Transcript What is the US position on this?

The Valcyte Decision
– An Analysis
Feroz Ali
Ali Associates
Srividhya
Ragavan
[email protected]
u
IN 207232
Patentee: F.Hoffmann-La Roche
AG
The Invention
Drug: Valganciclovir Hydrochloride
Hydrochloride salt of the L-valyl ester of ganciclovir
L-valyl ester prodrug of ganciclovir (two
diastereomers)
Diastereomers → ganciclovir (intestinal esterases)
Chemical Structure
Chemical Name:
2-(2-amino-1, 6-dihydro-6-oxo–purin-9-yl)
methoxy-3-hydroxy -1-propanyl –L-valinate
Patent History in India
Patent application: 27 July 1995
FER: 17 May 2006
Pre-grant Opposition: 12 July 2006
Grant published: 29 June 2007
Patent Expiry: 27 July 2015
Pre-grant Opposition
Oct 2008: Pre-grant opponent files writ in Chennai
Dec 2008: Order setting aside the grant; hear
opponent
Patentee → Supreme Court : hear opponent
Jan 2009: Controller dismisses pre-grant opposition
Pre-grant Opposition
Pre-grant Opponent → Supreme Court
Challenged the decision of Controller
March 2009: SC order to combine both the SLPs
Pre-grant opponent intervene in post-grant
proceeding
Post-grant Opposition
Five post-grant oppositions
Ranbaxy, Cipla, Bakul Pharma, Matrix, DNPP
(NGO)
Sep 2008: Roche sues Cipla in Mumbai
Apr 2010: Order rejecting product patent
Some Facts
Ester form of a known drug
Ganciclovir known since the 1980s (US 4,355,032 )
Product claims: 1 to 9; 10 to 12 for process
Main Grounds:
Lack of Novelty
Lack of Inventive Step
Not an invention under section 3(d)
Non-compliance with section 8
Prior Art
EP 0375329 (‘329)
US 5043339 (‘339)
US 6083053 (‘053)
US 4355032 (‘032)
US 4957924 (‘924)
Beauchamp et al, Drugs of the Future, 1993, 18(7): 619,-628
Beauchamp et al, Antiviral Chemistry and Chemotherapy (1992),
3(3), 157-164
Lack of Novelty
Anticipated by US ‘339
Held, an anticipating prior art document should name the claimed
compound individually and should contain sufficient description, which
would enable a person of ordinary skill in the art to arrive at the invention
without further experimentation.
Neither ‘339 or ‘329 disclose or contain an enabling disclosure to carry out
the claimed invention so as to render the US ’339 as anticipating the
claimed invention.
Held, US ‘339 or EP ‘329 do not specifically disclose the mono-(L)-valinate
ester of ganciclovir either expressly or inherently.
Although both the patents generally disclose the existence of mono esters
as a part of a large class of compounds, it does not particularly disclose the
compound or other property of the said compound . the information
provided may be relevant but not appropriate to obtain the compound of the
claimed invention.
Comparing the Novelty Analysis
US Standard
Four Corners Rule for novelty determination:
All the elements of the claimed invention should be
found within the ambit of a single prior art reference
Valcyte Novelty Question
• First prior art: US ‘339 discloses L valinate
ester of glanciclovir
• Second Prior art: EP ‘329- discloses the
mono esther form of the application
material
Counsel
for
patentee:
but,
with
a 3person
fold
the
activated
amino
acid
It an
was
argued that
a skilled
in the of
art
would
have
able
to
Such
argument
would
not work
forexcess
novelty
purposes
in thebeen
US since
the
accordingly
appreciate
the
reduction
requirement is that all the elements have to be disclosed in a single prior art.
• Counsel for patentee argued that US ‘339
is not a valid prior art because:
A test that is reminiscent of the TSM
test to prove non-obviousness – not a
novelty standard
An Enabling Reference
In the US too, a reference has to be fully enabled in order to anticipate.
Generally, to take care of the objectives of the patent system
• Citing from the Novartis (Glivac)
application:
• Citing from Union Carbide [1992] EPOR 312:
Inventiveness has to be determined at the time of the invention (and not at the time
of evaluation of the patent)
The same principle is codified in the statute
under Title 35, §103:
“A patent may not be obtained unless…
the subject matter…would have been obvious at the
time the invention was made …
Lack of Inventive Step
Opponents: US’924 discloses valine esters of acyclovir that exhibit more
bioavailability than acyclovir. Drugs having poor absorption are converted
into ester to make the drug more bioavailable when administered orally. The
amino acid ester of ganciclovir, preferable D-L and DL amino acids. It also
teaches bis-(l-valinate) ester of ganciclovir and example 6(b) teaches the
process to get mono-(L-alaninate) ester along with bis-(L-alaninate) ester of
ganciclovir in the ratio of 1:9.
US ‘032 discloses ganciclovir and pharmaceutically acceptable salts which
are active against Herpes Simplex virus I and II and related virus such as
cytomegalovirus, Epstein-Barr Virus and Varicella Zoster virus.
The oral form of parent drug ganciclovir has been commercially known from
the US Patent ‘032. The L valine ester of acyclovir has improved
bioavailability than the acyclovir after oral administration.
A skilled person in the art follows the route of L-valine ester of acyclovir, i.e.,
valacyclovir and apply same to ganciclovir to get valganciclovir. Valacyclovir
and valganciclovir are nucleoside analogs having similar structure and used
for similar treatment.
Lack of Inventive Step
Beauchamp in 1992 and 1992 disclosed the best amino-acid ester for acyclovir. L-valyl ester was
the best prodrug amongst 18 amino acid esters sysnthentised and tested as potential prodrugs.
Valacycolvir, the prodrug of acyclovir is more bioavailable than acyclovir that is proved to be rapid
hydrolysis in vivo than the parent compound.
Various forms of esters are prepared using hydroxyl group of the purine ring and the side chain of
acyclovir with amino acids. The modifications made to the purine ring was toxic and the
modifications made to the acyclic chain resulted in improved effect.
Acycolvir and ganciclovir are structurally similar and functionally similar nucleoside analog. It is
obvious to a person would try for similar ester which is alresdy proved with improved effect. US
‘924 patent discloses the L-valinate ester of acyclovir and hydorcholorde sasl of the L-valinate
ester. The disease targeted by the two drugs, L-valinate ester of acyclovir and ganciclovir are
similar. L-valine is a chiral compound, its derivative L- valinate ester of ganciclovir inherently will
be a chiral molecule, therefore (R) or (S) diastereoisomers can be expected by a skilled artisan.
A person skilled in the art would combine the teachings of Beauchamp’s publications, US 032, US
339 and EP 329 and US 924 to prepare the compound in the alleged invention.
Patentee - Combining the prior art, Beauchamp’s publications with US 924, a person skilled in the
art will be motivated to block all the free OH groups resulting in bi-ester.
Lack of Inventive Step
Controller held that the nucleosides such as acyclovir, penciclovir show low aqueous
solubility and low bioavailability when administered orally. To increase oral bioavailability
many modifications were done to the purine ring and acyclic side chain. Conversion of
acyclovir into L-valine ester of acyclovir was suggested by ‘924 patent.
The ‘329 patent discloses di-valyl amino acid ester of ganciclovir. Prior art suggests that
many similar nucleosides are converted into ester of amino acids, preferably L-valine to
increase oral bioavailability.
The preferred ester forming compounds suggested by ‘329 patent and ‘924 patent are
aminoacids, particularly valine, more particularly, L-valine to overcome the problem of oral
drug delivery.
Beauchamp suggests and motivates the involvement of stereospecific (L- vs D-) transport
process using common branched chain amino acids, L-valine and L-isoleucine, particularly
L-valine ester which makes the drug more bio available.
A skilled person would have been motivated to prepare mono L-valine ester of ganciclovir
from the teachings of ‘329, ‘924 and the Beauchamp articles. Claim 1 and its dependant
claims are not inventive.
Lack of Inventive Step
Ex 9 of the patent does not show the improvement in oral bioavailability of
the esters of ganciclovir
Comparison made between esters and HCl salt as an improvement with
regard bioavailability is not scientific and results provided are not proper to
meet the patentability requirement.
Since the object of the invention is to provide a prodrug of ganciclovir with
improved oral bioavailability, the comparison provided in the specification to
show such improvement is not scientific
Improved oral bioavailability not proved in the complete specification
Most drugs listed in the pharmacopoeias are in the salt forms, because salt
forms of the drugs influences the solubility for better therapeutic effect.
Process patent inventive
Neither ‘339 nor ‘329 specifically mentioned the
process for the preparation of the compound of the
claimed invention.
Identification of the compound of the invention from
‘329 is obvious, but the method for the preparation of
such a compound requires extensive research work.
Even though the method of hydrolyzing one of the
ester group of ‘329 patent or any other steps involved
in the preparation is by conventional method, it could
not have been ascertained before it was produced.
Process claim allowed but restricted to a single
process.
Not an invention [section 3(d)]
New form of a known compound already disclosed in US ‘339
Ester form of a known substance should show significant
enhancement in efficacy to merit a patent grant
Novartis v Union of India – efficacy means therapeutic efficacy (High
Court and IPAB) – ‘Efficacy’ and ‘bio-availability’ are two different
concepts.
Data provided in Ex 9 of the specification pertains to bioavailability
but not therapeutic efficacy.
The compound and its pharmaceutically acceptable salts, isomers,
crystalline form and composition do not fulfill the requirement of the
Act.
Inventive Step Issue
• Opponents traced the journey of L-valine
ester for acyclovir to arrive at L-valine
ganciclovir.
– Note that acyclovir and ganciclovir are
nucleoside analogs
• Test used – suggestion and motivation
from prior art
After KSR, the US has moved to a broader standard
POSITA would solve a problem by looking at
prior arts that solves different problem.
When a claimed invention implements a
predictable variation of the patent, then §103 bars it
Reason??
Efficacy Issue
• Proposition 1: Therapeutic efficacy is
different from bioavailability (property) and
clinical efficacy
2 Questions:
What is the US position on this?
The “teaching away” controversy
What is the US position on this?
Pfizer v. Apotex (Fed Cir) (2007) :
• Pfizer sued Apotex for infringing the patent on Norvasc besylate form of amlodipine.
– Norvasc is used to treat hypertension and forms of angina.
• Apotex alleged that Pfizer’s earlier ‘909 patent over
amlodipine anticipated the patent over amlodipine besylates –
(salt form of amlodipine).
• Federal Circuit agreed with Apotex on the grounds that the
besylate form lacked enhanced utility from the base
compound.
– The Federal Circuit reiterated an established principle that
Given this, the post-grant decision is commendable in clarifying
salts of known
compounds are deemed obvious unless
the constituents of the efficacy requirement
there is an unexpected utility or improvement or efficacy!!
The “teaching away” controversy
• Where the controversy comes from?
• “Teaching Away” – A secondary factor
• Secondary factors are employed where
court is unable to conclude using the basic
test for determining inventiveness
• “Teaching Away” – is persuasive but need
not tip the case towards the presence of
inventive step
• Further, I did not see any teaching away.
The Teaching Away Controversy
In Re Dillon (Fed Cir) (1991) :
• Dillon claimed tetraorthoesters
• Prior art taught triorthoesters
• Fed. Circuit held that a compound can be
prima facie obvious if the examiner can
show:
1. Structural similarity, or,
2. Suggestion or expectation that the prior art and claimed
compound will have same or similar utility
In the Valcyte dispute, acyclovir and ganciclovir
seems to have demonstrated
structural similarity and similar utility.
Other findings
Patent filed Form 4 declaring the status of the US Patent Application as
‘pending’ – application was abandoned on 16.06.1995 – this amounts to
furnishing false information. Patentee has met the requirements under
section 8 of the Patents Act.
Photocopy of prosecution history of US application was taken from the
USPTO website submitted during the proceedings as evidence is not an
authenticated document and hence not considered.
Amendment of statement of opposition not allowed
Since claim 1 is not inventive, making a composition of known drug with
known excipients cannot be considered as an invention. Therefore Claim 9
is a mere admixture resulting only in aggregation of known properties.
Controller ordered to amend the patent to process claims restricted to a
single process – within 15 days of the decision
Locus Standi
• Very important issue to determine the
course of intellectual property issues for
the country
• Individual farmers, animal husbanders and nonprofit
organizations, raised moral and ethical concerns
regarding patenting living organisms.
• Under Article III, § 2 of the US Constitution, standing is
established only for parties with either a threat of
personal injury or an actual personal injury.
• The injury to farmers as a class, the Federal Circuit held,
was due to increased competition from
commercialization of genetically improved animals and
not from the grant of patents.
• Since the appellants asserted no other adverse effects
on any individual rights under the patent statute, the suit
was dismissed for lack of standing.
Animal Defense Fund (Fed. Cir) (1991)
The European Position
•
Europe handled it differently; EPC has a morality provision
•
In the case involving Relaxin, a patent application for a DNA fragment
encoding human H2-relaxin (and its precursors), was opposed as offending
the provisions of “morality” and “ordre public” in Article 53(3) of EPC.
•
With reference to the famous LabCorp case, that dealt with a patent on a
diagnostic methods, in Europe, it is expected that the invention would be
scrutinized to determine whether it could be characterized as a method ‘‘of
treatment of the human or animal body by surgery or therapy and diagnostic
methods practiced on the human or animal body.’’ EPC Art. 53(3).
•
But, the chief tribunal of the European Patent Office, the Enlarged Board of
Appeal, has interpreted this exception narrowly in Diagnostic Method G 1/04
(Dec. 16, 2005).
•
A claimed method is deemed an unpatentable ‘‘diagnostic method’’ within
the meaning of Article 53(3) only if each of its steps involves the mental
activity of attributing particular symptoms to a disease.
Other Controversies
Can the procedure for post-grant be different from
the revocation proceeding?
US: Re-examination is completely different from
the pre-grant opposition – designed to prevent the
registration of a patent
US: Re-examination procedurally completely
different from the proceedings in courts - designed
to achieve the exact same result
Art. 14 – equal protection – does not apply because the objective with post-grant
is administrative removal of patents as opposed to judicial removal. Administrative
procedures are meant to be less burdensome as a rule.
Arguments Relating to Evidence
Should the evidence statute be implicated?
Both in the US and Europe, administrative
procedures rarely implicate the evidentiary
requirements.
There has to be a reason for India to do that.