1

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