of the same can be arrived at by applying the Retrosynthesis technique as is discussed in D3. The opponent submits that in view of the combined teachings of D2 13
and D1, a skilled person will be motivated to try out only the above substituents from D1 namely C1-6 alkyl substituted with CN (i.e. CH3CN); C2-6 alkenyl substituted with CN (i.e. CH2=CH-CN) and C2-6 alkynyl substituted with CN (i.e. HC≡CH-CN) at the R6c position of compound 69 of D2. In view of the aforesaid, a skilled person will have to identify methods for the preparation of only 3 intermediate compounds as provided below:
The opponent submitted that by applying retrosynthesis technique a skilled person will be able to identify the processes to be employed and the starting material to be used for each of the above intermediates. The opponent submitted that different types of chemical reactions are known for C-C coupling reactions depending on the group that needs to be coupled, such as if an alkyl group is to be coupled to an aryl group, the reaction which is normally adhered to is Freidel Crafts reaction, if an alkenyl group is to be coupled to an aryl group, the reaction which is normally adhered to is Heck reaction.
needs to be prepared, the reaction which would Thus if the intermediate have been adhered to is Freidel Craft reaction involving reaction of acetonitrile with an aryl group.
needs to be prepared, the reaction which would have been If the intermediate adhered to is Heck reaction involving reaction of acrylonitrile with an aryl group. The palladium-catalyzed C-C coupling between aryl halides or vinyl halides and activated alkenes in the presence of a base is referred to as Heck reaction. Schematic representation of Heck reaction as provided in Annexure D and Annexure E is as follows: Annexure D page 1087 provides schematic representation of Heck reaction which is as follows:
14
Annexure E on page 6089 provides a schematic representation of Heck reaction as follows
and refers to the following articles: 1)(a) Mizoroki, T; Mori, K; Ozaki A. Bull. Chem Soc. Jpn.1971, 44, 581. (b) Heck, R F; Nolley J P., Jr. J. Org. Chem, 1972 37, 2320-2322. The Opponent submits that from the above, it may be noted that it is well kown for decades that an aryl halide can be reacted with an alkenyl group in the presence of Pd catalyst and base so as to give a compound having an aryl group bearing an alkene substituent as also it is known that such reactions are known as Heck reactions. A comparison of the invention claimed in Independent amended claim 1 with the teachings of Annexure D/E/F is as follows: Claim 1 Annexure D Annexure E Annexure F Comments Starting Except for Compoun additional Wherein R substituents on d can be aryl, the starting X is halide, compound in triflate claim1, the reactant is the Wherein same. W3 is Halo Reacting Acrylonitril SAME with e wherein Y can be CN In the Suitable presence Palladium of catalyst, Suitable base, Suitable
SAME Claim 1 as well as teachings from Annexure D and E mention 15
the use of suitable Pd catlyst, suitable base and suitable solvent without specifically exemplifying the term “suitable” SAME The reaction occuring is the same as the coupling is between Aryl and C atom of alkenyl.
solvent
Product
Intermediat e (II) and
From the above table it may be noted that the applicant has sought to claim the Heck reaction by claiming reaction between an aryl group (with leaving group) and an alkenyl compound (with cyano substituent) in the presence of suitable Palladium catalyst, suitable base and suitable solvent. Thus though the applicant has claimed a process for the preparation of intermediate, in reality, the applicant has left it to the expertise of the skilled person to determine the critical parameters such as selection of leaving agent, selection of the catalyst, selection of base and selection of solvent as well as selection of other critical parameters such as temperature and pressure. Since amended claim 1 does not specifically identify suitable Palladium catalyst, suitable base and suitable solvent, the specification may be referred to identify if those suitable reactants (palladium catalyst/base/solvent) is different from those disclosed in prior art. Opponent further submitted that at Page 15 of the impugned specification provides a list of Palladium catalysts to be used which is reproduced for ready reference: The palladium (Pd) catalyst may be a homogeneous Pd catalyst, such as for example Pd (OAc) 2, PdCl2, Pd (PPh3) 4, Pd (PPh3) 2Cl2, Pd2 (dba) 3 (tris (dibenzylidene acetone) dipalladium), palladium thiomethylphenylglutaramide metallacycle and the like, or a heterogeneous Pd catalyst, such as for example palladium on charcoal, palladium on metal oxides, palladium on zeolites. Preferably, the palladium catalyst is a heterogeneous Pd catalyst, more preferably palladium on charcoal (Pd/C). Pd/C is a recoverable catalyst, is stable and relatively inexpensive. It can be easily separated (filtration) from the reaction mixture thereby reducing the risk of Pd traces in the final product. The use of Pd/C also avoids the need for ligands, such as for 16
example phosphine ligands, which are expensive, toxic and contaminants of the synthesized products. In this context, reference is made to Annexure D of the main representation wherein the following is disclosed at page 1087 “The Heck reaction works best with alkenes containing electron-withdrawing groups and in most cases gives the β-arylated products exclusively. Olefins with electron-donating groups give rise to mixtures of α- and β-arylated products. If palladium complexes with bidentate ligands are used the regioselectivity can be determined by the choice of leaving groups. Noncoordinating anions like triflate lead mainly to the aarylated products, whereas halides predominantly give the β-products (10e). ------Pd-catalysts are used with very few exceptions, usually PdCl2 or Pd(OAc)2 alone or in combination with Ph3P or o-Tol3P (2 or 3 equiv). Almost all Heck reactions require the presence of a base, which is often triethylamine. The combination Pd(OAc)2, MHCO3 (M = Na, K), KOAc or K2HPO4 with a phase transfer salt is also often used (Jeffery conditions)(10f). The ligand, the counter ion, the base, the phase transfer salt, and the solvent all have a profound influence on the rate and the selectivity of the reaction; many of these effects are related to the oxidation state and the coordination chemistry of the catalyst (23). It is also possible to use heterogeneous palladium catalysts such as Pd/C (24). Palladium clusters have also shown to be active (25); in fact Pd-clusters seem to form in most phosphine free Heck reactions. Palladium clusters have also shown to be active (25); in fact Pd-clusters seem to form in most phosphine free Heck reactions”. Opponent submitted that at Page 1088 of Annexure D further discloses “process involves the Heck reaction of p-bromoanisole with 2-ethylhexyl acrylate (Scheme 3). In this process, palladium on carbon is used as the catalyst without any ligands”. Thus Annexure D discloses about the use of heterogenous Palladium catalyst such as Palladium on carbon as an alternative for homogenous Palladium catalysts. Further Scheme 3 of Annexure D provides for C-C coupling reaction which is carried out in the presence of heterogenous Palladium catalyst (Pd/C) and base (Na2CO3) without the use of any phosphine ligand as also indicates that such reactions needs to be carried out at a higher temperature as compared to those reactions wherein homogenous Palladium catalyst (Pd(OAc)2/PdCl2) is used. Opponent submitted that annexure F on page 211 of the representation indicates the regiochemistry of addition involved in the addition of the aryl group to the alkenyl group wherein it is indicated that if the substituent present on the alkenyl group is Y (CN, CONH2 or CO2R) than 100% addition occurs at the terminal C atom of the alkenyl group and not on the C atom bearing the Y substituent. The opponent therefore submits that from the combined teachings of D1 and D2, a skilled person will be able to identify that at the most 3 compounds needs to be tested so as to identify the compound which would provide similar/better activity as compared to compound 69 as also will be able to deduce the intermediates required for such compounds. Through retrosynthesis (as discussed in D3) and teachings of Annexure D/ Annexure E/ Annexure F a skilled person will be able to deduce that the requisite intermediate could be arrived at by reacting aryl derivative with an alkenyl derivative in the presence of Pd catalyst, base and solvent with/without the use of phosphine ligand as also will be able to deduce that the reaction will necessarily occur at the terminal position of the alkenyl C 17
atom. Thus the manner in which the intermediate of formula (II) is deduced and the process could be arrived at by a skilled person is as provided in the below table. D2 Compound with best IC50 value
Compound 69 A skilled person being aware that the functioning of a compound depends on how well it binds at the specific binding sites in the body, will be inclined to carry out minimum modifications with regards to the substituents. As discussed above, a skilled person will note that the substitution needs to be done at the para CN position of the aminophenyl ring present at 4-position of the pyrimidine ring keeping all other substitutions intact for which substituents are available form D1
Substituents are C1-6 alkyl substituted with CN (i.e. CH3CN); C2-6 alkenyl substituted with CN (i.e. CH2=CH-CN) and C2-6 alkynyl substituted with CN (i.e. HC≡CH-CN)
Combination of D1+D2
And formula (II) intermediate D3 (retrosynthesis approach)
To be applied for preparation of Annexure D/Annexure E/Annexure F
Teachings about Heck reaction and the regiochemistry involved when the alkene group bears CN substituent
The Opponent further submits that as has been claimed/ instructed by the applicant to a skilled person in amended claim 1, the suitable leaving groups, suitable palladium catalyst, suitable base and suitable solvent as well as other critical parameters relating to the reaction involved therein can be easily arrived at by a skilled person with the teachings of the prior art documents cited herein and in the representation. The opponent therefore submits that 18
the process claimed in amended claim 1 does not provide any technical advancement over the prior art documents as the same can be arrived at through routine experimentation and the claim language (use of the word suitable) also indicates that the reaction parameters involved in the claimed reaction are within the realms of a skilled person. In view of the arguments provided herein and in the representation, the opponent states that amended Claim 1 of the impugned application lacks inventive merit and needs to be rejected in toto. Regarding claim 2, opponent submitted that a glance at the claimed process involving the reaction with acrylamide, indicates that though the applicant has claimed a process for the preparation of intermediate, in reality, the applicant has left it to the expertise of the skilled person to determine the critical parameters involved in the said reaction, such as selection of leaving agent, selection of the catalyst, selection of base and selection of suitable solvent as well as selection of other critical parameters such as temperature and pressure, thus effectively claiming the Heck reaction. On page 15 of the specification the applicant has acknowledged that the dehydration step claimed in amended claim 2 can be performed according to methodologies well-known to the person skilled in the art thereby acknowledging that the said step does not provide any inventive merit to the amended claim 2. The opponent submitted that the aforesaid applicant’s admission is also indicative of the fact that if known steps are followed (in this case dehydration step) or steps for which teachings are readily available even though the final product may be unknown, than the same does not amount to any inventive ingenuity rather forms a part of routine work for a skilled person and thus makes that specific step obvious. A comparison of the invention claimed in Independent amended claim 2 with the teachings of Annexure D/E/F is as follows: Claim 2 Annexure D Annexure E Annexure Comments F Starting Except for Compou additional Wherein R substituents on nd can be the starting aryl, compound in X is claim 2, the halide, reactant is the Wherein W3 triflate same. is leaving group which may be halo Reacting Acrylamide SAME with wherein Y can be 19
CONH2 In the Suitable presence Palladium of catalyst, Suitable base, Suitable solvent
SAME Claim 2 as well as teachings from Annexure D/ E /F mention the use of suitable Pd catlyst, suitable base and suitable solvent without specifically exemplifying the term “suitable”
Product
SAME The reaction occuring is the same as the coupling is between Aryl and C atom of alkenyl.
Intermediate (VI) and
Intermediate (VI)
Applicant has acknowledged on page 15 of specification that the conversion of intermediate (VI) into intermediate of formula (II) i.e. the dehydration step , can be performed according to methodologies well known to the person skilled in the art, such as the ones disclosed in----. Further Exhibit D4 indicates that
on dehydration
gives Intermediate (II)
20
From the above table it may be noted that the applicant has sought to reclaim the Heck reaction by claiming reaction between an aryl group (with leaving group) and an alkenyl compound (with amide) in the presence of suitable Palladium catalyst, suitable base and suitable solvent to give an acrylamide derivative which on dehydration gives the cyano derivative. Thus though the applicant has claimed a process for the preparation of intermediate, in reality, the applicant has left it to the expertise of the skilled person to determine the critical parameters such as selection of leaving agent, selection of the catalyst, selection of base, selection of solvent and selection of dehydrating agent as well as selection of other critical parameters such as temperature and pressure. Opponent submitted that extracts of Annexure D and E as reproduced above indicate the different types of palladium catalyts, bases and solvents to be used in Heck reaction. Annexure F on page 211 of the representation indicates the regiochemistry of addition involved in the addition of the aryl group to the alkenyl group wherein it is indicated that if the substituent present on the alkenyl group is Y (CN, CONH2 or CO2R) than 100% addition occurs at the terminal C atom of the alkenyl group and not on the C atom bearing the Y substituent. The schematic representation from page 211 (Annexure F) is provided below:
---
--
The opponent therefore submits that from the combined teachings of D1 and D2, a skilled person will be able to identify that at the most 3 compounds needs to be tested so as to identify the compound which would provide similar/better activiy as compared to 21
compound 69 of D2 as also will be able to deduce the intermediates required for such compounds. Through retrosynthesis (as discussed in D3) and teachings of Annexure D/Annexure E/Annexure F a skilled person will be able to deduce that the requisite intermediate could be arrived at by reacting aryl derivative with an alkenyl derivative in the presence of Pd catalyst, base and solvent with/without the use of phosphine ligand as also will be able to deduce that the reaction will necessarily occur at the terminal position of the alkenyl C atom. The opponent further submitted that technical advancement is achieved only when the process steps are reduced with similar/improved yield and quality and reduction in time whereas use of an acrylamide as a reactant is akin to inclusion of an additional step which in most likelihood going to add to the cost of the product and is therefore not economically beneficial. Thus substituting an intermediate with another intermediate for similar reaction steps does not involve any technical ingenuity. The opponent therefore states that amended claim 2 of the impugned application also fails to satisfy the criteria of technical advancement and hence fails to satisfy the criteria of inventive step as also is obvious to a skilled person. Regarding claim 7, opponent submits that in view of the arguments provided hereinbefore with regards to claim 1 and claim 2 being obvious and lacking in inventive merit and claim 7 being dependent on claim 1 and claim 2 is also obvious and lacks inventive merit. The prior art cited in the representation provides clear directions to arrive at the E isomer of intermediate (II) and hence does not satisfy the criteria of inventive merit. Further, opponent submitted that as per Section 57 read with Section 59 of the Indian Patents Act, any amendment to the claims should fall wholly within the scope of claims of the specification before the amendment. As filed claim 8 was dependent on claim 1-3 (which provided for a preparation of formula (I)) and provides for a preparation of the E isomer of the compound 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2pyrimidinyl]amino]benzonitrile of formula (I), whereas the amended claim 7 is dependent on amended claim 1 and 2 which relate to the preparation of intermediate of formula (II) and indicates that the same relates to the E –isomer of intermediate of formula (II). None of the as filed claims provides any indication towards the preparation of the E isomer of intermediate of formula (II). Thus amended claim 7 does not fall within the scope of the as filed claim and hence are in contravention of provisions provided under Section 59 of the Act. It is therefore respectfully submitted that amended claim 7 should be refused for failing to satisfy the provisions of Section 57 read with Section 59. In the instant application also the applicant’s contention is that the Rilpivirine compound was not in public domain on the priority date of the impugned application and hence its intermediate (intermediate of formula II) was also not in public domain on the priority date of the impugned patent application and hence there was no motivation to prepare Rilpivirine or intermediate of formula II. The opponent submits that the relation between the appellant’s reaction products in the claimed process and those provided in prior art is such that the processes claimed would be directly obvious from the references to a chemist of ordinary skill as the reactions involved in the claimed process involve the activities of the same radicals as those of the prior art reactions, a fact not disputed by the applicant. As has 22
been indicated in the cited case, use of an unobvious starting material to obtain a novel product may be novel but it itself does not provide any inventive merit to the process or makes the process non-obvious, as the subject matter of the claim should be looked into “as a whole”. In an order issued by the Ld Controller on July 2013 with regards to application no: 715/DELNP/2008, the Ld Controller has found intermediate of formula (II) to be obvious and lacking in inventive merit. The opponent further submitted that the arguments made by the opponent during the hearing which has been reproduced in the preceding paragraphs also point out to the fact that intermediate of formula (II) is obvious and lacks inventive merit. The opponent therefore submitted that the amended process claims are obvious and lack in inventive merit and should be refused in toto. Opponent relied upon case laws “In re John A. Durden, Jr. (763 F. 2d 1406)” to support its contention on the ground of obviousness/lack of inventive step.
II.
NOT AN INVENTION / NOT PATENTABLE (Section 25(1)(f))
Claims an invention not patentable as per Section 3(d) The opponent states that the claimed invention falls under the mischief of 3 (d) which clearly states that the mere use of a known process results in a new product or employs at least one new reactant is not patentable under this Act. The combined teachings of D2 with D1 provide an indication towards the usage of intermediates of formula (II) in the preparation of Rilpivirine. The applicant has also applied well known chemical reactions towards the preparation of the intermediate of formula (II) and the same has been claimed in independent amended claim 1 and claim 2. A comparison of the claimed reaction and details about the Heck reaction as is known from prior art is provided on the ground of obviousness: From the above table it is amply clear that the claimed reaction between an aryl halide and an acrylonitrile/acrylamide is well known in prior art as Heck reaction. The only teaching that is not directly available from the prior art is the use of a dimethyl aniline compound as the aryl derivative. Thus the claimed reaction can at the most said to be new use of a known process to produce analogous compounds of the product that is usually obtained in Heck reaction and is well documented in prior art. Further the indication towards the usage of suitable Pd catalyst, suitable base and suitable solvent indicates the applicant’s intention to claim monopoly over the Heck reaction by following routine procedures without providing any technical advancement in the said reaction. The opponent states that the documents relied upon under the ground of obviousness have made it very evident that the subject matter of the process claims are merely a combination of well known processes which ultimately lead to the formation of a well known compound. It is stated that these claims ought to be rejected on this ground alone.
23
III.
INSUFFICIENCY (U/S 25(1) (g))
The opponent submitted that the complete specification grossly suffers from insufficiency and therefore liable to be rejected on this ground alone. The opponent submitted that the representation provides a detailed analysis of the factors which leads to lack of clarity as regards the applicant’s invention and a brief of the same is provided below. Section 10 (4(a) specifically states that every complete specification should disclose the best method of performing the invention which is known to the applicant and for which they are entitled to claim protection. The glaring discrepancies with regards the data provided in the complete specification is as provided below: Page 17 of the impugned specification provides general definition of the terms “quaternary amine”, “N-oxide form” and stereochemically isomeric forms” with reference to compounds of formula (I) but no indication is provided with regards to compounds of formula (II). No examples with regards to the preparation of N-oxide, quaternary amine or stereochemically isomeric form of formula (II) is provided in the impugned specification. No data relating to what those specific N-oxide, quaternary amine or stereochemically isomeric form of formula (II) is provided in the impugned specification. Example 1 shows the process for making compound of formula II, which is limited to the free base of compound of formula V and there is no example to show how an N-oxide can be formed from a primary amine or a process of making the quaternary amine. The reaction processes for the preparation of formula (II) as disclosed in page 14 and page 16 of the impugned specification and which are subsequently claimed includes the term “if desired” and may be converted to stereochemically isomeric forms, N-oxide forms or quaternary amines of the product, though no specific examples have been provided for the preparation of those forms as also no data is provided as to what those stereochemically isomeric forms, N-oxide forms or quaternary amines may be. In absence of specific examples, the term “if desired” renders to claiming monopoly over the processes for the preparation of indefinite number of products which have not been specifically mentioned in the impugned patent application. In the absence of any specific processes exemplifying the above preparations, there would be undue burden of experimentation on the person trying to implement the teachings of the invention as no specific instructions has been provided as to in which form the reactants needs to be there so as to obtain the compounds in the specific form. The opponent states that though the applicant has stated that N-oxides, quaternary amines of formula (II) can be prepared, no data is provided as to what will be the reactant in those cases as the presence of these groups is likely to interfere in the Heck coupling reaction. The opponent submits that claim 1 and claim 2 claims processes for the preparation of compounds of formula (II) using a suitable base, a suitable solvent though none of the dependent claims provide what those suitable bases/suitable solvents are, 24
thereby rendering indefinite number of solvents/bases to be used in the processes claimed therein. The opponent therefore submitted that the data provided in the specification is insufficient to overcome any objections/pleadings of the Opponent. The opponent therefore submitted that the alleged invention claimed in the impugned application is liable to be rejected on this ground alone.
Applicants Argument & hearing submission I. 25(1)(e): Obviousness/Lack Of Inventive Step The Opponent's attorney acknowledged the novelty of the claimed process for the preparation of an intermediate of formula II, however argued that it is devoid of inventive merits. The Applicant's attorney argued that it is to be appreciated that while assessing inventive merits of an invention, the question to be asked is not whether the skilled man could perform the claimed invention, but rather whether he would perform the claimed invention. The skilled man always needs to have a motivation, a driving force, an incentive to perform a certain step, to explore a certain modification. It is emphasized that the Opponent has not satisfied this assessment in its frivolous opposition. The Applicant's attorney emphasized on the fact that the priority date of the subject patent application goes back to August 9, 2002, when rilpivirine was not known to the skilled man. The Opponent himself acknowledged that the target molecule, which is rilpivirine in this case, was not in the public domain on the priority date of the subject application. This also counts for the present intermediate of formula (II). Therefore, there was no incentive for the skilled person, to explore rilpivirine, let alone a process to prepare rilpivirine, let alone a process to prepare a key intermediate of rilpivirine. Accordingly, the assertion of the Opponent's attorney that the claimed process is devoid of inventive merits is completely unjustified and only based on hindsight which is not allowed. Therefore, this ground of opposition is liable to be rejected. With respect to the specific arguments taken up by the Opponent's attorney during the hearing, the Applicant submits the following: 1.Heck reaction is a well known reaction in the prior art and it is obvious to employ the teachings of Annexure D, Annexure E and Annexure F to arrive at the presently claimed process. In the present case, the reaction involves the use of reagents acrylonitrile or acrylamide to react with an intermediate of formula (V). These very specific reagents are not disclosed in any of the fully exemplified reactions of the cited prior art documents relating to the Heck reaction, let alone in a fully exemplified reaction with an aniline moiety like the present intermediate of formula (V). Hence for the processes subject of the present application, there is no clear and unambiguous expectation of success for the skilled person. 25
Moreover, Annexure E clearly indicates that the Heck reaction is not a general concept that is applicable to all olefins. See for instance, page 6990, left column "..we did not establish increased generality with respect to the olefins". And in the right column "we felt that important challenges remained includingdemonstrating broader scope (particularly with respect to the olefincompounds) ". So this cited prior art document (Annexure E) itself supports the fact that it is certainly not a given that the Heck reaction will work each and every time, and as indicated above, none of the cited prior art documents exemplify a reaction process with an acrylonitrile or an acrylamide. So the present process is clearly different from the 3 decisions cited by the Opponent. Not only is it unobvious for the skilled person to perform the presently claimed processes because of the complete lack of motivation to do so, but moreover, also the reagent that needs to react with an intermediate of formula (V) in order to obtain the intermediate of formula (II) is not exemplified as such in the cited prior art references relating to this type of reaction (Annexure D, E, F). So there is also no expectation for the skilled man, that even if he would be motivated to start from intermediate (V) in an attempt to make intermediate (II), the reaction will be successful. Dl, D2 and D3 The applicant submitted that Dl does not at all disclose the presently claimed type of reaction. Dl as such is silent on a palladium catalyzed reaction, let alone a palladium catalyzed reaction with acrylonitrile or acrylamide. The same applies to D2. D2 does not even disclose a cyanoethenyl moiety at all as a possible substituent for the compounds of D2. So it is not clear as to how a combination of the Annexure D, E, F and Dl and D2 would direct a skilled person in a clear and unambiguous way to the present invention. D3, Corey E., relates to retro synthesis starting from a desired target compound and then designing its synthesis from simpler precursor structures. The principle of retrosynthesis, supports the fact that the skilled person needs to have a clear motivation to start from the target molecule and then design its synthesis. Applicant argued that the Opponent himself acknowledges that the target molecule, which is rilpivirine, or its intermediate of formula (II) in this case, was not in the public domain on the priority date of the subject application. Applicant further argued that the skilled person was not in a position to appreciate rilpivirine and its excellent anti-HIV activity as evidenced by the US Food and Drug Administration approval and EMEA approval for Edurant®. As indicated above, there is no incentive for the skilled person, there is no motivation for the skilled person to explore rilpivirine and hence also not akey intermediate, the compound of formula (II). There was no reason for the skilled person to pick and choose very specific, undisclosed intermediates from the Markush scopes of prior art documents when there is completely no motivation, no incentive, no driving force for him to do so. There was also no reason for the skilled person to pick and choose very specific, undisclosed intermediates from the Markush scopes of prior art documents to prepare a key intermediate.
26
Therefore, an argument on retro synthesis does not apply here. The skilled person cannot start from a desired compound or a target compound since that compound is missing here and there is no suggestion in the prior art that would prompt a skilled person towards the desired compound. Hence there is certainly also no suggestion in the prior art towards a process to prepare the target compound or a key intermediate thereof. A skilled person will not be motivated to specifically react specific intermediates as in the present processes, also not in view of the disclosure of cited Dl and D2, when there is no clear and unambiguous teaching towards this in the prior art. As discussed above, it is clear that in order to arrive at the present invention the skilled person needs to take several steps for which there is no clear and unambiguous direction in the cited prior art. As stated above there is no clear and unambiguous motivation for the skilled man based on the cited prior art documents in order to explore rilpivirine and hence there is also not a clear and unambiguous motivation in the prior art for the skilled man to use the present intermediate of formula (II) and hence there is certainly no clear and unambiguous motivation towards the presently claimed processes. Therefore, the Applicant disagrees with these conclusions and submits that the said arguments can only be valid with the benefit of hindsight as neither rilpivirine nor the key intermediate of formula (II) were available in the public domain on the priority date of the subject application. The case that has been made by the Opponent in his representation is that of 'retrosynthesis' which, in the absence of the target molecule, cannot possibly be applied to the present invention. In the absence of any motivation to apply retrosynthesis, one can also not foresee applying Heck reaction to arrive at the intermediates of rilpivirine. The scheme depicting the concept of retrosynthesis and Heck reaction as asserted by the Opponent and as to how the same cannot be applied to the present invention is enclosed as Appendix A. The Applicant's attorney invited the attention of the learned Controller towards the case law: Windsurfing International Inc. v. Tabur Marine (Great Britain)Ltd. In the Court of Appeal; Before Lord Justice Oliver, Lord JusticeO'Connor and Lord Justice Slade, 28, 29, 20 November 1983 and 31 January 1984, enclosed as Appendix B. It was submitted that according to the said case law, there are four steps that are required to ascertain the obviousness. "The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any differences exist between the matter cited as being "known or used" and the alleged invention. Finally, the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention ". The Applicant's attorney explained to the learned Controller that all the four conditions as imposed by the above mentioned case law to ascertain the obviousness have been addressed to and the presently claimed invention has been found to be non-obvious over the teachings of the cited prior art documents. 27
With respect to the first step to identify the inventive concept, the Applicant's attorney submitted that the inventive concept in the claimed invention resides in the process for the preparation of intermediate of formula (II) by reacting an intermediate of formula (V), an appropriate acid addition salt or a quaternary amine thereof with acrylonitrile or acrylamide, in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent. To satisfy the second condition, the Applicant’s attorney submitted that on the priority date of the subject application, the common general knowledge was the teachings of the cited documents D1 and D2 which disclosed a Markush structure encompassing a large number of compounds by virtue of large number of possible permutations and combinations. With respect to the third requirement, the Applicant’s attorney submitted that the claimed process is for the preparation of a novel compound and thus the claimed subject matter is clearly different from the matter ‘known or used’. The Opponent has himself admitted that the target molecule, i.e. the rilpivirine or its intermediate of formula (II), were not in the public domain on the priority date of the subject application. Finally, to address the fourth requirement, the Applicant’s attorney submitted that the claimed process for preparing the intermediate of formula II involves non-obvious steps that could not have been arrived at in view of the teachings of the cited prior art documents and therefore, the claimed process is not obvious to a person skilled in the art. The Applicant relied upon some more case laws to support its contention on the ground of obviousness/lack of inventive step: (1)United States of Court of Appeals for the Federal Circuit 2007-1223 ORTHO-MCNEIL PHARMACEUTICAL, INC., MYLAN LABORATOIRES, INC., and MYLAN PHARMACEUTICALS, INC. (2) ELI LILY AND COMPANY, plaintiff, TEVA PHARMACEUTICALS USA, INC., Defendant. No. l:06-cv-1017-SEB-JMS. United States of District Court, S.D. Indiana, Indianapolis Division. (3) United States Court of Appeals for the Federal Circuit DAIICHI SANKYO COMPANY, LTD., AND DAIICH SANKYO, INC., v. MATRIX LABORATOIRES, LTD., MYLAN INC., MYLAN LABORATOIRES, INC., AND MYLAN PHARMACEUTICALS, INC. (4) Lexis Nexis IN re DIANE M. DILLON No. 88-1245, United States Court of Appeals For the Federal Circuit, 919 F.2d 688, 1990 U.S App. Lexis 19768; 16 U.S.P.Q.2D (UNA) 1897 D4 In relation to claim 2, Applicant argued that prior art document D4 was cited by the Opponent. It is not clear as to how this document attributes to a clear and unambiguous motivation for the skilled person to arrive at the present invention. D4 is solely related to acrylamide and mentions a dehydration step for acrylamide, but is completely silent on any type of reaction as in present claim 2. 28
2. The dehydration step in claim 2 is a conventional step and the same has been admitted by the Applicant in the complete specification of the present application. The Opponent cited page 15, lines 25 to 30 of the complete specification to support his argument. The Applicant disagrees with this conclusion of the Opponent's attorney and argues that the same cannot be taken as a ground as the Applicant has himself acknowledged in the specification that the dehydration step can be performed according to methodologies well-known to the person skilled in the art. The novelty and inventive step resides in the process of preparing intermediate of formula II by reacting intermediate of formula V with acrylonitrile or acrylamide and not in the dehydration step which only forms one of the steps of the claimed process. Therefore, this argument of the Opponent's attorney is untenable and liable to be rejected. 3. There was a permissible hindsight to arrive at the present invention. The Opponent’s attorney stated during the hearing that there was a permissible hindsight to arrive at the present invention, however, failed miserably to show as to how the said permissible hindsight was applied. On the other hand, by stating the same, the Opponent’s attorney has in fact shown to admit that hindsight has been used, which is generally not allowable. The Applicant once again wishes to emphasize on the fact that both rilpivirine and a key intermediates thereof, a compound of formula (II), were not available in the public domain on the priority date of the subject application and therefore there was no motivation for a person skilled in the art to arrive at the process of preparing the intermediate of formula (II). Therefore, the said argument of the Opponent's attorney is frivolous and liable to be rejected. 4.Pleadings not to be taken on record for issues not addressed in reply statement.
The Opponent's attorney asserted that the Applicant did not submit their arguments in respect of the Heck reaction in their reply statement and therefore pleading in this regard should not be taken on record. The Opponent cited two judgments passed by the Supreme Court of India wherein it has been held that "a decision of a case cannot be based on the grounds outside the pleadings of the parties" and "no arguments can be entertained on the matters where no foundation was laid in the pleadings." The Applicant's attorney responded to this assertion by arguing that the Applicant provided a para-wise reply to the representation and sufficiently dealt with all the paragraphs that were relevant to the amended set of claims. The Applicant's attorney emphasized that the Opponent had filed the representation on the original set of claims and therefore, the arguments presented by the Opponent majorly revolved around rilpivirine and processes for preparing the same. The Opponent's arguments were concentrated on the concept of Retrosynthesis which when employed would have required performing Heckreaction to arrive at rilpivirine and its intermediates. 29
The Applicant's attorney argued that since Retrosynthesis itself could not have been employed in the present case, performing Heck reaction also could not have been foreseen. The Applicant's attorney further emphasized that the reply statement addressed all the grounds taken up by the Opponent in the representation and since, in view of the amended claims, the representation of the Opponent has drastically changed, the Applicant may submit their pleadings accordingly so as to address the specific grounds maintained by the Opponent in respect of the amended claims. The Opponent's counsel also cited a decision issued in the Indian application no. 715/DELNP/2008 wherein the Controller had held that no submissions were given with respect to prior arts D1 and D4 and thus the invention was considered to lack in inventive step. The Applicant’s attorney argued that in the decision issued in the Indian application no. 715/DELNP/2008, the learned Controller had erred in concluding that the invention lacks inventive step in view of D1 and D4, as he had not considered the fact that these documents did not constitute closest prior art. Out of the four documents cited in the first examination report and the further official action, D3 represented the closest prior art. The learned Controller had himself twice acknowledgedD3 as the closest prior art, first in paragraph 3 of the first examination report and then again in paragraph 3 of the further official action of April 22, 2013 (Copy enclosed as Appendix G).The sudden change in position by the learned Controller in the final order in holding that the invention lacked inventive step in view of documents D1 and D4 was unexpected and was severely prejudicial to the Applicant. Moreover, besides providing submissions with regard to D3, the Applicant had also emphasized that the skilled person cannot arrive at the present compounds by combining the teachings of D3 with other prior art documents which include documents D1 and D4 (Copy of submission is enclosed as Appendix H). The Applicant’s attorney also submitted that the said matter is subjudice and an appeal is currently pending before the Intellectual Property Appellate Board (IPAB).
4.With respect to D2, the Opponent's attorney cited page 106, and asserted that the said document has the same objective as that of the present invention i.e. 'HIV replication inhibition'. He also cited Table 7 on page 142 and identified compound 69 as having the best IC50 value. He pointed out that upon comparing the substitutions at positions X, R5, R6a, R6b, R6c and R6d, the compounds 52, 56, 69, 75, 78 and 80 differed at only position R 6 c- Compound 69 having R6c=CN had higher potency (activity) which drastically reduced in cases where R6c was selected as Br, Cl or CH3. Therefore, a person skilled in the art would have had clear motivation to select R6c=CN (compound 69). The Applicant's attorney denies this conclusion and submits that the compounds employed in the current process do not contain a cyano moiety directly linked to the phenyl moiety. The present invention relates to the binding of a cyanoethenyl moiety (-CH=CH-CN) to the intermediate of formula (V). So without making any representation towards D2, even if the skilled person would be motivated to select cyano, then he would not at all be directed towards the present invention relating' to a cyanoethenyl moiety, even on the contrary, if D2,directs the skilled person to the selection of a cyano moiety, why would a skilled person then turn to the present cyanoethenyl moiety if there is not at all a motivation for him to do so. Onthe contrary, the skilled person would be taught away from the present compounds and processes. 30
Without prejudice, attention of the learned Controller is drawn to the IC50 values of other compounds in Table 7, particularly 76 and 81 which although have R6c as CN, yet show higher IC50 values. During the hearing, the Applicant's attorney highlighted that compound 76(R6c=CN) shows a higher IC50 value than compound 56 (R6c=Br) and thus there could not have been a clear motivation to select compound 69. In view of the foregoing, the instant argument put forth by the Opponent's attorney is misleading and ought to be rejected.
Proposed amendments Without prejudice, the Applicant humbly submits that only with an intention to accelerate prosecution of the subject application and only when the learned Controller has seriously considered the main request in view of the submitted arguments, the Applicant may be amenable to further restrict the claims to any one of the two claim sets enclosed herewith as Auxiliary requests I and II or any further amendment as deem fit by the learned Controller. Depending upon the claim set that meets with the learned Controller’s approval, the Applicant shall submit a formal request for the allowance of such voluntary amendment. The Applicant respectfully wishes to mention that the proposed amendments must not be considered as an acceptance of lack of inventive merits of the currently pending claims. Auxiliary request I- Claims have been amended to incorporate the following in claim 1 and claim 2 "...in the presence of a heterogenous palladium catalyst or a homogeneous palladium catalyst selected from the group consisting of Pd(OAc) 2 , PdCl 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd 2 (dba) 3 (tris(dibenzylidene acetone) dipalladium), or palladium thiomethylphenylglutaramidemetallacycle ". Support for this amendment can be found on page 12, lines 12-22 of the specification. By implementing the above restriction in claim 1 and 2, the present invention is removed even further from Annexure E and does no longer generically encompass the very specific catalyst of Annexure F. The skilled man could certainly not predict with a reasonable expectation of success that with the claimed process of auxiliary request I the reaction would be successful. Auxiliary request II- Claim 1 and claim 2 are amended to incorporate the subject matter of claim 3 into claim 1 and 2. In the cited prior art Annexure D, E and F, it is clear that homogenous catalysts are preferred (practically all examples are dealing with homogeneous palladium catalysts). On page 1087 (right column) of annexure D it is indicated that heterogeneous catalyst are also possible, but on page 1088 (left column, sunscreens) it is indicated that the heterogeneous palladium catalysts have lower reactivity and that they require higher temperatures (190 °C). So a skilled person would not be motivated to explore heterogeneous catalysts and the skilled person would certainly not expected that in the presently claimed reaction, high reactivity was obtained even with a reaction temperature of 130 °C (see example Al of the present invention). II. 25(1)(f): Not An Invention/Not Patentable The Opponent's attorney while, maintaining the said ground of opposition; he did not present any arguments to substantiate his assertion. The Applicant denies the said allegation and submits that 31
in view of the foregoing discussion, the claimed processes are patentable and Section 3(d) does not apply. The Applicant disagrees with the Opponent's assertion that claims of the subject application are merely a combination of well known processes which ultimately lead to the formation of a well known compound. This is not just incorrect but also contrary to what the Opponent admits himself in the opposition statement. The Opponent himself acknowledges the novelty of the claimed process. The Opponent also acknowledges that the target molecule, rilpivirine, was not in the public domain on the priority date of the subject application. The same applies to the present intermediate of formula (II) as well. As already discussed, there was no incentive or motivation for the skilled person, to explore rilpivirine and hence also not a key intermediate of formula (II) or any process to prepare the target compound or a key intermediate. Thus, the Applicant's attorney submits that the processes for preparing the intermediate of formula II are novel and inventive and cannot be regarded as mere use of a known process. Accordingly, the claimed processes are not a combination of well known processes which ultimately lead to the formation of a well known compound and thus do not fall under the prohibition of Section 3(d). Without prejudice, the Applicant's attorney submits that the presently claimed processes to prepare an intermediate of formula (II) relate to the reaction of unprotected aniline of formula (V) with acrylonitrile or acrylamide in the presence of a palladium catalyst. This specific type of reaction, this specific combination of unprotected aniline of formula (V) and acrylonitrile or acrylamide cannot be considered as a known process. The prior art documents cited by the Opponent do not describe this specific type of reaction or the specific combination of reagents that are used in the claimed processes. For this specific type of reaction there is no guarantee that it will work. A skilled person does not have a reasonable expectation of success that the reaction will succeed. There is the risk of forming side products at the aniline part. Polymerization of the acrylonitrile/acrylamide reagent can also not be ruled out. In support of their arguments, Applicant also submitted that the First Examination Report (FER) issued in the subject application wherein no objection pertaining to Section 3(d) was raised. This clearly signifies that the same was not considered as a relevant ground for rejection by the Patent Office. III. 25(1)(g): Insufficiency The Opponent's attorney while, maintaining the said ground of opposition during the hearing; he did not present any arguments to substantiate the same. As submitted previously in the Applicant's reply statement, the claims of the subject application have been amended and the expression ' if desired' as appearing in the present set of claims does not lead to the preparation of indefinite number of products. The Opponent's assertions are misleading and are not substantiated by any evidence. Further, the Applicant submits that the processes for the preparation of N-oxide or quaternary amines are not necessary to be disclosed through working examples in the description to establish 32
enablement. A person skilled in the field of invention would know the best methods of performing such processes. It must also be appreciated that examples are only illustrative in nature and the absence of any working example for processes that are expected to be well known to a person skilled in the art does not constitute insufficiency of disclosure. Without prejudice, the Applicant also draws the attention of the learned Controller to the First Examination Report (FER) issued in the subject application wherein no such objection was raised. This clearly signifies that the same was not considered as a relevant ground for rejection by the Patent Office. With respect to the solvents/bases that are to be used in the processes, the Applicant submits that a person skilled in the art would know which solvents/bases are to be used in the processes from the subject matter disclosed in the description- and the same does not render the scope of the claim unclear. Without prejudice, the Applicant submits that the terms solvent and base are sufficiently defined in the description on page 8, lines 7 to 13 and page 9, lines 14 to 20. Reference is also made to the specific examples in the Experimental Part. In view of the aforesaid, the instant ground of insufficiency of disclosure is untenable and ought to be rejected.
CONCLUSION Having considered the detailed arguments of both the parties, the teachings of the various prior art documents on record, I shall now deal with each ground of the opposition as discussed during the hearing. As far as p r e l i m i n a r y i ssues are concerned, all the relevant issues are taken into consideration while deciding the case. Regarding the opponent contention that the pleadings should not to be taken on record for issues not addressed in reply statement. In this regard, I am of the opinion that the Applicant has provided a para-wise reply to the representation and sufficiently dealt with all the paragraphs that were relevant to the amended set of claims. I. OBVIOUSNESS AND LACK OF INVENTIVE STEP [Section 25(1)(e)] It is observed from the description and claims of the impugned application, the amended claims are directed towards the process for the preparation of Rilpivirine intermediates and basically involved a well known name reaction i.e. Heck reaction. After careful consideration of the arguments of both the parties on the documents cited it is observed that Document D2 discloses the pyrimidine derivatives having HIV replication inhibition properties and methods for their preparation and the compounds of D2 and the present application are pyrimidine derivatives having the same use. Document D2 also teaches Noxides, pharmaceutically acceptable addition salt and stereo chemically isomeric forms. It is clear that while analyzing any prior art document a person skilled in the art will try to find out the compound of promising pharmacological activity and it is well known that lower the 33
IC50 value better is the compound. Now the question arises why the compound of promising pharmacological activity will be chosen if the compound of lowest IC value (best pharmacological effect) is already available. It has always been a challenge for the researcher associated with organic chemistry to develop the alternative compound of similar/better activity. Once a person skilled in the art working in the field of HIV inhibitors identifies a compound of promising pharmacological activity from any document, the first step is to subject the promising compound to further carry out clinical studies, to ascertain the quantum of probability of resistant strains that would develop. Alternately the skilled person will attempt further modifications in the compound having lower IC50 value (best pharmacological effect) starting with the modification of the substituents. On careful perusal of D2 it is observed that the compound 69 of Table 7 has the lowest IC50 value (best pharmacological effect) in which one of the phenyl group is attached to the amino pyrimidine group has cyano at para position and another phenyl group attached to the amino pyrimidine has cyano at the para position (marked as R6c) and methyl at 2 and 6 position which is represented as follows:
It is also observed from the compounds disclosed in D2, when the cyano group present at the R6c position, the compounds shows lowest IC50 value(best pharmacological effect). However, during the hearing, the Applicant’s highlighted compound 76 (R6c=CN) which shows a higher IC50 value than compound 56 (R6c=Br) and thus there could not have been a clear motivation to select compound 69. On analyzing the prior art D2, it is observed that the compound highlighted by the applicant though has CN substituent at the R6c position, those compounds differ with regards to substitutions at the other positions (such as X, R6a, R6d and R5) whereas the compound 69 has the same substituents/substituent pattern. It is clear from the above discussion the compound 69 of D2 is the best compound having lower IC value and a person skilled in the art will therefore be inclined towards the research to maintain cyano group(R6c position) at the para position of said phenyl group and to prepare any alternate compound with similar/better activity with a reasonable expectation of success. Further, Document D2 at page 15 teaches the reaction schemes for compounds similar to compound 69 as follows:
34
Wherein X1 is NR3 and R3 is H and R6 is phenyl trisubstituted with two methyl groups and cyano group, W1 is a suitable leaving group. Thus HX1R6 intermediate is
And the above intermediate taught by D2 differs from the intermediate of present invention only in that cyanoethenyl substituent(-CH=CHCN) is present in the impugned application claim whereas the document D2 teaches an intermediate comprising cyano substituent at the equivalent position(R6c position). Document D2 further teaches that depending on the nature of X , a suitable base or acid may be used to improve the reaction rate. For instance, in case X is -O-, sodium hydride may be used as suitable base; or in case X1 is NR3, HCl may be used as a suitable acid. Document D1 at page 18 teaches the intermediates of formula (II-a) which can be prepared by reacting an intermediate of formula (VIII) with the intermediate of formula (IX) under solvent-free conditions or in an appropriate solvent and at temperature ranging between 50 C and 250 C which is represented as
meaning of substituent of formula II-a as given in description clearly indicate that for the preparation of compound 69 of D2, the intermediate to be used is NHR7R3 wherein R7 is hydrogen and R3 substituent is phenyl trisubstituted with two methyl group and a cyano group. Thus the intermediate will be
35
In view of reaction scheme disclosed above it is observed that a skilled person would be clearly motivated to prepare the compound rilpivirine similar to compound 69 of D2 with the slight variation only at the R6c position i.e -CH=CHCN cyano ethysubstituent. Document D1 as cited by the opponent discloses the compound of formula
when we read as a1-a2-a3-a4 is a bivalent radical of formula -CH=CH-CH=CH-; each R2 independently is ----, C2-6alkenyl optionally substituted with one or more halogen atoms or cyano, -----; L is-Xl-R3 ------------wherein R3 and R11 each independently are phenyl, -------wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R2 ; and Xl ----each independently are-NR7-,------; Q represents hydrogen,------; and----R7 is hydrogen;------;Y represents hydrogen,----; When we restrict the compound with the above specific substituents will get the compound Rilpivirine of the structure
The teaching that flows from this document is that the substituent R2 is C2 alkenyl with cyano(CH=CHCN) and by using a combined teaching of D1 and D2, a person skilled in the art will try to prepare compound having slight different substituent (-CH=CHCN) at R6c position of compound 69 of D2. For the preparation of said compound, the intermediate will be NHR7R3 as discussed earlier in reaction scheme, where R7 is H, R3 36
is phenyl trisubstituted with two methyl groups and one substituent on phenyl is – CH=CHCN which gives the intermediate of formula
As the amended claims are directed to the preparation of Rilpivirine intermediate of above said formula, a skilled person would be inclined to look out for the reaction which involves the reaction of acrylonitrile with an aryl group(with the leaving group) to get the intermediate of formula II i.e Heck reaction. In view of aforesaid teaching, it is observed that the combination of documents D1 and D2 provides clear motivation and reasonable expectation of success for a person skilled in the art to prepare the intermediate of formula (II) as claimed in the impugned application with enhanced pharmacological properties. Document D3 discusses about the retrosynthesis technique which is applied for the preparation of organic compound. By applying such technique a skilled person will be able to identify the processes to be employed and starting material to be used for the preparation of target compound. The annexure D, E and F discusses about the Heck reaction and the regiochemistry involved when the alkene group bears CN substituent. It is clear from the comparison chart as provided by the opponent that annexure D and E teach the reaction of aryl group(with leaving group) and alkenyl compound(with cyano sustituent) in the presence of suitable Pd catalyst, suitable base and suitable solvent similar to the amended claim 1. Annexure D also teaches the use of heterogeneous catalyst such as palladium on carbon. Further annexure D at page 1087 teaches that the Pd-catalysts are used with very few exceptions, usually PdCl2 or Pd(OAc)2 alone or in combination with Ph3P or o-Tol3P (2 or 3 equiv). Almost all Heck reactions require the presence of a base, which is often triethylamine. On analyzing the prior art Annexure F, it is observed that, this prior art teaches the ragiochemistry involved in the addition of aryl group to the alkenyl group and it is observed that if the substituent present on the alkenyl group is Y which may be CN, CONH2 or CO2R, 100% addition occurs at the terminal C atom of the alkenyl group instead of Y substituent. In view of above discussion and the combined teaching that flows from the documents D1, D2, D3 and annexure D/E/F, a person skilled in the art will be able to prepare the intermediate of formula II through routine experimentation and the reaction parameters involved in the claimed reaction is well within the purview of skilled artisan. Thus the invention as claimed in amended claim 1, Applicant completely missed to establish any technical advancement over the prior art and the claimed invention is obvious to a person skilled in the art. Therefore claim 1 lacks inventive step. 37
The amended claim 2 relates to a process for the preparation of an intermediate of formula II which comprises reaction of intermediate of formula (V) with acrylamide. In claim 1, acrylonitrile was used in place of acrylamide. It is also an example of Heck reaction which involves the reaction of an aryl group(with leaving group) with an alkenyl compound(amide) which differs from claim 1 only in the formation of intermediate(VI) which gives the intermediate of formula (II) on dehydration. This step was clearly taught in the prior art D4 which indicated the dehydration of acrylamide by P2O5 produces acrylonitrile. In view of the above fact, a person skilled in the art can easily combine the teachings of documents D1-D4 and annexure D/E/F to arrive at the preparation of intermediate of formula (II). Thus claim 2 is also obvious to a person skilled in the art and does not involve any inventive merit. This obviousness may be overcome by showing the technical advancement in terms of improved yield, purity, lower by-products, reduced process steps and reduction in time or cost effectiveness but applicant completely failed to substantiate by demonstrating any superiority of the process in terms of above parameters in the body of the specification. The amended claims 3-7 are dependent on claims 1 or 2 which do not contain any additional feature. Therefore the process as claimed in the claims 3-7 of impugned application involves no inventive step of any sort and does not satisfy the criteria of nonobviousness. Therefore from the above it can be seen that the process for the preparation of intermediates of formula (II) as claimed in the impugned application was clearly taught in the prior art and fails to satisfy the criteria of inventive step. Opponent submitted that the amended claim 7 should be refused for failing to satisfy the provisions of section 57 read with section 59. Regarding claim 7, the opponents arguments are not convincing as the amended claims 1 and 2 relate to the preparation of intermediate of formula(II) whereas the amended claim 7 relate to the preparation of Eisomer of the intermediate of formula(II) which falls within the scope of as filed claims hence satisfy the provisions of section 57 read with section 59. Further, Applicant submitted that only with an intention to accelerate prosecution of the subject application and only when the learned Controller has seriously considered the main request in view of the submitted arguments, the Applicant may be amenable to further restrict the claims to any one of the two claim sets enclosed herewith as Auxiliary requests I and II or any further amendment as deem fit by the learned Controller. In view of the foregoing discussion regarding inventive step, I find that the amended claims made as auxiliary request I and II is also within the purview of skilled artisan hence do not involve any inventive step. In view of the above discussion, I conclude that this ground of opposition is validly established by the opponent. II. NOT AN INVENTION / NOT PATENTABLE (Section 25(1)(f)) Claims an invention not patentable as per Section 3(d) 38
Regarding process claims, Section 3(d) states “mere use of a known process unless such known process results in a new product or employs at least one new reactant”. The opponent admitted that the only teaching that is not directly available from the prior art is the use of a dimethyl aniline compound as an aryl derivative. In view of the above fact, I am of the opinion that Section 3(d) does not properly apply in this case and this ground of opponent is not validly established. III. INSUFFICIENCY (U/S 25(1) (g)) It is observed from the description of the impugned application that the opponent’s allegation that the description lacks the data relating to examples with regards to the preparation of N-oxide, quaternary amine or stereochemically isomeric form of formula (II) is true. The data relating to what those specific N-oxide, quaternary amine or stereochemically isomeric form of formula (II) is not provided in the impugned specification. Specification has no teaching or suggestion as to how to perform said process to arrive at N-oxide and quaternary amine of compound of formula II. In absence of all such data and examples it is concluded that the specification to certain extent suffers from insufficiency of description and a person of ordinary skill in the art would not be able to carry out the invention without undue burden. In view of the above mentioned discussion I conclude that the invention as claimed in claims of the application No. 4805/DELNP/2007 is not Patentable u/s 2[1(j)] of the Patents Act (As amended) as being devoid of inventive Step. The claims also lack sufficiency of disclosure as required u /s 10 of the Patent Act. In the light of the above discussion I refuse to proceed with the application for grant of patent. No order for cost.
Date – 08/05/2015 IPO New Delhi (N R MEENA) Deputy Controller of Patents and Designs
Copy to:1.M/S.Remfry & Sager,Remfry 27,Gurgaon…..Agent for Applicant
House
at
the
millennium
Plaza,Sector
2.M/S.S.Majumdar & Company,202,Elecon Chambers,Behind Saki Naka Tel.Ex.off Kurla Andheri Road Saki Naka,Mumbai-400072……….Agent for opponent
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