Post on 12-May-2018
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The Patents Act 1970
Section 15 and 25(1)
In the matter of Indian Patent Application no. 2315/DELNP/2007 filed on 26th
March 2007
In the matter of:
Pfizer Ireland Pharmaceuticals ……… Applicant
Versus
Mylan Laboratories Limited ...…..Opponent
Date of Hearing February 24 and 25, 2015
Present-
G. NATARAJ, SANDEEP RATHORE, SUFIA. …. Agent for the Opponent
ARCHANA SHANKER, NUPUR MAITHANI,
DEVINDER SINGH RAWAT, GITIKA SURI
of Anand and Anand ….. Agents for the Applicant
Inventor - DR. DENIS DRAPEAU
The application for grant of patent title “Production of Polypeptides”, entered national phase in India
on 26th March 2007. The international filing date of the instant application is 26th August 2005 (PCT
no.: PCT/US2005/030437). The application claims priority from US patent application Nos.
60/604,941, 60/605074, 60/605097 dated 27th August 2004.
The application was examined under Sections 12 and 13 of the Indian Patents Act, 1970 and the first
examination report was issued on 3rd December 2012. The applicant submitted their reply to the first
examination report on 10th April 2013 with the revised set of claims.
Mylan filed an opposition on 25th February 2014 along with the evidence of Dr. Suman
Bandophadhyay. The Notice in respect of the Opposition was forwarded on 7th March
2014. A response was filed on 9th June 2014
The following documents were filed by Mylan on 12th February 2015
• Counter Statement to the Reply statement;
• Declaration of Dr. Angelo Perani
• Declaration of Dr. Velu Mahalingam
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The Applicant filed declaration of Dr. Denis Drapeau the inventor dealing specifically
with the counter statement and declarations filed by Mylan.
The claims currently on record in respect of Indian patent application no. 2315/DELNP/2007 are
enclosed herewith. The pending claim 1 is as follows:
A method of producing a polypeptide in a large-scale production cell culture comprising the steps of:
providing a cell culture comprising;
mammalian cells that contain a gene encoding a polypeptide of interest, which gene is
expressed under condition of cell culture; and
a medium containing glutamine, having a cumulative amino acid amount per unit volume
greater than 70 mM, a molar cumulative glutamine to cumulative asparagine ratio of less
than 2, and wherein the cumulative total amount of histidine, isoleucine, leucine, methionine,
phenylalanine, tryptophan, tyrosine, and proline per unit volume in said medium is greater
than 25 mM;
maintaining said culture in an initial growth phase under a first set of culture conditions for
a first period of time sufficient to allow said cells to reproduce to a viable cell density within
a range of 20%-80% of the maximal possible viable cell density if said culture were
maintained under the first set of culture conditions; changing at least one of the culture
conditions, so that a second set of culture conditions is applied;
maintaining said culture for a second period of time under the second set of conditions and
for a second period of time so that the polypeptide accumulates in the cell culture.
I have heard both the parties extensively in the light of the affidavits and the notice of opposition as
well as the reply statement. I will now deal with each issue.
The Opponent read out the patent specification in order to explain the invention.
The applicant gave a presentation to provide an understanding of the invention and made the
following submissions:
Indian Patent Application no. 2315/DELNP/2007 is an invention that relates to an improved system
for large scale of production of protein and a polypeptide in cell culture. The process of Indian Patent
Application no. 2315/DELNP/2007 allows high levels of protein production and lessen accumulative
undesirable factors.
The main culture conditions highlighted by the Applicant are:
o Cumulative amino acid amount per unit volume greater than 70mM; cumulative
glutamine: a cumulative asparagine less than 2 and cumulative total amount of
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histidine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine and
proline per unit volume greater than 25mM.
o Metabolic shift - Changing the culture from a first set of culture conditions to a
second set of culture conditions
o Change is performed when the culture has reached about 20-80% of its maximal cell
density.
o The change involves changing the temperature, pH, osomlality, chemical inductant
level etc.
o Culture methods adjusted so that, after reaching a peak, lactate and/or ammonium
levels in the culture decrease over time.
The advantages/ unexpected results were also presented for the above conditions through a
presentation given by the applicants
The applicant also explained that the term cumulative was defined in the complete specification. The
term “cumulative” used in the claims and the description has been explained in the complete
specification on pages 3 and 26. Page 3 defines “cumulative” as “the total amount of a particular
component or components added over the course of the cell culture, including components added at
the beginning of the culture and subsequently added components. In certain preferred embodiments
of the invention, it is desirable to minimize “feeds” of the culture over time, so that it is desirable to
maximize amounts present initially. Of course, medium components are metabolized during culture
so that the cultures with the same cumulative amounts of given components will have different
absolute levels if those components are added at different times (e.g. all present initially vs. some
added by feeds.”
The applicant also stated that large scale had also been defined in the patent specification and,
therefore, these expressions should be given the meaning contained in the specification.
According to the Applicant the examples 1 to 14 help in arriving at features that were confirmed in
large scale. As per the Applicant example 15 uses 130L and 500L scale and Example 17 uses 6000
liter bioreactors. Examples 15 and 17 utilised media and steps that were optimised in the preceding
Examples. The preceding Examples inform the skilled person as to how to optimise the media and
method of production according to the claimed invention. Indeed, the last sentence of paragraph
[0278] (Example 15) states that “All the media tested were expected to show improvements over the
Phase 1 medium (Medium 10 fed with Medium 11 feed medium), based on small scale bioreactor
data.””
The applicant also tried to demonstrate distinction between molarity and cumulative molarity was
brought out during the discussion. It was clarified that molar cumulative is not just a simple addition
but is a function of volume and the cumulative molarities of simple addition calculated by the
opponents is incorrect. The calculation were also demonstrated which forms a part of the written
submissions as well as the prosecution of this case.
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The inventor Dr. Denis Drapeau was also present at the hearing and under Section 79 led
oral evidence and has filed a transcript of the said oral evidence (in the form of an
affidavit)
The applicant referred to the Supreme Court decision in ‘Bishwanath Prasad Vs. Radhey Shyam and
the Delhi High Court in Roche Vs. Cipla that clearly held that the inventor is the best person to
describe the invention and also dealt with issues of novelty and obviousness.
Further, the path of the invention has been provided in examples 1 to 17 of the specification.
Examples 1 to 15 relate to experiments conducted for the production of anti-GDF-8, anti-Lewis Y
and anti-A beta antibodies, and example 16 then show that the conditions established based on the
results of examples 1 to 15 were effective in the production of TNFR-Ig polypeptides, another
polypeptide (Example 16) and the process could be reproducibly scaled up to commercial scale
(Example 17).
The Applicant raised various preliminary objections. The same are discussed below:-
- The Applicant submitted that the Opponent, 10 days prior to the date of hearing,
decided to file a rejoinder along with affidavits of Dr. Velu Mahalingam and Dr.
Angelo Perani to the reply statement filed by the Applicant on 9th June 2014. The
applicant also submitted that the Indian Patents Act in a pre-grant opposition does
not provide for filing of any rejoinder.
Decision: However, in the interest of natural justice and equity, I have taken the
said rejoinder and affidavits on record
- The applicant submitted that it is a fundamental principle of Civil Procedure Code
and the law on pleadings that all proceedings have to be based on pleadings and in
the absence of pleadings and material facts having been pleaded, a ground is
unsustainable in law. The purpose of pleadings is also to ensure that the applicant
can lead evidence and rebut the objections or grounds taken by the Opponent. On
pleading of material facts, the Applicant relied on Kalyan Singh Chouhan Vs. C.P.
Joshi. [(2011)11 SCC 786], Paragraph 18,19,28; Union of India v. Ibrahim Uddin &
Anr, the Supreme Court para 62; F. Hoffmann-La Roche Ltd. & Anr. V. Cipla Ltd.,
2012 (52) PTC 1 (Del) para 7. In this regard, it was submitted that the representation
of the Mylan has no pleadings in relation to the invalidity of claims 2 onwards and
the ground of prior claiming under section 25(1)(c) of the Act. Therefore no oral
arguments of the legal counsel in relation to invalidity of claim 2 onwards and the
ground of prior claiming under Section 25(1)(c) can be entertained.
Decision: I agree with the applicant that the opponent should confine their
arguments only to what has been stated in their opposition, rejoinder and
affidavits
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- The Applicant submitted that in the absence of any challenge on claims 2 onwards,
the Opponent has admitted to the validity of claims 2 onwards. As stated on page
40 of the Manual of Patent Office Practice & Procedure, each claim has to be dealt
independently of the other.
Decision: I note from the pleading (opposition, rejoinder and affidavits) that the
opponent has not challenged claim 2 onwards.
- The Applicant submitted that mere statement of a ground is not enough. The ground
has to be pleaded and proved. The Opponent, Mylan has neither pleaded nor proved
the violation under section 8 by the Applicant.
Decision: I agree with the applicant and therefore dismiss the ground of non-
compliance Section 8. However, as the pregrant opposition is in relation to
appending application, I note that the applicant has complied with the Section 8
requirement
- As per the Applicant the evidence of Dr. Suman Bandyopadhyay and Dr. Velu
Mahalingam should be disallowed as they are employees of Mylan Laboratories.
Decision: As stated earlier, I have already allowed their affidavits and therefore
nothing remains
The Opponent also raised various preliminary objections, which are discussed below:-
- The opponent stated that the affidavit of Dr. Dennis Drapeau should be disregarded
due to improper verification.
Decision: I have checked the verification and note that the same is in order.
- Dr. Drapeau's evidence(s) is biased and lacking credibility.
Decision: In my opinion and in view of the decision of the Supreme Court and
High Court, I dismiss this objection of the opponent and have also allowed the
affidavits of the Opponent’s expert.
- On locus standi, the applicant has filed the necessary steps to bring the name of
Wyeth Research Ireland Limited (Wyeth) on record
The grounds taken by the opponent are as under:
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• Section 25(1)(b) – novelty
• Section 25(1)(e)- Obviousness
• Section 25(1)(f) – not patentable/ not an invention
• Section 25 (1)(g)- does not sufficiently define the invention
• Section 25(1)(h)- section 8
Opponent’s submissions on anticipation
W002/101019
The Opponent states the following:
- That 2315 stipulates that "cumulative” amounts are in terms of the total amount of
amino acids added to the culture over the entire course of the culture process are
expressly disclosed in WO 02/101019
- In W0'019, Medium A has a total amount of amino acids of 77.78 mM that
includes an amount of 11mM glutamine. The Opponent arrived at an amount of
71.98 by stating that in the second set of experiments at a mo u n t i s 5 mM
- In W0'019 the ratio of glutamine to asparagine in the combination of Medium
A (when used in the second set of experiments) and the fixed amount of
glutamine (5 mM) is 1.16 (5 mM divided by 4.28 mM).
- In 2315, the total amount of "histidine, isoleucine, leucine, methionine,
phenylalanine, tryptophan, tyrosine and proline" in the combination of
Medium A (when used in the second set of experiments) is 13.86 mM
which will increase above 25 mM .
- W0'019 discloses the possibility of change in pH, osmolality, osmolarity etc.,
all of which are identified as "culture conditions" and can be changed
in Claim 1of the impugned application.
- 2315 do not provide any guidance as to why this feature of "20-80% viable cell
density" is critical.
Anticipation based on US Patent 6,048,728 (hereinafter US'728)
The Opponent submitted that US 6,048,728 in Example 10 discloses a method which
anticipates claim 1of IN 2315. Example 10 teaches the use of a media referred to
as DM40, which encompasses and discloses the media characteristics disclosed
in claim 1of IN 2315. Further, the opponent stated that US ‘728 in Table 1
glutamine c a n be present in DM40 at a range of concentrations and that the
cumulative amount of all amino acids present is 73.38 mM. On the ratio, the
opponent state that the ratio of glutamine to asparagine in DM40 [based again on
the lowest concentration of glutamine in the stated range (8 mM) and the highest
concentration of asparagine in the stated range (10.59 mM)] is 0.76; the cumulative
amount of the specific subset of amino acids defined in claim 1 that is present
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in DM40 is 28.21 mM. The remaining features of claim 1 of IN 2315
accord ing to the opponent are a l so encompassed in the disclosure of US
'728.
Anticipation by GB 2251249 (hereinafter GB 249)
The opponent states that GB 249 describes highly concentrated media for use in high
density cell cultures. Table 1 on page 8 describes a medium called "MBRI 40-03" which
contains 18.9 mM {2500 mg/1) asparagine and. no glutamine. The "MBRI 40-02"
medium contains 3.78 mM (500 mg/1) asparagine and 10 mM (1500 mg/1) glutamine.
Example 4 on pages 14-15 describes culturing of a hybridoma cell line "2c3.1" (further
described on page 9, Example 1) in 250ml Bellco spinner flask used was a
combination of MBRI 40-02 as an initial medium and a feed of MBRI 40-03,
supplemented with 5.13 mM (0.75 g/1) glutamine (page 14, final paragraph). Taking
both of these media and the glutamine supplement into account, the cumulative amount
of glutamine used was 15.13 mM and the cumulative amount of asparagine used was
22.68 mM. It was further submitted that the cumulative total amino acid amount in the
MBRI 40-03 medium alone is approximately 234.8 mM. The cumulative amount of the
particular subset of amino acids defined in claim 1 of IN 2315that is present in the
MBRI 40-03 medium is approximately 67.2 mM (see Table 1 of GB 249). Thus, the
cumulative amount of total amino acids used in the combination of MBRI 40-03 and
MBRI 40-02 in Example 4 of GB 249 will exceed the 70 mM threshold defined in
claim 1. The cumulative amount of the particular subset of amino acids defined in
claim 1 of IN 2315 that is present in the combination of MBRI 40-03 and MBRI 40-
02 in Example 4 of GB 249 also exceeds the 25 mM threshold defined in claim 1. It is
therefore clear that Example 4 of GB 249 defines a method of cell culture using a
medium as defined in claim 1of IN 2315. Further that the addition of the MBRI 40-03 in
Example 4 of GB249 will change the osmolality of the medium used in the culture.
Therefore, Example 4 of GB 249 also discloses the change of culture conditions
described in claim 1of IN 2315.
WO 03/064630 (hereinafter WO '630}
The opponent submits that WO '630 describes a method of culturing GS-NSO cells
which have been transformed with glutamine synthetase, thereby allowing these
cells to grow on glutamine-free media. The Opponent relies upon Example 1 that
discloses a combination of the MBRI 40-02 and MBRI 40-03 media . Further the
Example 1 of WO '630 is carried out in a 10 litre bioreactor (which is "large scale",
under the broad definition of this term as it stands in claim 1of IN 2315). The Opponent
submitted that the batch feed addition will change the osmolality of the culture medium,
which according to IN 2315, is a "change in culture conditions".
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Applicants Submissions
The applicant replied to the ground of anticipation by first explaining the legal
principles. Any prior art document, in order to be an anticipating document, has to
enable a person skilled in the art to perform the invention without exercise of any
inventive ingenuity. The said disclosure has to be an “unambiguous clear and a direct
disclosure (enabling disclosure).” Therefore if the disclosure is not an enabling
disclosure, the said document cannot be said to anticipate the claims of the invention. It
was further submitted that in addition to all elements of the claim being present in a
single document for the purpose of establishing anticipation, the said elements have be
arranged in the prior art as in the claim. [Net MoneyIn v. Verisign (Fed. Cir. 2008)];
[Lallubhai Chakubhai Jariwala Vs. Chimanlal Chunilal and Co. [AIR1936Bom99], para
10 that states that even where the prior document and the present specification are
identical or nearly identical in language, it does not necessarily follow that the Court
must conclude that the first is an anticipation of the second. Some foreign cases were
also relied upon as well as IPAB order in India in Ideal Cures Vs. M/S.Colorcon Ltd
Paras 30-37.
On the documents, the applicant stated the following:
a. WO 02/101019
That WO’019 discloses that cell viability can be improved by controlling the
osmolality and production of waste products, such as lactic acid, during culturing of
mammalian cells. The teaching of this document is to use of relatively low amounts of
glucose in the culture medium, e.g., less than about l g/L. The document therefore
focuses entirely on the concentration of glucose. It was further submitted that the
principle objection of WO ‘019 is related to the effects of glucose concentration in the
media and glucose concentration is considered to be a critical factor in WO ‘019.
Nowhere does the document speak of or discloses the significance of total amino acid
concentration or the ratio of glutamine to asparagine or the total amount of the specific
sub-set of eight amino acids. In the absence of an enabling disclosure of the same,
anticipation of 2315 cannot be asserted. Furthermore, it was submitted that WO ’019
does not disclose that the culture conditions are to be changed when the viable cell
density is 20-80% of the maximum viable cell density possible to achieve the desired
protein titers.
The information provided in the WO ‘019 is insufficient for the calculation of
cumulative amounts per unit volume or cumulative molarity of any of the media
components or the total cumulative amino acid concentration, or the concentration of the
sub-set of eight amino acids, or the molar cumulative glutamine to cumulative
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asparagine ratio. In fact asparagine or cumulative amount per unit volume of total amino
acids or cumulative molarity of the subset of eight amino acids have not even been
discussed anywhere in the document.
The applicant further submitted that glutamine is referred to in the document but mention
is not in respect of asparagine as the document studies glutamine in respect of glutamate
(ratio of glutamine to glutamate is discussed and not glutamine to asparagine). Also
according to WO ‘019, the amount of glutamine can even be zero ( page 28, 3rd
paragraph. Further, on page 41, example 4 discloses that “Thus, Fig. 4 shows that 5 mM
glutamate (at OmM glutamine) leads to the lowest level of by-product accumulation
(shortest vertical bars at low NH +concentration) regardless of the culture temperature.”
According to the applicant, WO ‘019 teaches away from adding glutamine to the
medium, glutamine is an essential medium ingredient of the invention claimed in the
‘2315 application.
The applicant further stated that the opponent incorrectly calculated the cumulative
amounts/ molarity from Medium A and Medium B provided on pages 31 and 32 of WO
02/101019. The Applicant submitted that the opponent has arrived at the said three
media conditions by way of hindsight as there is no explicit or direct disclosure in WO
02/101019 to have the said three conditions. Moreover, not a single media satisfies all
three media conditions claimed in ‘2315.
In fact, it was submitted that the document does not provide sufficient information for a
person of ordinary skill in the art to calculate the cumulative values as the ratio or
relative or exact volumes of the feed and batch media are not provided in said document.
The Opponents’ counsel and their experts tried to compare the cumulative values
claimed in IN‘2315 with the molarity of the basal media, ignoring the fact that the
addition of feed media will change the cumulative molarity. Further, the Opponent
ignored the fact that the addition of feed does not always increase the cumulative
molarity as molarity is an inverse function of volume and with the addition of feed there
is an increase in volume too.
The calculation of 13.86 mM that will rise to above 25 mM is incorrect as the data
provided in WO ‘019 is not sufficient to calculate the cumulative amounts. From the
disclosure in example 1. Page 33 of ’019 the opponent assumed that the addition of the
feed would results in an increase in initial medium components by 30% which is
incorrect for the following reasons:
1. The data provided in example 1 is insufficient to simply assume an increase in
all initial media components by 30%. WO ‘019 discloses that “initial media
components” are in concentrated form, but does not say whether these initial
media components include amino acids, and if they do, how concentrated they
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are. WO’019 also teaches that the batch feed can contain peptone, glucose,
trace elements, and glutamine. Again, it is not disclosed anywhere if the initial
media ever contains any other amino acids, and if so, at what concentrations.
2. Further, the concentrations of peptone, glucose, trace elements, or glutamine in
the batch feed are also not disclosed.
3. The volume at which the batch feed was added is also not disclosed.
4. To calculate any of the values that are claimed in ‘2315 from the disclosure of
WO ‘019 one must assume that either (1) no other amino acid besides
glutamine is in the batch feed, and that introducing the batch feed dilutes the
initial medium, and thereby lowers the cumulative total amino acids per L and
cumulative asparagine per L, or (2) the presence of any other amino acids
besides glutamine that might be in the batch feed were irrelevant to the
invention.
5. Also, peptone which may be a part of the batch feed is an undefined media
component which when included in the composition will make it difficult to
determine the exact cumulative amounts.
Further, as per 2315, large scale cultures are described, e.g., at paragraph [0091] of
‘2315, which states, at least 500 liters and may be 1000, 2500, 5000, 8000, 10,000,
12,0000 liters or more, or any volume in between. Thus, large scale cultures have a
volume well above 3 L.
US 6048728
US 6048728 concerns the use of a Primary Supplement (protein-free) which has an
alleged synergistic combination of media components including glutamine, phospholipid
precursors, tryptophan and additional amino acids as required for a particular cell line or
product to be produced
US 6048728 does not disclose at least the following combination of critical aspects of
2315/DELNP/2007:
• A method for the large/ commercial scale production of polypeptides.
• The combination of medium characteristics recited in the claims (i.e., a
cumulative amino acid amount per unit volume greater than 70 mM, a molar
cumulative glutamine to cumulative asparagine ratio of less than 2, and a
cumulative total amount of histidine, isoleucine, leucine, methionine,
phenylalanine, tryptophan, tyrosine, and proline per unit volume greater than 25
mM).
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• Change in culture conditions when the viable cell density is in the range of 20-
80% of the maximal possible viable cell density. Example 10 makes it clear that
in the described method, pH and temperature are controlled (see column 22, line
32 – pH controlled at 7.0+/-0.05; and lines 34-35 – temperature controlled at
36.5+/-0.3C). Therefore, the experiments of US 6048728 do not require a shift in
culture conditions.
The Opponent suggested that addition of batch feed in Example 10 represents a change
from a first set to a second of culture conditions and would result in a change in
osmolality which will amount to a shift in culture conditions. The applicant state that this
is incorrect
Further the calculations done by Dr. Bandyopadhyay are incorrect and the expert has not
correctly applied and understood the term “cumulative”.
It was submitted that the molar ratio of glutamine to asparagine calculated by the
Opponent as being less than 2 is only one of the thousands of ratios possible from the
given range of glutamine concentration of 8-40mM. In fact if we take the highest
concentration of glutamine from the range provided in table 1 and calculate the molar
glutamine to asparagine ratio (using concentrations of 700mg/l and 1400 mg/l of
asparagine), the ratio turns out to approximately 8 and 4 which are way above 2. Thus
there is no disclosure with respect to a molar glutamine to asparagine ratio of less than 2.
F
u
r
t
her, it was submitted that the total amino acid amount or total amount of the subset of
eight amino acids claimed have been calculated by the Opponent by considering the
highest concentration of the amino acids, which gives results for only one of the
thousands of amounts possible from the given ranges. In fact if we take the lowest
concentration from the range provided in table 1, the amount turns out to be lower than
the claimed amounts. Thus, there is no disclosure of the total amino acid amount per unit
volume of greater than 70mM or the total cumulative molarity of the sub-set of eight
amino acids greater than 25mM.
It was also submitted that nowhere does the document speak of or discloses the
significance of total amino acid concentration or the ratio of glutamine to asparagine or
the total amount of the specific sub set of eight amino acids. In the absence of such
disclosure, the allegation of anticipation of the claims of ‘2315 in view of US 6048728 is
unsustainable.
Summary (based on
US6048728, DM40,
example 10)
Opponent’s
calculation
Applicant’s
calculation
Cumulative Gln: Asn 0.76 2.8
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c. GB2251249
It was submitted that ‘2315 does not lack novelty in view of GB 2251249 as said
document does not disclose at least the following combination of critical aspects claimed
in ‘2315:
• A method for the large/ commercial scale production of polypeptides.
• Change in culture conditions when the viable cell density is in the range of 20-
80% of the maximal possible viable cell density.
• The combination of medium characteristics recited in the claims (i.e., a
cumulative amino acid amount per unit volume greater than 70 mM, a molar
cumulative glutamine to cumulative asparagine ratio of less than 2, and a
cumulative total amount of histidine, isoleucine, leucine, methionine,
phenylalanine, tryptophan, tyrosine, and proline per unit volume greater than 25
mM).
It was submitted that in alleging lack of novelty, the Opponent alleged that the
cumulative amounts of various medium components claimed in ‘2315 were disclosed in
Example 4 of GB 2251249. The Opponent’s calculations again were incorrect and
cannot be followed for two reasons. First of all, the description of Example 4 does not
clearly describe the relative proportion of starting medium (MBRI 40-02) and feed
medium (MBRI 40-03) used in the cell culture process. Therefore, it is not possible to
calculate the cumulative amounts.
Secondly, the Opponent provides calculations for the media employed in Example 4 of
GB 2251249 which cannot be correct in any case. In calculating cumulative amounts of
glutamine and asparagine used in this example, the Opponent simply assumes that the
amounts of glutamine and asparagine in the two media should be added together. As
demonstrated in the preceding paragraphs, this is incorrect. Combining two media would
dilute the relative proportions of components in each (volume changes and molarity is
a function of volume).
In so far as volume is concerned, the size of the culture flask mentioned in said example is
250ml which was used for building the inoculum. Said volume can definitely not be
considered “large-scale”. The extrapolation of prior art based on knowledge of the present
invention (IN ‘2315) cannot be allowed. The applicant further stated that GB 2251249
does not disclose anything with respect to the change in osmolality with the addition of
feed media.
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In GB 2251249 according to the applicant Thus, MBRI 40-02 and MBRI 40-03 media
were designed to have equivalent osmolalities. The applicant therefore stated that neither
the change in culture conditions is taught by GB 2251249 nor, the importance of change in
culture conditions as being a critical factor for improved protein yield. GB 249 also does
not disclose a change in culture conditions when the viable cell density is 20-80% of the
maximal possible viable cell density.
d. WO 03/064630
It was submitted that ‘2315 does not lack novelty in view of WO 03/064630 as said
document does not disclose at least the following combination of critical aspects claimed
in 2315:
• A method for the large/ commercial scale production of Polypeptides.
• Change in culture conditions when the viable cell density is in the range of 20-
80% of the maximal possible viable cell density.
It was submitted that the Opponent relied on Example 1 of WO 03/06430 and stated that
said document describes the media characteristics claimed in claim 1 of ‘2315. GB
2251249 was cited in another section of WO 03/06430 as one document disclosing
media, the Opponent concluded that Example 1 could be performed using a combination
of MBRI 40-02 and MBRI 40-03 media described in GB 2251249. This disclosure in
WO 03/6430 does not anticipate the claims of ‘2315. In WO 430, GB 225149 is not the
only citation provided as a source for cell culture media formulations. WO 03/06430
also cites EP 425911 and EP 229809 as documents which describe media, among other
sources
WO 430 does not disclose large scale up process nor does it describe the specific feed
medium used, and whether a change in osmolality occurred with the addition of feeds in
the fed-batch process.
In addition to the above submissions, the applicant also made certain submissions on
specific issues:-
Significance of the 20-80% viability value in the claims
• The Applicant submitted table calculating the viable cell density when the
temperature shift is performed in terms of percentage of the maximum possible
viable cell density from the data provided in Figure 66.
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• The viable cell density when the temperature shift was performed when
calculated from the data provided in figure 66 spans over the claimed range of
20-80% of the maximum possible viable cell density. The significance of the
value of 20-80% of the maximum possible viable cell density cannot and should
not be assessed alone and the whole claim has to be taken in totality.
• That the shift in culture conditions is done towards the end of culturing process
when the viable cell density reaches nearly 100%. However, in the invention
claimed in IN ‘2315, if the media characteristics claimed are maintained, the
objective of the invention can be achieved when the metabolic shift in the culture
is performed when the viable cell density of the culture is anywhere between
about 20% to 80% of the maximal possible viable cell density. The value
therefore is of significance if the process is taken in totality.
• The Opponent further misinterpreted the specification of IN ‘2315 and contested
that the specification and the claims are contradictory as the specification
provides shift be anywhere between 1 to 99 %. It was submitted that the
paragraph that the Opponent refers to on page 31 is just one embodiment of the
invention claimed in ‘2315. Further, said paragraph only provides that the cells
may be grown to a viable cell density from 1 % to 99%. It however, does not
state that the shift in culture conditions has to be performed in this range.
• Further, the passage on page 32 which states that the timing of culture shift will
be determined by the practitioner based on the polypeptide or protein production
requirement does not indicate that the timing of temperature shift is state of art.
The range of 20-80% has been provided in the claims and also in the
specification as indicated in figure 66 and the skilled person to whom the
Condition reference Viable density at temp shift
Maximum Viable cell density
% of viable cell density at temperature shift of maximum possible viable density
Std seed 5 x 106 1.1x107 5/11 45.4 hi speed 6.5x106 1.3 x107 6.5/13 50 Lower levels of inductants
5 x 106 1.25x107 5/12.5 40
No HMBA 5.1x106 1x107 5.1/10 51 No chemical induction 5.6X106 1.9X107 5.7/19 29.4 Lower levels of cys c-c 4.8x106 9x106 4.8/9 53.3 Low levels of cys c-c, 2 step, 2 step temp shift
5x106 9.2X106 5/9.2 54.3
15
specification is addressed can from within the claimed range select the exact time
point for the shift in culture for a particular polypeptide and culture growth etc.
1L is large scale
It was further submitted that the invention claimed in IN ‘2315 demonstrates scaling up
of the process claimed and verifies that results like high titer, low waste, high cell
density and viability can be achieved in an intermediate scale as well as a large scale
bioreactor. Similar scaling up experiments have not been provided in even a single prior
art document.
Addition of feed leads to shift in culture condition
• An important feature of claim 1 of ‘2315 is that the media conditions are shifted
when the viability of the cells is between 20-80% of the maximum possible
viable cell density. It was further submitted that the Opponent assumed that a
shift in culture conditions would take place whenever a feed is added to the
medium. This assumption, however, like all other assumptions of the Opponent
is incorrect and has been made even for those prior art documents which
explicitly mention that the pH and osmolality of the culture has to be maintained.
It was further submitted that the Opponents have incorrectly analyzed the prior
arts cited by them to suit their case.
• ‘2315 makes it explicitly clear that the addition of feed and the shift in culture
are two separate independent steps. In fact, as the invention claimed in ‘2315 is
also workable using batch culture where feeds are not added, the shift in culture
conditions will still be applied when the cell density reaches 20 to 80% of the
maximal possible viable cell density.
Incorrect way of calculating cumulative molarity
Decision
• Applying the legal principles of novelty, I am of the opinion that there is neither an
unambiguous clear and a direct disclosure of the claims of the invention nor all the
features of the claim are present in the same order in a prior document as present in the
claim. I have also gone through the specification of IN 2315 and am of the opinion that
the cumulative molarity has been defined in the patent specification as also volume
of a large scale reactor. None of the prior art documents are in relation to
1. A method for the large/ commercial scale production of
polypeptides.
2. The combination of medium characteristics recited in the claims
(i.e., a cumulative amino acid amount per unit volume greater
16
than 70 mM, a molar cumulative glutamine to cumulative
asparagine ratio of less than 2, and a cumulative total amount of
histidine, isoleucine, leucine, methionine, phenylalanine,
tryptophan, tyrosine, and proline per unit volume greater than 25
mM).
3. Change in culture conditions when the viable cell density is in the range of
20-80% of the maximal possible viable cell density.
• In so far as WO 02/101019 is concerned the said document is in relation to
cell viability that can be improved by controlling the osmolality and
production of waste products, such as lactic acid, during culturing of
mammalian cells. This document is in relation to the use of relatively low
amounts of glucose in the culture medium, e.g., less than about l g/L. The
document therefore focuses entirely on the concentration of glucose. This
document does not discuss or discloses the significance of total amino acid
concentration or the ratio of glutamine to asparagine or the total amount of
the specific sub-set of eight amino acids. Further, the cumulative amounts /
molarity of the media components cannot be calculated from WO ‘019
• US 6048728 is in relation to the use of a Primary Supplement (protein-free)
which has an alleged synergistic combination of media components including
glutamine, phospholipid precursors, tryptophan and additional amino acids
as required for a particular cell line or product to be produced and does not
disclose or discuss the features of the invention of IN2315
• GB 2251249 does not disclose the combination of critical aspects claimed in
‘2315 such as large/ commercial scale production of polypeptides; Change in
culture conditions when the viable cell density is in the range of 20-80% of the
maximal possible viable cell density and the combination of medium
characteristics i.e., a cumulative amino acid amount per unit volume greater
than 70 mM, a molar cumulative glutamine to cumulative asparagine ratio of
less than 2, and a cumulative total amount of histidine, isoleucine, leucine,
methionine, phenylalanine, tryptophan, tyrosine, and proline per unit volume
greater than 25 mM.
• WO 03/064630 also does not disclose the critical aspects of 2315 as discussed
above
• The claims have to be seen in the light of the disclosure made in the patent
specification. It is well known to a person skilled in the art that media
conditions concentration and other parameters are critical for protein
development.
17
• Therefore, the claims of Indian Patent Application no. 2315/DELNP/2007
are novel and do not lack novelty in view of documents cited by the
Opponent.
• The ground taken by the opponent under Section 25(1)(b) is therefore
dismissed.
THE GROUND OF OBVIOUSNESS
Opponents submissions
The Opponent relied upon the Windsurfing test (1985 RPC 59 at 60-61, 73-74) was
established as a standard for assessment of obviousness in India.
The Opponent relied on the following documents to show lack of inventive step:-
• W0’019
• US 6048728;
• GB 225149
• WO 03/064630; and
• Kurano et al
The Opponent also relied on the evidence of Dr. Suman, Dr. Angelo Perani, Dr. Velu
Mahalingam. In addition to the above 5 documents, the following three additional
documents were relied upon by Dr. Velu Mahalingam:-
1. Fox et al.
2. Newsholme et al.
3. Nyber at al.
The Opponent stated that inventive feature of a specific glutamine to asparagine ration
was already disclosed in the cited art. IN 2315 states that the ratio of glutamine to
asparagine in the culture medium should be maintained at a low level ·IN order to
reduce the accumulation of ammonium (see, page 26, lines 6-8 and page 27, lines 2-5).
However, the partial substitution of glutamine with asparagine in order to reduce the
accumulation of ammonium was known in the art before the earliest priority da te of
IN 2315 Specifically, W0’019 on page 39, second. paragraph; column 6, line 40 to
column 7, line 4 of US 6,048,728; page 10, lines 24-31and page 11, lines 11-13 of WO
03/064630; and Kurano etal all disclose this feature. The Opponent further submitted as
follows:
- that the use of cell culture media containing high concentrations of amino
acids in order to increase titer of a protein produced in that cell culture was known
18
in the art before the earliest priority date of IN 2315 (see, e.g., US '728; GB '249; and
page 10, lines 3-19 of WO '630).
- The amounts of amino acids defined in claim 1of the impugned application were
clearly an arbitrary choice.
- Claims of IN 2315 would be clearly obvious over WO '019 and common general
knowledge. T h e o p p o n e n t s t a t e d t h a t even if W O '019 is not considered to
explicitly recite the total, cumulative amounts of all amino acids used in the second
set of experiments described therein, a skilled person would have been able to
calculate these final concentrations as a matter of routine.
- Kurano shows the effects of medium components and waste products in a loop
bioreactor. Kurano advocates at least partially substituting glutamine with asparagine in
CHO cell culture media in order to reduce the amount of toxic ammonia produced
during cell culture.
- The opponent further stated that WO 019 teaches that a medium having a starting total
amino acid concentration of greater than 70 mM ("Medium A" in W0019) should be
used.
- The use of culture media containing high concentrations of amino acids was generally
known to be advantageous in cell culture processes, particularly those which were
intended to be carried out in culture volumes of 500 liters or more as explained by
Dr. Perani
- Dr. Perani in his affidavit s t a t e s t h a t a person of ordinary skill would not believe
or assume that glutamine would be completely removed from mammalian cell
cultures (e.g., CHO cell cultures) because of the critical role glutamine plays in the
majority of metabolic pathways in these cells. As Dr. Perani states, cells are placed
at a high risk of cell death if the concentration of glutamine in the culture medium
drops to below approximately 1 mM.
It was further submitted that no comparative data has been provided in the
Application which might indicate the effect of removing one of the claimed subset of
amino acids from the culture medium, or of increasing the amount of another amino
acid which is not defined in the subset.
It was further submitted that the application also does not show any particular
technical effect of changing the culture conditions when the viable cell density is 20-
80% of the maximum possible viable cell density.
APPLICANT RESPONSE TO OBVIOUSNESS
With regard to the allegations made by the opponent that there is no data in the
specification which is unexpected, the applicant submitted that IN ‘2315 went
provides 17 examples and 76 figures in the complete specification which provide
extensive details on the medium characteristics, culture process, data with regard to cell
19
density, cell viability, titer etc and explain the complete inventor’s story regarding the
invention and the significance of each of the claimed values. With regard to the
allegation of the invention being only optimization of culture or medium conditions,
the applicant stated that the opponent have analyzed the obviousness of the present
application by hindsight. The applicant stated that large scale production of polypeptides
has not been disclosed in any of the cited prior art documents; the significance of the
cumulative amino acid amount per unit volume being greater than 70mM; molar
cumulative glutamine to cumulative aspargine ratio less than 2; cumulative total amount
of histidine isoleucine, leucine, methioxine, phenylalanine; tryptophan, tyrosine and
proline per unit volume of greater than 25nM has not been provide in any of the prior art
documents; that the calculations of the cumulative value claimed in the present
application made by the opponent is in hindsight from the different media provided in
the prior arts as POSA would not have been able to arrive at the claimed values on the
priority date without the knowledge of the present application.
The claimed media characteristics when used for culturing at large scale and the shift in
culture condition is performed when the cell viability reaches in the range of 20-80% of
the maximal possible viable cell density, improved results in terms of cell density,
viability, product titer and reduced waste product is achieved even at large scale. These
aspects are neither disclosed, nor suggested in any of the prior arts.
None of the prior art talk about a glutamine ratio nor its significance with respect to
asparagine and therefore do not study the significance of the glutamine asparagine ratio.
None of the prior art talk about the total amino acids or the amino acid sub-set amount.
The criticality of keeping the cumulative amounts above 70mM and 25 mM respectively.
WO 02/101019 does not provide any hint as to the claimed ratio of glutamine and
asparagine. In fact, WO 02/101019 does not even mention asparagine other than in the
list of media components in Table 1. Furthermore, the actual data provided in WO
02/101019, and the conclusions drawn in this prior art do not support the Opponent’s
assertions.
Example 3 of WO 02/101019 to the contrary inter alia offers the solution to add glucose
to increase osmolality (WO 02/101019, p. 39, line 29 to p. 40, line 2). In the same set of
experiments, it is again mentioned in this context that “glutamine did not have a
significant impact on titer” Thus a person skilled in the art would conclude that
glutamine is not an essential media component so far as the product titer is concerned.
It was further submitted that Example 4 of WO 02/101019 teaches that “Fig. 4 shows
that 5 mM glutamate (at 0 mM glutamine) leads to the lowest level of by-product
accumulation” (WO 02/101019, p. 41, lines 25-26). This statement is confirmed in that
“other researchers have reported generation of minimal quantities of lactate and
20
ammonium upon substitution of glutamine with glutamate” (WO 02/101019, p. 41, lines
27-28).
Based on this a person skilled in the art will conclude that glutamate can replace
glutamine in culture media or may work a ratio of glutamine relative to glutamate for
optimal protein titers instead of a cumulative glutamine to asparagine ratio.
It was further submitted that Fig. 1 suggests that the fourth set of experiments, i.e.,
Example 4 and a POSA would aim at a glutamine free media instead of a media
comprising glutamine as claimed in ‘2315.
The applicant stated that if the main goal would have been to reduce ammonium and/or
lactate levels, the person of ordinary skill in the art, starting from WO 02/101019, would
have replaced glutamine by glutamate, as glutamine was anyway not found highly
relevant for product titer (cf. WO 02/101019, Example 2, as discussed above). In
consequence, one would have to conclude that WO 02/101019 teaches away from the
solution provided by the application.
It was further submitted that in conclusion, regardless of whether the technical problem
solved by the present application is construed in a narrow or broad manner WO
02/101019 teaches away from the specific solution offered by claim 1 and its dependent
claims. Starting from WO 02/101019, the skilled person would hence not have arrived
at the invention of ’2315, but presumably at a different solution, i.e., a process for
producing any protein in any animal cell not containing glutamine.
It was further submitted that there is even less of a suggestion in WO 02/101019 that any
relative amount of glutamine is to be used. By no means is it anywhere recognized, let
alone specifically indicated that the maximal ratio or minimum cumulative total amount
of glutamine and asparagine as defined in claim 1 of ‘2315 would be of any importance.
The relevance of asparagine levels is not even mentioned by WO 02/101019.
The skilled person would have furthermore noted from WO 02/101019 that the amount
of glucose is of central importance in achieving high product titers (which is closer to the
actual technical problem of the application) rather than focusing on optimizing the
glutamine to asparagine ratio, or any of the media characteristics referred to in claim 1 of
‘2315, the skilled person would have therefore tried to work on the amount of glucose
when seeking to solve the technical problem underlying the application.
The Opponent cited US 6048728 at col. 6, line 40, to col. 7, line 4, as showing that the
importance of the glutamine/asparagine ratio was known. The applicant states that this
para makes no mention of asparagine other than as a possible substitute for glutamine.
21
WO 03/064630, page 10, lines 24-31, and page 11, lines 11-30 does not show that the
importance of the glutamine/asparagine ratio was known. None of these passages
suggest a ratio of glutamine to asparagine. It is only mentioned that glutamine may be
partially substituted by asparagine.
Kurano et al., does not teach or suggest either alone or in combination with WO
02/101019 the invention claimed in ‘2315. Kurano et al. does not make up for the
deficiencies in disclosure of WO 02/101019. Kurano et al. simply investigates the effect
of factors like medium components and metabolic by-products on growth of CHO cells
and carries out studies on glutamine degradation and ammonia formation. In fact,
Kurano et al., teaches away from the ‘2315 invention by teaching that glutamine can be
advantageously removed and replaced.
US 6048728 teaches a wide range of glutamine concentrations. No particular attention is
given to the glutamine to asparagine ratio, nor to total cumulative amino acid
concentration per unit volume.
GB 2251249 discloses media in which nearly all nutrient components in RPMI 1640
medium were simply multiplied. For example, in MBRI 40-02 medium, the nutrient
components of RPMI 1640 were fortified ten times. In MBRI 40-03, the nutrient
components of RPMI 1640 were fortified 50 times (see GB 2251249, page 7, lines 23-24
and page 7, line 26, to page 8, line 1). There is no suggestion to achieve particular ratios
or concentrations of given subsets of amino acids.
US 6048728 neither alone nor in combination with any of the other documents teaches
or suggests the invention claimed in ‘2315.
The applicant further submitted that the molar ratio of glutamine to asparagine calculated
by the Opponent as being less than 2 is only one of the thousands of ratios possible from
the given range of glutamine concentration of 8-40mM. Based on the calculation’s made
by the Applicant, the ratio turns out to approximately 8 and 4 which are way above 2.
Thus there is no teaching with respect to a molar glutamine to asparagine ratio of less
than 2.
GB 2251249 relates to the development of a balancedly-fortified high-density media for
animal cell culture and the achievement of high density suspension culture using said
media. It was further submitted that the calculation of ratio of molar cumulative
glutamine to asparagine from example 4 is one of the many ratios of cumulative
glutamine to asparagine possible from said patent application and there is no significance
whatsoever, indicated for the molar cumulative glutamine to asparagine ratio in the
application to motivate a person skilled in the art to use said ratio.
22
It was further submitted that Opponents have again failed to appreciate the concept of
cumulative molarity and ignored that it is a function of volume due to which they have
produced incorrect calculations for cumulative molarity/ amounts per unit volume. This
patent document is not relevant as it does not even provide the least of any hints to arrive
at the invention claimed in ‘2315
The applicant submitted that there is no teaching in GB 2251249 with respect to the
change in osmolality with the addition of feed media unlike what was alleged by the
Opponent. Change in culture conditions is not taught by GB 2251249. More
significantly, the relevance of change in culture conditions at the defined viable cell
density of 20 to 80% of the maximal possible viable cell density is not taught by said
document nor has a change in culture conditions been presented as a critical factor for
improved protein yield.
The applicants rebuttal to the opponents arguments made in the rejoinder with
respect to new documents
a. Fox et al. – It was further submitted that the Opponent relied on this publication to
show that the prior art discusses the effect of temperature shift in the production of
recombinant proteins.
b. Newsholme et al.- It was further submitted that the Opponent relied on this
publication to support their stand that the prior art teaches that glutamine is an important
precursor for peptide and protein synthesis, amino sugar synthesis, nucleotide synthesis
etc. Therefore, glutamine would not be completely replaced/removed by a person skilled
in the art and would be limited and substituted by aspargine.
c. Nyberg et al.- It was further submitted that the Opponent relied on this publication to
state that the prior art shows that glutamine starvation can limit glycosylation, which is
clearly an important factor for some proteins. Therefore, glutamine would not be
completely replaced/removed by POSA and would be limited and substituted by
aspargine.
It was further submitted that the aforesaid submissions of the Opponent are based on an
improper understanding of the state of the art and are incorrect. Temperature shift in
culture conditions is known and has been studied in the state of the art. However, what is
claimed in ‘2315 is not merely a temperature shift in culture conditions. ‘2315 claims a
process for large scale production of polypeptides, in which certain media characteristics
have to be maintained during culturing and with these media characteristics the culture
conditions are shifted when the viable cell density reaches 20-80% of the maximum
possible viable cell density. In obviousness analysis the complete claim has to be seen in
23
totality and if assuming that one feature is known from one document and second known
from the other, it is not enough to say that these may be combined. there has to be a
motivation, or a thread, linking the documents to combine the feature from the two
documents. It was further submitted that the media characteristics claimed in the present
application have not been known and when these are maintained, the culture shift in the
culturing process may be done when the viable cell density is in the range of 20-80% of
maximum possible viable cell density to achieve the desired results. The same has not
been taught or suggested by any of the prior art publications.
It was further submitted that, as far as glutamine and its importance are concerned, it is a
known fact that the 20 essential amino acids including glutamine are essential and
therefore have been termed so, this is the state of art. This does not in any way suggest
that they should always be present in cell culture media, or if they are present then in
what ratio with what other ingredients would they produce good results. The cited
documents do not suggest that the cumulative ratio of glutamine to asparagine has to be
maintained at a level of below 2. Absent any teachings on the aforesaid characteristics,
the prior art does not motivate, teach or suggest the invention claimed in ‘2315.
Decision:
I have heard both the parties and considered the opposition, evidence and submissions. In my
opinion, the allegation of obviousness is based on an incorrect reading of the prior art
documents as well as the invention. Also I am of the opinion that all the discussions of the
opponent have been made in hindsight which is impermissible in law. Furthermore, the
opponent failed to read the teaching of the prior art document as a whole and I see that there
are documents that teach away from the invention of 2315
2315 provides 17 examples and 76 figures in the complete specification which provide
extensive details on the medium characteristics, culture process, data with regard to cell
density, cell viability, titer etc. There is not teaching suggestion or motivation in any of the
prior arts either alone or in combination that relates to large scale production of
polypeptides; the significance of the cumulative amino acid amount per unit volume being
greater than 70mM; molar cumulative glutamine to cumulative aspargine ratio less than 2;
cumulative total amount of histidine isoleucine, leucine, methioxine, phenylalanine;
tryptophan, tyrosine and proline per unit volume of greater than 25nM. The calculations of
the cumulative value claimed in the present application made by the opponent is incorrect
and made hindsight from the different media provided in the prior arts
WO 02/101019 does not provide any hint as to the claimed ratio of glutamine and
asparagine. From WO 02/101019 it is clear that a POSA would conclude that
glutamine is not an essential media component so far as the product titer is
24
concerned and that glutamate can replace glutamine in culture media as glutamine
was anyway not found highly relevant for product titer (instead of a cumulative
glutamine to asparagine. The skilled person would have furthermore noted from
WO 02/101019 that the amount of glucose is of central importance in achieving
high product titers. US 6048728 also makes no mention of asparagine other than as
a possible substitute for glutamine. US 6048728 also does not provide any teaching
with respect to the glutamine to asparagine ratio or to total cumulative amino acid
concentration per unit volume. WO 03/064630, does not show that the importance
of the glutamine/asparagine ratio was known but mentions that glutamine may be
partially substituted by asparagine. Kurano et al. read with WO 02/101019 does not
render the claims of invention 2315 as obvious. Kurano et al studies the effect of
factors like medium components and metabolic by-products on growth of CHO
cells and carries out studies on glutamine degradation and ammonia formation.
This document teaches away as it suggest that glutamine can be advantageously
removed / replaced.
GB 2251249 discloses balanced-fortified high-density media in which nearly all
nutrient components in RPMI 1640 medium were fortified ten times in MBRI 40-02
medium and 50 times in MBRI 40-03, the nutrient components of RPMI 1640 were
fortified 50 times. This document also does not discuss the change in culture
conditions or the relevance of change in culture conditions as a critical factor for
improved protein yield.
In so far as Fox et al.; Newsholme et al. and Nyberg et al are concerned none of
these documents disclose the invention either alone or in combination with other
prior art documents
2315 claims a process for large scale production of polypeptides, in which certain
media characteristics have to be maintained during culturing and with these media
characteristics the culture conditions are shifted when the viable cell density
reaches 20-80% of the maximum possible viable cell density.
I agree with the Applicant that in obviousness, the invention has to be seen as a
whole and if one feature is known from one document and second known from the
other, it is not enough to say that these may be combined. There has to be a
motivation, or a thread, linking the documents to combine the feature from the two
or more documents. The media characteristics claimed culture shift in the culturing
process may be done when the viable cell density is in the range of 20-80% of
maximum possible viable cell density to achieve the desired results are not taught
or suggested by any of the prior art publications. The cited documents do not
suggest that the cumulative ratio of glutamine to asparagine has to be maintained
25
at a level of below 2. Absent any teachings on the aforesaid characteristics, the
prior art does not motivate, teach or suggest the invention claimed in ‘2315.
Thus m I conclude that WO’019, US’728, GB’149, WO’630, kurano et al., fox et al.,
Newsholmes et.al., Nyber et al. alone or in combination, do not render 2315 as obvious.
WO’019, US’728, GB’149, WO’630 do not disclose the medium characteristics claimed in
claim 1 of ‘2315. The cumulative amounts cannot be calculated from said documents as
details with regard to the feed medium/feed/starting media concentrations are missing.
WO’019, US’728, GB’149, WO’630 documents do not disclose the significance of any of the
media characteristics nor shifting culture conditions when the viable cell density is in the
range of 20 to 80% of maximum possible viable cell density. Further, experimental volumes
in ml, or 1L to slightly higher cannot be considered to teach a large scale culturing process
as presently claimed. Even , kurano et al., fox et al., Newsholmes et.al., Nyber et al. do not
overcome the shortcomings of WO’019, US’728, GB’149, WO’630. Even if glutamine has to
be present in the media, the cited documents do not suggest the relevance of the cumulative
glutamine to asparagine ratio. There is also no motivation , suggestion in any other
document to combine the media characteristic with a shift in culture conditions when the
viable cell density is 20-80% of the maximum viable cell density.
The inventor, Dr. Denis Drapeau has explained the significance of the media characteristics
which is demonstrated in the examples of the specification, such significance is not
suggested, in any prior art. Thus there is no suggestion or motivation or teaching in any
prior art of the relevance of the cumulative glutamine to asparagine ratio, cumulative total
amino acids per unit volume or cumulative molarity of the sub- set of eight specific amino
acids used in combination with shifting the culture conditions when the viable cell viability
is 20-80% of maximum possible viable cell density. This ground is therefore dismissed and
I hold that the claims of IN 2315 have inventive step and are non-obvious.
GROUND - NOT AN INVENTION
It was submitted by the Opponent that claims 1-52 do not constitute an invention under
section 2(1)(j) of the Act.
It was submitted by the Opponent that the Applicant admits that the polypeptide
a l l e g e d l y obtained at the end of the process of impugned claim 1is otherwise
known. The allegedly novel and critical feature of 'large scale' merely defines the
quantum, and not any novel characteristic of the product. The allegedly novel and
critical feature of change of culture conditions is exactly that- a change in culture
conditions. It is not a new product or a new reactant. Simply put, a change in pH,
osmolality, or temperature doe s not qualify as either a new product or a new
reactant. For this reason alone, the second allegedly novel and critical feature of the
alleged invention also falls foul of the prohibition of Section 3(d)
26
The applicant rebutted by submitted that the claims of the instant application are not only
novel but also inventive in view of the cited references. All the arguments made for
novelty and inventive step were relied upon.
Decision: I have already dealt with all the prior art documents and hold that the
invention is novel and inventive. Section 3(d) is also not attracted as the claims of
IN 2315 is not in relation to a new use of a known process but is a combination of
several features and aspects of each step and parameter disclosed therein.
I therefore dismiss this ground of the opposition.
GROUND - INSUFFICIENCY
It was submitted that a complete specification must necessarily fully and particularly
describe the invention and its operation, and must also provide the best method by
which it is to be performed. Indeed, Section 10(4)(b) mandates that the "best
method" be described in detail.
The attention was drawn to the earlier made submissions to show that the
claimed features present in Claim 1of IN 2315 had no support in any of the
Examples. For example, the term 'large scale' was described in two simple lines -
which repeated what was known in the art already, but did not provide any
guidance as to how this would be understood in the context of the impugned invention.
Similarly, the difficulty in construing the term 'cumulative' based on the absence of
disclosure was pointed out, as was the fact that there was no single example which
would actually provide support for each of the features of what is claimed as the
synergistically interacting inventive features of the method.
Example 16 which did not even disclose the volume of the bioreactor- thereby
establishing that there was no significance in the term 'large scale'. Similarly Pfizer
extensively relies on Example 17, but this example does not provide any reference to
any media at all or to any allegedly inventive media conditions. Pfizer argues that
the media of the preceding claims, specifically media 9 is obviously used in
Example 17. However, there is no support for any such assertion in any part of the
preceding written description. On the contrary, if this assertion is to be considered
valid, then equally, any media from any of the cited art could equally be used in the
6000L bioreactor of Example 17 with equally allegedly beneficial effect.
In view of the above, the Opponent submits that the Application completely fails to
provide a sufficient disclosure of the claimed subject matter. Instead, the
27
Application places an undue experimental burden on the person skilled in the art to
determine what cell culture parameters need to be applied in order to achieve any
particularly advantageous effect.
It was further submitted that Pfizer admits that production of a particular protein by
cell culture methods requires the use of cell culture media components which are
specifically tailored to the particular protein being produced. If this principle is
accepted, it must also be accepted that the Examples provided in the application only
provide a sufficient disclosure of the production of the particular proteins described
in the Examples, and no other proteins. In this regard, the Opponent notes that claims
1-48 of the Application are not limited to the production of the specific proteins
described in the Examples.
It was further submitted that that the complete Specification of IN 2315 does not
sufficiently and clearly describe the invention claimed or the method by which it is be
performed.
It was further submitted that Claims 1-52 of the application at hand suffer from lack
of adequate description and are liable to be rejected. The Specification does not
provide adequate teaching to a person skilled in the art to practice the invention. The
particulars thereof are as under:
a) Claim 1 recites a method of producing a polypeptide in a large scale
production in cell culture but suffers utterly with the lack of description of the
process that is the culture condition such as pH, temperature, osmolality, oxygen
concentration etc.
b) In claim 1 it is stated that the first set of culture conditions are maintained to
reproduce a viable cell density of 20-80% wherein the range of viable cell density to be
achieved before setting a second set of culture condition is too broad. The person
s k i l l e d i n t h e art will to have to unnecessarily pe r f or m several
experiments to replicate it.
c) Claim 1 suffers from indefiniteness by claiming a first and second of culture
conditions without the time line being specified.
d) claims 1and 2 are vague and indefinite in their description wherein it recite a
change in one of the culture conditions- but had not outlined what culture
conditions can be altered. Likewise in the same claim it is recited that any two of the
four listed medium characteristics will be selected and again is indefinite as
to exactly what will be the culture conditions.
e) Claim 3 is drawn to the culture without antecedent to claim 1and the claims in
entirety fail to recite the pH and the osmolality of the culture condition.
f) Claims 9-10 are drawn to the initial cell density of mammalian cells (seed
culture) and the range provided is too wide and not definite.
28
g) Claim 13 recites the temperature in the first culture condition is 30-42 and Claim
15 is drawn to the temperature t o be maintained during second culture condition as
25-41and as both the conditions overlap, the applicants are trying to mislead
temperature as one of the condition changed.
h) The growth temperature of any culture medium is very critical, whereas the claims
of impugned application state a mere approximation of the growth temperature of the
medium.
i) Several claims lack technical features and are mere description of the characteristic
feature of the medium (claims 26, 27).
j) Claims are i n c o n s i s t e n t . Claim 1 recites t w o culture conditions with
glutamine and claim 34-49 are with &lycylglutamine for other polypeptide production.
k) At page 45 it is stated that the initial concentration of the nutrient medium is very
high but no toxicity data is provided as how/ when the concentrated medium
itself can be toxic.
It was submitted by the Applicant that the Opponents tried to mix up the ground of
Inventive step and sufficiency and argued that the specification does not elaborate
on the significance of the claimed values. The Opponent argued that the claimed
values are arbitrary and insignificant.
It was further submitted that Opponents have at the outset mixed two different concepts.
For the ground of sufficiency the Applicant only needs to fully and completely describe
the invention for a person skilled in the art to perform the same without the burden of
undue experimentation. The specification of ‘2315 fully describes the large scale
production of at least four Polypeptides, namely, anti-GDF-8, anti-Lewis Y, anti-ABeta
and TNFR-Ig polypeptides.
It was further submitted that the complete specification of ‘2315 describes ingredients
and the reaction parameters for the large scale production of polypeptides. Details of the
bioreactor configuration and the biotechnological process to be performed in a bioreactor
are a part of common general knowledge which a person skilled in the art is familiar
with.
It was further submitted that the complete specification and even the claims fully
describe the medium and cell culture conditions. It was further submitted that figures
provide extensive information on the test results obtained on parameters like the cell
viability, specific ingredient levels, protein titer, lactic acid and ammonium generation
etc. The Applicant is not required to simplify the invention for the infringer to infringe
the invention claimed. The detailed components of the media and the manner in which
the production has to be performed are fully described by way of examples and the
results provided in the figures and this information is sufficient for a person skilled in the
art to work the invention. The inventor also does not have to provide the path followed in
29
arriving at the invention in the specification, although there are ample details in this
regard in the specification of ‘2315. The time point for shifting the culture conditions is
also provided in the specification as well as in the claims. The shift in conditions is
applied when the viable cell density is in the range of from 20 to 80% of maximum
possible viable cell density. Figure 66 completely and clearly elaborates this concept.
Refer to Page 34 to 35 above. The culture conditions which can be altered are also
defined in the dependent claims and in the body of the specification. Therefore, the
specification fully and particularly described the invention to enable a person skilled in
the art to perform the invention without undue experimentation.
Decision:
As the patent specification provides extensive disclosure as well as examples of the
invention, I find it in accordance with Section 10 of the Act and therefore dismiss this
ground of the opponent.
GROUND- SECTION 8
It was submitted that Section 8(2) places an onerous burden on an applicant to
promptly and within time notify the Patent Office of prosecution histories in other
jurisdictions. It is submitted that Applicant avers that it has now supplied copies
of the documents referred to in paragraph 146 to the Patent Office. What is critical
is that Applicant had possession of the documents significantly prior t o the pre-grant
representation, and deliberately did not submit it to the Patent Office.
For example, Applicant had possession of the Canadian office action and
response and claim amendments as far back as 2008. Similarly documents
pertaining to the corresponding Australian application were apparently in their
possession as far back as 2007. Similarly documents pertaining to the Chinese,
European and Japanese applications were in Applicant's possession significantly prior to
the issuance of the First Examination Report on December 1, 2012. However, these
were apparently submitted only along with Applicant's reply to the pre-grant
opposition or shortly there before, and significantly after the six month deadline
stipulated in Section 8(2).
Applicant also signally fails to provide any reasons for this delay, and will no doubt
rely on the tired and worn out excuse of 'being a foreign party'. In this connection,
it is submitted that being a 'foreign party' is no reason for not submitting documents
mandated by law within the stipulated time frame, particularly in this era of electronic
communication.
In particular, Pfizer deliberately failed to inform the Patent Office of the refusal of its
corresponding European applications in opposition proceedings. It is submitted that
this deliberate failure to timely comply with the requirement cannot be overcome by
filing the documents at a belated stage without sufficient and adequate reasons
30
explaining the delay.
It was submitted by the applicant that the Opponent raised an objection on the details of
the corresponding EP applications not having been filed at the IPO which was not
mentioned in their pleadings. The arguments in the oral hearing have to be restricted to
what has been pleaded and cannot go beyond the same. There cannot be any submissions
and any finding on what has not been pleaded. We request the Learned Controller to
kindly disregard any pleadings, in the written and oral submissions which were not part
of the pleadings of the Opponent. Without prejudice to the above, it was submitted that
the Applicant has complied with section 8 of the Act and all details of corresponding
foreign applications have been filed at the Indian Patent Office.
The applicant has provided the Patent Office with the updated details of foreign
applications on Form 3 on several occasions – 17th April 2008, 7th October 2008, 9th
March 2009, 31st July 2009, 16th February 2010, 5th June 2014, 24th February 2015,
and a copy of the US and JP granted patents were filed along with the response to the
first examination report. Applicant also filed the following documents in respect of
corresponding foreign applications of Indian Patent Application No. 2315/DELNP/2007
in the year 2014:
i. Documents in relation to US application No. 11/213, 308 – amendment under 37
C.F.R. 1.121, Notice of allowability, Notice of allowance and determination of patent
term adjustment, issued claims.
ii. Documents in relation to Korean application No. 10-2007-7004807- Notice of
Preliminary Rejection
iii. Documents in relation to Japanese application No. 2007-530166- office action dated
15 March 2011,
iv. Documents in relation to European Patent application no. EP - 05792494.6 -
Published Claims; prosecution history including the third party observations filed
v. Documents in relation to Chinese application number 200580036899.1 – first office
action, second office action, third office action
vi. Documents in relation to Chinese Application No. 201210189727.X – First office
action, currently pending claims
vii. Documents in relation to Canadian patent application No. 2578141 – Office action
dated September 30, 3008, June 3 2009, April 14 2010, December 10, 2010, September
22, 2011, Voluntary amendment dated February 27 2007, Response to office action
31
dated September 30, 2008, June 3 2009, Patent office communication dated January 12,
2010 and its response, response to office action dated April 14, 2010, December 10,
2010, September 22, 2011
viii. Documents in relation to Brazilian patent application no. PI0514703-4 – Pending
claims in English , Office action and response (Non English)
ix. Documents in relation to Australian Patent application no. AU 2005280034 - granted
patent, office action dated September 20, 2010, standard patent, Proposed amendment
submitted on 26th March 2007, 15th July 2009, Response to office action dated 20
September 2010
x. Granted claims in – Vietnam Ukraine, Taiwan, Russia, Philippines, Mexico, Macau,
Costa Rica, Colombia, China
The updated documents in relation to the prosecution of EP Application No. 05792494.6
and EP application no. 11156236.9 have also been filed at the Patent Office in February
2015.
The Applicant has therefore fully complied with the requirement under Section 8(1) and
8(2).
Decision: As the applicant has extensively complied with the Section 8(1) and 8(2)
requirement, I do not find any merit in this contention and is therefore dismissed.
In view of the above discussion, patent is granted on claims 1 to 40 filed on 10/04/2013. Date – 07/11/2016
(Dr Nilanjana Mukherjee) Assistant Controller of Patents and Designs