S-357, First Floor

Near HDFC Bank

Panchsheel Park,
RAJESHWARI & ASSOCIATES
Trademark & patent attorneys
New Delhi – 110017, India
Tel: + +91-11-41038911
Fax: +91-11-4385106

September 6, 2021

The Controller of Patents

The Patent Office
Boudhik Sampada Bhawan
Plot No. 32, Sector 14,
Dwarka, New Delhi-110078

Re: Opposition u/s 25(1) of the Patent act – By LOW COST STANDARD
THERAPEUTICS against Indian Patent Application Number No.
201717025098 dated 14/07/2017
Applicant: EMORY UNIVERSITY

Respected Sir,

We submit herewith Pre-Grant Opposition under Section 25(1) of the Patent Act, 2005 along
with evidence and Form 7A.

The Controller is requested to take the documents on record and proceed further in the matter
and keep the Petitioner advised of each and every step taken in the matter.

We crave the leave of the Controller to submit additional documents or evidence or if necessary
to support any of the averments in the representation as may be necessitated in the proceeding.

Lastly, we request the Controller to grant an opportunity of being heard before the above
representation is finally decided.

Thanking you,

Yours faithfully,

RAJESHWARI H. IN/PA - 0358

AGENT FOR THE OPPONENT
OF RAJESHWARI AND ASSOCIATES

Encl: As stated

C.C: Anand and Anand

B-41, Nizamuddin East,
New Delhi - 110013, India
Email.: email@anandandanand.com; archana@anandandanand.com

Also at: A - 202, First Floor, Shivalik Enclave, Malviya Nagar, New Delhi-110017
 BEFORE THE CONTROLER OF PATENTS, THE PATENT OFFICE, NEW DELHI
IN THE MATTER OF:
The Patents Act, 1970 as amended by the Patents (Amendment) Act 2005, and The Patents
Rules, 2003, as amended by The Patents (Amendment) Rules, 2006
AND
IN THE MATTER of Post grant opposition under Section 25(1)
AND
IN THE MATTER of Indian Patent Application No. 201717025098
IN THE MATTER OF:
LOW COST STANDARD THERAPEUTICS …….. OPPONENT
VS.
EMORY UNIVERSITY ……... APPLICANT

PRE-GRANT OPPOSITION BY LOW COST STANDARD THERAPEUTICS

INDEX
S. No. PARTICULARS Page
Nos.
1. Form 7 1
2. Opposition u/s 25(2) by the Petitioner/Opponent 2-93
3. Annexure - 1: Copy of claims currently on record 94-112
4. Annexure – 2: Copy of Article Dale L Barnard et al.; Inhibition of severe 113-120
acute respiratory syndrome–associated coronavirus (SARSCoV) by calpain
inhibitors and β-D-N4-hydroxycytidine; Antiviral Chemistry &
Chemotherapy 15:15–22, 2004
5. Annexure – 3: Copy of WO2014070771 121-286
6. Annexure – 4: Copy of WO2002032920 287-516
7. Annexure – 5: Copy of Article Maksim A. Ivanov et al;” NEW N4- 517-524
HYDROXYCYTIDINE DERIVATIVES: SYNTHESIS AND
ANTIVIRAL ACTIVITY” Chem. Commun. 2006, Vol. 71, No. 7, pp.
1099–1106; published in 19 Sep 2006
8. Annexure – 6: Copy of Article Fujan Li et al.; Prodrugs of Nucleoside 525-550
Analogues for Improved Oral Absorption and Tissue Targeting; JOURNAL
OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 3, MARCH 2008
9. Annexure – 7: Copy of Article Michael J Sofia;” Nucleotide prodrugs for 551-577
HCV therapy” Antiviral Chemistry & Chemotherapy 2011; 22:23–49
14. Power of Attorney Will
follow

Dated this 6th day of September, 2021

RAJESHWARI H. IN/PA – 0358

AGENT FOR THE OPPONENT
OF RAJESHWARI AND ASSOCIATES
TO
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, NEW DELHI
 1
FORM 7A
THE PATENTS ACT,
1970 (39 OF 1970)
AND
THE PATENTS RULES, 2003
REPRESENTATION FOR OPPOSITION TO GRANT OF PATENT
[See Rule 55]

We, LOW COST STANDARD THERAPEUTICS, an Indian Company of I Floor,

Premananda Sahitya Bhavan, Opposite Lakadipul, Dandia Bazar, Vadodara, 390 001,
Gujarat, India, hereby give representation by way of opposition to the grant of patent in
respect of application No: 201717025098 filed on 14/07/2017 made by EMORY
UNIVERSITY on the grounds:

(a) Section 25(1)(b)- Lack of Novelty

(b) Section 25(1)(e): Lack of inventive step
(c) Section 25(1)(f): Invention is not patentable under section 3 (d)& 3 (e)
(d) Section 25(1)(g): The complete specification does not sufficiently and clearly
describe the invention or the method by which it is to be performed.
(e) Section 25(1)(h): Failed to disclose to the Controller the information required
by section 8.

(Detailed grounds are set out in the Opposition as attached)

My address in India is:

RAJESHWARI & ASSOCIATES

S-357, First Floor
Near HDFC Bank
Panchseel Park,
New Delhi-110017, India
Tel +91-11-41038911
Mobile No: 9910206718

Dated this 6th day of September, 2021

RAJESHWARI H. IN/PA – 0358

AGENT FOR THE OPPONENT
OF RAJESHWARI AND ASSOCIATES

To,
The Controller of Patents
The Patent Office, New Delhi

1
 2
BEFORE THE CONTROLER OF PATENTS, THE PATENT OFFICE,
NEW DELHI

In the matter of Section 25(1) of The Patents Act,1970 as amended by The Patents
(Amendment) Act 2005;
And

In the matter of Rule 55 of The Patents Rules 2003 as amended by thePatent

(Amendment) Rules, 2006
And

IN THE MATTER of Indian Patent Application 201717025098 filed on 14/07/2017 by

EMORY UNIVERSITY

REPRESENTATION BY:

LOW COST STANDARD THERAPEUTICS ……….. OPPONENT

VS.

EMORY UNIVERSITY ……...APPLICANT

REPRESENTATION BY WAY OF PRE-GRANT OPPOSITION UNDER

SECTION 25(1) OF THE PATENTS ACT, 1970

We, LOW COST STANDARD THERAPEUTICS, hereby submit my representation

by way of oppostion to the grant of patent in respect of Indian Patent Application
201717025098 filed on 14/07/2017 by EMORY UNIVERSITY titled “N4
HYDROXYCYTIDINE AND DERIVATIVES AND ANTI VIRAL USES RELATED
THERETO”.

STATEMENT OF CASE OF OPPONENT

1. The Opponent has learnt that the Applicant has filed an Indian Patent Application
No. 201717025098 (hereinafter “the Impugned Patent Application”) on
14/07/2017. The Impugned patent application was published in the Official Journal
 3
of the patent office on 03/11/2017, which is currently pending before the Patent
Office. The Impugned Patent Application has a priority date 26/12/2014.

2. The Impugned application is titled “N4 HYDROXYCYTIDINE AND

DERIVATIVES AND ANTI VIRAL USES RELATED THERETO”.

3. The impugned application was initially filed with 22 claims which were later
amended by the Applicant in response to the First Examination Report issued by
the Indian Patent Office vide their letter dated 27/06/2019.

4. The opponent by way of this present pre-grant opposition submits that the claims
currently pending on record are not patentable under the provisions provided in this
Act. The claims as filed and currently on record are annexed herewith as
Annexure-1 and reproduced herein below for ready reference:
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
 22

5. Impugned Patent Application: The present pre-grant opposition is against Indian

Patent Application 201717025098filed on 14/07/2017titled “N4
HYDROXYCYTIDINE AND DERIVATIVES AND ANTI VIRAL USES
RELATED THERETO” and is drawn towardsN4-hydroxycytidine nucleoside
derivatives, compositions, and methods related thereto. It also relates to treatment
and prophylaxis of viral infections.

6. Disclosure in the impugned patent application: As per the Applicant, the present
invention relates to N4-hydroxycytidine and derivatives, pharmaceutical
compositions, and uses related thereto. In certain embodiments, the disclosure
relates to a compound having formula I,

7. Brief Background: The present application relates to antiviral compounds with a

broad spectrum of anti-viral properties. In 2002 the range of viruses and how
different virus infections should be approached from a therapeutic viewpoint was
known. Such interventions to design anti-viral drugs would include not only those
virus infections were familiar, but also new or old virus infections that could
 23
emerge or re-emerge, respectively. The basic strategies that are used to design
antiviral drugs have been discussed in De Clercq, E. Strategies in the design of
antiviral drugs. Nature Rev. Drug Discov. 1, 13–25 (2002). De Clercq. highlights
the different mechanistic strategies that could be followed or envisaged towards the
design and development of antiviral drugs.

8. The potential therapeutics for a broad range of viruses including coronaviruses,

include direct-acting antivirals which can be used to treat CoV infections. (((See
Potential antivirals and antiviral strategies against SARS coronavirus
infections.DeClercq E, Expert Rev Anti Infect Ther. 2006 Apr; 4(2):291-
302.Antiviral drugs specific for coronaviruses in preclinical development.Adedeji
AO, SarafianosSGCurrOpinVirol. 2014 Oct; 8():45-53.Zumla A, Chan JFW, Azhar
EI, Hui DSC, Yuen K-Y. 2016. Coronaviruses—drug discovery and therapeutic
options. Nat Rev Drug Discov 15:327–347. doi:10.1038/nrd.2015.37.)

9. It is well known that because the viral replication machinery is responsible for
increasing the number of virus (viral load), therapeutics approved to treat multiple
different viral infections are aimed to target this replication machinery (See Clercq
ED. 2004. Antivirals and antiviral strategies. Nat Rev Microbiol 2:704–720.
doi:10.1038/nrmicro975). Many approved antivirals are nucleoside and nucleotide
derivatives. Nucleosides are the natural building blocks for genetic material. A
nucleoside is a molecule which is comprised of a sugar moiety attached to a
nitrogenous base. Cytidine (C), adenine (A), guanine (G), thymine (T) and uracil
(U) are the naturally known nucleosides. In organisms, nucleosides are synthesized
through metabolic pathways, which further down the pathway get phosphorylated.
These phosphorylated nucleosides are called nucleotides, which are used by
enzymes to build the genetic material of all known organisms. The genetic material
is either DNA (which is made up of C, G, T, A) or RNA (which is made up of C,
G, U, A). When a pathogen (virus) infects a host, it uses the host resources to make
more copies of itself. More copies of itself is achieved by making more copies of
its genetic material. The optimum functionality of the virus is dictated by its
genetic material. Thus, one can either introduce error (mutations) in the genomic
information, or halt the information copying process itself, both of which could be
achieved by introducing different building blocks, with respect to the natural ones.
 24
Thus, to halt the virus from making more copies of its genetic material, scientists
often use non-natural analogues that mimic the natural building blocks for genes.

10. Since, the natural building blocks are cytidine, guanosine, etc., their synthetic
derivatives such as N4-hydroxycytidine (which is cytidine with a hydroxyl
group modification) are used as candidates for mimicking. These non-natural
synthetic compounds mimic the naturally available nucleosides (for example,
cytidine), and so get phosphorylated through the metabolic pathways and
eventually get incorporated in the genome of the virus. This incorporation results in
loss of information of the viral genes, and the loss of functionality for the virus,
thus halting the replication of the viral genome. Inhibition by nucleoside analogues
can be accomplished through a variety of known mechanisms. Well known
mechanisms of action include incorporation of the analogue by the viral
polymerase to induce premature termination of strand synthesis, and loss of
essential genetic information through mutagenesis, where mutagenesis means lack
of fidelity in genomic information owing to the incorporation of non-natural
constituents. [Advances in the development of nucleoside and nucleotide analogues
for cancer and viral diseases.Jordheim LP, Durantel D, Zoulim F, DumontetCNat
Rev Drug Discov. 2013 Jun; 12(6):447-64; 23. Deval J. 2009. Antimicrobial
strategies. Drugs 69:151–166. doi:10.2165/00003495-200969020-
00002; Mahmoud S, Hasabelnaby S, Hammad S, Sakr T. 2018. Antiviral
nucleoside and nucleotide analogs: a review. J Adv Pharm Res 2:73–88.
doi:10.21608/aprh.2018.5829.]

11. N4-hydroxycytidine was already identified as a deaminase inhibitor over 50 years

ago [ [M. R. Dollinger, J. H. Burchenal, W. Kreis, J. J. Fox (1967). Analogs of 1-b-
Darabinofuranosylcytosine. Studies on mechanisms of action in Burkitt’s cell
culture and mouse leukemia, and in vitro deamination studies. Biochem.
Pharmacol. 16, 689- 706.] Since then, many databases have accumulated the
structure-affinity data between small molecules and proteins. Under the similarity-
property principle the likely targets of any given molecule should be in consonance
with the targets of its chemical neighbourhood. [ M. A. Johnson, G. M. Maggiora
(1990). In Concepts and Applications of Molecular Similarity. New York: John
Wiley & Sons and R. B. Trimble, F. Maley. Metabolism of N-4-Hydroxy-Cytidine
 25
in Escherichia coli. J. Bacteriol. 1971, 108, 145-153.] β-D-N4-Hydroxycytidine
(NHC), a base-modified ribonucleoside analogue, was identified as a potent and
selective anti-HCV candidate since 2004. [Hernandez-Santiago, Brenda I., et al.
"Metabolism of the anti-hepatitis C virus nucleoside β-d-N 4-hydroxycytidine in
different liver cells." Antimicrobial agents and chemotherapy 48.12 (2004): 4636-
4642.]

12. It is also generally known that all pathogens have either DNA or RNA as the
genetic material. SARS-CoV is a virus whose genetic material is RNA. Enzymes
are used by the virus to copy the genetic material; the particular enzyme which
copies one viral RNA from another is called RNA-dependent RNA polymerase.
Thus, by targeting this RNA-dependent RNA polymerase enzyme, one can target
the viral genome copying process, and thus target viral replication itself. Thus, in
this regard, the skilled person will be aware that SARS-CoV RNA-dependent RNA
polymerase is a potential target for anti-SARS therapy (Xu, X. et al. Molecular
model of SARS coronavirus polymerase: implications for biochemical functions
and drug design. Nucleic Acids Res. 31, 7117–7130 (2003).). The substrates which
this enzyme needs for proper functioning and copying are the natural units that
build up the viral genetic material (C, G, U, A). Thus, any non-natural nucleoside
which would be able to mimic natural nucleosides structurally would act as a
substrate and bind to the enzyme. The enzyme would use these non-natural
nucleosides as substrates; it would either incorporate them in the genome which
would introduce error in genetic information and loss of function for the virus, or
these non-natural nucleosides would bind very tightly to the enzyme and not let the
natural nucleosides bind to it, and thus halting the genetic copying machinery.
Thus, by modifying the natural nucleosides one can synthesize non-natural
nucleoside analogues which would target the RNA-dependent RNA
polymerase enzyme. . Furthermore, this enzyme does not contain a hydrophobic
pocket for non-nucleoside inhibitors such as those that have proven active against
HCV polymerase or HIV-1 reverse transcriptase.[ Barnard, D. L. et al. Inhibition of
severe acute respiratory syndrome-associated coronavirus (SARSCoV) by calpain
inhibitors and β-D-N4–hydroxycytidine. Antiviral Chem. Chemother. 15, 15–22
(2004).]
 26
13. Many nucleoside analogues that are expected to target the SARS-CoV RNA
polymerase and for which efficacy has been determined, N4-hydroxycytidine—
incidentally, the same compound that has been accredited with anti-HCV
activity(Bray, M. Defense against filoviruses used as biological weapons. Antiviral
Res. 57, 53–60 (2003).)—showed activity, albeit at a low level (EC50 of 10 μM;
selectivity index of ≥10), against SARS-CoV replication in cell culture. [Barnard,
D. L. et al. Inhibition of severe acute respiratory syndrome-associated coronavirus
(SARSCoV) by calpain inhibitors and β-D-N4–hydroxycytidine. Antiviral Chem.
Chemother. 15, 15–22 (2004).]

14. Alleged invention relates to N(4)-hydroxycytidineanalogs, encompassed by claims

1-14,claims to exhibit broad spectrum antiviral activity against several different
viruses including, alphavirus infections, VEEV, norovirus, SARS coronavirus,
chikungunya virus, and MERV. The alleged invention is purported to disclose
anti-viral drug Molnupiravir, a drug repurposed to treat COVID-19. Regardless of
whether such drug is disclosed, the alleged invention does not merit a patent.

15. Admission by the Applicant: The applicant admits that β-d-N 4-hydroxycytidine
was already known, it was known to have antipestivirus and antihepacivirus
activities. [See specification page 1, lines 19-25]. The applicant also admits that the
efficacy of β-d-N 4-hydroxycytidine against certain viruses was known. The
opponents vehemently oppose the denial of admission of the fact that β-d-N 4-
hydroxycytidine was known and its efficacy against certain virus was known by the
applicant.

16. The Opponents state that the alleged invention is already disclosed in the prior
art and is generally known to a person skilled the art. The alleged invention is
also a new use of a already known compound. Thus, the application is devoid
of novelty, inventive step and does not satisfy section 3 of the patents act. The
invention is not sufficiently and clearly described in the specification and has
Markush claims, substitutions to which are ambiguous and vague and can lead
to compounds which are not contemplated by the application and its
description. The opponents thus pray that the application should be dismissed
in limine.
 27
17. PRIOR ARTS: The opponent submits that there are quite a lot of literatures which
disclose β-D-N4–hydroxycytidine as an antiviral agent. While in a pre-grant stage
all these documents are relevant for consideration as they form part of existing
knowledge. For the sake of brevity the Opponent wishes to rely on the following
prior arts as evidence in support of the grounds of opposition.

i. D1-Dale L Barnard et al.; Inhibition of severe acute respiratory syndrome–

associated coronavirus (SARSCoV) by calpain inhibitors and β-D-N4-
hydroxycytidine; Antiviral Chemistry & Chemotherapy 15:15–22, 2004 (as
annexed herewith Annexure – 2).
ii. D2-WO2014070771 (as annexed herewith Annexure – 3)
iii. D3-WO2002032920 (as annexed herewith Annexure – 4)
iv. D4-Maksim A. Ivanov et al;” NEW N4-HYDROXYCYTIDINE
DERIVATIVES: SYNTHESIS AND ANTIVIRAL ACTIVITY” Chem.
Commun. 2006, Vol. 71, No. 7, pp. 1099–1106; published in 19 Sep 2006 (as
annexed herewith Annexure – 5)
v. D5-Fujan Li et al.; Prodrugs of Nucleoside Analogues for Improved Oral
Absorption and Tissue Targeting; JOURNAL OF PHARMACEUTICAL
SCIENCES, VOL. 97, NO. 3, MARCH 2008 (as annexed herewith Annexure
– 6)
vi. D6-Michael J Sofia;” Nucleotide prodrugs for HCV therapy” Antiviral
Chemistry & Chemotherapy 2011; 22:23–49 (as annexed herewith Annexure
– 7)

18. It is submitted that all claims of the impugned patent application are liable to be
refused on following grounds as below:

(a) Section 25(1)(b)- Lack of Novelty

(b) Section 25(1)(e): Lack of inventive step
(c) Section 25(1)(f): Invention is not patentable under section 3 (d)& 3 (e)
(d) Section 25(1)(g): The complete specification does not sufficiently and
clearly describe the invention or the method by which it is to be performed.
(e) Section 25(1)(h): Failed to disclose to the Controller the information
required by section 8.
 28
(a) PRELIMINARY OBJECTION: (Lack of unity of invention)

19. As per section 10, the claims of the complete specification must relate to a single
invention, or to a group of inventions linked so as to form a single inventive
concept. The claims of the impugned patent application have no single inventive
concept. The claims are drawn to composition s containing compounds with
different independent Markush structures in the claims and none of them are related
to each other by any inventive concept. The impugned patent application relate to a
plurality of distinct inventions. Therefore, the impugned patent lacks unity of
invention and should be rejected on this ground alone.

20. The tables below to represent the lack of unity of invention between the claims.
Bothtables represents that there are numerous substituents present in compounds of
bothclaim 1 &claim 6 and claim 1& 9, none of them relate to each other.

LACK OF UNITY OF INVENTION BETWEEN CLAIM 1 AND 6:

Claim 6 of Impugned patent application Claim 1 of Impugned patent

application

 R1 : Definition of R1includes  R1 = Definition of R1 does not

hydrogen, monophosphate, includehydrogen, monophosphate,
diphosphate, triphosphate, diphosphate, triphosphate,

Comment:It is submitted that monophosphate, diphosphate, triphosphate

groupsare absent in the Markush structure of claim 1 whereas these are present in
the compound ofMarkush structure of claim 6. It is common in art that nucleoside
 29
get changed in to nucleotide after addition of these phosphate groups at 5’
position of nucleoside.
 R2: This substituent (hydroxyl  R2 : Definition of R2 include
group) is absent in thecompound of Hydroxyl group.
Markush structure of claim 6.

Comment: It is submitted that R2substituent (hydroxyl group) is absent in the

compound of Markush structure of claim 6 whereas it is present in the compound
ofMarkush structure of claim 1.
 R3: Definition of R3  R3 : This substituent could
includesHydroxyl group. behydrogen, (C1-C22) alkyl, halogen,
nitro, cyano, amino ,mercapto,
formyl, carboxy, carbamoyl, (C1-
C22) alkoxy, (C1-C22) alkylthio, (C1-
C22) alkylamino, ((C1-C22)
alkyl)2amino, (C1-C22) alkylsulfinyl,
(C1-C22) alkylsulfonyl, (C6-C12)
arylsulfonyl, (C3-C6) carbocyclyl,
(C6-C12) aryl, or heterocyclyl
Comment:It is submitted that thecompound of Markush structure of the claim 6
contain a Hydroxyl group at 3’ position whereas compound of Markush structure
of claim 1 discloses various different groups as mentioned above.
 R6: This substituent is absent in the  R6 : R6 is hydroxy, (C1-C22)alkoxy,
Markush structure of claim 6. (C1-C22)alkyl, ethynyl, allenyl,
halogen, nitro, cyano, amino,
mercapto, formyl, carboxy,
carbamoyl, (C1-C22)alkylthio, (C1-
C22)alkylamino, ((C1-
C22)alkyl)2amino, (C1-
C22)alkylsulfinyl, (C1-
C22)alkylsulfonyl, (C6-C12)
arylsulfonyl, (C3-C6) carbocyclyl,
(C6-C12)aryl, or heterocyclyl.
 30

Comment:It is submitted that R6is absent in the compound ofMarkush structure

of the claim 6 whereas Markush structure of claim 1 discloses various different
groups as mentioned above.
Q: These substituent O, -O(C=O)V, NR7 Q : This substituent could be hydrogen,
are absent in the Markush structure of the O, -O(C=O)V, NR7
claim 6.
Comment: It is submitted that these substituent O, -O(C=O)V, NR7 are absent in the
compound of Markush structure of the claim 6 whereas compound of Markush
structure of claim 1 discloses these substituent.

LACK OF UNITY OF INVENTION BETWEEN CLAIM 1 AND 9:

Claim 9 of Impugned patent application Claim 1 of Impugned patent application

 R1 : Definition of R1includes  R1: Definition of R1 does not

monophosphate, diphosphate, includehydrogen, monophosphate,
triphosphate, diphosphate, triphosphate,

Comment:It is submitted that monophosphate, diphosphate, triphosphate, are

absent in the compound of Markush structure of claim 1 whereas these are present
in Markush structure of claim 9. Generally these substituents are attached with “O”
but in claim 9 these substituents are attached with -CH2group.
 Q: Definition of Q includes -  Q: Definition of Q does not include-
O(C=O)Lipid, NH O(C=O)Lipid, NH
 31
Comment:It is submitted that O(C=O)Lipid, NHare absent in the Markush
structure of claim 1 whereas these are present in Markush structure of claim 9.
 W:Definition of W includes CH2,  W: Definition of W does not
NH, S includes, CH2, NH, S.

 Comment: It is submitted that Wincludes CH2, NH, S in the Markush structure of

claim 9 whereas, these are absent in the Markush structure of claim 1. These
substituents will change the structure of ribose sugar.
 X: Definition of X includes O  X: Definition of X does not includeO

 Comment: It is submitted that Xincludes O in the Markush structure of claim 9

whereas, it is absent in the Markush structure of claim 1.
 R2: Definition of R2 includes alkyl,  R2: Definition of R2 does not
alkenyl, alkynyl, ethynyl, includealkyl, alkenyl, alkynyl,
fluoromethyl, difluoromethyl, ethynyl, fluoromethyl,
trifluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl,
hydroxymethyl, halogen, nitro, chloromethyl, hydroxymethyl,
cyano, hydroxy, amino, mercapto, halogen, nitro, cyano, hydroxy,
formyl, carboxy, carbamoyl, alkoxy, amino, mercapto, formyl, carboxy,
(C1-C22)alkylthio, alkylamino, carbamoyl, alkoxy, (C1-C22) alkylthio,
(alkyl)2amino, alkylsulfinyl, alkylamino, (alkyl)2amino,
alkylsulfonyl, arylsulfonyl, alkylsulfinyl, alkylsulfonyl,
carbocyclyl, aryl, azido, or arylsulfonyl, carbocyclyl, aryl, azido,
heterocyclyl, or heterocyclyl,

 Comment:It is submitted thatR2 includes alkyl, alkenyl, alkynyl, ethynyl,

fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, hydroxymethyl,
halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl,
alkoxy, (C1-C22)alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, azido, or heterocyclyl, in the Markush structure of
claim 9 whereas, these are absent in the Markush structure of claim 1.
R5: Definition of R5 includes alkoxy,  R5: Definition of R5 does not includes
alkyl, alkenyl, alkynyl, ethynyl, alkoxy, alkyl, alkenyl, alkynyl,
 32
fluoromethyl, difluoromethyl, ethynyl, fluoromethyl,
trifluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl,
allenyl, halogen, nitro, cyano, amino, hydroxymethyl, allenyl, halogen,
mercapto, formyl, carboxy, nitro, cyano, amino, mercapto,
carbamoyl, alkoxy, alkylthio, formyl, carboxy, carbamoyl, alkoxy,
alkylamino, (alkyl)2amino, alkylthio, alkylamino, (alkyl)2amino,
alkylsulfinyl, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or arylsulfonyl, carbocyclyl, aryl, or
heterocyclyl. heterocyclyl.

 Comment: It is submitted thatR5includes alkoxy, alkyl, alkenyl, alkynyl, ethynyl,

fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, allenyl, halogen,
nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl,
aryl, or heterocyclyl, in the Markush structure of claim 9 whereas, these are absent
in the Markush structure of claim 1.

21. Thus, since the substituents of the compounds of claim 1 and 6 are no way related
to each other, the claims suffer from lack of unity of invention as there is no
common concept between these claims.

22. It is submitted that the compounds claimed in the composition of claims 1, 4, 6, 7,

8 and 9 are of diverse chemical structure and there is no common chemical
structure between these claims, since the substituents make the compounds
different. Additionally, the compounds as per the specification are for treatment of
diverse diseases/conditions. In other words, compounds claimed in each of these
claims do not overlap in scope i.e. are mutually exclusive. The compounds
represented by various Markush structure are claimed do not encompasses
overlapping subject matter. Hence, the Applicant through all these claims
claiminglarge no. of compounds with different functional groups that can be
activated at different locations to arrive at diverse compounds which have no
commonality with each other.
 33
23. It is submitted that even the pharmacophore of the compounds claimed are diverse.
For examplein claim 7, 8, and 9 Y and Z are N; W is S, NH and CH2. These are
shown below.

24. As shown above, the pharmacophore of the resultant compound of claims are
different. Since the compound do not show common structure and have structurally
different and distinctive portions, these compounds do not show structure
similarities. Hence, there is no single inventive concept between these claims and
all of these claims cannot be claimed or allowed in single application.
25. Therefore, the impugned patent application shows a plurality of distinct inventions.
Therefore, the impugned patent application lacks unity of invention and should be
rejected on this ground alone.

(a) GROUND 1: LACK OF NOVELTY: Section 25 (1)(b):

26. Claims 1 to 14 are not novel, and therefore liable to be rejected under section
25(1)(b) of the Patents Act.

27. The impugned patent application lacks novelty in view of WO2014070771 (WO’
771). This document was published on 8 may 2014 which is prior to priority date of
impugned patent application i.e.26/12/2014. The impugned patent application
 34
claim compounds as well as pharmaceutical composition which are already known
and covered in WO’ 771 patents.
28. The prior art relates compounds, methods and compositions for treating or
preventing cancer or an HIV-1, HIV-2, HCV, Norovirus, Saporovirus, HSV-1,
HSV-2, Dengue virus, Yellow fever, cytomegalovirus (CMV), or HBV infection in
a host. The methods involve administering a therapeutically or prophylactically-
effective amount of at least one compound as described herein to treat or prevent an
infection by, or an amount sufficient to reduce the biological activity of, cancer or
an HIV-1, HIV-2, HCV, Norovirus, Saporovirus, HSV-1, HSV-2 Dengue virus,
Yellow fever, cytomegalovirus (CMV), or HBV infection. The pharmaceutical
compositions include one or more of the compounds described herein, in
combination with a pharmaceutically acceptable carrier or excipient, for treating a
host with cancer or infected with HIV-1, HIV-2, HCV, Norovirus, Saporovirus,
HSV-1, HSV-2, Dengue virus, Yellow fever, cytomegalovirus (CMV), or HBV.
The formulations can further include at least one further therapeutic agent. In
addition, the present invention includes processes for preparing such compounds.

29. The impugned also lacks novelty in view of WO2014070771 (WO’ 771), since
claims in the application are covered under WO’ 771. It can be shown that, using
Markush structure and substitutions disclosed in WO’ 771, one can arrive at
compounds claimed by the impugned patent application.

30. Claim 1 of the impugned application is drawn to pharmaceutical composition

comprising pharmaceutically acceptable excipientsand compound having formula I
as shown below.
 35

Therefore, said composition of claim 1 is drawn to several compound embraced

within the Markush formula I.

31. As stated in foregoing paragraphs compound EIDD-1931 is disclosed by Bernard et

al, the Applicant realized this and hence they claim same compound by giving
other code EIDD-2216 which is shown below.

Example 3 page no. 55 Example 24 page no. 82

32. It is submitted that the disclosure of WO 2014/070771anticipates claims of

impugned patent application.

Table 1: Prior art WO 2014/070771 (WO’ 771) anticipate claim 1 of impugned

application:
 36
Prior art WO 2014/070771 (WO’ 771) Impugned Application
201717025098
(Claim 1)

I
 X1 is H (Page no. 14)  R6 is H

 X2 is COR1 (Page no. 14)  Q is –O(C=O)

 R1 is C1-20 alkyl (Page no. 14)  R7 is C1-22 alkyl

 37

 X3 and X4 are H (Page no. 14)  Y and Z are CR” and R” is H

 Sugar is (Page no. 14)  or

 R4’, R5, R6, R7’ are H; A is O; R5’  R2 and R5 are H; W is O; R3

and R6’ are OH; W is CL2 and L is and R4 are OH

H so W is CH2((Page no.15)
 38
 R1 is carboxyl and substituted
by R20 and R20 is alkyl

 D is COOR1 (Page no. 15) and R1 is

alkyl (Page no. 14)

33. It is submitted that the table as mentioned above discloses that after the substitution
in both (Prior art WO’ 771 and impugned application) Markush structure, a
common structure is arrived. Thus, WO’ 771 anticipates claim 1 of the impugned
application.

34. Without prejudice to the above, it is further submitted that the claims of the
impugned application is also anticipated by WO’ 771. The tables are given below.

Table 2: Prior art WO 2014/070771 (WO’ 771) anticipates claim 4 of impugned

application:
Prior art WO 2014/070771 (WO’ 771) Impugned Application
201717025098
(Claim 4)
 39

 X1 is H (Page no. 14)  Nitrogen already contain H

 X2 is COR1 (Page no. 14)  V is absent

 R1 is C1-20 alkyl (Page no. 14)  R15is C1-22 alkyl

 Y is H
 X3 and X4 are H (Page no. 14)
 40

 Sugar is (page no. 14)  or

 R5 is H; R4 is OH; X is CH2
 R4’, R5, R6, R7’ are H; A is O; R5’
and R6’ are OH; W is CL2 and L is
H so W is CH2(page 15)

 R1 is carboxyl and substituted by

R20 and R20 is alkyl

 D is COOR1 (Page no. 15) and R1

is alkyl (Page no. 14)
 41

Table 3: Prior art WO 2014/070771 (WO’ 771) anticipates claim 6 of impugned

application:

Prior art WO 2014/070771 (WO’ 771) Impugned Application 201717025098

(Claim 6)

 X1 is H (Page no. 14)  N already contain H

 X2 is COOR1 (Page no. 14)  or

 42

 R1 is C1-20 alkyl (Page no. 14)  R15 is C1-22 alkyl

 X3 and X4 are H (Page no. 14)  Y is H

 Sugar is (page no. 14)  or

 R4’, R5, R6, R7’ are H; A is O; R5’ and  R5 is H; R4 is OH; X is CH2

R6’ are OH; W is CL2 and L is H so W
is CH2 (page 15)
 43

 D is COOR1 (Page no. 15) and R1 is

 R1 is carboxyl and substituted by R20
alkyl (Page no. 14)
and R20 is alkyl

Table 4: Prior art WO 2014/070771 (WO’ 771) anticipates claim 7 of impugned

application:

Prior art WO 2014/070771 (WO’ 771) Impugned Application

201717025098
(Claim 7)

I
 X1 is H (Page no. 14)  R6 is H
 44

 X2 is COR1 (Page no. 14)

 or

 R1 is di (C1-C6 alkyl)-amino (Page no.

14)
 R15’ and R15are C1-22 alkyl

 X3 and X4 are H (Page no. 14)  Y and Z are CR” and R” is H

 45
 Sugar is (Page no. 14)  or

 R4’, R5, R6, R7’ are H; A is O; R5’  R2 and R5 are H; W is O; R3

and R4 are OH
and R6’ are OH; W is CL2 and L is H
so W is CH2 ((Page no.15)

 R1 is carboxyl and substituted by

R20 and R20 is alkyl
 D is COOR1 (Page no. 15) and R1 is
alkyl (Page no. 14)
 46
Table 5: Prior art WO 2014/070771 (WO’ 771) anticipates claim 8 of impugned
application:

Prior art WO 2014/070771 (WO’ 771) Impugned Application

201717025098
(Claim 8)

I
 R6 is H
 X1 is H (Page no. 14)

 Q is –O(C=O)
 X2 is COR1 (Page no. 14)

 R1 is C1-20 alkyl (Page no. 14)  R7 is alkyl

 47

 X3 and X4 are H (Page no. 14)  Y and Z are CR” and R” is H

 Sugar is (Page no. 14)  or

 R2 and R5 are H; W is O; R3 and

R4 are OH
 R4’, R5, R6, R7’ are H; A is O; R5’
and R6’ are OH; W is CL2 and L is
H so W is CH2 ((Page no.15)

 R15’ and R15 are alkyl

 48

 D is COR1 (Page no. 15) and R1 is

di(C1-C6 alkyl)-amino (Page no. 14)

35. The above mentioned tables disclose that WO’ 771 anticipate the claims of
Impugned application.

36. Without prejudice to the above, it is further submitted that WO 02/32920 (WO’
920) which was published before the priority of impugned application also
anticipate claim 1 of impugned application.

Table 6: Prior art WO 02/32920 (WO’ 920) anticipate claim 1 of impugned

application:

Prior art WO 02/32920 (WO’ 920) Impugned Application

201717025098
(Claim 1)
 49
R6 Q
N R7

Y N

Z
N O
R1O X
W

R2
R5
R3 R4
[I-a]
 X1 is NHOR4 (Page no. 17) and R4  R6 is H; Q is O and R7 is alkyl

is alkyl(Page no. 17)

 R1 and R1’ are H (Page no. 17); Y1  Y and Z are CR” and R” is H
is O (Page no. 17)

 R2 and R5 are H; W is O; R3 and

 R2 and R3 are H (Page no.17); R2’
R4 are OH; X is CH2
and R3’ are OH (Page no.17);
 50

 D is alkyl (Page no. 17)

 R1 alkyl

37. It is submitted that the table as mentioned above discloses that after the substitution
in both (Prior art WO’ 920 and impugned application) Markush structure, they
arrived at a common structure. It discloses that WO’ 920 anticipate claim 1 of the
impugned application.

38. It is submitted that the prior art is replete with compounds that fall within the
claimed Markush and thus composition containing the compounds represented by
formula I lacks novelty.

39. Without prejudice and in addition to above, it is submitted that the compound
EIDD-2051 which is claimed in claim 5 falls within the scope and ambit of
compounds disclosed by WO’ 2014/070771 (WO’ 771). The said compound has
been assigned EIDD-2051 and represented below.
 51

40. The manner in which EIDD-2051 is disclosed by WO’ 771 is shown below.

Table 7: Substitution as per teaching of WO2014070771 (WO’ 771) to achieve

EIDD-2051

S.NO. Markush structure Resultant Structure

1.

Formula I
Page no. 14
2. X1 is H

X2 is COOR1

R1 is alkyl C1-20

Page no. 14
 52
3. X3 and X4 is H

Page no. 14

4. Sugar is ribose or a modified

ribose of the general
Formula (II):

Page no. 14
5. R4’, R5, R6 and R7’ are H
Page no. 15
And
R5’, R6’ are OH
A is O
Page no. 15

6. W is CL2 and L is H
Then W is CH2
Page no. 15

7. D is H

Page no. 15
 53

EIDD-2051

41. Without prejudice to the above, and in addition to above compound EIDD-2476
which is one of the compound falling within the ambit of claim 1 is also disclosed
by WO’ 771 as under.

42. EIDD-2476 is derived as per the teaching of WO2014070771 (WO’ 771) by

following substitution.

Table 8: Compound EIDD-2476 of impugned patent application also encompasses

in WO’ 771.

S.NO. Markush structure Resultant Structure

1.
 54
Formula I
Page no. 14
2. X1 and X2 is H

Page no. 14

3. X3 and X4 is H

Page no. 14

4. Sugar is ribose or a modified

ribose of the general
Formula (II):

Page no. 14
5. R4’, R5, R6 and R7’ are H
Page no. 15
And
R5’, R6’ are OH
Page no. 15
 55
6. W is CL2 and L is H
Then W is CH2
Page no. 15

7. D is COR1
And R1 is C1-C20 alkyl
Page no. 15

EIDD-2476

43. Without prejudice to above and in the alternative, it is submitted that the compound
EIDD-2476 which fully covered by claim 1 of impugned application is disclosed
by WO’ 02/32920 (WO’ 920).

Table 9: Compound EIDD-2476 of impugned patent application is also

encompassed ant anticipatedby WO’ 920

S.NO. Markush structure Resultant Structure

 56
1.

Formula I-a
Page no. 16
1
2. R and R1’ is H

Page no. 17

3. Y1 is O X1

N
Page no. 17
O N

DO
O

R3 R2

R3' R2'
4
4. X1 is NHOR
And R4 is H
Page no. 17
 57
5. R2 and R3 are H
Page no. 17

And

R2’ and R3’ are OH

Page no. 17

6. D is acyl
Page no.17

EIDD-2476

44. In light of above, the claims of the impugned patent application lack novelty and
should be rejected on this ground alone.

(b) GROUND 2: LACK OF INVENTIVE STEP:[Section 25 (1)(e)]

45. It is submitted that the invention as claimed is obvious and does not involve any
inventive step in view of whatever was known and published in India or elsewhere
prior to the priority date of impugned patent application i.e. prior to 26/12/2014the
earliest claimed priority.

46. It is submitted that all the claims of the impugned patent application are not
inventive and are obvious in view of common general knowledge in art and
combined with teachings of various prior arts.
 58
MOTIVATION FROM DOCUMENTS:

47. The alleged invention attempts to solve was providing new pharmaceutical
compositions for treating viral infections. The specification alleges that it includes
a broad spectrum of antivirals including SARS coronavirus, chikungunya, Eastern
equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine
encephalitis virus (VEEV), MERS coronavirus, Ross River infection, H5N1
influenza virus, filoviridae virus and/or Ebola virus.

A. Compound EIDD-2050 which is claimed in claim 5 is obvious in view of

prior art:

48. First and foremost, Dale L. Bernard et al discloses that β-D-N4-hydroxycytidine

was the most selective nucleoside analogue inhibitor with an EC90 of 6 μM by
virus yield reduction assay. These compounds or analogues warrant further
evaluation as potential therapies for treating SARS or could be used as lead
compounds for discovery of more potent SARSCoV inhibitors.

β-D-N4-hydroxycytidine
49. β-D-N4-hydroxycytidine is nothing but a molecule that mentioned in the impugned
patent application code named EIDD-1931. Therefore, EIDD-1931 cannot be
inventive in view of Dale L Bernard et al. Moreover, the other compounds like
EIDD-2050 and EIDD-2476 are also lack inventive steps in light of cited prior arts.

50. It further discloses that the cytosine-type compounds, β-D-N4-hydroxycytidine was

very active, with an EC50 of 5 μM, but with some cytotoxicity detected, the IC50
was equal to 50 μM by NR assay. It also discloses that β-DN4-hydroxycytidine
 59
reduced virus yields by 90% at 6 μM, which confirmed the activity demonstrated
by CPE reduction assay and NR assay.

51. Bernard et al. further discloses that β-D-N4-hydroxycytidine was one of the active
compounds found in the current study. β-D-N4-hydroxycytidine has previously
been shown to inhibit bovine viral diarrhoea virus and hepatitis C virus (HCV)
replicon RNA production in Huh7 cells, at concentrations similar to those
inhibiting SARS in this study.

52. Thus, it was postulated that β-D-N4-hydroxycytidine might affect the

thermodynamics of the secondary structure of the polymerase to cause inhibition of
viral replication.

53. WO2014070771 (WO’ 771) discloses that the compounds include β-D and β-L-N4
hydroxycytidine (Page 13) nucleosides derivatives and modified monophosphate,
phosphonate prodrugs are inhibitors of HIV-1, HIV-2, HCV, Norovirus,
Saporovirus, herpes viruses (HSV-1, HSV-2), Dengue virus, Yellow fever,
cytomegalovirus (CMV), cancer, and/or HBV. Therefore, these compounds can
also be used to treat patients that are infected or co-infected with HIV-1, HIV-2,
HCV, Norovirus, Saporovirus, HSV-1, HSV-2, Dengue virus, Yellow fever,
cancer, and/or HBV. The active compound is of formula I.

54. WO’ 771 further discloses the synthetic route to obtain various N4 hydroxycytidine
nucleosides derivatives with antiviral properties. A relevant extract from WO’771
is as below; (Page 99 of WO’ 771).
 60

55. The WO0232920 (hereinafter ‘920) discloses modified nucleosides for the
treatment of viral infections and abnormal cellular proliferation. It further discloses
a β-D or β-L nucleosides or its pharmaceutically acceptable salt or prodrug for the
treatment of a host infected with a virus belonging to the Flaviviridae infection
including all members of the Hepacivirus genus (HCV), Pestivirus genus (BVDV,
CSFV, BDV), or Flavivirus genus (Dengue virus, Japanese encephalitis virus group
(including West Nile Virus), and Yellow Fever virus); Orthomyxoviridae including
all members of the Influenza A, B genus, in particular influenza A and all relevant
subtypes - including H1N1 and H3N2 - and Influenza B; and Paramyxoviridae
family including Respiratory Syncytial Virus (RSV) infection or for the treatment
of abnormal cellular proliferation including malignant tumors.

56. WO’ 920 further discloses the anti-virally or anti-proliferatively effective

nucleoside is a β-D nucleoside of the general formula (I). Page no. 16

57. It further discloses the anti-virally or anti-proliferatively effective nucleoside is a β-

D nucleoside ofthe general formula XXI. Page no. 28.
 61

58. A person skilled in the art can synthesize the compound EIDD-2050 by following
above scheme. As evident to scheme above, compound 29 can be easily converted
to compound 30 by following the reaction scheme 11 of WO’ 771. R1 as per WO’
771 is C1-20 alkyl which includes nonyl. The Applicant has chosen only a particular
group for R1 as mentioned in above scheme. The relevant scheme for EIDD-2050
as present in impugned patent application is given here.

59. Therefore, merely selecting a particular group for R’ cannot be considered as

inventive step.

60. Furthermore, the teaching to use a particular group at a specific position as

mentioned in EIDD-2050 is well taught by Maksim A, Ivanov.

61. Maksim A. Ivanov et al. discloses that the derivatives of β-D-N4-hydroxycytidine

possess potential antipox viral activity. This document prepared a series of N4-
(acyloxy) derivatives of β-D-N4-hydroxycytidine and 5’ phosphonate nucleoside
analogues.
 62

Acyloxy derivatives of N4-hydroxycytidine

5’ phosphonate nucleoside analogues (4a-c) of N4-hydroxycytidine.

62. By making therefore said substitution the compound EIDD-2050 is derived

including by following reaction scheme 11 disclosed by WO’ 771. Thus the
compound EIDD-2050 falls within the compound derived and resulting from
scheme 11 of WO’ 771. So, therefore, EIDD-2050 is obvious and disclosed by
WO’771.

63. Furthermore, Claim 5 of impugned application drawn to various compound which

are obvious from the prior art for example one of the compound EIDD-2050 with
the name 1-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-
((nonanoyloxy)amino)pyrimidin-2-one is prepared by reaction of the compound
EIDD-1931 with pyridine and nonanoyl chloride, The compound EIDD-1931 is
 63
disclosed by Dale L. Bernard et al. Therefore, EIDD-2050 is obvious to a person
skilled in the art given teaching of Ivanov read with Bernard et al.

64. Bernard et al. teaches N4 hydroxycytidine which is EIDD-1931 that possess

antiviral activity. Ivanov teaches use of acyloxy group at N4 position to get
potential activity. The compounds2a (benzoyl derivative of N4 hydroxycytidine)
and 2b (pivaloyl derivative of N4 hydroxycytidine) disclosed by Ivanov shows
higher antiviral activity than the parent compound (N4 hydroxycytidine). Ivanov
discloses CC50 for 2a and 2b are 165 and 175 uM whereas N4 hydroxycytidine
possess 50μM for vero cell culture.

65. Ivanov prepared series of acyloxy derivatives by acylation of N4 hydroxycytidine

to obtain acyl derivative at N4 position. Thus a person skilled in the art would read
the teaching of Bernard et al with Ivanov et al to arrive compounds such as EIDD-
2050.

66. Ivanov et al has demonstrated that phosphorylation at 5’ position does not yield
desirable compound and acylation at N4 position to give desirable activity. In view
of above the compound EIDD-2050 which is claimed in claim 5 is obvious.

B. Compound EIDD-2476 is obvious in view of prior art:

67. Yet another compound which falls within the ambit of claim 1 is EIDD-2476.
Bernard et al already teaches the compound EIDD-1931. When esterification was
carried out of EIDD-1931 at 5’ position, the resultant compound is EIDD-2476.
Such esterification is taught by Fujan Li et al. Though Fujan Li et al worked on the
compound R-1479 and derived R-1628, the same principle would apply to EIDD-
1931, since R-1479 as well as EIDD-1931 are polar molecules with low
permeability.

68. Human clinical studies showed an oral absorption of 6–18% based on urine
recovery. To increase oral absorption of R1479, three prodrug approaches were
investigated by Fujan Li et al.
 One approach focused on increased lipophilicity using mono- di- and
triesters.
 64
 A second approach had a dual focus of increased lipophilicity with liver
targeted cleavage using carbamate prodrug at the N4 position.
 A third approach utilized amino acid esters.

69. Fujan Li et al disclose that none of the carbamate prodrugs (second approach as
mentioned above) showed significant improvement in plasma exposures of R1479
in monkey PK studies. Hence, third approach was ruled out. Significantly increased
plasma exposure was observed for several mono-, di-, and tri-ester prodrugs of
R1479 in monkeys.The Applicant has utilized the first approach to obtain EIDD-
2476.

70. Michael J Sofia, also discloses that 4′-C-azidocytidine nucleoside R1479 was
reported to be an inhibitor of HCV replication (EC50=1.28 μM) and subsequently
its 2′,3′,5′-tri-Oisobutryate ester prodrug R1626 was taken into clinical
development as a treatment for HCV infection.
 65

4′-Azido cytidine nucleoside and nucleotide phosphoramidate prodrug

inhibitors of HCV replication

71. The document further discloses that in a Phase Ib monotherapy clinical study in
HCV infected patients dosed with 500, 1,500, 3,000 and 4,500 mg twice daily for
14 days, R1626 demonstrated a mean decrease in viral load of -0.3, -1.2, -2.6 and -
3.7 log10 IU/ml, respectively. R1626 was subsequently taken into a Phase IIa study
where at a dose of 1,500 twice daily in combination with IFN/RBV a -5.2 log10
IU/ml reduction in viral load with an 81% rapid virological response (RVR) was
observed after 28 days of therapy.

72. In an effort to increase the potency of R1479,a 5′-phosphoramidate nucleotide

prodrug strategy was also investigated hoping that the increased lipophilicity would
facilitate transport of the nuclesoside and further increased efficiency. However the
preparation of the 5′-phosphoramidate derivative 21 did not provide any
appreciable improvement in potency over the nucleoside R1479, indicating that this
nucleoside is already efficiently phosphorylated and that application of the
phosphoramidate technology was not able to boost its potency.
 66
73. The document teaches the isobutyrate esters for masking the hydroxylgroup of the
nucleosides. Therefore, in light of above EIDD-2476 also lacks inventive step.

74. Without prejudice to above and in the alternative the compounds represented by
Markush structure shown in claim of the composition of claim 1 represented by
Markush formula I are obvious in view of Markush structure disclosed by WO’
771. The relevant submissions in this regard are made at para53 and 54 above and
same are reiterated and not repeated for sake of brevity.

75. In addition to above, the compounds represented by Markush structure shown in

claim of the composition of claim 1 represented by Markush formula I are also
obvious in view of Markush structure disclosed by WO’ 920. The observation in
para above 55 to 57and same are reiterated and not repeated for sake of brevity.

76. Considering above, the present impugned patent application lacks inventive steps
and therefore, this application should be rejected on this ground alone.

(c) GROUND 3: Claims not patentable under Section 25(1)(f)

77. It is submitted that the claims of the impugned patent application are not patentable
allowed under Section 3(d) of the Act, which states that“the mere discovery of a
new form of a known substance which does not result in the enhancement of the
known efficacy of that substance or the mere discovery of any new property or new
use for a known substance or of the mere use of a known process, machine or
apparatus unless such known process results in a new product or employs at least
one new reactant.
Explanation –For the purposes of this clause, salts, esters, ethers, polymorphs,
metabolites, pure form, particle size, isomers, mixtures of isomers, complexes,
combinations and other derivatives of known substance shall be considered to be
the same substance, unless they differ significantly in properties with regard to
efficacy.”

78. It is submitted that the compounds claimed in claim 1, 4, 6, 7, 8, and 9 lack

therapeutic efficacy. In example 56 the antiviral activity of certain compounds is
shown wherein EIDD-1931 is shown to has an efficacy EC50 <0.1 ug/ml.
 67
However, this compound has been disclaimed. Similarly the efficacy of certain
compounds is shown with respect to Chikungunya virus. In this class the most
active compound i.e. compound EIDD-1931was disclaimed. The rest of the
compounds have not been tested for showing efficacy.

79. Example 58, 60 and 62 demonstrates efficacy of certain compounds whose

structure and process of preparation has not disclosed. Thus, no efficacy for any
compound is demonstrated in specification.

80. The efficacy for EIDD-1931 is already disclosed by Bernard et al.

81. Therefore, the claims of the impugned patent application claim compounds which
do not show any enhancement of known efficacy and thus not patentable under
section 3 (d). Thus, the subject matter of impugned patent application squarely falls
within the purview of Section 3(d) of the Act. Hence the impugned patent
application should be rejected under section 3(d) of the act.

Claims of impugned application is not patentable as per section 3(e)

82. The Opponent states that the claimed invention clearly falls under the section 3(e)
which clearly states that a, substance obtained by a mere admixture resulting only
in the aggregation of the properties of the components thereof or a process for
producing such substance is not considered as an invention and not patentable.

83. The opponent submits that the subject matter of Claims 1 to claim14 aredrawn to
compositions. The claimed composition in claim 1to 14 is not defined in terms of
its constituents ratio and concentration of the components which constitute the
impugned patent application and thus a mere admixture.

84. In absence of any comparative data highlighting the synergistic effect of the
components of the claimed composition of the impugned patent over its individual
components, the claims of the impugned patent application should be rejected
under section 3(e) read with section 25(2)(f) of the Act.Thus, impugned application
is liable to be rejected on this ground alone.
 68

(d) GROUND 4: INSUFFICIENCY OF DISCLOSURE

85. The complete specification does not sufficiently and clearly describe the invention
or the method by which it is to be performed.

86. The opponent states that it is a well settled rule that the specification should clearly
and fairly describe the invention and disclose the best mode of working the
invention so that the person skilled in the art could perform the invention without
any undue efforts and it is hereby stated that the applicant has failed to do so.

87. It is submitted that claims are not fairly based on the specification and complete
specification does not describe the invention and the method of performing the
invention. The invention is claimed for composition comprising certain
pharmaceutical compound formula I as claimed in claim 1, formula I-B in claim 4,
formula IC in claim 6, formula ID in claim 7, formula IE in claim 8 and formula II
in claim 9.

88. However, several categories of compounds though embraced by the claims are not
supported by description. Examples are as under.

Claim 1:
S. Markush structure Comment
No.
1

2 R5 is hydroxyl  There are no

such
 69
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

3 R2 is hydroxyl  There are no

such
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

4 Y and Z are CR” where R” are H, D, F, CI, Br, I,  There are no

CH3, CD3, CF3, alkyl, acyl, alkenyl, alkynyl, such
hydroxyl, formyl or SCH3 compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

5 R1 is  There are no
such
 70
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

halogen, nitro, cyano, amino, mercapto, formyl,

carboxy, carbamoyl, carbanoyl, esteryl, alkoxy, (C1-
C22) alkylthio, (C1-C22) alkylamino, ((C1-
C22)(alkyl))2amino, (C1-C22)alkylsulfinyl, (C1-C22)
alkylsulfonyl, (C6-C12) arylsulfonyl, (C3-C6)
carbocyclyl, (C6-C12) aryl, or heterocyclyl,
phosphoramidyl, or phosphate wherein R1 is
optionally substituted with one or more, the same or
different, R20;
6 R3 is (C1-C22) alkyl, halogen, nitro, cyano, amino,  There are no
mercapto, formyl, carboxy, carbamoyl, (C1-C22) such
alkoxy, (C1-C22) alkylthio, (C1-C22) alkylamino, compounds
((C1-C22) (alkyl))2amino, (C1-C22) alkylsulfinyl, (C1- whose
C22) alkylsulfonyl, (C6-C12) arylsulfonyl, (C3-C6) preparation is
carbocyclyl, (C6-C12) aryl, or heterocyclyl, shown in the
specification.
 No process of
 71
preparation
 No efficacy

7 R4 is (C1-C22) alkyl, fluoromethyl, difluoromethyl,  There are no

trifluoromethyl, hydroxymethyl, halogen, nitro, such
cyano, amino, mercapto, formyl, carboxy, compounds
carbamoyl, (C1-C22) alkoxy, (C1-C22) alkylthio, (C1- whose
C22) alkylamino, (C1-C22) (alkyl)2amino, (C1-C22) preparation is
alkylsulfinyl, (C1-C22) alkylsulfonyl, (C6-C12) shown in the
arylsulfonyl, (C3-C6) carbocyclyl, (C6-C12) aryl, or specification.
heterocyclyl  No process of
preparation
 No efficacy

8 R6 is hydroxyl, (C1-C22) alkoxy (C1-C22) alkyl,  There are no

ethynyl, allenyl, halogen, nitro, cyano, amino, such
mercapto, formyl, carboxy, carbamoyl, , (C1-C22) compounds
alkylthio, (C1-C22) alkylamino, ((C1-C22) whose
(alkyl))2amino, (C1-C22) alkylsulfinyl, (C1-C22) preparation is
alkylsulfonyl, (C6-C12) arylsulfonyl, (C3-C6) shown in the
carbocyclyl, (C6-C12) aryl, or heterocyclyl, specification.
 No process of
preparation
 No efficacy

9 Q is NR7  There are no
such
compounds
whose
preparation is
shown in the
specification.
 No process of
 72
preparation
 No efficacy

10 R7 is -(C=O)Oalkyl(C1-C22), - (C=O)alkyl(C1-C22),, -  There are no

(C=O) NHalkyl(C1-C22), -(C=O)N-dialkyl(C1-C22), - such
(C=O)Salkyl(C1-C22), halogen, nitro, cyano, amino, compounds
mercapto, formyl, carboxy, carbamoyl, (C1- whose
C22),alkylthio, (C1-C22) alkylamino, ((C1-C22) preparation is
(alkyl))2amino, (C1-C22) alkylsulfinyl, (C1-C22) shown in the
alkylsulfonyl, (C6-C12) arylsulfonyl, (C3-C6) specification.
carbocyclyl, (C6-C12) aryl, or heterocyclyl,  No process of
phosphoramidyl, or phosphate wherein R7 is preparation
optionally substituted with one or more, the same or  No efficacy
different, R20

Claim 4:
S. Markush structure Comment
No.
1

2 R5 is hydroxyl  There are no

such
compounds
whose
preparation is
shown in the
specification.
 73
 No process of
preparation
 No efficacy

3 R4isfluoromethyl, difluoromethyl, trifluoromethyl,  There are no

hydroxymethyl, halogen, nitro, cyano, 73 ydroxyl, such
amino, mercapto, formyl, carboxy, carbamoyl, compounds
alkoxy, alkylthio, alkylamino, (alkyl)2amino, whose
alkylsulfinyl, alkylsulfonyl, arylsulfonyl, preparation is
carbocyclyl, aryl, or heterocyclyl, shown in the
specification.
 No process of
preparation
 No efficacy

4 Y is D, F, CI, Br, I, CH3, CD3, CF3, alkyl, acyl,  There are no

alkenyl, alkynyl, hydroxyl, formyl or SCH3; such
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

5 R1 is  There are no
such
compounds
whose
preparation is
shown in the
specification.
 74
 No process of
preparation
 No efficacy

halogen, nitro, cyano, amino, mercapto, formyl,

carboxy, carbamoyl, carbanoyl, esteryl, alkoxy, (C1-
C22) alkylthio, (C1-C22) alkylamino, ((C1-C22)
(alkyl))2amino, (C1-C22)alkylsulfinyl, (C1-C22)
alkylsulfonyl, (C6-C12) arylsulfonyl, (C3-C6)
carbocyclyl, (C6-C12) aryl, or heterocyclyl,
phosphoramidyl, or phosphate wherein R1 is
optionally substituted with one or more, the same or
different, R20;
6 V is S  There are no
such
compounds
whose
preparation is
shown in the
specification.
 No process of
 75
preparation
 No efficacy

Claim 6:
S. Markush structure Comment
No.
1

2 R5 is hydroxyl  There are no

such
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

3 R4 is(C1-C22) alkyl, fluoromethyl, difluoromethyl,  There are no

trifluoromethyl, hydroxymethyl, halogen, nitro, such
cyano, amino, mercapto, formyl, carboxy, compounds
carbamoyl, (C1-C22) alkoxy, (C1-C22) alkylthio, (C1- whose
C22) alkylamino, (C1-C22) (alkyl)2amino, (C1-C22) preparation is
alkylsulfinyl, (C1-C22) alkylsulfonyl, (C6-C12) shown in the
arylsulfonyl, (C3-C6) carbocyclyl, (C6-C12) aryl, or specification.
heterocyclyl,  No process of
 76
preparation
 No efficacy

4 Y is D, F, CI, Br, I, CH3, CD3, CF3, alkyl, acyl,  There are no

alkenyl, alkynyl, hydroxyl, formyl or SCH3; such
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

5 R1 is monophosphate, diphosphate, triphosphate,  There are no

such
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

halogen, nitro, cyano, amino, mercapto, formyl,

carboxy, carbamoyl, carbanoyl, esteryl, alkoxy, (C1-
 77
C22) alkylthio, (C1-C22) alkylamino, ((C1-C22)
(alkyl))2amino, (C1-C22)alkylsulfinyl, (C1-C22)
alkylsulfonyl, (C6-C12) arylsulfonyl, (C3-C6)
carbocyclyl, (C6-C12) aryl, or heterocyclyl,
phosphoramidyl, or phosphate wherein R1 is
optionally substituted with one or more, the same or
different, R20;
6 R15 is Lipid,-(C=O)Oalkyl(C1-C22), -(C=O)alkyl(C1-  There are no
C22), -(C=O) NHalkyl(C1-C22), -(C=O)N-dialkyl(C1- such
C22), -(C=O)Salkyl(C1-C22), (C1-C22) alkoxy, compounds
halogen, nitro, cyano, amino, mercapto, formyl, whose
carboxy, carbamoyl, (C1-C22) alkylthio, (C1-C22) preparation is
alkylamino, ((C1-C22) (alkyl))2amino, (C1-C22) shown in the
alkylsulfinyl, (C1-C22) alkylsulfonyl, (C6-C12) specification.
arylsulfonyl, (C3-C6) carbocyclyl, (C6-C12) aryl, or  No process of
heterocyclyl, wherein R15 is optionally substituted preparation
with one or more, the same or different, R20  No efficacy

Claim 7:
S. Markush structure Comment
No.
1

2 R5 is hydroxyl  There are no

such
 78
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

3 R4 is (C1-C22) alkyl, fluoromethyl, difluoromethyl,  There are no

trifluoromethyl, hydroxymethyl, halogen, nitro, such
cyano, amino, mercapto, formyl, carboxy, compounds
carbamoyl, (C1-C22) alkoxy, (C1-C22) alkylthio, (C1- whose
C22) alkylamino, (C1-C22) (alkyl)2amino, (C1-C22) preparation is
alkylsulfinyl, (C1-C22) alkylsulfonyl, (C1-C22) shown in the
arylsulfonyl, (C3-C6) carbocyclyl, (C6-C12) aryl, or specification.
heterocyclyl,  No process of
preparation
 No efficacy

4 R2 is hydroxyl  There are no

such
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

5 R3 is hydrogen, alkyl, halogen, nitro, cyano, amino,  There are no

mercapto, formyl, carboxy, carbamoyl, alkoxy, (C1- such
 79
C22)alkylthio, alkylamino, (alkyl)2amino, compounds
alkylsulfinyl, alkylsulfonyl, arylsulfonyl, whose
carbocyclyl, aryl, or heterocyclyl preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

6 R1 is monophosphate, diphosphate, triphosphate,  There are no

such
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy


halogen, nitro, cyano, amino, mercapto, formyl,

carboxy, carbamoyl, carbanoyl, esteryl, alkoxy, (C1-
C22) alkylthio, (C1-C22) alkylamino, ((C1-C22)
(alkyl))2amino, (C1-C22)alkylsulfinyl, (C1-C22)
alkylsulfonyl, (C6-C12) arylsulfonyl, (C3-C6)
carbocyclyl, (C6-C12) aryl, or heterocyclyl,
phosphoramidyl, or phosphate wherein R1 is
 80
optionally substituted with one or more, the same or
different, R20;
7 Y and Z are N  There are no
such
compounds
whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

8 R6 is hydroxy, alkoxy, alkyl, ethynyl, allenyl,  There are no

halogen, nitro, cyano, amino, mercapto, formyl, such
carboxy, carbamoyl, alkoxy, (C1-C22)alkylthio, compounds
alkylamino, (alkyl)2amino, alkylsulfmyl, whose
alkylsulfonyl, aiylsulfonyl, carbocyclyl, aryl, or preparation is
heterocyclyl, shown in the
specification.
 No process of
preparation
 No efficacy

9 R15is -(C=O)Oalkyl(C1-C22), -(C=O)alkyl(C1-C22), -  There are no

(C=O) NHalkyl(C1-C22), -(C=O)N-dialkyl(C1-C22), - such
(C=O)Salkyl(C1-C22), (C1-C22) alkoxy, halogen, compounds
nitro, cyano, amino, mercapto, formyl, carboxy, whose
carbamoyl, (C1-C22) alkylthio, (C1-C22) alkylamino, preparation is
((C1-C22) (alkyl))2amino, (C1-C22) alkylsulfinyl, (C1- shown in the
C22) alkylsulfonyl, (C6-C12) arylsulfonyl, (C3-C6) specification.
carbocyclyl, (C6-C12) aryl, or heterocyclyl, wherein  No process of
R15 is optionally substituted with one or more, the preparation
 81
same or different, R20  No efficacy

10 R15’ is -(C=O)Oalkyl(C1-C22), -(C=O)alkyl(C1-C22), -  There are no

(C=O) NHalkyl(C1-C22), -(C=O)N-dialkyl(C1-C22), - such
(C=O)Salkyl(C1-C22), (C1-C22) alkoxy, halogen, compounds
nitro, cyano, amino, mercapto, formyl, carboxy, whose
carbamoyl, (C1-C22) alkylthio, (C1-C22) alkylamino, preparation is
((C1-C22) (alkyl))2amino, (C1-C22) alkylsulfinyl, (C1- shown in the
C22) alkylsulfonyl, (C6-C12) arylsulfonyl, (C3-C6) specification.
carbocyclyl, (C6-C12) aryl, or heterocyclyl,  No process of
preparation
 No efficacy

Claim 8:
S. No. Markush structure Comment
1

2 R5 is hydroxyl  There are no such

compounds whose
preparation is shown in the
specification.
 No process of preparation
 No efficacy

3 R4 is(C1-C22) alkyl, fluoromethyl,  There are no such

difluoromethyl, trifluoromethyl, compounds whose
 82
hydroxymethyl, halogen, nitro, preparation is shown in the
cyano, amino, mercapto, formyl, specification.
carboxy, carbamoyl, (C1-C22)  No process of preparation
alkoxy, (C1-C22) alkylthio, (C1-  No efficacy
C22) alkylamino, (C1-C22)
(alkyl)2amino, (C1-C22)
alkylsulfinyl, (C1-C22)
alkylsulfonyl, (C6-C12)
arylsulfonyl, (C3-C6) carbocyclyl,
(C6-C12) aryl, or heterocyclyl,
4 R2 is hydroxyl  There are no such
compounds whose
preparation is shown in the
specification.
 No process of preparation
 No efficacy

5 R3 is hydrogen, alkyl, halogen,  There are no such

nitro, cyano, amino, mercapto, compounds whose
formyl, carboxy, carbamoyl, preparation is shown in the
alkoxy, (C1-C22)alkylthio, specification.
alkylamino, (alkyl)2amino,  No process of preparation
alkylsulfinyl, alkylsulfonyl,  No efficacy
arylsulfonyl, carbocyclyl, aryl, or
heterocyclyl
6 R15is -(C=O)Oalkyl(C1-C22), -  There are no such
(C=O)alkyl(C1-C22), -(C=O) compounds whose
NHalkyl(C1-C22), -(C=O)N- preparation is shown in the
dialkyl(C1-C22), -(C=O)Salkyl(C1- specification.
C22), (C1-C22) alkoxy, halogen,  No process of preparation
nitro, cyano, amino, mercapto,  No efficacy
formyl, carboxy, carbamoyl, (C1-
C22) alkylthio, (C1-C22)
 83
alkylamino, ((C1-C22)
(alkyl))2amino, (C1-C22)
alkylsulfinyl, (C1-C22)
alkylsulfonyl, (C6-C12)
arylsulfonyl, (C3-C6) carbocyclyl,
(C6-C12) aryl, or heterocyclyl,
wherein R15 is optionally
substituted with one or more, the
same or different, R20
7 R15’ is -(C=O)Oalkyl(C1-C22), -  There are no such
(C=O)alkyl(C1-C22), -(C=O) compounds whose
NHalkyl(C1-C22), -(C=O)N- preparation is shown in the
dialkyl(C1-C22), -(C=O)Salkyl(C1- specification.
C22), (C1-C22) alkoxy, halogen,  No process of preparation
nitro, cyano, amino, mercapto,  No efficacy
formyl, carboxy, carbamoyl, (C1-
C22) alkylthio, (C1-C22)
alkylamino, ((C1-C22)
(alkyl))2amino, (C1-C22)
alkylsulfinyl, (C1-C22)
alkylsulfonyl, (C6-C12)
arylsulfonyl, (C3-C6) carbocyclyl,
(C6-C12) aryl, or heterocyclyl,
8 R6is hydroxy, alkoxy,  There are no such
alkyl,ethynyl,allenyl, halogen, compounds whose
nitro, cyano, amino, mercapto, preparation is shown in the
formyl, carboxy, carbamoyl, specification.
alkoxy, (C1-C22)alkylthio,  No process of preparation
alkylamino, (alkyl)2amino,  No efficacy
alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or
heterocyclyl
9 Q is –O(C=O)-, -O(C=O)lipid, -  There are no such
 84
O(C=O)V, NH, NR7 compounds whose
preparation is shown in the
specification.
 No process of preparation
 No efficacy

10 R7is -(C=O)Oalkyl, - (C=O)alkyl,  There are no such

-(C=O) NHalkyl, -(C=O)N- compounds whose
dialkyl, -(C=O)Salkyl, hydroxy, preparation is shown in the
alkoxy, alkyl, higher alkyl, (C6- specification.
Ci6)alkyl, (C6-C22)alkyl, halogen,  No process of preparation
nitro, cyano, amino, mercapto,  No efficacy
formyl, carboxy, carbamoyl,
alkoxy, (C1-C22) alkylthio,
alkylamino, (alkyl)2amino,
alkylsulfinyl,
alkylsulfonyl, arylsulfonyl,
carbocyclyl, aryl, or
heterocyclyl,wherein R7 is
optionally substituted with one or
more, the same or different, R20

Claim 9:
S. No. Markush structure Comment
1
 85
2 R5 is hydroxyl  There are no such
compounds whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

3 R4 is(C1-C22) alkyl, fluoromethyl,  There are no such

difluoromethyl, trifluoromethyl, compounds whose
hydroxymethyl, halogen, nitro, cyano, amino, preparation is
mercapto, formyl, carboxy, carbamoyl, (C1- shown in the
C22) alkoxy, (C1-C22) alkylthio, (C1-C22) specification.
alkylamino, (C1-C22) (alkyl)2amino, (C1-C22)  No process of
alkylsulfinyl, (C1-C22) alkylsulfonyl, (C6-C12) preparation
arylsulfonyl, (C3-C6) carbocyclyl, (C6-C12)  No efficacy
aryl, or heterocyclyl,
4 R2 is hydrogen, alkyl, alkenyl, alkynyl,  There are no such
ethynyl, fluoromethyl, difluoromethyl, compounds whose
trifluoromethyl, chloromethyl, hydroxymethyl, preparation is
halogen, nitro, cyano, hydroxy, amino, shown in the
mercapto, formyl, carboxy, carbamoyl, alkoxy, specification.
(C1-C22) alkylthio, alkylamino, (alkyl)2amino,  No process of
alkylsulfinyl, alkylsulfonyl, arylsulfonyl, preparation
carbocyclyl, aryl, azido, or heterocyclyl,  No efficacy

5 R3 is hydrogen, hydroxy, alkyl, halogen, nitro,  There are no such

cyano, hydroxy, amino, mercapto, formyl, compounds whose
carboxy, carbamoyl, alkoxy, (C1-C22) preparation is
alkylthio, alkylamino, (alkyl)2amino, shown in the
alkylsulfinyl, alkylsulfonyl, arylsulfonyl, specification.
carbocyclyl, aryl, or heterocyclyl,  No process of
 86
preparation
 No efficacy

6 R1 is monophosphate, diphosphate,  There are no such

triphosphate, compounds whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

7 W is CH2, NH, S or O  There are no such

compounds whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

8 X is CH2 or O  There are no such

compounds whose
preparation is
shown in the
specification.
 No process of
 87
preparation
 No efficacy

9 Y is N or CR";  There are no such

Z is N or CR"; compounds whose
Wherein each R" is independently selected preparation is
from is H, D, F, CI, Br, I, CH3, CD3, CF3, shown in the
alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl specification.
or SCH3;  No process of
preparation
 No efficacy

10 R6 is hydrogen, hydroxy, alkoxy, alkyl,  There are no such

ethynyl, allenyl, halogen, nitro, cyano, amino, compounds whose
mercapto, formyl, carboxy, carbamoyl, alkoxy, preparation is
(C1-C22)alkylthio, alkylamino, (alkyl)2amino, shown in the
alkylsulfinyl, alkylsulfonyl, arylsulfonyl, specification.
carbocyclyl, aryl, or heterocyclyl,  No process of
preparation
 No efficacy

11 Q is O, -O(C=O)-, -O(C=O)Lipid, -O(C=O)V-,  There are no such

NH, or NR7; compounds whose
preparation is
shown in the
specification.
 No process of
preparation
 No efficacy

12 V is O, NH, NR7, S, CH2, or CHR7;  There are no such

compounds whose
preparation is
 88
shown in the
specification.
 No process of
preparation
 No efficacy

13 R7 is independently selected from absent,  There are no such

hydrogen, -(C=O)Oalkyl, - (C=O)alkyl, - compounds whose
(C=O) NHalkyl, -(C=O)N-dialkyl, - preparation is
(C=O)Salkyl, hydroxy, alkoxy, alkyl, higher shown in the
alkyl, (C6-C16)alkyl, (C6-C22)alkyl, halogen, specification.
nitro, cyano, amino, mercapto, formyl,  No process of
carboxy, carbamoyl, alkoxy, (C1-C22)alkylthio, preparation
alkylamino, (alkyl)2amino, alkylsulfinyl,  No efficacy
alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl,
or heterocyclyl, wherein each R7 is optionally
substituted with one or more, the same or
different, R20

89. Thus, the Applicant has claimed large number of hypothetical compounds without
any basis in the specification. These claims are therefore entirely unsupported by
the specification. The combination of the substituents would yield large number of
compounds which are neither disclosed nor described by the specification. The
claims to these compounds is nothing but speculative. These claims are wholly
unsupported by specification.

90. Example 58, 60 and 62 represent tables of various compounds with their activities.
The Applicant has shown numerous compounds like EIDD-01931-04, EIDD-
02053-01, and many more. The impugned patent Application has not disclosed the
structure and process of preparation of these compounds. Furthermore, Applicant
has not shown that whether these compounds fall in claimed Markush or not.
Applicant has mentioned merely the efficacy data of these compounds.
89
 90

91. Furthermore, the Applicant has claimed composition with a certain Markush
structure in claim 9, but has failed to provide any relevant example that would
show preparation of compounds that fall within this claim 9. Claim 9 is not related
to claim 1 as the Markush structure of the compounds is different. No efficacy of
any such compound is demonstrated. Thus, this claim is entirely unsupported by
the specification.

92. As stated in foregoing paragraphs compound EIDD-1931 is disclosed by Bernard et

al, the Applicant realized this and hence they claim same compound by giving
other code EIDD-2216 which is shown below.

Example 3 page no. 55 Example 24 page no. 82

 91
93. It is submitted that though the application discloses various example 1-35. The
specification fails to provide any evidence such as analytical characteristics IR,
NMR etc. that would support a conclusion that the inventors were in fact in
position of any of the compound at the time of filing of impugned application, thus,
the only conclusion can be drawn that these compounds ar hypothetical.

94. It is further submitted that the claims embraced countless compositions containing
compounds that are not generated by the Applicant and not known in
pharmaceutical arts. The 35 examples do not adequately support the breadth of
these claims. As such the claims are unduly broad and not based on the
specification. The specification does not provide adequate breadth to support the
broad generic claims.

95. Thus Applicant claims several hundred hypothetical compounds without any basis
in the specification. The claims being un-supported by the specification and
specification being deficient in supporting claims falls in the bar section 25 (1) (g).

96. Further the claims of the impugned invention are drawn tocompositions; however
the specification is silent about any composition. The breadth of the claims is too
wide which is not supported by the disclosures. The claims do not define the
constituents of the compositions.

97. Applicant claim effectiveness against a wide range of viruses, but do not show
efficacy data for all.

98. The above clearly discloses that impugned patent application does not sufficiently
and clearly describe the invention. Therefore, impugned patent application should
be rejected.

99. The impugned patent application does not provide adequate teaching to a person
skilled in the art to practice the invention. Considering above, impugned patent
application does not sufficiently and clearly describe the invention. Therefore, the
impugned patent application should be refused on this ground alone.
 92
(e) GROUND 5 -Section 25(1)(h)

100.The Applicant has failed to disclose to the Controller the information required
under Section 8.The applicant is required to provide all the information
regarding the prosecution of the equivalent applications till the grant of the
Indian application to the Controller in writing from time to time and also
within the prescribed time. It is observed that applicant has not updated the
status of corresponding application in the Form-3 which information has not
been provided to the learned Controller.

101.The applicant has not informed the patent office about the status of the
corresponding patent applications; JP2018500354- notice of refusal. The applicant
has failed to inform the Indian patent office of the same and therefore, on this
ground alone the patent application should be rejected.

102.Therefore, the applicant has failed to comply with the requirements of the
section 8 of the act and the opponent demands rejection on this ground also. It
is submitted that the Applicant has failed to disclose the details of
corresponding foreign applications and impugned patent application to be
refused.

CONCLUSION

In view of the above, the claims are not inventive, not patentable and insufficient.
The pre-grant opposition as filed may be allowed and the subject patent application
may be refused.

HEARING REQUESTED

The Opponent hereby requests a hearing under section 25(1) of the Patents Act,
1970 (hereinafter referred to as “the Patents Act”) and Rule 55 of the Patents Rules
(hereinafter referred to as “the Rules”).
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PRAYER

In the fact and circumstances of the case, the Opponent prays as follows:

i. that the Indian Patent application number 201717025098 filed on14/07/2017

in the name of EMORY UNIVERSITY, be refused under Section 25(1) of the
Patents (Amendment) Act, 2005;

ii. the Opponent may be allowed to file further documents as evidence if

necessary, to support its averments;

iii. the Opponent may be allowed to make further submissions in case the
applicant makes any amendments in the claims;

iv. the opponent may be allowed a hearing under section 25(1) of the Patents Act
read with rule 55(1) of the Patents Rules;

Dated this 6th day of September, 2021

RAJESHWARI H. IN/PA - 0358

AGENT FOR THE OPPONENT
OF RAJESHWARI AND ASSOCIATES

TO,
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, NEW DELHI