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This Revocation Application has been filed against the patent No.219504 “Combination of Brimonidine and Timolol” for topical Opthalmic use. The revocation is sought for on various grounds viz., that the Patent was obtained on a false suggestion or representation, that it is not an invention that it is obvious, that it does not sufficiently disclose and that Section 8 of the Patents Act, 1970 was violated.= As regards Section 3(e), according to the applicant it is merely an admixture and each drug provides the effect that any way individually it would do. We have already seen that the two drugs work in a different way in reducing IOP. The tests do not compare the composition with sequential combination as shown in Yuksel. The nearest prior art is the serial administration. A comparison with that would have shown if the improvement is only additive or more. That evidence is not before us. In view of our holding against the respondent on obviousness and S.8.Compliance it is not necessary for us to decide the 3(e) issue. 104. We have found the claimed invention as obvious. The BID administration was known and % / w of the drugs was also knownWe are not inclined to accept the amendments at this stage. =For the above reasons ORA/21/2011/PT/KOL is allowed and patent No.219504 is revoked. M.P. No.2/2012 is closed. As regards M.P. Nos.59/2012, 128/2012 and 134/2012 no orders are necessary. M.P. Nos. 60, 61, 72, 73, 127, 135/2012, 12/2013 and 15/2013 are allowed.

published in  http://www.ipab.tn.nic.in/173-2013.htm

English: Timolol Structural Formulae

English: Timolol Structural Formulae (Photo credit: Wikipedia)

chemical structure of Brimonidine

chemical structure of Brimonidine (Photo credit: Wikipedia)

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Conventional surgery to treat glaucoma makes a...

Conventional surgery to treat glaucoma makes a new opening in the meshwork. This new opening helps fluid to leave the eye and lowers intraocular pressure. Description: Conventional surgery to treat glaucoma makes a new opening in the meshwork. This new opening helps fluid to leave the eye and lowers intraocular pressure. Credit: National Eye Institute, National Institutes of Health Ref#: EDA11 (Photo credit: Wikipedia)

BOARD

Guna Complex Annexe-I, 2nd Floor, 443, Anna Salai, Teynampet, Chennai-600 018

ORA/21/2011/PT/KOL

AND

M.P. NOS.60/2011, 2/2012, 59-61/2012, 72/2012, 73/2012, 127/2012, 128/2012, 134/2012, 135/2012, 12/2013 AND 15/2013

IN

ORA/21/2011/PT/KOL

 

THURSDAY, THIS THE  8TH DAY OF AUGUST , 2013

 

Hon’ble Smt. Justice Prabha Sridevan   … Chairman

Hon’ble Mr. D.P.S.Parmar                         …Technical Member (Patents)                                                                                            

AJANTHA PHARMA LIMITED,

A Company Incorporated under the Companies Act, 1956

Having its Regd. Office at Ajantha House,

Charkop, Kandivili,

(West ) Mumbai-400 067 (India)                                     … Applicant

(Represented by Shri S.Majumdar, Ms. Mythili Venkatesh & Ms.Sultana Kader Sheikh Amirta Majumdar)

Vs.

1. ALLERGAN INC.

2525 Dupont Drive,

T2-7H Irvine,

CA (USA)

2. ALLERGAN INDIA PVT. LTD.,

Prestige Obelisk,

2nd Floor Kasturba Road,

Bangalore-560 001. India.

3. THE CONTROLLER OF PATENTS,

intellectual Propoerty Office Building,

CP-2, Sector V.Salt Lake City,

Kolkatta -700 091.  (India)                                       … Respondents

(Represented by Mr. Pravin Anand, Ms. Archana Shankar, Ms.Geetanjali Viswanathan & Ms.Gitika Suri)

ORDER (No.173 of 2013)

 

Hon’ble Smt. Justice Prabha Sridevan, Chairman

This Revocation Application has been filed against the patent No.219504 “Combination of Brimonidine and Timolol” for topical Opthalmic use. 

The revocation is sought for on various grounds viz., that the Patent was obtained on a false suggestion or representation, that it is not an invention that it is obvious, that it does not sufficiently disclose and that Section 8 of the Patents Act, 1970 was violated.

2.         The following prior arts were relied on, these were published prior to the priority date of this invention viz., 19.4.2002, and they are:-

Yuksel, N. et al: “the short term effect of adding brimonidine 0.2% to timolol treatment in patients with open–angle glaucoma” published in OPTHALMOLOGICA Vol.213, page 228-233 (hereinafter referred to as d1) in 1999 is annexed hereto as EXHIBIT “D1”

Larsson: “Aqueous Humor Flow in Normal Human Eyes treated with Brimonidine and Timolol, alone and in combination”, published in arch OPTHALMOL, Vol. 119 April, 2001 (2001-04) pages 492495 (hereinafter referred to as d2) published on April, 2001 is annexed  hereto as EXHIBIT “D2”.

US 5502052 (hereinafter referred to as D3) published on March 26, 1996 is annexed hereto as EXHIBIT “D3”.

3.         According to the applicant, the only advantage of the ophthalmic pharmaceutical composition of the impugned patent is that the patient is exposed to lesser amount of benzalkoniuim chloride (preservative) (BAK in Short) during daily treatment regimen.

According to the applicant, Exhibit D1 relates to the effect of addition of brimonidine (0.2%) to timolol treatment (0.5%) in patients with open angle glaucoma.

The abstract of Exhibit D1 shows that intra ocular pressure (in short ’IOP’) was reduced by brimonidine and timolol treatment where the two drugs were administered serially.   A single drop of brimonidine 0.2% or placebo was added to treatment with timolol. The reductions in IOP at all time intervals observed with brimonidine + timolol were significantly greater than those with timolol + placebo.  The maximum mean net decrease in IOP was 9.23 +/- 10.60% at 4 h. Statistically significant decreases in systemic blood pressure and pulse rate without clinical symptoms were observed in the group receiving Brimonidine + Timolol. This study suggests that a combination of brimonidine and timolol may have potential in the treatment of glaucoma. The clinical result in Tables 3 and 4 of this prior art shows that IOP was reduced with the combination of timolol and brimonidine when compared with Timolol + Placebo.  Exhibit D1 also shows that single drop of Brimonidine 0.2% causes a significant additive reduction in IOP in glaucomatous eyes in which IOP was not adequately controlled using Timolol alone.   “We conclude that there is an additional statistically significant IOP lowering effect of approximately 20% when a single drop of brimonidine 0. 2% is administered adjunctively to patients whose pressures on timolol are in the low twenties.  The systemic side effects were minimal. This study indicates that combination of brimonidine and a β blocker may have potential in the treatment of glaucoma.”

4.         Therefore the person skilled in the art would have definitely considered formulation as a single composition in view of Exhibit D1.  According to the petitioner, the palpable difference between the impugned patent and D1 is the combination in a single composition and combination as individual composition. This is obvious. It would also be obvious to a person with sound intellect that the amount of BAK required for a combination in a single composition would be less than that required in when the two drugs are administered separately.

5.         According to the applicant, Exhibit D2 is also a relevant prior art. The treatment group of study in Exhibit D2 comprised. 1. Placebo treated eyes; 2. Brimonidine treaded eyes; 3. Timolol treated eyes; and 4. Brimonidine and Timolol treated eyes. It showed that Brimonidine suppresses aqueous humor formation, but not as efficiently as Timolol. However, the effects on the IOP of both drugs separately were comparable.  When Timolol and Bimonidine were applied in combination, a further reduction of aqueous humor flow and IOP was seen.  The effect on the IOP was greater than expected from reduction of flow.

6.         Therefore according to the petitioner, Exhibit D1 and Exhibit D2 teach that

1) addition of Brimonidine at concentration of 0.2% to timolol 0.5% treatment regimen achieves additive reduction in IOP; hence claim 1 and 2 of the impugned patient is obvious and devoid of inventive step;

2) Co-administration of Brimonidine (0.2%) and Timolol (0.5%) twice daily showed benefits/advantages of Brimonidine when incorporated in glaucoma treatment regimen comprising Timolol thereby making the alleged invention obvious on its technical facet;

3) Minimal occurrence of adverse effects when both the drugs are co administered to patient; and 4) Much assured/reasonable expectation of success to formulate combination in single composition.

7.         Therefore the mere fact that Brimonidine and Timolol were administered in a single installation cannot indicate any inventive step.  According to the applicant, Exhibit D3, which relates to ophthalmic pharmaceutical composition containing combination of α-2,-agonist and  a β-blocker  indicated that  a significant number of glaucoma  patients required administration  of more than one drug in order to achieve therapeutic control of IOP.

According to the applicant, the greater reduction in IOP was due to the combination therapy.  

Exhibit D 3 postulates that “β Blockers inhibit the formation of aqueous humor in the ciliary processes by binding with beta-2 receptors, thereby preventing the receptors from being stimulated to form aqueous humor; while alpha-2 agonists appear to act by means of a three part mechanism involving;

(1) vasoconstriction in the ciliary processes;

(2) binding with presynaptic Alpha-2 receptors to inhibit the release of neurotransmitters that act on beta-2 receptors to cause aqueous humor formation, and

(3) binding with inhibitory afpha-2 in ciliary  epithelial cells thereby preventing aqueous humor formation”. 

8.         Given the teachings of these three prior arts and the addition of BAK and the state of the art at the time of invention the invention is obvious. Exhibits D1 and exhibit D2 motivated the combination of the two drugs. Exhibit D3 taught the manner in which it can be done.

 

9.         According to the applicant, the complete specification merely disclosed the constituents of the composition and not about the prior art that lead to the proposed composition.

10.       According to the applicant, the invention is a mere admixture the benefit provided by the invention is additive where each of the two drugs caused the respective therapeutic effect independent of each other. The advantages of combination of two drugs were known in the state of the art.

11.       According to the applicant, the invention is not patentable under Section 3 (d) of the Patents Act, 1970.

There is no data in the specification to show that the ophthalmic composition of Brimonidine and Timolol has an enhanced efficacy when concomitant administration of both Brimonidine and Timolol was known in the art.

Section 3 (d) includes “combination.”  The respondent has only shown the advantageous effect of combination of the two active ingredients over the individual active ingredients. According to the applicant the respondent ought to have shown the advantages of the single composition over the serial administration of the two drugs

12.       According to the applicant, the respondent has failed to disclose to the controller the information required by Section 8 of the Act, in particular, the European counterpart of the subject Patent which was refused vide decision dated 11.12.2007. This is marked as Exhibit E.  According to the applicant, the respondent had not tendered the following details:-

a) US7323463: non final rejection dated March  24, 2005; non final rejection dated July 15, 2005; final rejection dated February 28, 2006; non final rejection dated December 14, 2006, final rejection dated June 4, 2007.

b) US7030149: non final rejection dated October 3, 2002; non final rejection dated May 7, 2003; final rejection dated August 26, 2003; non final rejection dated February 13, 2004; non final rejection dated March 29, 2004, final rejection dated December 16, 2004; .non final rejection dated July 14, 2005., and

c) US7320976: non final rejection dated December 19, 2005; final rejection dated May 26, 2006; non final rejection dated May 26, 2006; non final rejection dated December 15, 2006, final rejection dated June 4, 2007.

 

13.       On these grounds the Patent was sought to be revoked. Along with the petition, the applicant had filed the evidence of Dr. Sudhakar G. Deshpande,  the Professor and Principal of C.U. Shaw College of Pharmacy. This evidence was subsequently withdrawn and therefore we have not taken it into account.

14.       The applicant mainly relied on the grounds of obviousness, S.3(d) , S.3(e) and S. 8 violation for seeking revocation of the patent.

15.       The respondent’s patent was filed as a national phase application of International Application no.PCT/US03/10885 with the Indian patent office. The national phase entry was effected on 14th Oct.2003 with a priority date of 19th April 2002.

In the counter statement, the respondent submitted that the invention claims a fixed composition for the treatment of glaucoma or ocular hyper tension which comprises a blend of Brimonidine and Timolol in a single bottle.  More specifically, the claimed composition comprises of a)  0.01% to 0.5% by weight of Brimonidine; b)   0.1% to 1.0% by weight of Timolol; and c)   A pharmaceutically acceptable carrier. The commercial product is known as Combigan®. It comprises the combination of Brimonidine tartarate and Timolol maleate is covered within the scope of the impugned invention.  The U.S. FDA approved Brimonidine   to be administered thrice a day (TID) and  Timolol   twice a day (BID). Serial administration of the two drugs was also known. But the combination of two drugs in a fixed combination was neither taught nor suggested by the prior art. This combination is the result of an inventive step.  Brimonidine tartarate 0.2% was marketed by respondent no.1 as Alphagan ®, and was first developed by respondent No.1 as a new glaucoma medication in the late 1980s and 1990s. Brimonidine is an alpha-2 adrenergic agonist that lowers intraocular pressure in glaucoma patients by reducing aqueous humor production in the eye while also increasing uveoscleral outflow from the eye. Alpha was dosed thrice a day (TID) since administration twice a day (BID) resulted in lowered efficacy. It was found to cause a high rate of ocular allergy and other side effects. 

 

16.       The respondent relied on

1) L. Jay Katz, twelve Month Evolution of Brimonidine-Purite versus Brimonidine in patients with Glaucoma or Ocular Hypertension, Journal of Glaucoma 11:119-126, document marked and exhibited as Exhibit R1; and

2) Sherwood et al., Twice-Daily 0.2% Brimonidine-0.5% Timolol Fixed-Combination Therapy vs Monotherapy with Timolol or Brimonidine in patients with Glaucoma or Ocular-Hypertension, Arch Ophthalmol/Vol 124, September 2006, document marked Exhibit R2.

Because of the side effects of Brimonidine, the respondent began to try and improve products. But it could not get approval for (BID) dosing.

The respondent submitted that Timolol is a beta blocker which lowers intraocular pressure by suppressing aqueous humor production. This drug was developed and marketed by Merck under the trade name Timoptic®,

 

17.       According to the respondent, serial administration and combination are two different modes of administration. The most common form of treatment was serial or concomitant administration of two or more different medications provided in two or more separate bottles.  This type of serial administration is considered “unfixed,” because the same amount of each of the drugs may not be administered.  This is in contrast to “fixed” combination.  The “unfixed” administration has certain advantages over the fixed combination. According to the respondent, the former was more flexible and when they are used serially they do not react in the patient’s eyes. Therefore recommended dosing means they are administered at least 5 minutes apart.  However, serial administration means administration of the drugs a number of times in a day and at different times.  Timolol is a BID while brimonidine is TID.  The majority of patients with glaucoma are elderly and therefore there is the problem of patient compliance.  Exhibit R3 is Tony Realini,” Two Drugs, one bottle; the Pros and Cons, Review of Ophthalmology.”  It says that “For many reasons, not every possible pair of glaucoma drugs can be combined in one bottle; many stars must be aligned for such a combination to be feasible. For instance, both drugs must be soluble at the same pH or one of the drugs could end up in a clump of powder at the bottom of the bottle. More importantly, the two drugs to be combined must have comparable dosing frequency and timing.” The respondent stressed this challenge to show that there would be no motivation.

18.       According to the respondent the teachings and prior art were against such combination. The respondent produced Exhibit R4, which (Alphagan®) (Alphagan®) and Timolol package inserts.   This contains the following warning “However, since Alpha-agonists, as a class, may reduce pulse and blood pressure, caution in using concomitant drugs such a beta blockers (ophthalmic and systemic) antihypertensive and/or cardiac glycosides is advised.” The respondent submitted that there were several failed attempts formulating the combination of products and also that FDA approval could not be obtained. The difficulties faced by the respondent were as follows: a)  The use of two different active ingredients posed challenges to the formulators because these ingredients have different physico-chemical characteristics, and therefore would required two different formulations. The challenge was to accommodate the requirements of these two different active ingredients in single formulation;    b) Further, there was a possibility of reactivity between Brimonidine and Timolol because the secondary amines in brimonidine can act as nucleophiles that attach the electron poor carbon-nitrogen double bonds present in Timolol; c) Another challenge was the use of active ingredients in two different salt forms.  This is because the salts are dissociated in solution and at certain pHs the counter ion forms can react with active ingredients; and d) The pH difference between previous formulations of brimonidine tartarate and timolol maleate was an additional challenge. PH is a very important factor as it affects the solubility, stability and bioavailability of the active ingredients. Brimonidine tartarate was formulated at pH range of 6.3 to 6.5 in commercial formulations comprising said active (Alphagan®) while Timolol maleate was formulated at a ph of 7.0 (Timoptic®) (Exhibit R4; and Sterile Ophthalmic Solution Timoptic® 0.25% and 0.5% at page 1, document marked and exhibited as Exhibit R5) because pH is measured on a logarithmic scale, this difference of up to 0.7 pH units is significant. The difference between the previous formulations of the two drugs was an additional challenge. The two drugs had been previously formulated with different buffer systems and respondent referred to exhibit R-5, Timolol maleate ophthalmic solution had been previously formulated with two different concentrations of BAK. According to the respondent, these were some of the challenges which would have discouraged the person skilled in the art from trying the invention combination. Further BAK was known to be toxic to cells.  Therefore the ingredients in the uptake  were not desirable. Purite which is a mild preservative had also been used and therefore there was no reason why BAK which is cyto-toxic would be selected.

19.       Another unique clinical challenge in formulating the combination was the reduction of the dose Brimonidine from TID to BID without losing efficacy. The reason for respondent No.1’s prior failure was the significant difference in the intraocular pressure-lowering effect of Brimonidine dosed BID compared to Brimonidine dosed TID.  It was seen in clinical studies that two hours after the TID group received their second dose of Brimonidine and nine hours after the first (and only) dose of Brimonidine was administered to the BID group, there was an additional mean decrease in IOP in the TID group as compared to the BID group. This phenomenon is known as “after trough” of IOP with BID dosing of Alphagan®. The added effect of the third dose in the afternoon is known as the “afternoon peak” of TID dosing, so named because the effect of that afternoon dose is at its “peak”.

20.       Therefore the person skilled in the art knew that if brimonidine was (BID) there would be a significant decrease in efficacy. In two clinical trials on Combigan®, numbered 190342-012T (marked and exhibited as Annexure R6) and 190342-013T (marked and exhibited as Annexure R7), it was demonstrated that Combigan ® dosed BID showed numerically better and statistically equivalent intraocular  pressure lowering compared to Brimonidine monotherapy dosed TID. The studies also showed that there was a significant allergy reduction which appeared to be attributable to the single fixed combination formulation.  There were fewer incidents of nervous system side effects. The respondent referred to a clinical review of the year 2007, which showed  “(b) finding a significant between-group difference in the current severity of Sleepiness Responders (a clinically  relevant endpoint associated with decreased reaction time and impaired cognitive performance), Allergan has demonstrated that the fixed combination, alternative dosing regimen would provide a useful product because the safety  profile of the proposed combination is better than that of the individual agents taken as currently permitted in the approved labeling (emphasis added)”

21.       According to the respondent, the invention had following advantages:-

A. The composition claimed in IN 219504 is reasonable chemically stable;

B. The combination reduces the exposure of patients to high concentrations of  BAK;

C. The combination reduces side effects;

D. The combination  is approved by the US FDA for twice a day dosing instead of thrice a day dosing thereby substantially reducing the exposure of patients to brimonidine, which in spite of being very effective in controlling ocular hypertension also causes various side effects; and

E. The composition is more effective than its components.

According to the applicant, Exhibits D1 and D3 do not teach the invention because both teach only serial administration. The prior art documents are different from the invention and a prior art which teaches serial administration cannot render the fixed combination as obvious.

 

22.       According to the respondent, the process of combining two active anti-glaucoma agents may have the potential for increased activity.  However, it cannot be assumed that a combination of the two anti-glaucoma agents will constitute a successful formulation.  It cannot be deemed obvious that drug combinations result in improved therapeutic activity. Drug stability may become an issue when two drugs are combined. Unexpected drug-drug interactions could occur leading to profound effects, e.g., rendering the combination inactive. The case is similar with reduction in side-effects which cannot be predicted with drug combinations. A combination of the two drug moieties could in fact increase side-effects due to simultaneous exposure of the two drugs to the patient.

23.       The respondent also pointed out that Exhibit D1 states only the short term effect.  The respondent relied on Derrick et al, which published Phase 2 results of a one month dose response and according to the respondent, the findings in these documents that short term exposure is not representative of long term exposure. According to the respondent, Exhibit D1 showed that the serial administration is not necessarily predictive of the kind of drug interactions that may occur or the hurdles that one of skill in the art would need to overcome to stably put the two drugs together in a single bottle.

24.       According to the respondent Exhibit D2 is also irrelevant and deals with two days’ study with a Healthy Human subjects. Both do not teach or suggest the effect of administration of a combination like the invention.  According to the respondent exhibit D2 is speculative and not conclusive. Neither of the prior arts rendered the invention obvious. As regards Exhibit D3, it was submitted that a mere suggestion that a combination of drugs may be needed to cure a disease does not indicate that any two drugs can be combined in a single formulation. Drugs may react in different ways that cannot be predicted when placed with other drugs. The field of formulation chemistry is highly unpredictable, and in fact Exhibit D3 refers to the serious pulmonary side effect of timolol and given the lengthy list of beta-blockers Exhibit D3 does not teach any particular beta-blocker. Further the ‘052 patent states that clonidine derivatives are the preferred alpha agonists and specifically discloses a list of 17 clonidine derivatives and brimonidine does not find a mention in said list. Moreover, because brimonidine was considered a “far from perfect drug” due to its systemic side effects and potential for allergy, a person skilled in the art would be motivated to look for better options.

25.       According to the respondent, Exhibit D3 is a laundry list of possibilities and there is no mention of Brimonidine. Formulation chemistry is a highly unpredictable field and the availability of so many possibilities of creating a combination of ophthalmic drugs does not provide any direction to the claimed invention. Exhibit D3 suggests thousand possible combinations, none of the cited prior art documents teach the invention. According to the respondent the invention is not a mere admixture. The claims contain no requirement that the compositions have increased stability. Furthermore, the specification does not represent that the claimed compositions have increased stability.  Rather, the background section merely observes that there is a need for compositions with increased stability.  Further in the complete specifications it is found that side effects like incidence of oral dryness, eye purites, foreign body sensation and conjunctival folliculosis were statistically significantly lower with the combination than with Brimonidine (p<  0.034… There were no statistically significant differences in adverse events between the combination and Timolol.  The Combination administered BID demonstrated a favourable safety profile that was comparable to Timolol BID and better than Brimonidine TID with regard to the incidence of adverse events. Therefore it is clear that this fixed combination shows a synergy of the two drugs.

26.       According to the respondent the invention does not fall within the ambit of Section 3(d) and even if it were to be held that it did the clinical trial with the fixed combination of the two drugs produced a reduction in IOP and therefore this is an improved efficacy as compared to Brimonidine or Timolol monotherapy.

As regards the non-compliance of Section 8 it is stated that the respondent had kept patent office duly informed regarding the status foreign applications from time to time and had thereby complied with section 8. 

27.       The respondent filed two affidavits of experts Mr. Gary J.Beck  &  Ms. h.  Mr Beck affidavit speaks of the challenges in development of Combigan ®, which is explained in Exhibit R3 (referred to as R.W.2).  According to him, this combination is highly complex. Another challenge was in view of the difference of  pH values.  He has also referred to the number of failed attempts.  As indicated, after the failure of the Purite formulation, Respondent tried BAK. Commercially available timolol maleate contained 0.01% BAK and respondent believed that the combination product being developed would require this amount of BAK. The expert stated that the respondent expected that a reduction in the concentration of BAK may result in a reduction in the efficacy of the combination product. Nevertheless, due to BAK’s side effects, respondent conducted experiments to investigate whether a lower amount of BAK could be used as a preservative in the combination.   According to this expert, Exhibit D3 does not teach the invention. It discloses almost all the possible alpha and beta blocker and all possible concentration ranges, resulting in around 244,944 possibilities.  Therefore the prior art do not teach the invention.

28.       Ms.  Amy Batoosingh affidavit refers to the significant side effects and the contra indication of timolol. According to her, in addition, a fixed-combination of 2 agents eliminates the risks associated with washout of the first administered IOP lowering agent in concurrent therapy. This witness was also speaks of regulatory hurdles. “Fixed-combinations limit clinician’s ability to individualize treatment for patients: a) The concentration of each component is fixed; and b) the dosing frequency of a fixed-combination may differ from the frequency with the individual components. The goal of a fixed-combination product would be to offer the most likely pairing of drugs in the most likely concentration at a convenient dosing frequency for the patient.”   According to her, “there was a little reason to believe that the fixed combination would be successful in reducing the dosing frequency of Brimonidine from three to two times a day and still meet FDA expectations. Allergan had already tried several times and failed to convince the FDA that Brimonidine could be given twice a day. “.   The person skilled in the art would know that if Brimonidine is dosed (BID) the efficacy would be lowered in the afternoon.  According to her, Brimonidine monotherpy dosed (BID) when compared with the Combigan® showed that Combigan® had clinically meaningful reduction of side effects, which was initially unbelievable. The improved allergy profile was also not predicted. According to her, the reduced concentration of BAK in the fixed combination when compared to the serial use was another benefit.  According to her Exhibit D1 which is a two day study suggested if at all a thrice a day dosing to the Person Skilled in The Art because a12 hour point would be important to a twice daily regimen. As regards Exhibit D2, this witness raised the same point of teaching away. Further according to her, Exhibit D2 was not aimed towards using a fixed combination to lower IOP.

29.       As regards exhibit D3, she has again spoken of  the huge number of possibilities which the other expert referred to.  She has given evidence that the invention is not mere admixture that there is synergy.  She also spoken of the entire improved efficacy and the list of North American Studies conducted by the respondent to determine safety. According to the respondent none of the grounds raised by the applicant merited acceptance.

30.       Thereafter the applicant filed a reply, wherein it is stated that FDA approval cannot be a reason to justify the validity of patent.

The applicant has produced Exhibit RCS-1 to show that fixed dose combination was a topic of debate and that Indian Drug Shelves are packed with fixed dose combination drugs. Selection of known individual drugs and adjusting it with the quantity or percentage of excipients is known. Exhibit R1 is a post patent document and cannot be relied on.

Exhibit R2 is also post patent document and cannot be relied on. There is enough teaching in the art to motivate towards invention. It was also stated that the rationale for combination therapy relates to the concept that antihypertensive efficacy may be enhanced when 2 classes of agents are combined. In addition, combination therapy enhances tolerability-1 drug of a fixed combination can antagonize some of the adverse effects of the second drug.  Fixed-dose combination therapy simplifies the treatment regimen, preventing treatment failures that might result from missed doses. The invention is obvious in view of the prior art, the impugned patent can be arrived at by routine trial and error methods. There is no  invention. The reduction in aqueous humor flow with brimonidine and timolol combination was 58.9% as against 33.5% by brimonidine alone and 49.9% by timolol alone. The reduction in IOP with brimonidine and timolol combination was 34.7% as against 20.3% by brimonidine alone and 22.9% by timolol alone. The studies under question are short term studies but would undoubtedly provide motivation/impetus to a skilled artisan to formulate a fixed dose combination.

31.       According to the applicant, the prior art teaches serial application and it is the first step and once it is successful it would pave the way for fixed dose combination. For the purpose of specification of D3, all such compounds are defined as being “clonidine derivatives”. The applicant states that brimonidine falls in the definition of clonidine like derivative as brimonidine differs only by the aryl portions (but still falls in the same category of halogen substituted aryls) and the remaining two functionalities (the bridge and imidazolidine moiety) are same/identical belonging to the class described above as “clonidine derivatives. The applicant  maintained that arriving at fixed dose combination is obvious in view of teachings of the prior art. According to the applicant,

A. A formulation combining brimonidine and timolol in single composition is obvious to try with teachings in the art at the time the alleged invention was being made;

B. Teachings in the art were indicative of BID dosing as the studies were conducted by addition of brimonidine BID to. Timolol therapy;

C. The challenges and difficulties is the subject matter of routine optimization trial and error methods undertaken to formulate a combination composition.

32.       The respondents have not demonstrated the synergy in efficacy, it is a mere admixture.  The respondents have not demonstrated the enhancement in therapeutic efficacy.  The respondent contend that the IOP reduction by brimonidine and timolol combination claimed are comparable with the serial administration of brimonidine and timolol. However, they have not demonstrated the enhancement in therapeutic efficacy. The respondents have not supported the specification with any data demonstrating enhanced efficacy allegedly claimed of the composition as against the activity of the individual actives. The respondents have incorrectly deciphered enhancement in therapeutic efficacy as “reduction in intraocular pressure comparable to serial application.” The respondent has not shown that it had complied with Section 8 of Patents Act, 1970.

For the above reasons, the patent deserves to be revoked.

 

 The complete specification reads as follows:

 

COMBINATION OF BRIMONIDINE AND TIMOLOL FOR TOPICAL

OPTHALMIC  USE

 

 

 

BACKGROUND OF THE INVENTION.

This invention relates to the topical ophthalmic use of brimonidine in combination with timolol when indicated for treatment of glaucoma or ocular hypertension. Such combinations or formulations are available for separate use in ophthalmic art and have been combined in serial application….. There is moreover, a long felt need for an effective and safe topical ophthalmic pharmaceutical composition including brimonidine and timolol which has increased stability and requires a lower effective concentration of preservative as compared to the individual agents taken alone. Finally, there is a need to increase the efficacy of many topical ophthalmic agents, without increasing the efficacy of a many topical ophthalmic agents, without increasing the systemic concentration of such topical agents, since it is well known that many of such topically applied ophthalmic agents cause systemic side effects e.g., drowsiness heart effects etc., Unexpectedly it has been discovered that brimonidine in combination with timolol meets these criteria…………………..

Brimonidine is available from Allergan, Inc., Irvine, California as an ophthalmic pharmaceutical product having the name Alphagan®. Timolol is available from various sources, including Merck Co., Rahway, New Jersey.

The compositions of the present invention are administered topically. The dosage is 0.001 to 1.0 e.g., mg/per eye BID; wherein the cited mass figures represent the sum of the two components, brimonidine and timolol. The compositions of the present invention can be administered as solutions in a suitable ophthalmic vehicle.

In forming compositions for topical administration, the mixtures are preferably formulated as 0.01 to 0.05 percent by weight brimonidine and 0.1 to 1.0 percent by weight timolol solution in water at a pH of 4.5 to 8.0 e.g about 6.9……..

Antimicrobial Preservatives:

Ophthalmic products are typically packaged in multidose form.  Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: Benzalkonum chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate  disodium, sorbic acid, Onamer M, or other agents  known to those skilled in the art. In the prior art ophthalmic products, typically such preservatives are employed at a level of from 0.004% to 0.02%.  In the compositions of the present application the preservative,   preferably benzalkonium chloride, may be employed at a level of from 0.001% to less than 0.01%, e.g. from 0.001% to 0.008%, preferably about 0.005% by weight. It has been found that a concentration of benzalkoniium chloride of 0.005% by weight.  It has been found that a concentration of benzalkonium chloride of 0.005% is sufficient to preserve the compositions of the present invention from microbial attack. This concentration may be advantageously compared to the requirement of 0.01% benzalkoniium chloride to preserve timolol in the individual, commercially-available ophthalmic products. Moreover, it has been found that  adequate lowering of intraocular pressure has been obtained when administering the compositions of this invention twice a day as compared to the FDA approved regimen wherein brimonidine ophthalmic solution, i.e. Alphagan® ophthalmic solution is administered three times a day and timolol ophthalmic solution i.e. Timoptic® ophthalmic solution is administered twice a day. This results in the exposure of the patient to 67% to 50% of benzalkonium chloride, with the compositions of this invention, as compared to the administration of Alphagan® and Timoptic® respectively. In FDA approved adjunctive therapy, wherein Alphagan® and TImoptic®  are serially administered, the patient is exposed to almost three times the concentration of benzalkonium chloride as compared to the  administration of the compositions of this invention twice a day. (It is noted that it is known that benzalkonium chloride at high concentrations is cytotoxiic.  Therefore, minimizing the patient’s exposure to benzalkoniuim chloride, while providing the preservative effects afforded by benzalkonium chloride, is clearly desirable.)…………

The following example is a representative pharmaceutical composition of the invention for topical use when indicated for treating glaucoma.

EXAMPLE – I

The combination of active pharmaceutical ingredients is as follows:

Brimonidine Tartrate 0.20 % (w/v) and Timolol Maleate 0.68% (w/v) (Equivalent to 0.50 % w/v) Timolol).

The Brimonidine-Timolol combination formulation presented in the Table, below, is a sterile, preserved, aqueous solution.  The formulation vehicle is based upon a timolol ophthalmic solution which contains an isotonic phosphate buffer system at pH 6.9. The formulation preservative is benzalakonium chloride (BAK) at a concentration of 0.005% (w/v) (50 pm). The formulation passes regulatory required preservative efficacy testing (PET) criteria for USP (United States Pharmacopoeia) and  EP (European Pharmacopoeia-A    and B over 24 months.

TABLE

                      Ingredient Function Concentration %  w/v
Brimonidine Tartrate Active 0.2
Timolol Maleate EP Active 0.68
Benzalkonium Chloride, NF, EP Preservative 0.005
Sodium Phosphate, monobasic monohydrate,USP Buffer 0.43
Sodium Phosphate, dibasic heptahydrate USP Buffer 2.15
Sodium Hydroxide, NF pH Adjust Adjust  pH to 6.9
Hydrochloric Acid, NF Ph Adjust Adjust pH to  6.9
Purified Water, USP, EP Solvent q.s. sd

Equivalent to 0.5% (w/v) Timolol, free base

Pharmaceutical composition of Example- I is used in the clinical study reported below;

EXAMPLE-II

Objectives:

 

To compare the safety and efficacy of twice-daily dosed brimonidine tartrate 0.2% timolol 0.5% Ophthalmic solution combination (henceforth referred to as Combination) with that of twice-daily dose timolol ophthalmic solution 0.5% (henceforth referred to as Timolol) and three-times-daily dosed ALPHAGAN® (Brimonidine tartrate  ophthalmic solution) 0.2% (henceforth referred to as Brimonidine) administered for three months (plus 9-month masked extension) in patients with glaucoma or ocular hypertension………

Summary – Conclusions:

Efficacy:

At baseline, mean values of diurnal IOP ranges from 22.2 mm Hg. to 24.9 mm Hg. in the combination group, 22.5 m Hg. to 25.0 mm Hg in the Brimonidine group, and 22.3 mm Hg. to 24.8 mm Hg in the Timolol group. There were no statistically significant differences between treatment groups.

…………………………………………………..

At the month 3 or exit visit a statistically significant greater “yes” response to the Investigator Pharmacoeconomic Evaluation was recorded for patients receiving Combination(91.1% .173/190) than for patients receiving Brimonidine (73.4% 141,192, p<0.001). A “yes” resposne was recorded for 92.7% (179/193) of patients receiving Timolol. There were no statistically differences in the change from baseline treatment comfort between Combination and each of the monotherapy groups.

Safety

……….

The most frequently reported adverse events (>3% in any treatment group) were as follows, tabulated by descending order in the Combination group:

Combination

Brimonidine

Timolol

        Preferred Term        N = 193       N = 196       N =197
 Burning sensation in eye    23 (11.9%)    11 (5.6%)

25 (12.7%)

 Conjunctival hyperemia    16 (8.3%)     23 (11.7%)

11 (5.6%)

Stinging sensation eye     13 (6.7%)      4(2.0%)

11 (5.6%)

 Infection (body as a whole)      11(5.7%)      6 (3.1%)

8 (4.1%)

 Visual disturbance       6 (3.1%)      11 (5.6%)

3 (1.5%)

 Epiphora      5 (2.6%)      8 (4.1%)

3 (1.5%)

 Oral dryness      4 (2.1%)      19 (9.7%)

1 (0.5%)

 Eye pruritus      3 (1.6%)       13(6.6%)

3 (1.5%)

 Allergic Conjunctivitis      3 (1.6%)        7 (3.6%)

0 (0.0%)

 Asthenia       3 (1.6%)        6 (3.1%)

1(0.5%)

 Foreign body sensation       2 (1.0%)        10 (5.1%)

5 (2.5%)

  Conjuctival Folliculosis       2 (1.0%)         9 (4.6%)

(0.05%)

  Somnolence       2 (1.0%)         7 (3.6%)

0 0.0%)

Adverse events led to the discontinuation of 3.6% (7/193) of patients in the Combination group, similar to 3.0% (6/197) of patients in the Timolol group, and statistically significantly less than 14.3% (28/196) of patients in the Brimonidine group (p < 0.001).  Serious adverse events were reported for 1.0% (2/193) of patients in the Combination group, 2.0% (4/196) of patients in the Brimonidine group, and 2.0% (4/197) of patients in the Timolol group. Two patients receiving Timolol had 4 serious adverse events (emphysema in one patient; nausea, sweating, and tachycardia in the other patient) which were considered possibly related to the study-drug. There was 1 death in the Brimonidine group, possibly due to complications from cardiac surgery, and not related to study drug.

There were no clinically relevant differences between the Combination and either of the individual components in the mean change from baseline to month 3 for any hematology, chemistry, or urinalysis parameter. Statistically significant (p0.048) within-group changes from baseline were found, but were small and not clinically relevant.

Small but statistically significant (p.< 0.001) mean reductions in heart rate ranging from -2.1 to -3.7 bpm were seen with the combination, similar to Timolol. Small but statistically significant (p 0.003) mean reductions in blood pressure at hour 2 (postdose) were seen with the combination, similar to Brimonidine. These small changes in mean heart rate and blood pressure were associated with clinical symptoms in only a few patients.

Increases from baseline in the severity of conjunctival erythema and conjunctival follicles on biomicroscopy were statistically significantly less with the Combination than with Brimonidine (p < 0.011). The majority of patients in each treatment group showed less than a 2 line change from baseline visual acuity. There were no significant between group difference for changes in visual fields or cup/disc ratio.  …………………………………………….

 

Conclusions:

 

The combination treatment (brimonidine tartrate 0.2% timolol 0.5%) administered BID for 3 months was superior to Timolol (timolol 0.5%) BID and Brimonidine (brimonidine tartrate 0.2%) TID  in lowering the elevated IOP of patients with glaucoma or ocular hypertension.  The Combination administered BID demonstrate a favourable safety profile that was comparable to Timolol BID and better than Brimonidine TID with regard to the incidence of adverse events and discontinuations due to adverse events.

The invention has been described herein by reference to certain preferred  embodiments.  However, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto.

WE CLAIM:

1.         An Ophthalmic pharmaceutical composition useful in the treatment of glaucoma or ocular hypertension comprising a concentration of 0.01 to 0.5 per cent by weight of Brimonidine and a concentration of 0.1 to 1.0 per cent by weight of timolol in pharmaceutically acceptable carrier therefor.

2.         A composition as claimed in claim 1, wherein the concentration of brimonidine is 0.2 per cent by weight and the concentration of the timolol is 0.5 per cent by weight.

3.         A composition as claimed in claim 1, optionally comprising from 0.001 % to 0.008% benzalkonium chloride.

4.         A composition as claimed in claim 2, optionally comprising from 0.001 % to 0.008% benzalkonium chloride.

5.         An ophthalmic pharmaceutical composition as claimed in any of claims 1 to 4 for treating glaucoma.

6.         An ophthalmic pharmaceutical composition as claimed in any of claims 1 to 4 lowering intraocular pressure.

COMBINATION OF BRIMONIDINE AND TIMOLOL FOR TOPICAL OPHTHALMIC USE

ABSTRACT:

Disclosed are  pharmaceutical compositions comprise brimonidine and timolol for topical ophthalmic delivery and a method of treatment comprising administering said composition when indicated for glaucoma and associated conditions such as elevated intraocular pressure in the eyes of humans.

33.       Mr. S. Majumdar for the Applicant and Mr. Praveen Anand for the respondent argued at length their respective cases and also filed their written submissions.

34.       The respondent has proposed to amend the claims and restrict themselves to two specific claims. The claims are as follows:-

(1) Twice a day daily dosage ophthalmic pharmaceutical composition for the treatment of glaucoma or ocular hypertension, comprising a concentration of about 0.2 per cent by weight of brimonidine, a concentration of about 0.5 percentage by weight of timolol, a concentration of about 0.005 percentage by weight of benzalkoniuim chloride, and a pharmaceutically acceptable carrier thereof.

 

(2) The twice a day daily dosage ophthalmic composition as claimed in claim 1,. Wherein the concentration of brimonidine is 0.2er cent by weight and the concentration of the timolol is 0.5 percent by weight.. 

 

35.       Mr. S. Majumdar submitted that in the complete specifications the advantages claimed are better compliance and reduction of the use of Brimonidine and BAK and thirdly the reduction in side effects.  In addition, the respondent had claimed other advantages not found in the specifications that there is elimination of afternoon trough, stability in the presence of novel degradants and that it is a synergistic composition. According to the applicant    these additional aspects   which are alleged to be factors which prove non-obviousness and inventive steps supported by post Patent documents and the evidence of two experts Gary Beck  Ms. Amy Batoosingh. The documents are Exhibit R3 Tony Realini (2008). Exhibit RW 1/15 Gillion McDernott (2005) Exhibit RW 1/16 Matt Young(2007). Exhibit R.W.1/21  Jaenen (2007). According to the applicant the aim of the invention is to have two drugs in one bottle instead of individual administration of two drugs. The specifications mentioned the need for stability only in one place and nowhere else there is data in support of higher stability nor data relating to toxicity profile. The counter statement clearly says that the stability is not part of the alleged invention.  The specification does not represent that the claimed compensation had increased the stability.

On the contrary, the witness had spoken of the several predictabilities of the safety profile and also the toxicity studies.  For this, there is no basis in the pleadings.  According to the applicant since the side effects of BAK was known,  a single bottle composition was clearly desirable which would result in better compliance and reduction in side effects.   The reduction of the quantity of the preservative required was a natural consequence when both the drugs are put in one bottle.

36.       The learned counsel submitted that Exhibit R5 which is a Timoptic label shows that it contains all the ingredients  of the Invention except Brimonidine and once you had that you would arrive at the Patent. The learned counsel submitted that the specifications compared the combination with Brimonidine TID monotherapy and Timolol BID monotherapy whereas the comparison should have been done between Brimonidine and Timolol combination and Brimonidine and Timolol given serially.  It was submitted that it was only in USA that Brimonidine was given TID in many European countries it was BID.  It was submitted that the Regulatory Body is different from the authority under the Patent law.  The learned counsel for the applicant referred to Cantor, Exhibit RCS-4 in which it is stated  that “Brimonidine + 0.2% TID is highly appropriate first and second line therapy for long term management of glaucoma and ocular hyper tension”. According to Mr.S.Majumdar Brimonidine 0.2% was labelled as a first line agent since 1996 due to its favourable safety and efficacy profile.  Cantor was published in 2000 and the study was supported by the respondent and it teaches that brimonidine would be selected over other clonidine-like compounds. Brimonidine with its good tolerability and safety profile and high receptor selectivity was a promising molecule and therefore there was a strong motivation.  Exhibit D1 suggests that Brimonidine and Timolol combination may have potential in glaucoma treatment.   According to the applicant the Cantor study was supported by the respondent and therefore the respondent would be aware of its teachings. Exhibit D1 teaches the additional IOP lowering effect with Brimonidine and that Brimonidine 0.2% instilled BID offered long term IOP control comparable with Timolol. The only difference is Exhibit D1 is a combination of the two drugs given individually whereas the Invention is the same combination in a single composition. Exhibit D2 also compares the effect of application Brimonidine and TImolol alone and in combination on aqueous humor and IOP. The reduction in aqueous humor flow with Brimonidine and Timolol combination was seen when compared to Brimonidine and TImolol monotherapy.  Similar was the case of reduction in IOP.  Therefore from Exhibit D2 the Administration of BID with Timolol was obviously advantageous and that Brimonidine BID would not have the trough effect since the Timolol had longer duration of action. Exhibit D3 relates to combination of Apraclonidine and Timolol to control intra ocular pressure. According to the applicant the prior art refers to Timmermans’  “Structure activity relationship in clonidine like imimidazolidine ring and related compounds” and it is incorporated by reference Timmermans mentions brimonidine and therefore D3 must be held to teach Brimonidine.  When this document is incorporated by reference it forms part and parcel of Exhbit D3. The applicant could not produce Timmermans, but both the experts Mr. Gary Beck and Ms. Amy Batoosing acknowledged that this document discloses Brimonidine. According to the applicant Exhibit D3 teaches in no uncertain terms, the combination and it says “It is believed that the Alpha -2 agonist Beta blockers utilized in the present composition reduce the inflow aqueous humor by means of a complementary mechanisms and action.”  It clearly teaches that the present combinations have a powerful and surprising IOP lowering effect. According to the applicant unless serial administration is defeated, the respondent cannot claim inventive step and non obviousness.

37.       According to the applicant the decision revoking the EP counterpart of Exhibit D3 shows that the person skilled in the art who wanted to solve the problem would combine the beta blocker with the Alpha 2 agonist. The presence of a synergistic effect cannot be surprising for the persons skilled in the art since such effects are already known for such combinations.  Mr. Majumdar submitted that Exhibit D3 would clearly motivate Ms. P.Sita (Person Skilled In The Art) to combine the two drugs in one bottle and once she knew the beneficial effect of sequential combination of the two drugs, she would straightaway proceed to combine them in a fixed combination as taught by Exhibit D-3.  The teachings of the prior  art were summarized by the learned counsel to show that Ex 1 and 2 together with Ex 3 clearly led the Person Skilled In The Art to the Invention.   The applicant relied on Court of Appeals judgment in respect of US counterpart of the impugned patent Allergan Inc vs. Sandoz  where it was held :

“There is no requirement in patent law that the person of ordinary skill be motivated to develop the claimed invention based on a rationale that forms the basis for FDA approval. Motivation to combine may be found in many different places and forms; it cannot be limited to those reasons the FDA sees fit to consider in approving drug applications. When viewed under the proper standard, the evidence of record establishes a motivation to combine brimonidine and Timolol into a fixed combination product. Not only does DeSantis teach the fixed combination of timolol with an alpha 2-agonist, numerous other references teach the fixed combination of other ophthalmic drugs.” It further held that,

“In view of DeSantis, one of ordinary skill would have a reasonable expectation of success  in formulating a fixed combination produce containing brimonidine, timolol, and BAK.” And that “ There is extensive evidence in the prior art showing the concomitant administration of brimonidine and timolor multiple times per day, that the combination had benefits over the administration of either alone, and that there was a motivation to combine the two achieve better patient compliance. (Emphasis added) KSR, 550 US at 426. Whether or not the combination also solved problems associated with the afternoon trough, we find the motivation to make the combination was real.  Accordingly, we conclude that the claims of ‘463 patent are invalid as obvious.”

38.       The petitioner relied on T 0757/89 where it was held that if “on the basis of the study of art something falling within the term of a claim would have been obvious to a person skilled in the art, because the combine teachings of the prior art could be expected to produce advantageous effect then the claim has no innovative step even if the extract effected is unforeseen”. The applicant  also relied on TO3-93-01 which held “enhanced effect cannot be adduced as evidence of inventive steps if they emerge from obvious tests”. He relied on CIPLA LTD. & OTHERS Vs. GLAXO GROUP LTD.( 2004) EWHC (Pat) Page 477), where it was held that the “combination was an obvious combination as a combination.” And as regards the doubts relating to questions which could only be resolved by clinical trial and the long-term effects of salmeterol, the Court held that “ The skilled man would understand this and accordingly the combination was entirely obvious…” Since the respondent had strongly relied on Canadian Judgment Allergan & others Vs Minister of Health in respect of the corresponding Canadian patent , the applicant submitted that Canadian judgment had failed to consider the prior arts in combination c patients, and that the Canadian judgment had considered the elimination on afternoon trough and unexpected difficulties have been faced by the respondent while considering the innovative step, but these do not form part of the Patent specifications. The applicant submitted that clinical challenges mentioned by the respondent were really not so in view of the prior art because the prior art showed that the two drugs were well tolerated and that the two could be successfully combined, there were no formulation challenges as well and the respondent did not face any unexpected difficulties in putting two salts in a single compositions.. There is no invention in deducing the concentration of BAK and even otherwise the  BAK is optional as seen from the claims  The respondent cannot claim that the structures of Clonidine  and Apraclonidine are different and Brimonidine are different since both have  -NH  bridge and imidazoline ring, just as the clonidine-like compounds that form part of the prior art.

Brimonidine a) Aromatic portion-

Substituted Bicyclic

b) Bridge –NH

c) Imidazoline ring

-present

Apraclonidine a) Aromatic portion-

Substituted monocyclic

b) Bridge –NH

c) Imidazolidine ring

-present

Clonidine a) Aromatic portion-

Substituted monocyclic

b) Bridge –NH

c) Imidazolidine ring

-present

39.       Larsson was considered as prior art in the US decision, and the argument that Exhibits D1 and D2 are short system studies cannot be accepted since Exhibit D1 states that short and long term correlation with the said combination does exist and the purpose of the short term study is to extrapolate the results to long term study, and Ms. P. Sita would know that glaucoma would require long-term treatment.

40.       According to Mr.S.Majumdar, D1 and D2 taught that

Addition of Brimonidine at concentration of 0.2% to timolol 0.5% treatment regimen to achieve additive reduction in IOP;

Coordination of bjrimonidine (0.2%) and timolol (0.5%) twice daily;

Benefits/advantages of brimonidine when incorporated in glaucoma treatment regimen comprising timolol;

Systemic side effects are minimal. i.e. minimal occurrence of adverse effects when both the drugs are coordinated to patient.

Much assured/reasonable expectation of success to formulate combination in single composition.

When this is combined with D3 which taught that,

Combination of apraclonidine and timolol.

Using two or more drugs to achieve better therapeutic control.

Complimentary mechanisms of action of alpha -2 and beta-blocker

Patient compliance.

Combination has potent and surprising IOP lowering effect.

Benzalkonium chloride as preservative.

The invention became obvious.

41.       The cumulative teachings in Exhibits D1 and D3, and D2 and D3 must be looked at the inventive merit of I must be determined from the specification. All the other submissions regarding the challenges have been faced and work done is not part of the specifications.

42.       According to the applicant the invention is a mere admixture. According to the respondent, the synergy is the safety profile of the two drugs in fixed combination being much improved over serial administration.  In the counter statement, it is stated that the safety profile of the fixed combination is much improved over safety profile Brimonidine monotherapy and is comparable to the safety profile Timolol monotherapy. The counter has referred to the complete specifications and studies with the data provided from the clinical trial that demonstrate that the benefit provided is merely additive.. Synergy has to be something more surprising than what was known. The benefit provided by the invention is additive where each drug elicits the respective therapeutic response independent of each other and the potential decrease in IOP was an expected technical effect. Unless the impugned patent demonstrated synergy composition over and above what is known for serial administration, the respondent cannot claim to have overcome Section 3 (e) objection.

43.       Section 3 (d) refers to “combinations”. According to the applicant the combination serially was known. The two substances in use in isolation were known.   Therefore while applying Section 3 (d) it is important to show that the “combination” is significantly more efficacious than the serial application of the two drugs as shown in Exhibits D1 and D2.  So the comparison must show the significant enhancement of efficacy between serial application and single composition. The learned counsel submitted “That IOP lowering with brimonidine and timolol in D2 achieved was around 7.7 + 1.8 mm Hg and the IOP lowering with combination  was around 5.2 to 7.9 mm Hg” The revocation was filed in 2011.  The respondents should have come up with some data after Revocation was filed. But this was not done.” The applicant referred to the test of therapeutic efficacy as laid down in the Novartis’s case and stated that the clinical data does not furnish proof of enhancement therapeutic efficacy.

44.       Next, Mr Majumdar concentrated on the failure to disclose information as per the requirements of Section 8. The FER asked the respondent to furnish details regarding search or examination report in respect of the same or substantially the same invention filed in any one of the major Patent Offices such as USPTO, EPO  and JPO  etc., The respondent has stated that to this what was furnished was a copy of the granted Canadian Patent No.CA 2440764,.This document does not  amount to compliance.  The respondent had also failed to indicate in Form III that there are three US Patents US 7323463, US 7030149 and US 7320976.   The office action in EPO is dated 6.4.2005 and it had taken place before the Indian Application. The search and examination report were available with the respondent and in the EPO office action, five documents were cited. EPO stated that the application does not seem to meet the requirements of Article 56 EPC regarding to inventive step. This was available with them. The Examining Division had stated “The difference with the present application is that the present application a composition is claimed which contains the two components together, whereby it is not shown that this technical feature leads to any advantageous therapeutic effect…It would be obvious for the skilled man to try an alternative fixed combination comprising timolol and brimonidine, given the big amount of information available.”  The Patent in EP was rejected. The patentee had chosen not to furnish the details of the proceedings in USPTO, or EPO or JPO. The Prosecution History of the corresponding US patent stated that the claims as   non-patentable over Exhibits D2 and D3 and that the person with the ordinary skill would have been motivated to combine the reference. This document was available. This office action has concluded as “No claim is allowed”. According to the applicant, had this been shown, the Controller in India may not have granted the patent. The contention that the documents are available on the website is not acceptable.. The learned counsel relied on the earlier decisions of the IPAB in Tata Chemicals vs Hindustan levers (Order no 166/2012) and VRC Continental vs Uniroyal Chemical (Order No 207/2012)and more importantly the judgment of the Delhi High Court in Chemtura Corporation (MANU/DE/1880/2009) and submitted that on this ground the Patent should be rejected. According to the learned counsel, the respondent is also guilty of false suggestion or representation since they had not made fair disclosure by showing Exhibits D1 and D2. The applicant referred to the communication exchanged between the respondent and its Attorney to show that the ground of Section 64 (1) (j) has been made out. As regards the absence of expert evidence, it was submitted that expert evidence may not be always required and even then the need for expert evidence must be decided on a case to case basis. For all the above reasons, the applicant prayed that the Patent must be revoked.

45.       Mr.Praveen Anand the learned counsel for the respondent submitted that the revocation application must be dismissed outright for lack of evidence and for not discharging the burden of proof.  The only evidence that was filed was  the affidavit of Dr. Sudhakar G. Deshpande  and it was withdrawn.  The learned counsel relied on (ORA/44/2009/PT/CH) Travancore and   Mats & Matting Co.  Vs. Controller of Patents (ORA/44/2009/PT/CH) where the revocation petition was dismissed because no substantial objections were raised nor was it supported by documentary proof or evidence. He also relied onTRA/3/2007/PT/DEL. LML Limited Vs. Bajaj Auto Limited, where for want of evidence the ground relating to insufficiency was dismissed. He also referred to the IPAB’s order in ORA/8/2009/PT/CH where it was held that in cases of chemical and biotechnological inventions, evidence is critical in view of the complex nature of the field in question. He submitted that the ground of false suggestion and misrepresentation, was not pleaded and therefore it must be rejected. At the oral hearing, the respondent filed amendments to be granted claim which covers the commercial embodiment Combigan®.   He relied on AGR – Flat Glass Europe SA Vs. Anand Mahajan and others (2009 (41) PTC 2007 Delhi) where it was held that a limitation to a sub combination and properly falling within the scope of the original wider combination to discord or eliminates from the invention claimed everything except this sub combination the amendment would come within the meaning of disclaimer.  It was submitted that the use of the expression “about” would not render the claim vague.  For this he relied on 476 F.3D 1321 – OrthoMcNeil Pharmaceutical Incorporated Vs. Caraco Pharmaceutical Laboratories Limited. Learned counsel for the respondent explained the background of the invention which is a drug for Glaucoma disease affecting the optic nerve due to IOP. He submitted that Beta blockers are one of those types of drugs, which are used for Glaucoma and since it affected the elderly, patient compliance was a crucial issue and since it related to the eye after a patient noticed an allergy, it can no longer be used.  He referred to the various types of challenges and the study of the art at the relevant time which discouraged combination.  He submitted that the two drugs worked in different ways and he drew an analogy with someone trying to combine juice and milk to make a drinkable beverage.  Timolol  was known since 1970 and was sold as Timoptic® by Merck. It had side effects, which included Cardio vascular and pulmonary issues.  He referred to the Timoptic label which listed the adverse reactions. He referred to the US Patent    5502052 which again spoke of the serious side effect of Timolol. He referred to Leblanc et al which spoke contra indications to the use of non selective Beta blockers for example Timolol.  He also referred to Ms. Amy Battoosingh’s affidavit, which too spoke of the side effects. Then he explained the action of Brimonidine and its effects.  It had obtained FDA approval in 1996. It was marketed as 0.2% Brimonidine Tartrate under the brand name  Alphagan®. He explained the “afternoon trough” which occurs when Brimonidine  is administered BID.  He also referred to Ms. Amy  Battoosingh’s affidavit that spoke   of the significant difference in the IOP lowering effect that was observed   in the afternoon trough  with Brimonidine BID. The phenomenon at Hour  9, was representive of the “trough” effect because at that hour the effect of the drug had largely worn off, Tom Walters ( Ex RW 1/8 “Development of Brimonidine in treating Acute and Chronic Elevations of intraocular pressure” 1996) also speaks of this.  The decrease in the IOP lowering effect with Alphagan®  was shown by this group

46.       The learned counsel also referred to the side effects associated with Brimonidine and  that the development of an allergy to Brimonidine rules out the use of Brimonidine as a therapeutic  for Glaucoma in patients with said allergy. The learned counsel then submitted that while the expression “fixed combination” is used to indicate two different medications in a single bottle, the use of two different two medications in the same eyes at least five minutes apart is indicated by the following terms, “serial administration”, “unfixed combination”, “concomitant administration” and “concurrent administration”. The advantages of using serial therapy are that there is no chance of drug interaction inside the eyes and it is easy to get approval for independent usage of drugs.   The learned counsel referred to the long felt need for an effective and safe topical ophthalmic pharmaceutical composition including Brimonidine and Timolol which has increased stability and which requires a lower effective concentration of preservative as compared to the individual agents taken alone. According to the respondent, this objective was achieved by the present invention. The unexpected finding was that in the fixed composition claims the BAK concentration is reduced to half and still the composition is preserved and uptake of Timolol is not affected. BAK is known to be cytotoxic and minimizing concentration of BAK is desirable. The exposure is to BAK is three times more in serial administration as compared to the invention which is a fixed combination and there is adequate lowering of  IOP and reduction in side effects. Learned counsel referred to the studies 12T and 13T mentioned in the counter statement and 23T and 24Tconducted after the counter statement was filed.  12T and 13T were referred to in Gary Beck’s affidavit.  The results show that treatment satisfaction was better in the fixed combination group than in the Brimonidine group and the Timolol group, and the incidence of oral dryness, eye pruritis, foreign body sensation and conjunctival folliculosis  were statistically significantly lower with the fixed combination than with Brimonidine.

47.       According to the respondent the Patent specifications not only make it possible for the person skilled in the art to be able to formulate the composition but they also provide the clinical data to show that the fixed combination  has superior efficacy and reduced side effects.   Therefore it shows that invention shows enhanced therapeutic efficacy and also reduced toxicity. The specifications clearly show that the fixed combination is superior to Timolol BID and Brimonidine TID in lowering the elevated IOP. The safety profile was also favourable. Mr.Praveen Anand referred to the challenges in formulating the fixed combination. The drug formulation is unpredictable, success cannot be guaranteed in forming ophthalmic drug combination challenges are bigger because of the small surface area of the eye. He said that Tony Realini is relevant and indicates the unpredictability of drug combinations. “Many stars must be aligned for such a combination to be feasible”. Several considerations have to be taken into account because of the different pH levels; different buffers etc. of the two drugs. The combination of the two drug moieties could in fact increase the side effects due to simultaneous exposure to the two drugs. The inventors also had to consider the fact that BAK response for increasing the uptake of Timolol also caused disruption of ocular surface.  The inventors found surprisingly that the fixed combination could be preserved with half of the concentration of BAK as compared to the concentration needed to preserve Timolol. The other preservatives were tried like Synergel a viscous polymeric substance but it failed.  Purite too was tried but it degraded Timolol too quickly.  The adequate stability of the combination was not predicted. There were also clinical challenges in formulating a combination because of the possibilities of clinical incompatibility and finding the right concentration of each drug at a dosing frequency which maximized efficacy of each drug without introducing new side effects and possibly reducing side effects.  The learned counsel referred to unexpected reduction in dosing Brimonidine from TID to BID by referring to the study 12T and 13T. He referred to the same studies to show unexpected reduction in side effects and the incidence of ocular allergy.

48.       Mr.Praveen Anand referred to  Michael A. Motolko ( Ex R.8 “Comparisons of Allergy  Rates in Glaucoma Patients…Monotherapy vs Fixed Combinations” 2008)  to show that reduction in the incidence of ocular allergy caused by the fixed combination may be due to the presence of the Timolol in the combination therapy establishing synergy of the fixed combination. “It has been suggested that the presence of Timolol in fixed combination may limit the allergic response to Brimonidine through efforts on conjunctival Epithelial cell volume and intercellular space.” Amy Batoosingh the expert has also given the opinion that the reduction in ocular allergy was likely due to combining the two drugs. It was submitted that there was a significant reduction in Somnolence and oral dryness with fixed combination as compared with adjunctive or serial therapy using Brimonidine  TID and Timolol BID.  Amy Becker’s affidavit also indicates the same thing.

49.       It is the respondent’s case that reduction in sleepiness is a meaningful benefit to patients of Glaucoma, since the majority of the patients are elderly.  There is also an unexpected reduction in the concentration of BAK.  The undesirable side effects of BAK has been spoken of by L. Jay Katz and the reduction of this made this invention a desirable one. Gary Beck in his deposition before the High Court of Delhi (this has been filed before us) had stated  the inventors did not know the effect of uptake of Timolol through cornea due to the combination of a lowering BAK concentration.  While Timolol monotherapy formulations required 0.01% BAK the fixed combination used only 0.005% BAK without compromising on efficacy.  The learned counsel referred to T386/89 where the Board of Appeal held that the Patentee may put forward a modified version of the problem particularly if the issue of inventiveness has to be considered on an objective basis.  He also relied on KNOLL PHARMACEUTICAL COMPANY VS. TEVA PHARMACEUTICAL USA , Inc in 367 F 3fd, 1381 which says that there is no requirement  that  an invention’s properties and advantages should be fully known before the Patent application was filed.

50.       He referred to in BISHWANATH PRASAD Vs. HINDUSTAN METAL INDUSTRIES (1979 (2) SCC 511) where it was held that if the alleged discovery lies so much out of the track of what was known before as not naturally to suggest itself to a person thinking on the subject, it must not be obvious. He also referred to the judgment of the Delhi High Court in     ROCHE   Vs. CIPLA and the judgment of this Board in ORA/08/2009/PT/CH ENERCON INDIA Vs. ALLOYS WOBBEN and OA/08/2009/PT/CH SANKALP  REHABILITATION TRUST  Vs. HOFFMANN LA- ROCHE AG.   “Had the document been placed in the hands of a competent draftsman (or engineer as distinguished from a mere artisan), endowed with the common general knowledge at the ‘priority date’, who was faced with the problem solved by the patentee but without knowledge of the patented invention would he have said, “this gives me what I want?”  (Encyclopaedia Britannica; ibid).  To put it in another form: “Was it for practical purposes obvious to a skilled worker, in the field concerned, in the state of knowledge existing at the date of the patent to be found in the literature then available to him, that he would or should make invention the subject of the claim concerned?” {Halsbury, 3rd Edition, Volume 29, page 42 referred to by  Vimadalal J. of Bombay High Court in Farbwerke Hoechst & B. Corporation  v. Unichem Laboratories} (vide Bishwanath Prasad)

51.   He submitted that this test that has to be passed. He submitted that Hindsight deduction is not permissible and it must be ascertained if the invention would have been obvious at the time the invention was made. According to the learned counsel Ex D 1 alone are in combination did not teach or suggest invention. It only teach frequently administration before the prior art cannot be said to teach a fixed combination. In fact, D1 performed an 8 hour diurnal IOP curve would suggest a thrice a day dosing to a person skilled in the art because a 12  hour  point would be important for twice daily regimen. D1 did not study the side effects profile.  He referred to the relevant passage of Amy Batoosingh’s evidence as regards D2.  It was submitted that D2 was a short term study on Healthy volunteers and not on Glaucoma patients.  The short term exposure to Brimonidine is not indicative of long term exposure. D2 is speculative of the effect of  Brimonidine and Timolol serial administration, it does not teach the invention. As regards D3 Amy Batoosingh had stated that it discloses on tens of thousand if not millions of combinations.  It only discloses generically a fixed combination of an Alpha2 agonist and a beta blocker for use.  There is no information in DeSantis about  Brimonidine. The reference to clonidine derivatives will not include Brimonidine.  The former includes compounds in which aromatic ring is Aryl whereas in Brimonidine the aromatic ring is a bicylic fused ring.  The compounds are structurally and functionally different.  Though clonidine apraclonidine and Brimonidine are all considered alpha2 agonist they do not behave similarly in the clinic. The main objective of the prior art D3 was patient compliance and there is no clinical data regarding efficacy or safety.

52.       The learned counsel submitted that it is not permitted to rely on a vague prior art which discloses thousands of combinations and conclude that it taught the invention. Mr. Praveen Anand submitted that persons skilled in the art on that date would know about the disease and the need for  IOP lowering structure that were used at the time , that both Brimonidine and Timolol were established as IOP lowering drugs and that they were used in concomitant therapy. It was known that BAK had side effects and should be avoided and that  Purite  was a safe  and well tolerated preservative. Therefore the teaching was towards purite and not BAK. The state of the art was towards serial administration and there was no encouragement to arrive at the fixed combination. It was submitted that the safety profile is part of the inventive step.  Reliance was placed on Pfizer Canada Inc. Vs. Apotex ( 2009 FCA 8) which said that it is one thing  to have an idea that potential product would or might have certain beneficial properties it is quite another  thing to actually create that product.  According to the respondent, none of the prior arts Yuksel, Larsson or DeSantis ( D1, D2 and D3) had taught this fixed combination, or   explore the BAK levels nor did they address the  allergy and other local side effects.  The other crucial difference is that the invention overcomes the” afternoon trough” seen with Brimonidine TID. The learned counsel also dealt with the significant number of difficulties that are encountered in the development of the fixed composition.  These difficulties are set out in the evidence of experts; the use of synergel and the fact that they had to abandon it, the difficulties faced in Purite formulations and then the commencement of work with BAK, the degradation that developed in the BAK stability study and so on.  Therefore the inventor had engaged in a significant amount of difficult non routine work to invent the compositions and it cannot be considered obvious. There was no motivation to combine the two drugs and in fact the prior art taught away.  The Drug Labels actually warned against using alpha2 agonist and beta blockers.  The learned counsel referred to the secondary considerations viz., long felt need.  It was also submitted that the U.S. FDA requirement for fixed combination approval is in line with Indian Act’s requirement of inventive step and the decision of the Supreme Court in the Novartis’s case. For all these reasons, it was submitted that the Invention was not obvious.

53.       As regards S.3(d) it was submitted that this  is not applicable since a “fixed combination” is not a “new form of a known substance”. The word “known substance” in 3(d) cannot include comparison of dosing regimen where two actives are administered serially one TID and the other BID.  Without prejudice to this contention it was submitted that the invention did not fall within the scope of Section 3 (d). He submitted that there were surprising and unexpected results in Brimonidine and Timolol fixed combination as compared to Brimonidine mono therapy and Timolol monotherapy or Brimonidine and Timolol serial administration. The reduction of IOP, the improved safety profile, the reduced ocular allergy, the reduced side effects were cited to show the significant enhanced efficacy of the invention.

54.       As regards Section 3 (e) it was submitted that the combination shows synergistic effect since Brimonidine behaves differently in combination with Timolol as indicated by the decreased allergy rate. Synergy is shown by the need for less concentration of BAK and by the fact that afternoon trough was eliminated. Therefore Section 3 (e) ground should also be rejected.

55.       Finally, the learned counsel for the respondent addressed the ground relating to Section 8. It was submitted that the applicant had not identified the Section 8 violation.  It was submitted that the European decision is dated 11th December 2007.The date on  which documents have to be filed under Section 8 (2) has to be determinative, it cannot be open ended. The last date for placing the application in order was 9th June, 2007, the date of the decision of the EP Patent was 5 months later and the respondent cannot be expected to file this document. According to the applicant Section 8 (2) requirement was complied with by filing a copy of the Canadian Patent. After the submission of the Canadian Patent, the Controller did not maintain the objections of Section 8. Hence he was satisfied. The US Patent office action referred to by the petitioner was produced in 2013. The petitioner had not explained the delay in filing the IPER and ISR issued by the EPO and therefore the Patentee filed more not less information by filing the Canadian Patent. It is submitted that the Indian Patent office had access to the International search report, since the present Patent is a National Phase application. The seven prior art documents were cited in the FER and in the Second office action Larsson and Yuksel were cited by the Patent Office. It was submitted that the applicant acted on the advise of the Indian Agent. This referred to John Wurst’s affidavit dt.14.2.2013 and submitted that a party cannot be penalized for incorrect advise provided by the Advocate and referred to in RAFIQ & ANOTHER VS. MUNSHILAL & ANOTHER(AIR l981 Supreme Court 1400)

56.       It was submitted that Patent was granted in USA and revoked only in Appeal and that the Canadian order in respect of the same invention was in favour of the Patentee. He submitted that the first office action issued by the Patent office on 9th June 2006 required the applicant only to submit the office action issued in any one of the major patent offices, such as, U.S. PTO, EPO and JPO etc.  He submitted that since Section 8 (2) speaks of processing of the application in a country outside India .It meant that the patentee’s compliance was complete if one  foreign application was filed. The Patentee cannot be asked to furnish details regarding the proceedings in all countries, contrary to the statute. According to the respondent as per Rule 12 (3) includes documents such as

(a) Copies of the granted patents;

(b) Office action of the single country;

(c) Only one office action of a single country;

(d) Search reports;

(d) Copies of granted claims; and

(f) International search report and international preliminary examination report.

57.       According to the respondent Section 8 (2) will be complied with, if he submits a copy of a granted claim in any one jurisdiction. According to the respondent Section 8 and Rule 12 are discretionary provisions. After the receipt of the information it is open to the Controller to proceed to grant Patent or maintain the objection.  Learned counsel submitted that in 2006 (2) SCC Page 1 (RAMESHWAR PRASAD AND OTHERS Vs. UNION OF INDIA), it was held that the court should not interfere with Administrator’s decision unless it is illogical or procedural impropriety  etc., and the court cannot substitute its decision to that of the Administrator. The discretionary power cannot be interfered with by the judicial review. According to the respondent counsel, since all the documents for which information is sought for are already in public domain.  The Patentee cannot be penalized. According to the learned counsel for the respondent, who referred to the various paragraphs of the Ayyangar Committee Report with regard to the need for provisions like this, at that time ISO did not have this infrastructure or technical support, but this no longer holds good, since all the information are available by accessing websites and databases

58.       He relied on THERASENSE INC VS.  BECTON, DICKINSON AND COMPANY and submitted that Section 8 should not be used as a tool to defeat the grant of Patents to worthy inventions and to use this tool it must be proved that Patentee knew all the references, know that it was material and still made a deliberate decision to hold it. He also referred to the decision of the Delhi High Court in ROCHE  Vs. CIPLA where it was held that the discretionary power may be used not to revoke a Patent only on the ground of non-compliance of Section 8.  It was submitted that the respondent is entitled to invoke the ‘De minimis” because rigid application of Section 8 would stifle creativity.

59.       The learned counsel also submitted that the Board must take note of the difference between the remedial and punitive provision and as regards penal provision, the Court must lean towards that construction which exempt the subject from penalty rather than the one which imposes penalty. For all these reasons, the respondent prayed that the Patent shall not be revoked.

60.       The two experts’ evidence that were filed by the respondent are Gary Becker affidavit and Amy Batoosingh. We will refer to the statements made by these two experts.  According to Mr. Gary Becker by the time the team responsible for developing a combination product for treatment of glaucoma had done clinical testing; they discovered that this combination was reasonably chemically stable, it reduced concentration of BAK, it  reduced side effects, it is FDA approvable for dosing BID  instead of  TID and it is more effective than either of its active components. He has spoken of the challenges of drug formations because the surface of the eye is very small and the residence time of eye drops is very short. The other challenges that the drugs which are used in the combination must be soluble at the same pH.  According to this witness, out of 20 different glaucoma medications available only two drug combinations have been approved by the FDA.  The inventors had the task of   putting two different drugs which had two different salts. The challenge was to accommodate the different requirements of the two drug ingredients in  a single formulation to produce a stable and effective formulation.  The formulators did not know how the two drug candidates would behave in single formulation.  Brimonidine had a pH which was different from Timolol and Brimonidine had a citric acid buffer system while Timolol had a phosphate buffer system. According to the expert the respondent had made a number of attempts to formulate these two drugs in a single fixed combination, trying other drug preservatives like Purite and Synergel. It was only after the initial failure that the respondent investigated BAK.  Fortunately, the respondent  was able to create a successful formulation because the novel degradants in the combined product formulated with  BAK turned out to be non-toxic at the levels predicted from the stability study.  According to him, the respondent conducted experiments to see if a lower amount of BAK could be used preservatives. According to him D3 does not teach or suggest invention.  It is a mere suggestion that combination of drugs may be needed to treat or manage a disease. It is not indicative of whether two specific drugs can be combined.  According to this witness D3 discloses almost all possible alpha agonist and beta blockers resulting in innumerable permutations and combinations.  According to him it is difficult to comprehend how the person skilled in the art would be directed by D3 to the specific combination of Timolol and Brimonidine claimed in the invention. Therefore this witness has given evidence that DeSantis D3 does not teach the invention.

61.       The evidence of Ms. Amy Batoosingh shows she is one of the co-inventors and according to her she is giving her opinion whether the person skilled in clinical development in April, 2002 would have found the invention obvious.  According to her, there are different classes of medications that lower IOP by different mechanisms of action and two such classes are Alpha2  agonists and beta blockers.  Brimonidine tartrate 0.2% is marketed under the trade name Alphagan®  by the respondent. This is given BID in Europe and TID in USA.  Brimonidine has side effects.  Timolol is a beta blockers which has side effects including Cardio Vascular and Pulmonary side effects.  The concurrent administration is inconvenient and likely to result in decreased patient compliance. “The combination of two commonly prescribed IOP lowering agents into a single formulation provides the benefit of adjunctive therapy (Potentiation of the IOP lowering effect by a second agent acting through a different mechanism), more conveniently than the individual products used separately.” This would ensure the patient compliance better than serial administration, but there were regulatory hurdles. The US FDA has a high bar for approval of fixed combination. Historically ophthalmic drug fixed combinations have suffered failure. The goal of fixed combination product would be to offer the “most likely pairing of drugs in the most likely concentration at a convenient dosing frequency for the patient.” As regards the clinical challenges in formulating this combination, this witness referred to the warning in the Alphagan label.  According to the witness the labeled warnings, the reduction of Brimonidine from TID to BID and the optional concentration of drugs are factors that taught away. The challenge was also to combine drugs that may be incompatible clinically and find the   right concentration of each drug at a dosing frequency that maximized efficacy of each drug without introducing new side effects. According to this witness there was little reason to believe that this fixed combination would work successfully.  She has spoken of the afternoon trough that occurs with Brimonidine and that the difference in IOP at Hour 9 is not only numerically significant, but it is clinically and statistically significant. The person with ordinary skill in the art would have been aware that there was lowering of efficacy if Brimonidine was dosed BID instead of TID. There was no teaching in the prior art to indicate that Brimonidine BID could be used without loss of efficacy and surprisingly Combigan® overcame the challenges. She has spoken of the symptoms of  ‘ocular allergy‘  that are often  related to the use Brimonidine and there was no reason  to believe that reducing frequency from TID to BID  would result in significantly less  ocular allergy. The improved allergy profile was not predicted when compared to Brimonidine monotherapy. According to her, the treatment with Combigan®  had significantly less side effects.  The clinical trials 23T and 24T demonstrated the significant reduction in somnolence  and oral dryness as compared to adjunctive therapy using Brimonidine  TID and Timolol BID.  Apart from the above benefits, the invention has  better safety profile since it has used reduced concentration of BAK compared to the serial use the two drugs.

62.       As regards non-obviousness this witness deals with Yuksel,   Larsson and DeSantis   According to her, the finding in Yuksel indicates that the short term exposure to Brimonidine is not indicative of long term exposure  and Yuksel performed an 8  hour diurnal IOP curve but to fully assess the IOP lowering effects at minimum a 12 hour point time should have been performed. According to her, Yuksel only suggests that a third dose of Brimonidine might be required whereas the invention works well with BID. As regards Larsson, this witness says that Larsson did not perform the 12 hour time point and this too only suggests that a third dose Brimonidine might be required. It studied Brimonidine action on 20 healthy volunteers and It said that” the differences in IOP reduction not explained by reducing aqueous humor production could be an error in the pressure measurement”. This prior art is only speculative and further Larsson only aimed to study the mechanism of action of serial administration of Brimonidine and Timolol and not IOP lowering. She also says that serial administration of drugs cannot predict whether the drugs can be safely put together into a single bottle. According to her in serial administration there is no interaction between the serially administered drugs and the first drug was absorbed before the second drug is given.  According to her neither Yuksel nor Larsson studied safety profile of the fixed combination. Because of the contra-indication in the label of Alphagon®, the person skilled in the art would be wary of the possibilities of additive effect of the side effects and would refrain from preparing a fixed combination.

63.       According to her, DeSantis also does not teach the invention and she gives the same reason as Beck regarding innumerable combination.  According to her the invention is not an admixture since it achieves improvement and different results than what would be achieved by the constituents independent of each other. She says that it demonstrates improved safety profile in comparison with independent constituents as well as in comparison with serial administration of the independent constituents.  She has also spoken of the improved efficacy of the Invention over monothearpy  as well as that the invention” shows non-inferior effects over serial administration of Brimonidine and Timolol”.  For all these reasons, she would say that invention was superior in reducing IOP than both Brimonidine tartrate  and Timolal  maleate alone.

64.       Now we will consider the applicant’s objections to the grant one by one.

First is Section 8.   We have dealt with this ground in case after case to the point of creating ennui. We will again do it. The Inventors and the Challengers must remember that

–           S 8 must be complied with.

–     It must be pleaded and proved that the lapse was with regarding applications in respect of the same or substantially the same invention( vide ORA 17/2012/PT/KOl order no 162/2013)

–     The documents to prove this must be filed at the earliest if they are filed belatedly , costs may be imposed.

–                         The law does not say that the failure to furnish the S.8 details must be deliberate and willful or that the failure must be in regard to material particulars.

–     It has been introduced to facilitate examinations and therefore the   patentee must be candid and fair.

–     The Controller cannot deal with this ground casually. They must adhere to the law nor can they dilute it. .

–     The Patentee has a statutory duty under S.8, he cannot say that the particulars are available on the website. Nor can the Examiner condone the non-disclosure by saying the details are on the website.( vide Sugen vs Cipla IPAB)

–                         It is not a penal provision and the object of the law is clear disclosure and there can be no dilution.

–                         Rule 12(3) is part of the statute and indicates why this provision has been introduced and reflects the sentiments of the Ayyangar Committee report.

–                         The article “a” in the law cannot be understood to mean only one. Once the S.8(1) detailed particulars are given, the Controller may ask for the details relating to ‘a’ country. This means any. The Controller May ask for the Rule 12(3) details regarding any application.

–           It is repeated that S.8 must be complied with.

  

65.       According to the applicant, the respondent has not complied with the provisions of Section 8.  The patent was granted on 07.05.2008.  Section 8 deals with information and undertaking regarding foreign applications.  The provision will be invoked where the applicants for patent under the Patents Act, 1970 are also prosecuting an application in respect of the same or substantially the same invention in any country outside India or this application is prosecuted by a person through whom he claims title or whom claim title through him.  In such a case, he must file along with this application a statement giving the detailed particulars of such applications for patent outside India. The Act gives the applicant a grace period and allows him to file this statement within the prescribed period, the Controller may allow.  Along with this statement, he will also give an undertaking that he will keep the Controller informed in writing of detailed particulars as required under Section 8(1)(a) in respect of every other application relating to the same or substantially the same invention if any filed outside India.  This duty to keep the Controller informed in writing as per the undertaking under Section 8(1)(b) commences from the date of application till the date of grant of patent in India.  Therefore he has to give the Controller this written information “from time to time” as the Act says ie. periodically and regularly the information has to be submitted.  The Act also requires the patent applicant to give the detailed particulars in respect of every other application filed outside India.  Therefore the Act does not pick and choose, it says that the applicant should give an undertaking to keep the Controller informed of all other applications relating to the same or substantially the same invention.  This requirement under Section 8 (1) is given by the patentee himself and in fact, the patentee is obliged to do so.  No exception is made in this regard.

66.       Next comes S.8(2). This deals with the applicant’s duty to furnish details relating to processing of the application in a country outside India, if the Controller requires the applicant to furnish such details at any time after the application has been filed in India and till the patent is granted or refused by the Controller   The Controller calls upon the applicant to furnish the details.  The applicant shall do so within such period as made prescribed.

67.       We have seen that this provisions was made pursuant to the suggestions in the Ayyangar Committee Report which stated that

“It is noted in the Report that the majority o the applications for patents in India are from foreign nationals and therefore it would be an advantage if the applicant is required to state whether he has made any application for a patent for the same in any foreign country or countries and the objections raised by the Patent Offices of such countries on the ground of want of novelty or patentability and the amendments directed to be made or actually made to the specification or claims in the foreign country up to the date of acceptance of the application.  The learned author felt that this information would be of great use for a proper examination of the application.”

 

68.       Therefore the Patent office receives along with the application or subsequently, the statement and undertaking as per Section 8(1)(a) & (b).  Therefore the patent applicant is expected to filing from time to time detailed particulars of every other application relating to same or substantially the same invention.  The statement and undertaking is given in Form-3 of Patent Rules and the details that must be furnished are the name of the country, date of application, application number, status of the application, date of publication, date of grant.  The undertaking given is that the applicant would keep the Controller informed in writing the details regarding to corresponding applications.

69.       Rule 12 of the Patent Rules speaks of Form-3.  Rule 12(1) (A) gives the applicant a six months time for filing the statement and undertaking from the date of filing the application.

As regards 8(2), Rule 12(3) clearly says that the applicant shall furnish information relating to objections if any in respect of novelty and patentability of the invention and any other particulars as the Controller may require  which may includes claims of application allowed . In Para 56 above we have given the documents which according to the respondent are required to be produced. They curiously omit the patentability destroying objections which are the documents the law wants.  The Act and Rules have to be read together.  No patent applicant can plead ignorance of his obligation to file the statement to abide by the undertaking and to furnish details as required by the Controller and these details relate to objections in respect of novelty and patentability of the invention.

70.       In the present case, in the revocation application, the applicant has made clear that the European counterpart of the subject patent was refused vide decision dated 11.12.2007.  We note that the patent was granted on 07.05.2008 and we also bear in mind that the applicant’s obligations continue till the grant of patent.  In the same paragraph 19 of the revocation application, the applicant had alleged that the respondent had failed to inform the Controller in various stages of prosecution in the US counterpart of the application filed in India.  And these applications are the 1st US7323463 in respect of which there were two Non Final Rejections dated 24.03.2005; and 15.07.2005.  A Final Rejection dated 28.02.2006; Non Final Rejection dated 14.12.2006, and a Final Rejection dated 04.06.2007 all of them before the grant of patent.

The 2nd US application is US7030149 in respect of which there were two Non Final Rejections on 03.10.2002 and 07.05.2003.  A Final Rejection dated 26.08.2003 then two Non Final Rejections dated 13.02.2004 and 29.03.2004 then a Final Rejection dated 16.12.2004 and a Non Final Rejection dated 14.07.2005.

The 3rd US application is US7320976 in respect of which there was a Non Final Rejection dated 19.12.2005.  A Final Rejection dated 26.05.2006; a Non Final Rejection dated 15.12.2006 and Final Rejection dated                                 04.06.2007.

US 463 is for a Combination of Brimonidine and Timolol for Topical Ophthalmic Use.

US 149 is also for Combination of Brimonidine and Timolol for Topical Ophthalmic Use.

US 976  again bears the same title.

Therefore the applicant alleged that this information was withheld defeating the very purposes of section 8.

71.       In the counter statement, the respondent had merely stated that the failure to disclose denied.  The respondent claimed that it had kept the patent office duly informed regarding the status of foreign applications from time to time and that the petitioner has not substantiated the objection under section 64(1)(m) and the meritorious patent must not be revoked on this ground.

72.       In the reply to this, the applicant has stated that the respondent was required to furnish complete details on events in major patent offices.  It is alleged that this was omitted because those actions were unfavourable and could jeopardize the grant of the patent and the factors had been concealed. The respondent’s  stand is that the office action issued by the Controller here on 09.06.2006 only required the patent application to submit the office action issued in any one of the major Patent Offices, such as USPTO, EPO and JPO, and that ‘a’ country means a single country.  Therefore whatever documents are required under Rule12(3) had been given and since the Patent office now had  several search engines, data base and is a Member of the Paris convention and patent  cooperation treaty and is also now an international searching authority , this requirement must be read in the context of the present position.  We do not agree with the stand of the respondent, we have already held so in several decisions.

  • Tata Chemicals vs. HUL; Order No.166 of 2012
  • Chemtura corporation vs Union of India & Ors. Order of Hon’ble Delhi High Court – MANU/DE/1880/2009.
  • VRC Continental vs. Uniroyal Chemical Company (IPAB Order No.207 of 2012).

73.       We have held the importance of compliance of section 8, the fact that there are search engines from which information can be culled out is no answer.  The respondent had given a solemn undertaking to furnish the particulars from time to time in Form-3.  Without this Form-3 statement, his application will not be examined. Having given an undertaking which is a pre-requisite was consideration of the application, he cannot avoid the solemn obligation by stating that the information is available in the internet or the website.  In the counter statement, there is absolutely no explanation regarding the compliance or non compliance or difficult in compliance provisions.  And inexplicably the respondent has accosted the applicant for filing the particulars belatedly. It is the respondent’s duty and it has been breached.

74.       However, there is an affidavit by one John E. Wurst, Vice President and Assistant General Counsel of the respondent  dated 14.02.2013, in which he states that he is acquainted with the prosecution of Indian Patent Application  and in their letter dated 13.06.2006, the former attorney had informed the patentee that to meet the objections raised in para 8 of the FER, the applicant must submit” the relative Notice of allowance with allowed claim  or   copy of the granted patent as the case may be in respect of any one such country” and in the event that no corresponding application has proceeded to grant “then search/examination report of any one of the foreign patent application would be required”. According to this affidavit, the attorneys also advised that they shall shortly be submitting the corresponding granted Canada Patent and therefore section 8 would be complied with and that this was submitted in response to the FER.  According to him, he provided from time to time update in respect of Form-3, and since the corresponding US and EP application were pending until 29.01.2008 and 11.12.2007.  The information provided on Form-3 was correct.

75.       We find from the documents that in the letter had been sent to  the respondent by the Patent attorney, Rule 12(3) is clearly extracted, which says, that when the Controller required information to be furnished under section 8(2), the applicant must furnish information relating to the objections if any, in respect of novelty and patentability of the invention and any other particular.  The letter has indicated that if the corresponding patent has been allowed or granted, the respondent may send those details (the letter has been extracted above).  But if no corresponding application has been provided to grant the applicant, must send search examination report of any one of the foreign patent.  The respondent cannot plead that Rule 12(3) was not made known to him.  Rule 12(3) clearly says that the applicant must furnish information relating to patentability objections raised in other countries.  The FER which is dated 09.06.2006, requires the respondent to furnish details regarding the search and/or examination report as required to in Section 12(3) in any one of the major Patent Offices USPTO, EPO and JPO.  In spite of this, the respondent had furnished only the Canadian granted patent.  .

76.       The respondent had the EP application with him.  The respondent had the USPTO application with him.  Even if he had furnished any one of them, he may have pleaded that he had complied with the requirement under Section 8.  The respondent did not provide any search or examination report.  The Form-3 just filed referred to the European Application and published on 19.01.2005.  This is filed on 07.09.2006.  The office action in respect of the EP counterpart which is dated 06.04.2005.  This was available with the respondent when the FER was issued which is dated 09.06.2006.

77.       On 06.04.2005, the above office action refers to D1 – Yuksel, D2 – Larsson, D3 – Wang, D4 – Hommer and D5 – Stewart had clearly stated that the present application does not seem to meet the requirement regarding inventive step.  It also states that it is obvious for the skilled man to try an alternative combination comprising Timolol and Brimonidine given the big amount of information.  If this search report had been furnished to the Controller here, his conclusion may have been otherwise.

78.       Now let us look at the office action relating to the three US applications.

In US 463 – the office communication has been mailed on 15.07.2005 and the claims directed to ophthalmic composition were rejected and this office action considered Larsson and DeSantis.  It indicated that Bowman and DeSantis Jr. are supplied as reference to demonstrate use of BAK.  The conclusion was “no claim is allowed” and that one having ordinary skill would have been motivated to combine these references.  This information was with the respondent but was not made available to the Controller.  There are responses and against the final rejection, the respondent had filed an appeal and therefore it is clear that the rejection of this application was known to them and yet it was not brought to the notice of the Controller.

79.       In the search and examination report of US ‘149 in the Final Rejection 2002 there is reference to Larsson, Yuksel and another prior art refer to Arichi.  Then there is the Non Final Rejection dated 16.12.2004, which refers to Yuksel, DeSantis, Bowman. It says that teaching of Yuksel differs from the invention in that the invention is a single composition, there is incorporation of BAK and the specific dosage range but that to incorporate that into teachings to itself was obvious in view of DeSantis.  It clearly says that one having ordinary skill in the art would have been motivated to modify the teaching of Yuksel to administrate Brimonidine and Timolol in a single composition.  It also refers to the enhancement of therapeutic outcome and the convenience.  The Non Final Rejection dated 14.05.2005 also says that “no claim is allowed”.  This was with the respondent and it was not discloses.

80.       Next we come to US 976 – The development at the USPTO with regard to this patent shows that at least the 2005 Non Final Rejection and 2006 Final Rejection were before 07.09.2006.  The Final Rejection shows that this office action refers to Larsson and another prior art Bandyopadhyay et al.  This says that the teaching of Larsson differs from the claimed invention in the administration of Brimonidine and Timolol in a single composition and to incorporate such teaching into Larsson would be obvious in view of Bandyopadhyay.  This office action was also not shown.

81.       We are not convinced by the belated explanation given in the Wurst affidavit which was not pleaded in the beginning in the counter statement to the effect that it was only because of the lawyer they had furnished the allowed Canada patent.  The lawyer had extracted on Rule 12(.3).  The respondent is not a novice to litigation.  Though the first examination report had mentioned USPTO, JPO or EPO as the Major Patent Offices whose office action must be furnished, the respondent wants us to believe that it was doing the right thing by giving  the Canadian patent, though the respondent had in its possession  the office actions relating to both EPO and US PTO. The fact both of them were adverse to them makes the case worse and the respondent come out of the S.8 test squeaky clean.

82.       In the Therasense case, the Federal Court US held by a majority opinion that the enforcement of an otherwise valid patent does not ensure the public merely cause of misconduct that was immaterial to the patent issues.  The court recognized an exception in case of affirmative egregious misconduct.  Our law does not make any qualification regarding the failure to disclose.  In Therasense, the minority view observed that under the majority’s rule, the applicant is no worse as the patent will be lost only if the claims would otherwise be held invalid and so, there is little to lose by following a course of deceit.  As we have observed above there is no “but for standard” concept to be adopted in our law. But even if we assume that it was so in the present case, we are of the opinion that but for that the fact that the EP office action and/or US office action were kept away from the Controller, the patent may not have been granted.  It is not a defence to say that Controller accepted the Canadian Patent as sufficient compliance. The Controller did not know of the adverse office actions, had the Controller known, the consequence may have been otherwise.  It is no response to say that standard must be more lax today because information is available on the internet.  It is no defence to say that if the patent is valid otherwise then discretion should be exercised in the respondent‘s favour.  In any event it has been brought to our knowledge that EPO has rejected the patent and it has become final.  On appeal USA has also rejected the patent. So it is not as if the respondent held an infallible patent. Above all, it is clear that the respondent withheld information that ought to have been furnish under Section 8.  The patent deserves to be revoked on this ground alone. This ground is answered in favour of the applicant.

83.       Next we take up the S.3(d) ground. According to the applicant this invention falls within the mischief of Section 3(d).  This invention is for a combination of Brimonidine and Timolol and since the Explanation to Section 3(d) refers to “combinations”, the patent cannot be granted, unless the respondent shows enhanced efficacy of IOP lowering effect of the invention compared to the serial application of Brimonidine and Timolol.  The case of the applicant is that the safety profile which was shown to be improved by the trials 23T and 24T will not help since even in the complete specification it is clear that safety and efficacy are regarded as separate parameters.

84.       According to the respondent this combination is not “a new form of a known substance” and can by no stretch of the imagination be considered as encompassing a comparison of dosing regimens where two actives are administered serially one TID and the other BID.  Therefore assuming without admitting 3(d) applies, the comparison can be done only with monotherapy of the two drugs. According to the respondent, the clinical trial 12 T and 13 T shows numerically better and statistically significant IOP lowering compared to Brimonidine Monotheraphy.  Moreover, the fixed combination of the invention shows an improved safety profile.  Therefore according to the respondent, the section 3(d) describes one category of substance or process which is not an invention, but it is a “mere discovery”.  The section explained that a mere discovery of which is not to be considered as an invention if it is a new form of a known substance, new property of new use of known substance or a known process or the use of a known process, machine or apparatus.  But this discovery would be considered as an invention if the new form results in enhancement of known efficacy of that substance and so on as described in the section.  The explanation to the section enumerates various derivatives of the known substance which shall be considered to be the same substance unless, there is significantly different in therapeutic efficacy.  Therefore all the forms of the known substance that are mentioned are derivatives of the known substance which could be salts, esters, ethers and so on.  Combination is also mentioned here. The respondent had argued that this cannot be considered as a form of a known substance. The respondent is right.  This is invention is a combination of Brimonidine and Timolol.  The applicant perhaps wants us to consider it either as a derivative of Brimonidine or as a derivative of Timolol.  It is not a derivative. The combination  mentioned in the Explanation can be only mean a combination of two or more of the derivatives mentioned in the Explanation or combination of one or more of the derivatives with the known substance  which may result in a significant difference with regard to the efficacy.  A combination of two active drugs like Brimonidine and Timolol cannot be considered derivatives of each other.  This ground is rejected.

85.       Next we come to obviousness In this case, we have three decisions relating to counterpart inventions. The EPO rejected the counter part patent.  In USA on appeal, the patent was removed.  In Canada, the patent was affirmed.  We will first deal with the Canadian judgment which is in favour of the respondent.  The Canadian judgment proceeded on the basis that the common general knowledge of the persons skilled in the art would know about ocular hypertensive and glaucoma, the IOP lowering medications,  that IOP lowering medications were commonly used concomitantly or combined, that Brimonidine and Timolol were well established. IPO lowering medication, that Brimonidine and Timolol had been used in concomitant therapy and it resulted in a larger IOP reduction than with Brimonidine and Timolol alone, that commercially available combination product, typically included Timolol as one of the active agents, and that BAK is a commonly used preservative.  The Canadian Court also accepted that DeSantis suggested combinations of Anti Glaucoma composition comprising one or more beta blocker with one or more alpha2 agonist and that this person would also be aware that the benefits associated with fixed combination as compared to concomitant therapy would include less preservative and greater patient compliance. The Canada judgment accepted that the improved safety profile was part of the inventive step.  According to this judgment, the differences between the prior art and the innovative concept, invention are that the composition combines Brimonidine and Timolol into a single chemically table formulation which had not been made before;  it had a superior safety profile compared to Brimonidine TID; it permits BID dosage without an afternoon reduction in efficiency and the composition received a significantly reduced daily load  of BAK relating to concomitant treatment. The judgment further held that even if the composition is simply as effective as concomitant administration the demonstrated advantages are requiring the administration of two drops a day compared to 5 in the US (Brimonidine TID and Timolol TID) and 4 elsewhere (Brimonidine BID + Timolol BID) and eliminating the afternoon trough.

86.       In that case, the opponent contended that the clinical trial did not compare the invention with concomitant administration but only with monotherapy of the two drugs and the respondent had replied that it had no obligation to explain his clinical trials to include a comparison with concomitant administration. This was accepted by the Court in Canada.  The judgment held that the overcoming of this afternoon drought was an innovation, even if the principle commercial benefit arose in the USA. The Canada Court rejected the contention that the skilled formulator would be easily able to manufacture this combination and questioned that there was no explanation why no one had ever done it before.  The Canada Court held that the improved side effects were unexpected and so was the improved allergy profile.  The Canada Court also expected that the person skilled in the art would not have initially selected BAK as the preservative. The Canada Court also held that the persons skilled would have chosen Purite and not BAK for its gentler side effect profile.  For all these reasons, it held that it would not have been obvious to the persons skilled to formulate this combination.  The other fact that prevailed with the Canada   Court  was that several obstacles that the respondent team had faced and the extent and nature of work that was done to arrive at the invention.  As regards motive to try this combination, the Canada Court considered that the extent of time, effort and resources required to conduct clinical trials, the difficulty in obtaining FTA approval would have been discouragement.  For all this reasons, It held that it would not have been obvious to try c

87.       In Allergan VsSandoz, the U.S.Federal Court held that DeSantis provides an express motivation to combine alpha2 agonists and beta blockers in order to increase patient compliance. It held that the District Court had erred in holding that one of ordinary skill would not be motivated to develop a fixed combination.  It said that motivation to combine may be found in many places and forms.  It held that it was common at the time of an invention to provide Brimonidine and Timolol serially and DeSantis taught that fixed combination increased patient compliance and therefore this was enough motivation.  As regards reasonable expectation of success, the Court agreed that formulation science is unpredictable but that DeSantis showed that alpha2 agonists and beta blockers are complementary and should be used together.  And it also showed that BAK is successful to use in the formulation therefore the court held that the person of ordinary skill would reasonably expect to succeed in formulating a fixed combination containing Brimonidine and Timolol and BAK. The factual finding of the District Court regarding the difficulties in developing the combination was accepted but the Appeal Court held that the difficulties are not probative with respect to obviousness.  The person of ordinary skill need only have a reasonable expectation of success.  And it held that the formulative struggles were associated with their intention to utilize the proprietary preservative rather than BAK and once switched     to BAK there would have been a reasonable expectation of success.

88.       As regards teaching, the Appellate Court held that the aspects of prior art which said to have taught away was not found to have an impact on the clear motivation to combine expressed in DeSantis.  Then the Court considered the increased efficacy and reduction in side effects.  But the Court held that these factors do not outweigh the other evidence of obviousness.  And it held that there is extensive evidence in the prior art showing the concomitant administration of Brimonidine and Timolol multiple times per day. There was motivation to combine to achieve better patient compliance.

89.       Next we take up the European decision which has considered Yuksel, Larsson and others but not DeSantis.  This decision held that Yuksel taught that Brimonidine is used in treatment of Glaucoma.  It disclosed the advantages of Brimonidine and Timolol, serial therapy.  It said that Larsson also taught the enhancement effect and elevated IOP compared with Brimonidine and Timolol alone.  Therefore it was well known from the prior art that the sequential administration (5 minutes interval) of Brimonidine and Timolol leads to improved control of elevated IOP and Glaucoma. It held that from D1 a person skilled in the art would learn that although present and statistically significant, the systemic side effects of sequential combination are minimal and not relevant.   It held that without any numerical data with the closest prior art i.e. D1 it is not possible to make a clear comparison with D1 and to quantify the extent of reduction of side effects.  Therefore purely on the basis of D1 alone, the European office rejected the claims

90.       With regard to the inventiveness of a combination drug, we have the judgment of Justice Pumfrey in (2004 EWHC 477 (Ch) Cipla Limited Vs. Glaxo Group Limited.  The patent related to an Asthma drug, which combines two drugs one a 2 Agonist and the other a steroid.  In that case also compliance was difficult and the invention made the compliance easier.  They held that the combination was an obvious combination, it was not obvious that it would be safe or that it would represent any advance of what had gone before.  The court said it was a reasonable prediction for the skilled man knowing the properties of the drugs.

91.       Now we come to the prior arts filed before us.  Yuksel is D1 – it dealt with the short term effect of adding Brimonidine 0.2% with Timolol.  The reduction in IOP at all time intervals observed with brimonidine + timolol was significantly greater than the reduction with timolol + placebo. The study suggests that a combination of brimonidine and timolol may have potential in the treatment of glaucoma. Brimonidine tartrate is a new relatively selective a2 agonist that, because of its distinct chemical structure, may have theoretical advantages over apraclonidine. It appears to lower IOP in humans through a reduction of aqueous humor inflow and by an increase in uveoscleral overflow .It said that the chemical structure of Brimonidine is similar to that of clonidine and apraclonidine. However, the effects of brimonidine on aqueous humor dynamics are different from aparclonidine.  Brimonidine reduced aqueous flow and increased uveoscleral overflow in human eyes; however, apraclonidine did not increase uveoscleral outflow. The different mechanisms of action of α2   -agonists may be related to their receptor selectivity. Possible receptors targeted by these drugs include two imidazoline subtypes and for different    α2adrenergic subtypes.  Brimonidine is an imidazoline receptor agonist and an a2 agonist. It said that recent reports indicate that the ocular hypertensive effect of brimonidine in the primate may be mediated through stimulation of an imidazoline receptor rather than an α receptor. The receptor is different from α2receptors in the rabbit and bovine iris-ciliary body. Brimonidine may reduce IOP via  imidazoline receptors in the ciliary body..  A single drop of Brimonidine 0.2% or placebo was added to treatment with Timolol.  The reduction in IOP at all time intervals observed that Brimonidine + Timolol were significantly greater when those with Timolol + Placebo.  It says this study suggest that a combination of Brimonidine and  a β blocker (Timolol is one) may have potential in the treatment of Glaucoma and that further clinical trials with brimonidine are indicated to further its role as an adjunctive agent.  The respondent reiterated that the combination mentioned here was serial administration.  This prior art shows that 2 agonists (Brimonidine is one), are promising drugs for long term therapy of Glaucoma. It also taught that Brimonidine has therapeutic advantages over apraclonidine.  It reduces IOP by reducing aqueous humour and increasing Uveoscleral outflow.  Those response studies showed that Brimonidine 0.2% twice daily is safe and effective in lowering IOP in patients.  The common knowledge seen from this prior art also shows that a single therapeutic agent was inadequate to maintain a desirable IOP over the long term. The study demonstrated that “single drop Brimonidine .2% causes a significant additive reduction in IOP where the IOP was not controlled with Timolol alone.  It also showed decreases in main systemic blood pressure and pulse rate without clinical symptoms.  It showed that though the chemical structure of Brimonidine was similar to that of clonidine and Apraclonidine, the effects are different.  The apraclonidine did not increase Uveoscleral outflow. It was known that Apraclonidine when used with Timolol reduced IOP by decreasing aganous formation.  Therefore Brimonidine may also have an additive IOP lowering effect. It said that Brimonidine 0.2% is twice daily offered long term IOP and control comparable as that achieved with Timolol 0.5% and Betoxolol.  The report also showed that a side effects including  was less with Brimonidine than with Apraclonidine.  It concludes that study indicates that the combination of Brimonidine and the  blocker as having potential.  Therefore D1 teaches that of the 2 agonist Brimonidine had obvious advantages.  Brimonidine and Timolol was found to be efficacious and there was a decrease in systemic blood pressure and pulse rate.  Therefore, the serial administration of Brimonidine and Timolol was an advantage and deserved further study is the teaching of this prior art.

92.       Exhibit  D2 – which is Larsson dealt with Aqueous Humour Flow in normal human eyes treated with Brimonidine and Timolol alone and combination.  The result showed Brimonidine reduces it by 33.1%, Timolol by 49.9% and the combination by 58.9%. The reduction of Aqueous humour flow lowered IOP is something that we saw in D1.  Therefore the fact that this prior art dealt only with aqueous humour flow does not mean that nothing to do with the problem on hand.  Further D2 itself states that studies with Apraclonidine shows that IOP lowering effect is attributed to suppression of aqueous humour flow. The result of the study shows that though Brimonidine was not efficient as Timolol in suppressing aqueous humour flow, the effects of IOP of both the drugs separately were comparable and in combination a further reduction of aqueous humour flow and IOP was seen.  The effect on the IOP was greater than expected from the reduction of flow. Here also Brimonidine was instilled twice daily i.e. BID in combination that is serially with Timolol.  Table 1 shows the Aqueous Humor Flow from 8 am to 4 pm and it shows that Brimonidine reduced aqueous humour flow significantly compared with placebo but less efficiently than Timolol.  But in the combination of the two drugs the Aqueous Humor Flow is reduced by 17.9% compared to the Timolol treated eye.  Table 2 indicates the intraocular pressure at 4 pm.  This showed the response to the afternoon trough of Brimonidine.  Even here, the reduction in intraocular pressure, by serial administration of Brimonidine and Timolol was more than Brimonidine and Timolol alone.  The concept of apparent resistance to outflow was also seen.  The reduction in aqueous humour flow and IOP where the combination  was used was greater  than either of the individual drugs.  And this shows that Brimonidine may have some additional anti hypertensive effect that is not mediated through inhibition of aqueous formation but rather through enhancement of aqueous out flow.  And in conclusion, it found that in a short term administration Brimonidine was partly additive to Timolol, the combination treatment causes a further reduction of Aqueous Humor Flow and IOP

93.       Now we come to DeSantis – DeSantis is a combination of Apraclonidine and Timolol.  DeSantis refers to 5 types of drugs which are used in Glaucoma treatment.  All the 5 have potential side effects and Timolol has serious pulmonary side effects.  Therefore there was a need for a new potent anti-Glaucoma composition which reduced the above side effects and enhanced patient compliance.  It says that 2agonists and  blockers reduce the inflow of aqueous humour by means of complementary mechanism.  The extract from this prior art in this regard has been given earlier. It says that these combinations have a greater potency in suppressing IOP lowering effect than that achieved by either ingredient alone.  It refers to a publication by Timmermans which is incorporated by reference. According to the respondent merely because Timmermans was admitted to have mentioned Brimonidine, the applicant cannot contend that DeSantis taught a Brimonidine combination.  The respondent is correct. Without the whole document, we would not know the context and the observations made about brimonidine in the said document.  However, DeSantis clearly encourages a combination and it also tells us a very important fact that both these two drugs act in a complementary mode to each other. According to the respondent no one would have been encouraged to combine and referred to Tony Realini “Two drugs in one bottle” where the author speaks of the difficulties in combining and that not every possible pair can be combined in one bottle and many stars must be allied.  It is a post patent document and it says that the formulation of drugs is not a predictable one and not all formulation will guarantee success.  That is true. But this document does conceive the advantages of having two drugs in single bottle and it  also says that given the practical advantages of a combination, clinicians may opt to build a simpler regimen using the fixed combination. These practical advantages of a single composition were always known. The respondent’s case is that finding the correct combination out of million options was the test.

94.       The other document that the respondent relies on is the  Alphagan and Timolol package  labels which refer to warnings and the contraindications like cardiovascular reactions.  It is true that there are warnings. At the same time as we have seen in the Canadian judgment which is strongly relied on by the respondent that both Brimonidine and Timolol were well established IOP lowering medications.  Therefore the fact that the label contains warnings cannot be a discouragement since the respondent was selling Alphagan and Merck was selling Timoptic. The respondent has also referred to the trials 12T and 13T which show that the incidence of oral dryness, ocular allergy etc. was significantly less with the combination than with Brimonidine.  And it was contended that the reduction in allergy in the Invention is not due to the reduction in dosing of Brimonidine from TID to BID and it had been established that the development of allergy to Brimonidine is independent of dosing of the Brimonidine and the respondent referred to Micheal A.Motolko Ex R8. This is also a post patent document and it says that in the present study all patents were dosed twice daily and the incidence of ocular allergy was evaluated between patients having combination therapy and patients having monotherapy.. According to the respondent the reduction in the incidence of allergy may be due to the presence of Timolol in the combination. The respondent had also referred to trials 23T and 24T which showed a significant reduction in somnolence and oral dryness with the fixed combination as compared with adjunctive or serial therapy using Brimonidine TID and Timolol BID.  This study showed that the combination demonstrated statistically and clinically significant safety.  This has been spoken by the witness Amy Batoosingh. We have already seen that Gary Beck had referred only to one prior art viz DeSantis.  It is Amy Batoosingh who has compared all the three prior arts.  Amy Batoosingh says that there was no reason that a fixed combination reducing Brimonidine from TID to BID would meet the FDA expectations. This has nothing to do with the obviousness question. 12T and 13T did not compare the fixed combination with serial therapy .using Brimonidine and Timolol both BID.

95.       As regards the drug effect, Yuksel-D1the percentage decrease in IOP with timolol + brimonidine was significantly greater than with timolol + placebo. And Larsson showed that at 4 pm which is when the afternoon trough occurs, the reduction in IOP with a Brimonidine and Timolol Serial combination was 34.7% which is higher than the reduction achieved by Brimonidine  mono therapy.  As regards reduction in aqueous humour flow, in comparison with placebo between 8 am to 4 pm with Brimonidine the reduction is 33.1%  whereas in combination with Timolol it is 58.9.   Amy Batoosingh does not consider this instead  she says that there is a significant decrease in efficacy when Brimonidine is dosed BID and when it is dosed TID and therefore, no one would have been taught to  combine Brimonidine and Timolol in the same bottle.  We cannot accept this, as it was evident from the prior arts that the serial combination showed clearly that when Brimonidine and Timolol were serially administered where the effect of the individually administered drug should be at its lowest, it is higher. That is the afternoon trough effect gets minimized even with serial administration.

96.       The one issue with the affidavit of this witness is that she compares the combination which is the invention with the two drugs administered individually and NOT with the drugs given serially. Ms.P.Sita already knows from D1 and D2 that the serial combination has an additive effect and therefore the closest prior art was this combination. It may not be “a known substance” for the purposes of S.3(d.)  But it was common general knowledge that IOP lowering medications were used concomitantly or combined together.  It was known that two IOP lowering medications resulted in greater IOP reduction and it was also known that Brimonidine and Timolol could be and in fact were used concomitantly.  Therefore if the inventive step lay in the significant reduction of   allergy  or oral dryness or the reduction of IOP the trials should have compared the fixed combination with the Yuksel combination that is administering the drug serially or the Larsson combination. The administration of the two different drugs one after the other was known to be advantageous and one of the problems that this manner of administration had was the difficulty in having to put the drops several times a day.  Glaucoma patients are generally elderly and if they had been prescribed the Yuksel combination a single drop of Brimonidine and Timolol each dropped in each eye twice a day meant 8 drops in a day.

97.       DeSantis had a composition in which Timolol and an alpha-agonist were combined.  DeSantis does not mention Brimonidine directly but it mentions apraclonidine and we have seen from D2 Larsson that Brimonidine was better. The label-warnings notwithstanding the persons in the field knew that it was advantageous   serially combining the two anti-glaucoma drugs.  Therefore, there was definitely   motivation to combine in one composition so that the patient would have to administered four drops a day, two drops in each eye.  This is only convenience.  The question, why should I not try to combine these two drug would definitely have occurred to Ms.P.Sita. So to combine the two in one bottle was definitely obvious in view of D1 .D2 and D3

98.       In the European Patent Office decision revoking European Patent No.365662 which is a combination of Timolol and an Alpha -2 agonist which was composition for making medication to control IOP, the Patentee was Alcon and Allergan, the respondent herein was the opponent. The opponent raised the grounds of lack of synergy and obviousness and also novelty.  The patent was revoked holding that the claims were novel but rejected Alcon’s contentions.   It was held that the prior art showed that there is augmented response to Timolol with Alpha agonists as compared with either agent alone, if topical pre treatment with Timolol is foreseen.  It says that D3 clearly indicates with Timmermans a synergistic effect when combined. As regards synergistic effect it was held that the presence of synergistic effect cannot be considered surprising for the person skilled in the art, since synergistic action has already been disclosed for Beta blockers of different structures in combination with Alpha2 agonist with different structure.  The Patentee Alcon pointed out that the persons skilled in the art would not have considered the composition in view of the washing out effect. It was the respondent’s  case which was accepted by the authority that the person skilled in the art was well aware of such an effect and he would mix  such pharmaceuticals in such a  way that no washing out occurs and that he would in fact prepare such composition for the convenience of the patients in the expectation of success. Therefore the authority held that since the invention lacked inventive steps, it was not necessary to decide on the issue of synergy. This order was passed in 1998.

99.       In Cantor which was also relied on, we find that non selective Beta blockers tend to show reduced efficacy with long term use and therefore patients who receive Beta blocker therapy will require an additional medication for IOP control within two years. It also states that cardio selective Betaxolol had a more favourable safety profile but not as efficacious as Timolol.  The other Sympathomimetics were less effective than Timolol. It specifically states that Brimonidine has a favourable safety profile and is comparable to Timolol in IOP lowering efficacy at peak effect. The document was actually considering the utility of brimonidine 0.2% BID as mon- and adjunctive therapy. It shows that brimonidine BID was being considered actively by the persons in the field.  It shows the evolving Pharmacotherapeutic profile of Brimonidine and that post-market studies have demonstrated the utility of Brimonidine 0.2% BID which was comparable with Timolol 0.5%. The long term results suggest that Brimonidine 0.2% BID is highly appropriate as first and second line therapy for glaucoma patients.  The European decision which has been mentioned earlier held that the skilled man would receive from D1 that a person’s systemic side effects in sequential administration of Brimonidine, plus Timolol was minimal. It held that the inventive steps cannot be acknowledged because the composition of the present application did not present advantages over D1 neither in terms of the Pharmaceutical effects achieved nor in terms of reduction of side effects.

100.     The decision of the Federal Court in Allergan Vs. Sandoz held that DeSantis expressly teaches the use of the Beta Blockers TImolol, it teaches preferred Beta blockers, it discloses the use of  BAK as a preservative and though it does not expressly state that Brimonidine is one of the Alpha +2 agonist that can be used. It, however, teaches that Alpha + 2 agonist that may be used are described in Timmermans. It also held that at the time of the invention the topical administration of 0.2% Brimonidine with 0.5% in combination spaced 5 minutes apart was in Larsson. It held that both Timolol and Brimonidine were commercially available. Both were available in the claimed concentration and contained preservative BAK. It was known that serial administration of Brimonidine and Timolol reduced IOP greater than better than TImolol and Brimonidine alone. It held that DeSantis expressly provided motivation for two formulae fixed combination to increase patience compliance.  It held that when viewed under   a proper standard the evidence establishes a motivation to combine since it was common at that time to provide Brimonidine and Timolol sequentially and DeSantis taught fixed combination.

101.     As regards reasonable expectation of success, we have in our discussion of the Canadian judgment held how a reasonable expectation should be considered and we too are of the opinion like the Federal Court that there was a reasonable expectation of success in view of the DeSantis.  Therefore for the above reason, we find that the invention is obvious.

102.     Having found that the invention is obvious, we must state that it is the duty of the applicant to adduce evidence to prove obviousness. In pharmaceutical patent revocations it may not always be possible to rest on just prior arts. In this case the history of the state of the art showed that the two drugs were popular, and that the two drugs were combined serially, and that the serial administration showed advantages over single therapy, and that Brimonidine BID was not unknown and in fact except for USA Brimonidine was given BID elsewhere, and that composition of two drugs in one bottle was known, and the claimed preservative (it was optionally claimed in fact in Claim 3) was used, and so the invention was obvious. This may not be so clear in other cases. We do not know why the affidavit originally filed was withdrawn. We reiterate as we have done in other cases before that the applicant must plead and prove his case.

103.     As regards Section 3(e), according to the applicant it is merely an admixture and each drug provides the effect that any way individually it would do.  

We have already seen that the two drugs work in a different way in reducing IOP. 

The tests do not compare the composition with sequential combination as shown in Yuksel. The nearest prior art is the serial administration.

A comparison with that would have shown if the improvement is only additive or more. That evidence is not before us. In view of our holding against the respondent on obviousness and S.8.Compliance it is not necessary for us to decide the 3(e) issue.

104.     We have found the claimed invention as obvious.  The BID administration was known and % / w of the drugs was also knownWe are not inclined to accept the amendments at this stage.

105.     For the above reasons ORA/21/2011/PT/KOL is allowed and patent No.219504   is revoked.   M.P. No.2/2012 is closed.  As regards M.P. Nos.59/2012, 128/2012 and 134/2012 no orders are necessary.   M.P. Nos. 60, 61, 72, 73, 127, 135/2012, 12/2013 and 15/2013 are allowed. 

 

 

 

(D.P.S. PARMAR)                                           (JUSTICE PRABHA SRIDEVAN)

TECHNICAL MEMBER (PATENTS)              CHAIRMAN

Reportable:    Yes/No

(Disclaimer: This order is being published for present information and should not be taken as a certified copy issued by the Board.)

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