Eli Lilly & Co (Application No. 85/DEL/1995) v Ajanta Pharma Ltd, Delhi Patent Office

20 Pages·2008·0.1 MB·English

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.85/DEL/1995
filed on 23/01/1995
AND
In the matter of opposition by way of representation
U/s 25(1) on said application no.85/DEL/1995

Eli Lilly & Co., Lilly Corporate Center, Indianopolis,
IN 46285, USA ……… The Applicant
Ajanta Pharma Ltd., Ajanta House, Govt. Indl.Area,
Charkop, Kandivili (W), Mumbai 400067, India ..……..The Opponent

Hearing held on 30th MAY 2006

Present:

Sh. Sanjay Kumar, Smt Ranjana Mehta Dutt,
Smt Richa pandey, Smt Deepa Tikko
M/s Remfry & Sagar,……………………………………Attorneys for the Applicant

Sh S Majumdar
M/s S. Majumdar & Co………………………………….Attorney for the Opponent
And
Sh Sonewane, Company Secretary,
M/s Ajanta Pharma Ltd…………………………………...The opponent

DECISION

An application titled as ,’Tetracyclic derivatives, process of preparation and use’ was
filed on 23rd January 1995 by Laboratoires Glaxo S.A., 43, Rue Vineuse, 75016 Paris,
France for grant of the patent as indicated in the application form filed by their agents,
M/s Remfry & Sagar, Gurgaon, NCR, India. The application was assigned to ICOS
Corporation, 22021-20th Avenue SE, Bothell, WA 98021, USA as recorded in the Patent
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Office, Delhi in December 1997. A change in the name of the applicant from
Laboratoires Glaxo S.A to Laboratoires Glaxo Wellcome was recorded in the Patent
office, Delhi on 17th February 1998. ICOS Corporation further assigned rights to M/s Eli
Lilly & Co., Lilly Corporate Centre, Indianapolis, IN 46285, USA and recorded change
of applicant in the Patent office on 29th August 2003. Thus presently on record the
applicant is M/s Eli Lilly & Co. The application claimed priority of UK application no.
9401090.7 dated 21st January 1994. The present application was filed u/s 5(2) of the
Patents Act, 1970. The application was also filed for grant of EMR (EMR/3/2003)
granted on 26th August 2004. The application has been published u/s 11(A) of the Act on
4th March 2005 in the VIIth volume of the Patent Office journal, page 8408. However,
later to this the EMR ordered as “no effect should be given to EMR certificate issued on
26/8/2004 without the leave of the court” by the Hon' High court of Kolkatta on a WP no.
2075/2004 and T no. 359/2004. This order was notified in Gazette of India, part III,
section 2 on November 27, 2004. The order is effective till date.

The application relates to tetracyclic derivatives of formula I, sub groups of compounds
of formula I, its isomers and tautomers, pharmaceutically acceptable salts and metal salts,
individual compounds of formula I and pharmaceutical composition comprising the
compound of formula I. The application also discloses processes for preparation of
compounds of formula I and its individual compounds and method of treatment of
various ailments by the use of compound of formula I. It is disclosed that the tetracyclic
derivatives of formula I are potent and selective inhibitors of cyclic guanosine 3’, 5’-
monophosphate specific phophodiesterase (cGMP specific PDE). Thus compounds of
formula I are useful for treatment of such conditions where inhibition of cGMP specific
PDE is thought to be beneficial, including treatment of cardiovascular disorders. Various
use of the tetracyclic derivatives of formula I has been disclosed in page 2 and 7 to 10 of
the complete specification.

No prior art of the claimed invention has been discussed in the application. The
application as filed had 16 claims. Claims 1 to 11 (product claims) pertained to the
compound of formula I and its isomers, Claims 12, 13 and 14 pertained to the use of the
compound, method of treatment by the compound and pharmaceutical composition
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comprising the compound of formula I, respectively. Claim15 (product claim) related to
the intermediates in the preparation of compound of formula I. Claim16 pertained to the
omnibus claim of the compound of formula I. Later on the applicant added 44 claims
voluntarily by applying in prescribed manner on 7th January 2003. The application came
up for examination and first examination report was issued on 12th April 2005. The
application as examined had 60 revised claims. The added claims 16 to 57 pertained to
processes of preparation of the compound of formula I and claims 58 to 60 pertained to
omnibus claims of the process and product.

The examiner raised objections on the grounds of non-patentability u/s 2(1)(j), 3(i), 3(e)
and 3(d), conflicting claims with the claims of 792/DEL/1999 and non-allowability of
product claims as the compound was invented prior to 1995 and this application was filed
under WTO category. In reply, the applicant made amendments and the number of claims
were reduced to 28. Presently the claims 1 to 7 relate to the tetracyclic derivatives of
formula I, claims 8 to 10 relate to its isomer, claims 11 to 25 relate to the process of
preparation of the tetracyclic derivatives of formula I and its cis isomer and claims 26 to
28 are omnibus claims of the compound, its isomer and process of preparing the isomer.

A pre grant opposition by way of representation was filed by Ajanta Pharma Ltd. u/s
25(1) of the Act on 30th January 2006. The opponent filed a revised opposition on 30th
March 2006 which included an expert evidence of Dr Nityanand. The reason for filing
revised opposition was stated that the original representation dated 30/1/06 was based on
the corresponding US patent application because the specification as published in India
was not available during the filing of the earlier representation. In the interest of justice,
the revised representation was taken on record by the office. The applicant filed a reply
statement u/r 55(4) of the Patent Rules, 2003 on 2nd March 2006 and a revised reply
statement was filed on 28th April 2006 to contest the revised opposition of the opponent
with the prayer that the revised representation may not be taken on record. The opponents
in view of prayer of applicant that the revised representation, which is containing expert
evidence, should not be taken on record filed an interlocutory petition on 25th May 2006
to take their evidence on record. The applicant opposed on 26th May 2006, the
interlocutary petition and such allowance of revised opposition dated 30/3/2006 including
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an evidence of Dr Nityanand, due to absence of any such provision in the Patent law.
However, in the interest of justice and keeping in view the basic intent of section 25(1) of
the Patent Act, 1970 i.e. to help the controller in allowing the valid patent, I take the said
revised opposition with evidence on record filed by the opponent. The said evidence of
the opponent serves as evidence in support of grounds of opposition for deciding the
validity of the claims of the present application. To arrive on my abovesaid conclusion, I
rely on 49 RPC 565 as detailed below.

“In his decision the Controller disregarded the publications on the ground that they were
inadmissible at this stage. The opponent appealed to the Law officer- Held, that the
Comptroller is bound in the public interest to consider any alleged prior publication
which may be brought to his notice after the hearing and before the issue of his
decision.”

Opponents raised various issues in their representation and argued the various grounds of
opposition at length. The grounds taken up in the representation are as under –

1. Prior publication
2. Prior claiming
3. Prior public knowledge or prior public use
4. Lack of Inventive step
5. Not an invention u/s 2(1)(j), 3(d), 3(e), 3(i)
6. Insufficiency of description
7. Non disclosure regarding foreign filing of the invention

During the hearing, the opponents withdrew 1st, 2nd and 7th grounds. Now I shall discuss
each remaining issue in details herein below.

1. Lack of Inventive step
The opponent has cited and relied upon the following two documents to show that the
claims of the present application are obvious.

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(i) US 3,917,599 dated 4th Nov 1975 (Exhibit 1)
(ii) Journal of Medicinal Chemistry, 1973, Vol 16, No.5, pages 561-564 (Exhibit 2)
The opponent has also furnished an expert evidence of Dr Nityanand in respect of
obviousness supported by Exhibit 3 (Indian Journal of Chemistry, Vol 11, May
1973, pp-417-421 by Anil Kr Saxena et al.), Exhibit 4 (Synthesis from dl-
tryptophan and aldehydes, Jan 1948) and Exhibit 5 ( Journal of American Chemical
Society, 1980, 102, 6976-6984).

Exhibit 1 relates to 2-substituted-1,2,3,4,6,7,12,12a-
octahydropyrazino[2’,1’:6,1}pyrido[3,4-b] indoles that corresponds to formula I(E)
where Z and Y = H,O ; R2 = H, lower alkyl group ; X = straight or branched chain
alkylene group optionally interrupted by a CO or CHOH group ; R = H, lower alkyl, aryl,
aryloxy, cyano, carboxy, dialkylamino, benzodioxanyl or 4-pyridyl and X and R may
together be H.. The Opponents in their statement has tried to point out similarities
between the process for preparation of compound of formula I of present invention and
compounds as disclosed in Exhibits 1 and 2. The process steps followed in exhibit 1 are –
(i)Condensation of dl-tryptophan with aldehyde to yield formula II,
(ii)Condensing formula II with acetyl chloride to yield formula V,
(iii) Condensation of formula V with primary amines to yield compounds of formula I.
The opponent alleges that the steps (i) and (ii) are same as that of the process disclosed in
the instant application. In step (iii) the compounds of formula I of instant application
differs from compounds of formula (I ) of exhibit 1 only in the presence of substituent R2
on the pyrazino pyrido indole ring where R2 is optionally substituted monocyclic
aromatic ring selected from benzene, thiophene, furan, pyridine or optionally substituted
bicyclic ring attatched to the rest of the molecule of the formula I via one of the
benzene ring carbon atoms and wherein the fused ring A is a 5,6 membered ring which
may be saturated or partially or fully unsaturated and comprises carbon atoms and
optionally one or two hetero atoms selected from O, S and N. The above process
essentially employs the same starting material (dl-tryptophan and aldehyde) to yield same
intermediates as that of the process of the instant application.

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The opponent has compared the structure of the compound claimed in the instant
application with the compound as disclosed in exhibit 1 and has shown that the said two
compounds differs only in the presence of R2 substituent on the pyrazino pyrido indole
ring. The opponent alleges that the claimed compound of formula I is mere substitution
of groups in the generic compound of Exhibit 1, that is obvious to a person skilled in the
art.

The opponent further has compared the use of the compound of the instant application to
that of the exhibit 1. The compounds of exhibit 1 has strong tranquilizing and
hypotensive activities and are used to treat cardiovascular disorders. The compounds of
the instant application are potent and selective inhibitors of cyclic guanosine 3’, 5’-
monophosphate specific phosphodiesterase having various therapeutic utilities including
the treatment of cardiovascular disorder. The opponent points out at example 122 in the
specification of the instant application which shows the hypotensive effects of formula I.

According to the opponent a case of obviousness can be made when chemical compounds
have very close structural similarities, can be prepared by same process steps and have
similar utilities. Different uses of the claimed compound are obvious extension over the
prior art. Changing a substituent group in the claimed class of compound would still
render the compound as obvious and not a subject matter of subsequent patent. The
opponent argues that upon the expiration of the patent referred as Exhibit 1, the public
should be free to use not only the claimed invention but also the obvious modifications or
variants of the invention. Hence, the opponent states that the applicant’s compound is
obvious with respect to exhibit 1 and lacks inventive step.

Exhibit 2 (Article by Saxena et al, Journal of Medicinal Chemistry, 16(5), 1973, 561-564
entitled,’Agents acting on CNS’) relates to the synthesis of 1,2,3,4,6,7,12,12a-
octahydropyrazino[2’,1’:6,1}pyrido[3,4-b] indoles, a ring system which incorporates both
tryptamine and piperazine. The Opponents in their statement has compared the process
claimed in the instant application with the process as disclosed in exhibit 2. The process
steps followed in exhibit 2 are –
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(i) Cyclization of dl-tryptophan (starting material) with formaldehyde followed by
esterification yields dl-methyl 1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole-3-carboxylate,
formula (a),
(ii) Condensation of formula (a) with chloro acetyl choride yields dl-methyl-2-
chloroacetyl-1, 2,3,4-tetrahydro-(H-pyrido[3,4-b]-indole-3-carboxylate of formula (b),
(iii) Reaction of formula (b) with diethylaminoethylamine gives dl-2-(beta-
diethylaminoethyl-1)-1,4-dioxo-1,2,3,4,6,7,12,12-octahydropyrazino [2’,1’: 6,1] pyrido
[3,4-b] indole, formula (c ),
(iv) Formula (c ) on LiAlH4 reduction gives the compound (Ia).
The opponent alleges that the steps (i) and (ii) are same as that of the process disclosed in
the instant application. In step (iii) secondary amines are used instead of primary amines
as used in instant application. The compounds of formula I of instant application differs
from compounds of formula (c ) of Exhibit 2 only in the presence of substituents R1 and
R2 on the pyrazino pyrido indole ring, R1 being diethylaminoethyl substituent and R2
being hydrogen. The opponent states that the process disclosed in exhibit 2 essentially
employ the same starting material i.e. dl-tryptophane, formula IV of the instant
application. Formula III and formula II of the instant application are same as formula (a)
and formula (b) respectively of exhibit 2. The only difference in the process disclosed in
the instant application is reacting formula II with primary amines to make the same
generic compound as disclosed in prior arts Exhibit 1 and 2.

The opponent has quoted Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990)
(Annexure I)

The opponent argued based on the above judgment that the class of compounds claimed
by the applicants is a mere substitution of groups on the generic compound (intermediate
compound, formula (c ) of Exhibit 2) and thus an obvious extension of teachings of prior
art as disclosed in Exhibits 1 and 2.

The applicant has denied the ground of obviousness and argued that the process of the
Exhibit I has not been claimed in the present application. The claimed compounds are not
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produced from formaldehyde but from an aldehyde having different structure from any
aldehyde disclosed in exhibit 1.

The applicants stated that the single compound tested in Exhibit I (column 8, line 30
through column 9, line 36) does not have similar structure and differs in three ways from
the presently claimed compound i.e. (i) A substantial difference exists at the R2 position
of the compound, (ii) the sole compound tested is free of oxo groups in the tetracyclic
ring structure, (iii) corresponding R1 group of the tested compound is not encompassed
by the presently claimed R1 groups. The compounds of Exhibit 1 contains an R1 group
that corresponds to the R2 group of the claimed compounds and an –X-R moiety that
corresponds to the R1 group of the claimed compound. The applicant pointed that in the
broadest disclosure, R1 of compounds of Exhibit 1 is H or a lower alkyl group and –X-R
is an alkylene group, optionally containing CO or CHOH (i.e. X), bonded to hydrogen,
lower alkyl, aryl, aryloxy, cyano, carboxy, carbalkoxy, dialkylamino, benzodioxanyl or
4-pyridyl (i.e.R) or –X-R is H. The presently claimed compounds contain a cyclic
aromatic R2 group that is substantially different from the R1 group of the compounds
disclosed in Exhibit 1.

The applicants denied the strong hypotensive effects of the compounds of Exhibit 1 and
invited the attention of tribunal towards column 9, lines 28-30 of Exhibit 1 which states
that “compound produced no significant effect on blood pressure or respiration”.

The applicant argued that the opponent has not pointed out any test in Exhibit 1 using a
compound having a structure similar to the presently claimed compound.

Regarding Exhibit 2, the applicant argued that the compounds of Exhibit 2 and the
presently claimed compounds do not have similar structure viz. (i) substantial difference
exists in both R1 and R2 groups, (ii) compounds of Exhibit 2 are free of oxo groups on
the ring structure. The Exhibit 2 discloses compounds having only an H at the R2
position of the present claims and an R group corresponding to R1. The applicant stated
that the Exhibit 2 contains three compounds (compounds 10, 13 and 14) having an R1
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group being lower alkyl, but these compounds either lack activity (10) or are depressants
(13,14).

Further the applicant argued that the presently claimed compounds are not produced from
formaldehyde. Also the tested compounds of Exhibit 2 differ greatly in activity.
Therefore, due to unpredictability of the compounds to provide a specific
pharmacological effect, a person skilled in the art could not anticipate the activity of
tested compounds, let alone the activity of compounds in a different class of compounds
i.e presently claimed di-oxo compounds. The applicant argued that Exhibit 2 fail to
suggest or provide any motivation to modify the disclosed compounds to arrive at the
presently claimed compounds as a whole in addition to the fact that Exhibit 2 shows that
the art is quiet unpredictable. The applicant invited the tribunals attention to Table 1,
Gross effects and Remarks columns and page 561 of Exhibit 2. The applicant stated that
the Table 1 shows that very minor changes in the R group results in substantial changes
with respect to the activity of the compounds, including a change to inactivity. Very few
compounds demonstrated hypotensive activity and this activity is disclosed as mild (page
562-563, Exhibit 2).

Further, the applicant submitted that an important feature of the presently claimed
compounds is the existence of two stereo centers. The Exhibits 1 and 2 do not teach or
suggest how to provide a compound having the correct stereochemistry at the carbon
atom of the R2 group. The compounds disclosed in Exhibit 2 have hydrogen at this
position, which completely eliminates this asymmetric carbon atom.

The applicant stated that one must examine the invention as a whole, rather than looking
at a snapshot of segments found in the reference and drawing a conclusion. The applicant
also stated that anticipation exists only when the disclosure of a single prior art reveals
every element of claimed invention.

During the hearing, the opponent drew the attention of the tribunal to the affidavit filed
by Dr Nityanand, who has opined that the presently claimed compounds are obvious in
view of disclosure of Exhibits 1 and 2. The opponent stated that according to the
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affidavit, Pfizer conducted studies in the year 1986 and discovered the anti hypertensive
effects of Viagra (sildenafil citrate). Later in 1992 Viagra was used to treat erectile
dysfunction. Sildenafil citrate acts by inhibiting PDE5 and thereby maintaining high
concentrations of cGMP. The presently claimed compounds are also potent and selective
inhibitor of cGMP specific PDE having utility in variety of therapeutic areas including
treatment of cardiovascular disorders. Therefore, it is evident form the evidence filed by
the opponent that the drugs that inhibit PDE5 may share both properties of anti
hypertensives and treatment of erectile dysfunction. Exhibit 1 also discloses that the same
class of compounds are useful to treat hypertension. Dr Nityanand also pointed out in his
affidavits that distribution of stereocenters and R2 substitution in generic compound as
claimed in Exhibit 1 is obvious derivatization to obtain compound of the present
invention as discussed in the prior art disclosures submitted as Exhibits 3, 4 and 5.
According to him, when a claim recites an invention in generic terms, the disclosure of a
specific example within the definition of the generic claim anticipates and/or obviates the
generic claim.There is nothing on record to dispute the expertise of Dr Nityanand in the
relevant field of technology. Furthermore, the applicants did not have any material
arguments or evidence to dispute the opinion of Dr Nityanand.

During the hearing, the opponent drew attention of the tribunal to Exhibit 1, lines 1-3,
column 2, which states that ‘the compounds of this invention have useful biological
activities, in particular, strong tranquilizing and hypotensive activities. The opponent also
quoted paragraphs bridging columns 3 and 4, which specifically teaches the stereo
chemical configuration at the asymmetric centers.

The opponent relied upon the following decisions to argue their point during hearing–
Decision of the Technical Board of Appeal T 882/94 (para 4.4.3) where it is stated -

“Where it is obvious from the state of the art that is certain measure will bring about an
improvement of a certain property, a surprising degree of this improvement cannot make
this per se obvious measure non obvious”.

Decision of the Technical Board of Appeal of the EPO T 913/94 where it is stated -
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