INTELLECTUAL PROPERTY APPELLATE BOARD
Guna Complex Annexe-I, 2nd Floor, 443, Anna Salai, Teynampet, Chennai-600018
ORA/20/2011/PT/KOL
AND
M.P.NO.59/2011, 25, 63-64,129, 136-138/2012 & 14/2013
IN
ORA/20/2011/PT/KOL
THURSDAY, THIS THE 8TH DAY OF AUGUST, 2013
Hon'ble Smt. Justice Prabha Sridevan …Chairman
Hon'ble Shri D.P.S. Parmar …Technical Member (Patents)
Ajanta Pharma Limited,
A Company incorporated under the
Companies Act, 1956, having its
Registered Office at
Ajanta House,
Charkop, Kandivali (West)
Mumbai – 400 067, India … Applicant
(Represented by – Shri S. Majumdar, Ms. Mythili Venkatesh,
Ms. Aditi Kamath & Ms. Sultana Shaikh)
Vs.
1. Allergan Inc.
2525 D upon Drive,
T2-7H, Irvine,
CA, USA.
2. Allergan India Private Limited,
Prestige Obelisk,
2nd Floor, Kasturba Road,
Bangalore – 560 001, India.
3. The Controller of Patents and Designs,
Intellectual Property Office Building,
CP-2 Sector V, Salt Lake City,
Kolkata – 700 091. …Respondent
(Represented by – Shri Pravin Anand, Ms. Archana Shankar,
Ms. Gitanjali Viswanathan and Ms.Gitika Suri)
ORDER (No.172 of 2013)
Hon’ble Shri D.P.S. Parmar Technical Member (Patents)
This application u/s 64 read with section 117D of the Patents Act, 1970 is filed for revocation of patent No.212695 (herein referred to as 695) granted to Allergan Inc. for invention “Hypotensive Lipid (prostaglandin derivatives) and Timolol composition and methods of using same”. This application for revocation was filed by Ajanta Pharma Limited.
2. Mr. S.Majumdar senior Advocate appeared for the applicant and Mr. Praveen Anand senior Advocate represented the respondent. Both the counsels, besides arguing the matter at length, have also filed their written submissions on the preliminary issue as well as on merits.
3. The subject patent relates to ophthalmic pharmaceutical compositions for treatment of ocular hypertension.
In particular it relates to fixed combinations of Hypertensive lipid and Timolo component.
Hypertensive lipid component is selected from cyclopentane N-ethyl heptamide-5-cis-2-(3α-hydroxy-phenyl-1-pentenyl )-3,5-dihydroxy,[1 α,2 β,3 α,5 α] (referred as BIMATOPROST) pharmaceutically acceptable salts thereof and mixtures thereof.
The inventors claimed to achieve enhanced treatment of ocular hypertension with reduced side effects.
PRELIMINARY OBJECTIONS
Limitation
4. Mr.Anand submitted that
the revocation petition filed by the Applicant is clearly time barred as the patent was granted on 14.12.2007 and the present revocation petition was filed by the Applicant on 12.08.2011, almost after four years.
According to the learned counsel
the factum of an application having been filed and granted to the Respondent was published by the Indian patent office on two occasions: Under Section 11 (A) of the Indian Patents Act on 24th March 2006, and on 14th December 2007 under Section 43(2) of the Indian Patents Act.
5. He contended that
both the publications provided adequate constructive notice to file objections to the patent. The learned counsel submitted that
the Applicant chose not to file either post grant opposition proceedings or even revocation proceedings under Section 64 of the Indian Patents Act within three years from the date of grant of the patent but moved an application for revocation almost four years after grant of the patent, which is clearly beyond the limitation period of three years prescribed by the Limitation Act.
The learned counsel submitted that
the grant of a patent has a limited term of 20 years from the filing date.
He submitted that
the Hon'ble IPAB may pass necessary orders in order to ensure that a limitation period is applied for instituting revocation proceedings under Section 64, even though the Indian Patents Act does not specifically provide for the same.
6. The learned counsel argued that
a revocation petition under Section 64 can clearly be distinguished from a counter claim for a revocation filed in an infringement suit as the said counter claim is more in the nature of being a defence as opposed to being a direct validity attack.
Therefore it becomes extremely critical for the Hon'ble IPAB to exercise its discretionary power and apply Article 137 of the Limitation Act, 1963 to the present revocation petition.
He relied on Bayer AG vs. Controller of Patents (AIR 1982 Calcutta 30), Para 6, where it was held
"In my opinion, the decision reported in MANU/SC/0323 /1976: [1977] 1SCRC) 96 puts an end to the controversy regarding applicability of 1963 limitation Act to special laws or local laws. There is no doubt that in this case Article 137 will apply as no time limit was put by the Act itself and this application has to be made to the High Court. This application should have been made within 3 years from the date when the applicants right to apply accrued. It was not disputed by the applicant that the relevant patent was sealed on 23-4-1977, recorded in the register on 4-6-1977 and the Patent documents were issued to the applicant on 28-6-1977. This application made on 1-12-1980, was clearly beyond three years from the date of accrual of right to apply and is barred by limitation on the face of the application."
7. The learned counsel for the Applicant submitted that in the present case the revocation was filed after the filing of an infringement action which is a statutory remedy available to the patentee.
Simultaneously, it was submitted that revocation too is a statutory remedy.
If an infringement suit is filed the defendant is entitled to claim revocation of the patent by way of a revocation application to the Hon'ble IPAB or by way of a counter claim.
Therefore, the limitation if at all applicable, in case of revocation proceedings would have to be computed from the date of filing of the suit.
The suit and the revocation both were filed in 2011 and therefore the date of filing of the suit has to be taken as the date of cause of action for the purpose of revocation and only thereafter limitation completed.
This could be a case at the highest in favour of the respondent.
8. The learned counsel for the Applicant submitted that the Calcutta High Court judgment, is differentiated as revocation is different from rectification and does not follow as a consequence of infringement action normally. Under the scheme of statute revocation is a remedy under Law when an infringement action has been filed.
9. The cousel for the Applicant submitted that
the Law of Limitation is applicable to Courts and the Hon'ble IPAB is not a Court but a techno-legal quasi-judicial authority having certain trappings of a Court.
This Hon'ble Board in the case of Tata Global Beverages Limited vs. Hindustan Unilever Limited and Anr. - Order No: 240 of 2012 dated 18/10/2012 in TRA/l/2007/PT/MUM; was pleased to has held that Limitations Act, 1963 does not apply to an application under section 64 of the Patents Act filed before the Appellate Board.
The relevant paragraph from the aforesaid case -law is reproduced below for ready reference:
"7. We agree with the applicant that section 64 of the Patents Act 1970 does not provide any time limit for filing the application for revocation before Appellate Board. Section 64 states that ".......a patent whether granted before or after the commencement of this Act, may be revoked on a petition by any person interested ..............by the Appellate Board........".We do not agree with the argument of the counsel of the respondent that since the right to apply for revocation of the impugned patent accrued from the date of publication of notification of sealing on -12.12.2007 and the revocation petition filed in August 2011 is clearly beyond the limitation period of three years time under Article 137 of the Limitation Act, 1963 which expired on 2.12.2010. The right to revoke patent any time after the grant of patent under section 64 cannot be extinguished after three years from the date of the publication of the grant by applying limitation of three years under Article 137 of the Limitation Act. This will run contrary to the scheme of the patent law. It is immaterial as to when the applicant for revocation came to know about the existence of patent or when the right to revoke the patent accrued. Thus the application for revocation can be filed before Appellate Board any time after the grant of a patent. This application is therefore not time barred.
10. The learned counsel for the Applicant submitted that it was at a higher pedestal than this case, as there was an impending infringement action that was filed by the Respondent. Due to this, the period of limitation ought to be construed along the lines of infringement limitation determination, wherein every instance of infringement gives rise to a fresh cause of action.
11. The learned counsel for the Applicant submitted that the Respondent had not included such an argument in their pleadings due to which the same ought not to be considered.
However, the Ld. Board stated that such determination of the applicability of Limitation may be done by the Court suo moto, as per the provisions of Section 3 of the Limitation Act.
12. We have already dealt with issue of limitation in IPAB order 240/2012 in TRA/1/2007/PT/MUM we find same is applicable here.
“The right to revoke patent any time after the grant of patent under section 64 cannot be extinguished after three years from the date of the publication of the grant by applying limitation of three years under Article 137 of the Limitation Act. This will run contrary to the scheme of the patent law. It is immaterial as to when the applicant for revocation came to know about the existence of patent or when the right to revoke the patent accrued. Thus the application for revocation can be filed before Appellate Board any time after the grant of a patent. This application is therefore not time barred’.
This revocation application is not time barred.
Onus not discharged" Lack of Evidence and Burden of Proof
13. Mr. Anand submitted that
the applicant did not file any evidence in support of their revocation petition and clearly did not discharge their onus of establishing the invalidity of IN' 695.
He submitted that
on 18.10.2012 the Applicant filed the affidavit of Dr. Sudhakar G Deshpande through their M.P. No. 25 of 2012 but at the first hearing before the Kolkata Circuit Bench on 4th December 2012, the Applicant withdrew the affidavit of Dr. Sudhakar G Deshpande which was clearly recorded by the Hon'ble IPAB in their Order dated 4th December 2012 communicated vide letter No. ORA 19, 20 & 21/2011/PT/KOL/9552 dated 13th December 2012.
He argued that
the entire proceeding of the Applicant now is based on the pleadings without evidence and the unsubstantiated averments made by the Applicant's Counsel at the hearing.
Mr Anand contended that
the onus of establishing invalidity in a revocation proceeding is clearly on the party who is challenging the validity of the patent and in the absence of any evidence on behalf of the Applicant in the present revocation proceedings, the revocation petition be dismissed in limine.
14. The counsel for Respondent relied on the following procedures and provisions of law:
· Sections 101 and 102 of the Evidence Act.
"101. Burden of proof.- Whoever desires any Court to give judgment as to any legal right or liability dependent on the existence of/acts which he asserts, must prove that those facts exist. When a person is bound to prove the existence of any fact, it is said that the burden of proof lies on that person.
102. On whom burden of proof lies.- The burden of proof in a suit or proceeding lies on that person who would fail if no evidence at all were given on either side. "
· In F & H v. Unichem (AIR 1969 BOM 255 (V 56 C40) Para 13), the following was held:
“13. …..[I]t may be stated that the onus in regard to all objections to validity lies on the defendant (Halsbury, (3rd ed.) Vol. 29 p. 106 paragraph 218).”
· In The Travancore Mats & Matting Co. v The Controller of Patents and Ors in ORA/44/2009/PT/CH, the Hon'ble IPAB in para 13 held:
“The Petition and the Miscellaneous Petition accompanying the same do not contain any substantial objections nor are supported by any relevant 'documentary proof or evidence Thus, the onus of establishing invalidity of a Patent lies on the party seeking to revoke the patent and this has been laid down in several cases. The Applicant has not put forth any valid submissions in support of his petition for revoking the Patent. The onus lies on the Applicant to validate its contentions and it has failed to do the same".
· Further, Roche v/s Cipla MANU/DE/4182/2012 in paras 67 and 69 the Hon'ble Single Judge held that the burden of proof in invalidation proceedings is clearly on the defendant.
15. We find the applicant has relied on the prior patents and certain non patent documents to prove the obviousness. We find these documents are relvant per se as prior teachings.Just because the Expert evidence in this case has been withdwrawn would not persude us to look away the prior art staeing at the impuned patent. We find on the facts of this, prior art documents in the form of patent document or non-patent literature filled by the applicant sufficient to decide the issue before us.Therefore this objection of the respondent is not maintainable.
Grounds of revocation
Section 8 violation
16. The learned counsel for the applicant submitted that the respondent has under a duty to disclose information as per the requirements of Section 8 of the Act and Section 8(1) of the Patent Act makes it mandatory that information, pertaining to foreign filings in respect of the same or substantially the same invention be provided. The counsel submiited that Form 3 of 20.01.2004 furnished by the respondent in IPO indicated that Korea, New Zealand, Canada, China and Japan were pending applications. However, the application numbers of the same were not disclosed. Exhibit EA 1 of the Miscellaneous Petition clearly indicates that these application numbers had been generated. The Korean application was published barely 4 days after the last Form 3 of January 20, 2004 and the New Zealand application was granted the following year i.e. in 2005. Also, it was submitted that the EP application number was published on March 3, 2004 i.e. more than 2 months after the Form 3 was filed. However Applicant did was not press.
17. The learned counsel for the applicant submitted that Section 8(2) is a requirement that is borne out of the Controller's direction in paragraph 14 of the FER dated September 21, 2004 (Exhibit O of the revocation petition), required compliance with Section 8(2).
18. The learned counsel for the applicant submitted that the Respondent vide letter dated January 20, 2005 stated that
"... we would refer to the discussion... had with the Learned Controller General of Patent and Design………….. Pursuant thereto, it has been settled that the applicant will be required to submit the "prosecution" details of any one of the major Patent Offices. Accordingly, we'll submit copies of documents pertaining to the processing of one of the corresponding applications filed in a country outside India, as and when those will be available to the applicant".
However, no such information was provided to the Patent Office.
19. The learned counsel for the applicant submitted that no information on the prosecution of EPO and US counterpart applications was furnished .According to the counsel corresponding US application No. 10/153,043 which was being prosecuted by the respondent and response to the office actions in US were filed before the response to FER in India. Furthermore, as early as September 22, 2003, there was a "restriction and/or Election requirement". Therefore the statement of the applicant in its response to FER is clearly false.Similalarly barely a month after the response to FER in which the applicant stated that processing details outside India will be provided as and when available, the EPO issued its own Examination report February 11, 2005 in respect of the corresponding application (Page 388-385; Exhibit EA3 to the MP).This information was also not furnishedby the respondent.Therefore this amounted to gross violation of Section 8(2).
20. The learned counsel for the applicant verbally relied on Tata Chemicals vs. HUL; Order No. 166 of 2012, Chemtura Corporation vs Union Of India & Ors on 27 May, 2009 and IPAB Order No. 207of 2012.
21. The learned counsel submitted that the Applicant through their miscellaneous petition No. 138 of 2012 submitted several documents to substantiate the Section 8 ground. Each of the documents filed by the Applicant were internet downloads and, therefore, are not admissible under Section 65 (B) of the Evidence Act.
22. The learned counsel submitted that in relation to the compliance of Section. 8 requirements the Respondent in their reply to the M.P. No. 138 of 2012 filed an affidavit of Mr. John E. Wurst. The said affidavit along with the documentary evidence clearly establishes that Respondent took all steps as and when advised by their patent agents in India to comply with the requirements of Section 8(1) and Section 8(2) of the Indian Patents Act. Copies of the information disclosure statement as filed in the corresponding US application were provided by Respondent No. 1 to their Indian patent agent on 26th May 2004.
23. The learned counsel submitted that that Respondent was advised by their Indian patent agents vide letter dated 25th September 2004 that to meet the objection raised in paragraph 14 (which dealt with submission of search and examination reports of corresponding foreign applications) of the first examination report dated 21st September 2001, the applicant has to submit the prosecution details of any one of the major offices viz, USPTO, EPO etc. On 5th October 2004, the Respondent informed their counsels that the copy of the prosecution of the US case will be sent to them which was eventually sent on 12th January 2005.
24. The learned counsel submitted that from time to time the information and documents necessary to comply with the Section 8 requirement were sent to the Indian patent agents and Respondent had no reason to believe that their representatives in India being a reputed IP Law firm would fail to comply with this requirement. Therefore it is submitted, that merely based on the acts of the agents of the Respondent, a valid patent cannot be revoked despite the Respondent themselves having dealt with each and every requirement of the Indian Patents Act based on the advice received by them from their agents in India.
25. The learned counsel submitted that in order to decide as to whether the Respondents complied with the requirements under Section 8 and in view of the aforementioned circumstances the conduct of the Respondent ought to be looked into. The learned counsel relied on Therasense Inc vs. Becton, Dickinson and Company. In the Therasense judgment it was held that in order to prevail on a claim of inequitable conduct such as misrepresentation or concealment, the Respondent has to prove by clear and convincing evidence that the applicant
(i) knew of the reference,
(ii) knew that it was material and (iii) made a deliberate decision to withhold it.
"with these far-reaching consequences, it is no wonder that charging inequitable conduct has become a common litigation tactic. One study estimated that eighty percent of patent infringement cases included allegations of inequitable conduct. Committee Position Paper at 75; see also Christian Mammen, Controlling the “Plague": ^forming the Doctrine of Inequitable Conduct, 24 Berkeley Tech. -LJ. 1329, 1 358 (2009). Inequitable conduct "has been overplayed, is appearing in marly every patent suit, and is cluttering up the patent system." Kimberly-Clark Corp. v. Johnson v!y Johnson, 745 F.2d 1437, 1454 (Fe. dr. 1984). "The habit of charging inequitable conduct in almost every major patent case has become an absolute plague, reputable lawyers seem to feel compelled to make the charge against other reputable lawyers on the slenderest grounds to represent their client's interests adequately, perhaps." [Page 22]
"To prevail on a claim of inequitable conduct, the accused infringer must prove that the patentee acted with the specific intent to -deceive the PTO. Star, 537 F.3d at 1366 (citing Kingsdown, 863 F.2d at 876). A finding that the misrepresentation or omission amounts to gross negligence or negligence under a "should have known" standard does not satisfy this intent requirement. Kingsdown, 863 F.2d at 876. "In a case involving nondisclosure of information, clear and convincing evidence must show that the applicant made a deliberate decision to withhold a known material reference." In other words, the accused infringer must rove by clear and convincing evidence that the applicant know of the reference, knew that it was material and made a deliberate decision to withhold it. This requirement of knowledge and deliberate action has origins in the trio of Supreme Court cases that set in motion the development of the inequitable conduct doctrine. [Page 24]
"Intent and materiality are separate requirement. However, to meet the clear and convincing evidence standard, the specific intent to deceive must be "the single most reasonable inference able to be drawn from the evidence." [Page 25]
26. The learned counsel submitted that Therasense Inc vs. Becton, Dickinson and Company is a very important Federal Circuit Opinion (only the US Supreme Court is higher). The Therasense judgment requires intent to deceive and overruled the McKesson case which did not require an intent to deceive. According to the counsel as per John E Wurst's declaration, it is clear that the Respondent who knew nothing about Section 8 (a foreign concept to American and European applicants and practitioners) did what they were told by their Indian patent agents. Mr Anand submittedthat the best that a foreign applicant can do while prosecuting their applications in India is to follow the advice of their Indian patent agents. Further, the Respondent did submit the status of corresponding foreign applications and though that their duty had been met.
27. The learned counsel relied on Roche vs Cipla, where it was held that the Controller/ Court has ^discretionary power" not to revoke a patent solely on one ground of non-compliance of Section 8.Mr Anand argued that Section 8 has become a common litigation tactic to defeat the substantive provisions on novelty and inventive step. However, Section 8 should not be used as a tool to defeat the grant of patents to worthy inventions.
28. The learned counsel submitted that the Respondent has been granted a patent in Europe and Japan among several other countries. The corresponding US application has been reconsidered and "The Patent Trial and Appeal filed by the Respondent from the final rejection of the patent office has reversed the decision of the Examiner by the decision dated 31st January 2013. The relevant extracts from the said decision on pages 9 and 10 are reproduced herein below:
"Nevertheless: we agree with Appellants that the combination of timolol maleate and CNEH unexpectedly "decreases the incidence of hyperemia seen using the same daily dose of CNEH alone" (App. Br. 18), at least at the concentrations used in the 2008 study. That is, the incidence of hyperemia was 43.4 among subjects who received a solution containing 0.03 CNEH once daily (CNEH Monotherapy), but only 25.7 among subjects who received the identical amount of CNEH in a single solution containing 0.03 CNEH and 0.5 timolol maleate once daily (Combination Therapy) (FF7). Moreover, the 2008 study demonstrated that timolol alone causes a modest amount of hyperemia (8.7 in the Timolol Monotherapy arm), thus, we agree with Appellants that its presence in the combination formula makes the lower incidence of byperemia "even more surprising" (Dec. II. 8).
Claims 53 and 54
As claims 53 and 54 are limited to the same concentrations of timolol maleate and CNEH used in the 2008 study, we will reverse the rejection with respect to these claims. "
29. The learned counsel submitted that a fair and balanced approach ought to be followed while invoking Section 8 in invalidation proceeding.The adjudicating authority has held in Roche Vs. CIPLA that the court should exercise discretion in deciding an objection under section 8. He submitted that the Respondent has been granted or allowed patents in several countries including US, having claims more or less identical in scope with that of the Indian patent is a good reason to maintain the patent and dismisses the ground of the Applicant.
30. The learned counsel relied upon Article 42 of the PCT which states that “No elected office receiving the international preliminary examination report may require that the applicant furnish copies, or information on the contents, of any papers connected with the examination relating to the same international application in any other elected Office." and submitted that impuned patent is a national phase application and entered national phase in India after the ISA issued the ISR and the written opinion and the IPEA issued the IPER.He added that the Applicant acknowledged that all the documents that have been filed on December 17, 2012 are available in public domain. Thus for the information that is available in public domain, the patentee cannot be penalised for the same.He cited the para 95 of the Tata Chemicals Limited v. Hindustan Unilever Limited & Anr. - order passed by the IPAB on 12th day of June 2012.
Page 30 para 95
"The PCT makes it possible for the PCT applicant to obtain patent protection simultaneously in a number of countries by filing an international patent application. They are absolved of the requirement to file application separately. Then an international search is made, this is issued as an international search report which gives a list of citations which may affect patentability of the invention. A separate opinion is also written prepared by the ISA on Patentability. These are communicated to the applicant who then will take a decision whether to proceed with the application or not. There are many advantages that a PCT applicant has, firstly he has 18 months more, next by IPER, the search and examination work of the patent office is considerably reduced because of the international search report, the written opinion and the international preliminary examination report."
31. The learned counsel submitted that without prejudice to the aforementioned submissions and without admitting to the fact that there has been a violation of Section 8 by the Respondent, the equitable rule of reason be applied that permits the Hon'ble IPAB to avoid the rigid application of tile Patent statute as it would stifle the very creativity for which the said statute is designed to foster. Thus, the five well known principles of rules of de minimus ought to be applied to this case namely: die size 'and type of harm; die cost of adjudication; the purpose of violated legal obligation; the effects of legal rights of third parries and the intent of wrong doers. (Indian TV Indipendent News Service vs. Yashraj Film Pvt. Ltd.; MANU/DE/3928/2012).
32. The learned counsel submitted that Section 8 violation is not a penal provision and is a remedial provision as was also recognized by the Hon'ble Judge in Roche vs. Cipla. In this regard, the Respondent relied on the following:
· Principles of statutory interpretation by GP Singh 9th Edition 2004 wherein it was stated that "if a statute laid a mandatory duty but provided no mode of enforcing it, the presumption in ancient days was that the person in breach of the duty could be made liable for the offence of contempt of the statute. This rule of construction is now obsolete and has not application to a modem statute."
· If there is a reasonable interpretation which will avoid the penalty in any particular case we must adopt that construction. If there are two reasonable constructions we must give the more lenient one. The rule has been stated by MAHAJAN, C.J.I, in similar words:
"If two possible and reasonable constructions can be put upon a penal provision, the court must lean towards that construction which exempts the subject from penalty rather then the one which imposes penalty. It is not competent to the court to stretch the meaning of an expression used by the Legislature in order to carry out the intention of the legislature."
· Alembic Chemical Works Co. Ltd. vs. the Workmen (MANU/SC/0218/1960) stated that
"if Section 79(1) is capable of two constructions that construction should be preferred which furthers the policy of the Act and is more beneficial to the employees in whose interest the Act has been passed. It is well settled that in construing the provisions of a welfare legislation courts should adopt what is sometimes described as a beneficent rule of construction; but, apart from this general consideration about the policy and object of the Act, Sections 78 and 84 occurring in the same Chapter as Section 79 clearly indicate that Section 79(1) is not intended to standardise leave provisions as contended by the Appellant, and that is the second reason why the Appellant's argument cannot be accepted."
· Aneeta Hada vs. Godfather Travels and Tours Pvt. Ltd (page 21, para 21) stated that
"it will be seemly to quote a passage from Maxwell's The Interpretation of Statutes (12'" 'Edition'): The strict construction of penal statutes seems to manifest itself in four ways: in the requirement of express language for the creation of an offence; in interpreting strictly words setting out the elements of an office; in requiring the fulfillment to the letter of statutory conditions precedent to the infliction of punishment; and in insisting on the strict observance of technical provisions concerning criminal procedure and jurisdiction”.
· The State of Tamil Nadu vs. M.K. Kandaswami and Ors. (page 7, para 25) stated that
"....If more than one construction is possible, that which preserves its workability and efficacy is to be preferred to the one which would render it otiose or sterile. The view taken by the High Court is repugnant to this cardinal canon of interpretation."
In view of the above, it is respectfully submitted that the Respondent has not violated the provisions of the Indian Patents Act
33. We have dealt with this issue in detail in IPAB order 161 0f 2013 in para 60 to 75. In present case the respondent in the counter statement stated that
“ On 20th January 2004 the respondent filed an updated Form 3.The BPAI,Non final rejection and final rejections on the corresponding US office action were issued after the date of grant and as on the date of grant the US application was pending ,which status was communicated to the Indian Patent Office .”
That being reply of the respondent in respect of the compliance of section 8.The records before us show that the respondent has given in their Form 3, details of 2 applications which are for the same/substantially the same invention. An updated Annexure to Form 3 with the country list of applications was also furnished on 20th Jan 2004. On 21st September 2004, the FER requires the patentee to give the details mentioned therein in any one of the major Patent offices as per S.8 (2) of the Patents Act (para 14). Here we like reiterate what we said in above order in para 60.
“……This request is vague and gives room for manipulation. If out of the three offices mentioned in this request, the examination report issued by EPO is adverse to the Patentee and the report issued by JPO is in favour, the patentee would be justified in giving only the JPO report and not the EPO report. But that would defeat the object of the provisions. The intent of the provision is to make known to the officer in India the objections raised to the same/substantially the same application outside India. Curiously this 14th Dec 2005 letter is followed by a letter dated 15th which states that the Patentee’s Counsel had a discussion with the Assistant Controller and “Pursuant thereto, it has been settled that the appellant will be required to submit the ‘prosecution‘ details of any one of the major Patent offices……..”
34. We find para 14 of the respondent letter dated 18 January 2005 in to reply FER dated 21st September 2004 quite interguing wherein it is stated that
"14. ... we would refer to the discussion... had with the Learned Controller General of Patents and Designs….. and also with Learned Assistant controller ………….. Pursuant thereto, it has been settled that the applicant will be required to submit the "prosecution" details of any one of the major Patent Offices.
Accordingly, we'll submit copies of documents pertaining to the processing of one of the corresponding applications filed in a country outside India, as and when those will be available to the applicant".
In this context we reiterate what we said in para 75 of IPAB order 161 0f 2013.
“75. …………….Settled? We do not understand what “settled” means. It is unfortunate that the office has failed to understand the importance of the S.8 requirement and leaves it to the Patentee to decide what he will give. We earnestly hope that this practice has died a natural death. It is important that the Patentee furnishes details of those search reports where there are objections like obviousness objections and shall not suppress them. If one of the major Patent offices alone has raised an obviousness objection, it is the duty of the Patentee to disclose it, considering the Object of the Act………………….”
35. We also adopt and reiterate what we said in that decision..
60. S.8 disclosure and non-compliance:- This needs some elaborate discussion. S.8 destroys a patent which is otherwise patentable on grounds which have nothing to do with the invention, but only with the Inventor’s lapse during the grant proceedings. So one must carefully apply the provision. The law demands compliance at the same time it must be shown that the Section would apply. S.8 of the Act is not intended to be a bonanza for all those who want an inconvenient patent removed. In The Ayyangar Committee Report it was said, ”It would be of advantage therefore if the applicant is required to state whether he has made any application for a patent for the same or substantially the same invention as in India in any foreign country or countries, the objections, if any, raised by the Patent offices of such countries on the ground of novelty or unpatentability or otherwise and the amendments directed to be made or actually made to the specification or claims in the foreign country or countries.”
61. In the Hindustan Lever case the FER required the “Foreign filing particulars”. The respondent gave wrong particulars about the GB application, and suppressed the IPER relating to EP 1106578 which was not pursued and the IPER had rejected the claims 1to3 on the grounds of both novelty and inventive step. We held that the ground under S.64 (1) (m) was made out.
62. In Therasense the disclosure obligations were discussed, and the majority ruled that the materiality required to establish inequitable conduct is but-for materiality, and that in assessing the materiality of a withheld reference, the Court must determine whether the PTO would have allowed the claim if it had been aware of the undisclosed reference. In making the patentability determination, the Court should apply the preponderance of the evidence standard and give claims their broadest reasonable construction.
63. In India TV Independent News Service Pvt Ltd. vs Yashraj Films Pvt Ltd, the Delhi High Court considered the de minimis doctrine and the factors to be considered in applying them namely size and type of harm, cost of adjudication, purpose of violated legal obligation, effect on legal rights of third parties and intent of wrong doer. In that case the use of the song was held not to cause any harm to the copyright owner. Here the de minimis doctrine is invoked by the patent owner.
64. If the obligation under S.8 has been violated then the harm caused is the continuance of a patent which must be removed. It appears to us then that the harm is not of a minimal nature. The public is affected by the exclusive monopoly to a patent that law makes revocable.
65. The law relating to Interpretation of Statutes was referred to and it was submitted that while construing penal sections and two constructions are possible then the lenient one should be adopted. This provision is not a penal provision. A penal provision is one which enacts an offence or imposes a penalty. Failure to comply with S.8 is not an offence. It is a duty cast on the patentee which results in adverse consequences if flouted. Dishonour of cheque (AIR 2012 SC 2795 Aneeta Hada vs Godfather travels and Tours was cited) fastens a criminal liability. S.8 does not. So the cases arising out of the former will not apply. The State of Tamilnadu vs M.K. Kandaswami (AIR 1975 SC1871) related to a tax statute. Evasion of tax has its consequences. But in this judgment there is a paragraph which is worth extracting. “ It may be remembered that Section 7A is at once a charging as well as a remedial provision. Its main object is to plug leakage and prevent evasion of tax. In interpreting such a provision, a construction which would defeat its purpose and in effect, obliterate it from the statute book, should be eschewed. If more than one construction is possible, that which preserves its workability and efficacy is to be preferred to the one which render it otiose or sterile”
66. The Ayyangar Report makes it clear that the purpose for introducing this provision was to ensure that it would be an advantage for our Patent Office to know the objections raised by the patent offices outside India regarding the patentablity of the invention and the amendment if any made or to be made. It also says that it would be of great use for the proper examination to know if the invention was anticipated. In the Hindustan Lever case we had held that it was in order to secure disclosure of the relevant information regarding the foreign applications that the Ayyangar Report recommended that failure to disclose would be a ground for challenge. In Chemtura Corporation vs Union of India the Delhi High Court said, “45. It is not possible to accept the submission, made by referring to the Halsbury’s Laws of England, that since the omission to furnish particulars is not serious enough to affect the grant of the patent, it did not impinge on its validity. Section 64 (1) (j) and (m) indicate to the contrary. Further under Section 43 (1) (b) a patent can be granted only when the application has been found not to be contrary to any provision of the Act. It cannot be said that the omission to comply with the requirement of Section 8 (2) was not serious enough to affect the decision of the Controller to grant the patent to the Plaintiff. The information, if provided, would have enlightened the Controller of the objections raised by the US patent office and the extent to which the Plaintiff had to limit its claims to the torus shape of the compression spring, which was a key feature of the subject device.”
67. The object of this provision is to ensure disclosure. We will adopt that construction which is to advance the object. When we refer to the object we mean the object of this provision and not the object of the Act. This section has been introduced to make sure that the person who is given an exclusive monopoly is candid and fair in his conduct. So we cannot adopt a construction which relieves the patentee of this duty.
68. In the Sugen vs Cipla case we said, “The respondent had also filed OA 6/2013 against the finding on S.8 violation. Now that the matter is to be heard de novo right from the stage of the Constitution of the Opposition Board, this issue will also be decided by the Controller. The IPAB has in its decisions clearly held that it is the duty of the Patentee to furnish the particulars under S.8. We are surprised that the Controller should have held to the contrary and observed that such information is available on the internet. This is not the law. This duty under Sect 8 cannot be breached and if violated results in revocation. It deserves to be accorded due respect. What should be furnished by the Patentee shall be furnished by the Patentee. So the Controller shall bear this in mind while considering the ground under S.8 and examine whether the Appellant has fully complied with the S.8 Requirements.”
69. We must remember that we are not the law makers. For good reasons S.8 is there. The Controllers cannot ignore it and condone the breach. The patentee cannot tell the Examiners, ” We are filing applications nineteen to the dozen, compliance is very difficult, and in any case there is the Super Kamadhenu the Internet which will give you what you want.” We cannot wish S.8 a relieved farewell. Tough for Inventors it may be, but S.8 must be complied with. When George Mallory was asked “Why do you want to climb Mount Everest?”, he is supposed to have replied, ”Because it is there.” To the question “Why should we comply with S.8?” The Answer is “Because it is there.
70. The IPO must have a consistent stand with regard to S.8. It can not be East West Who is best. We request the Controller General to educate and instruct the officers regarding the requirements of law. We must remember what the Supreme Court said in the Novartis case, ”In order to understand what the law really is, it is essential to know the “why” and “how” of the law. Why the law is what it is and how it came to its present form? The adage is more true in case of the law of patents in India than perhaps any other law.” The why is clear from the Ayyangar report. We must remember it and the IPO must too.”
“73. When we look at the Ayyangar Committee Report it indicates that the object behind introducing S.8 is that the applicant should disclose all foreign applications so that the examiner here may know if it contains obviousness objections or any amendments and so on. The application outside India must be for the same invention or for substantially the same invention. The Ayyangar Committee Report also speaks of anticipation coming to light if the disclosure is made. So the Ayyangar Committee Report is clearly talking of the same invention or almost the same invention. The subject matter of the invention must be the same or almost the same. …………………. ………………………………………….”
74. …………………………………………………..We understand that the S.8 ground is being raised regularly only after the Delhi High Court’s Chemtura judgment and the IPAB orders mentioned above. The Examiners have not given this provision the attention that it deserves. But these proceedings have to be conducted correctly, consistently and fairly. Patentees must comply with S.8(1) provision however inconvenient it is.”
36. The respondent filed an affidavit of Mr. John E. Wurst wherein it was stated that ‘US prosecution details were sent to agent on on 26th May 2004. On 5th October 2004, the Respondent informed their counsels that the copy of the prosecution of the US case will be sent to them which was eventually sent on 12*January 2005’.From last letter sent by the respondent on 12 September 2005 [on last date] it is implied that they did not have with them any one of USPTO, EPO or JPO reports. In this case there is non compliance of section 8(2) as no information relating to prosecution of same application in other countries was provided even when the respondent agreed to do so as when it would be available vide letter dated 18th January 2005. A petition under Rule 137 for condonation of delay and irregulaty inrespect of ‘foreing filling particulars’ was filed on 18 January 2005. But the information relating to WO 2002096432, US 10/153,043 and EP 02739579.7 and Office action relating to US and EP application was not filed. USPTO rejections (claims 18-33 rejected) were dated 21.11.2003 very much before issue of FER on 21.09.2004. Similarly the US final rejection dated 12.10.2004 was also not furnished to IPO. EPO Examination report was available on 11.02.2005 and that was also not submitted. Even the International Serach Report in respect of WO /02/096432 which was available on 8th May 2003, very much before issue of FER, was not submitted to IPO. We are not looking at this moment why it was not given.But the fact remained that there was non compliance of Section 8. We have indicated the principles behind the S.8 objection, how it should be raised, defended and decided. The Act says failure to disclose the information required by S.8 is a ground for revocation. It does not qualify it by saying that the failure must be deliberate nor are there any words to indicate that the failure must be in regard to material particulars. In the present case the gound of the violation of section 8 has been clearly made out and we have no hesitation say applicant succeed on this ground of revocation.
Obviousness : The issues
37. In general terms, the impugned patent is for a fix combination of Bimatoprost and Timolol for treatment of treatment of ocular hypertension. The only issue which was focused was whether this combination was obvious in view of simultaneous (five minute gap) administration of these known drugs referred to as serial, adjunct or noncommittal or monothrapy. A number of citations were relied on but principal basis of obviousness argument rest on the previous combined fixed dose containing Latanoprost and TImolol disclosed in publication Comparision of two fixed dose combination of latanoprost and timoloi open angle glaucoma by Diestelhorst (Exh.D) as COMB.10 and COMB.50 well before the priority date which form part of the common general knowledge of Ms.Psita. US 4952581 which disclosed ‘use of a prostaglandin in combination with an adrenergic blocking agent for reducing of intraocular pressure was also cited wherein one of the combination is PGF2a-1-isopropylester [latanoprost] with timolol maletate (claim 13 and 14) was known prior art.
Background
38. It is known that Glaucoma is cause of irreversible blindness. The medical treatment using ocular hypotensive agents for this chronic disease is aimed at reducing levels of intraocular pressure (IOP). At times more than one IOP-reducing drug is used. A fixed-combination (FC) ophthalmic solution consisting of the prostaglandin, latanoprost (0.005%), and the beta-blocker, timolol (0.5%), is known.
Bimatoprost is a prostaglandin analog, also referred to as a prostamide. It reduces intraocular pressure by increasing aqueous humor outflow and Timolol is a beta blacker that also reduces intraocular pressure by decreasing aqueous humor production. Timolol is one of the oldest anti- hypertensives, and has been used to treat glaucoma since 1980s.
39. In the specification in respect of prior art following is mentioned.
Latanoprost: Latanoprost was the isopropyl ester of PGF 2a, which was described as the most potent ocular hypotensive agent ever reported. (Page 3, paragraph 3 of the patent specification)
Whereas prostaglandins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign body sensation have been consistently associated with the topical ocular use of such compounds, in particular PGF2a and its prodrugs e.g. 1-isopropyl ester in humans.. (Page 3, paragraph 4)
Bimatoprost (referred to as hypotensive lipids)
Woodward et al US Patent No. 5688819 discloses certain cyclopentane heptanoic acid, 2-cycloalkyi or arylalkyi compounds as ocular hypotensives. These compounds can properly be characterized as hypotensive lipids, are effective in treating ocular hypertension. (Page 4, paragraph 2)
Timolol: Timolol maleate ophthalmic solution, for example, sold under the trademark TIMOPTIC by Merck, is a non- selective beta-adrenergic receptor blocking agent which is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open- angle glaucoma. (Bridging paragraph at pages 3 and 4)
Invention
40. Claim1 of the 695 is reproduced below.
1. A composition comprising a blend of a timolol component present in an amount effective to reduce ocular hypertension when applied to a hypertensive eye, and a hypotensive lipid component, different from the timolol component, present in an amount effective to reduce ocular hypertension when applied to a hypertensive eye, said composition when applied to an eye being effective to treat ocular hypertension, the hypotensive lipid component being selected from the group consisting of cyclopentane N-ethyl heptenamide -5- cis -2- (3a– hydroxyl – 5 – phenyl -l- trans - pentenyl) -3, 5-dihydroxy, [la,2b,3 a,,5a], pharmaceutically acceptable salts thereof and mixtures thereof.
41. Claim 1 is independent claim which referred to composition comprising blend and claims from 2 to 11 are dependent on this claim that is to say that they rise and fall with this claim.
2. The composition as claimed in claim 1 which, when applied to an eye, produces at least one reduced side effect relative to a similar composition comprising a larger, amount of said timolol component without said hypotensive lipid component.
3. The composition as claimed in claim 1 which, when applied to an produces at least one reduced side effect relative to a similar composition comprising a larger amount of said hypotensive lipid component without said timolol component.
4. The composition as claimed in claim 1 which is effective, when applied to an eye, to provide an enhanced treatment of ocular relative hypertension relative to applying a composition having said timolol component. Without said hypotensive lipid component.
5. The composition as claimed in claim 1 which is effective, when applied to an eye, to provide an enhanced treatment of ocular hypertensive relative to applying a composition having said hypotensive lipid component without said timolol component.
6. The composition as claimed in claim 1 which, when applied to an eye, is effective to reduce intraocular pressure in the eye.
7. The composition as claimed in claim 1 wherein said timolol component comprises an acid salt.
8. The composition as claimed in claim 1 wherein said timolol component comprises -timolol maleate.
9. The composition as claimed in claim I wherein said hypotensive lipid component comprises cyclopentane N-ethyl heptenamide-5-[[cis2-]]cis-2-(3 –hydroxy-5-phenyl-l-trans-pentenyl)-3 5-dihydroxy, l a,2b,3a,,5a].
10. The composition as claimed in claim 1 wherein the composition is in the form of a solution.
11. The composition as claimed in claim1 wherein the composition is in the form of an aqueous solution.
42. Claim 12 is independent claim for composition in the form of solution which read as follows.
12. A composition comprising a timolol component present in an amount effective to reduce ocular hypertension when applied to a hypertensive eye, and a hypotensive lipid component present in an amount effective to reduce ocular hypertension when applied to a hypertensive eye, said composition when applied to an eye being effective to treat, ocular hypgytension, the; hypotensive lipid component being selected from the group consisting of cyclopentane N-ethyl heptenamide-5-cis-2- (3a-hydroxy-5-phenyl-l-trans-pentenyl) -3,5-dihydroxy, [1a, 2b, 3a, 5a], pharamaceutically acceptable salts thereof and mixtures thereof, the composition in the form of a solution.’
43. Claims from 13 to 20 are dependent on this claim that is to say that they rise and fall with this claim.
13. The composition as claimed in claim 12 wherein the composition is in the form of an aqueous solution.
14. The composition as claimed in claim 12 which, when applied to an eye, produces at least one reduced side effect relative to a similar composition comprising a larger amount of said timolol component without said hypotensive lipid component.
15. The composition as claimed in claim 12 which, when applied to an eye, produces at least one reduced side effect relative to a similar composition comprising a larger amount of said hypotensive lipid component without said timolol component.
16. The composition as claimed in claim 12 which is effective, when applied to an eye, to provide @ an enhanced treatment of ocular hypertension relative to applying a composition comprising said timolol component without said hypotensive lipid component,
17. The composition as claimed in claim 12 which is effective, when applied to an eye, to provide an enhanced treatment of ocular hypertension relative to applying a composition comprising said lipid component without said timolol component.
18. The composition as claimed in claim 12 which when applied to an eye, is effective to reduce intraocular pressure in the eye.
19. The composition as claimed in claim 12 wherein said timolol comprises an acid salt.
20. The composition as claimed in claim 12 wherein said timolol component comprises timolol maleate.
Applicant’s case
44. Mr. Majumdar submitted that impugned patent pertains to a combination of two actives (drugs) i.e. Bimatoprost and Timolol, wherein a combination is said to have reduced side effects as well as increased performance as compared to the individual actives. This combination is used to reduce intraocular pressure and ocular disorders associated with the same such as glaucoma. The counsel submitted that combinations of Timolol and Prostaglandins or other anti-hypertensives were employed before the date of priority of the impugned patent. These combinations are Latanoprost/Timolol, Pilocarpine/ Timolol and Dorzolamide/ Timolol
45. According to the counsel for the applicant it is admitted by the respondent that both Bimatoprost and Timolol individually, were known. The claimed composition comprises a hypotensive lipid component and a timolol component present in an amount effective to reduce ocular hypertension when applied to a hypertensive eye. It has benefits such as reduced dosage of actives, reduced side effects (as compared to the individual components administered at twice the concentration) and enhanced reduction of Intraocular pressure (as compared to the individual components administered at twice the concentration).
46. The learned counsel for applicant argued that intraocular pressure due to over- production of aqueous humor, may be reduced via two mechanisms .i.e. reduction of aqueous humor production and increase in aqueous humor outflow. When two drugs performing each function are used together there would be an expected and obvious additive effect.
47. The learned counsel for applicant cited the following prior art documents .
US 5688819 [November 18, 1997] D1 and W09730710 published on August 28, 1997 D3
The counsel for applicant submitted that the combination of Bimatoprost and Timolol was obvious in light that D1 and D3 i.e. the product patents of Bimatoprost disclose the fact that Bimatoprost in addition to other hypotensive lipids were more potent at treating a variety of disorders including intraocular pressure. It was also indicated in these documents that the prostaglandin analog, Latanoprost was a predecessor of Bimatoprost such that the latter was more potent than the former.
Diestelhorst M. et al (1998) 236:577-581 D2 and US4952581 published on August 28, 1990 D4
The counsel for applicant submitted that D2 pertains to "Comparison of two fixed combinations of latanoprost and timolol in open angle glaucoma' published Graefe's Arch Clin Exp Ophthalmol discussed that fixed dose combinations of Latanoprost and Timolol are preferred to their individual monotherapy, wherein the optimal concentration of Timolol was tested andUS’581 D4 pertain to combinations of Latanoprost and Timolol. it disclosed the fact that a combination of Latanoprost and Timolol is expected to result in an enhanced treatment of intraocular pressure as well as a reduction in side effects. The counsel submitted that in light of these disclosures, a person skilled in the art would be motivated with a reasonable expectation of success, to employ Bimatoprost instead of Latanoprost in combination with Timolol. This accrues due to the fact that D1 and D3 clearly indicated that Bimatoprost is preferred to Latanoprost. As combination therapy is a conventional practice in all pharmaceutical sectors, and as Timolol is the preferred beta blocker that is conventionally employed in such combinations, it would be obvious to employ the same in combination with the currently popular drug that has a mechanism of action that is complementary to that of Timolol.
48. The learned counsel for applicant submitted that motivation to combine these two drugs would be the fact that though Bimatoprost was more efficacious than its predecessor, the incidence of hyperemia as a side effect was twice as much. As directed by prior art, one of the ways to reduce these side effects would be combination with a beta blocker such as Timolol. Thus, it is only a matter of conventional and routine experimentation, to arrive at the claimed combination.
49. The learned counsel for applicant submitted that the technical advance, as claimed by the Respondents has not been established or substantiated. In the absence of data that compares the claimed combination to combinations known in prior art, specifically, closest prior art combinations employing Timolol and a prostaglandin analog i.e. Latanoprost, there is no inventive merit or enhanced treatment that is exhibited.
50. The learned counsel for applicant submitted that Latanoprost and Bimatoprost share the same structural backbone wherein the two only differ in the fact that one is ester while the other is an amide.
BIMATOPROST LATANOPROST
He also stated that D1 and D3 are family members of each other as they share a common priority i.e. US60/5567 dated Feb 22, 1996. He submitted that this difference is highlighted by means of WO 97/30710 D3 wherein the specific disclaiming of Latanoprost is evident in claim 1 as highlight below.
1. A method of treating ocular hypertension which comprises applying to the eye an amount sufficient to treat ocular hypertension of a compound of formula I
a pharmaceutically-acceptable salt thereof, provided however that when B is not substituted with a pendant heteroatom-containing radical and Z is =0, then X is not -OR4.
51. The learned counsel for applicant submitted that the following sections of DIESELHORST ET AL D2 highlight the factor of obviousness accruing from the same:
“In glaucoma treatment, satisfactory control f intraocular pressure (IOP) is not always obtained with monotherapy. In fact a large percentage of patients treated for glaucoma or ocular hypertension use a combination of eye pressure reducing substances. It is known that the use of multiple drugs, with upto five or six drops to be instilled daily in each eye, has a negative influence patient's compliance and thereby also on the efficacy of the treatment. Furthermore, with the number of drops the daily exposure to preservatives is increased, with the risk of concomitant comeal reactions, e.g. punctuate epithelial erosions.
The beta- adrenergic receptor antagonist timolol is traditionally regarded as the treatment of choice and acts by reducing the aqueous humor production. It has commonly been combined with drugs which increase aqueous humor outflow, e.g. Pilocarpine, a drug with short duration of action and troublesome side effects such as miosis, transient myopia in young patients and visual disturbances. Recently, Latanoprost, a prostaglandin (PC) F2a analogue, was demonstrated to lower the IOP efficiently in patients with glaucoma or ocular hypertension; after 6 months of treatment, Latanoprost 0.005% given once daily was at least as effective as timolol 0.5% given twice daily. Latanoprost, like PGF2a increases the aqueous humor outflow. However, the mechanism of action is unique in that the increase in outflow mainly takes place through the uveoscleral pathway, as demonstrated in both pre-clinical and clinical studies. Jims, since Latanoprost and Timolol have. complementary mechanisms of action and both are efficacious with regard to IOP reduction, u combination of these drugs seems advantageous.
An additive effect of the two drugs instilled from separate bottles was previously demonstrated. However, to optimize the convenience and the patient compliance a fixed combination of the two drugs have to be preferred. Differences in duration of action then have to be considered; Latanoprost is more effective given once daily than twice daily while Timolol generally has been administered twice daily. However, the IOP lowering effect of Timolol has been reported to last atleast 24 hours. Therefore, the aim of a fixed combination of latanoprost and timolol is to provide the patient with one single solution to be administered once daily. In addition to the expected improved compliance, the lower daily dose of benzalkonium chloride may also reduce comeal side effects. The present study was undertaken to evaluate the concentration of Latanoprost, 0.001 or 0.005, to be used in fixed combination with Timolol 0.5%.”
52. The learned counsel for applicant submitted that in light of the above disclosures it was amply obvious that Timolol remained a treatment of choice, especially in combination therapies, such that the mechanism of action of the other drug would be complementary to that of Timolol. It was submitted that this introduction to the study allowed a person skilled in the art to attempt once daily fixed dose combinations of prostaglandin analogs such as Latanoprost and in that breath Bimatoprost, with Timolol. This choice of actives arose from the complementary mechanisms of actions such that one would reduce aqueous humor production while the other would increase aqueous humor outflow. At this juncture, the Applicant stated that Bimatoprost was known as a more potent prostaglandin analog as compared to Latanoprost, and it was also known that it functioned by increasing aqueous humor outflow which was obviously complementary to the mechanism of action of Timolol. It was submitted that this it self would provide motivation to a person skilled in the art to attempt a combination of Timolol and Bimatoprost with a reasonable expectation of success. Also, it would be known to a skilled person that there would be better patient compliance when the combination is administered in one dose.
Interchangeability of Bimatoprost and Latanoprost:
53. The learned counsel for applicant submitted that no matter what receptor Bimatoprost acts upon, or whether it was an ester or an amide, at the fag end of the day, it belonged to the same class as Latanoprost, i.e. Prostaglandin Analogs. In addition to this, Bimatoprost and Latanoprost happened to reduce intraocular pressure by increasing aqueous humor outflow. Due to all these similarities, the counsel contended that Bimatoprost and Latanoprost are interchangeable compounds. It has known that Bimatoprost was more effective than Latanoprost due to which it would definitely be considered as a replacement to Latanoprost, especially in combinations such as those with Timolol. According to the counsel, this did not amount to a significant or noteworthy accomplishment.
54. Referring to the label of Bimatoprost (EXHIBIT XA3) the learned counsel submitted that Bimatoprost had plenty of side effects. It would also be known to a person skilled in the art that Latanoprost i.e. the predecessor compound of Bimatoprost was in effect used with Timolol as a fixed dose combination; such that the side effects accruing from both actives i.e. Latanoprost and Timolol were reduced. The counsel for applicant contended that this itself would be motivation to attempt a combination of Birnatoprost and Timolol, or rather a replacement of Latanoprost with Bimatoprost in a combination therapy of Timolol and Latanoprost.
US4952581 D4
The learned counsel submitted US’581 disclosed a combination drug or drug regimen that acts by decreasing aqueous humor secretion, such as an adrenergic blocking agent and a prostaglandin/prostaglandin analog. The disclosures of this document clearly indicate that a combination of this sort would not only lead to enhanced treatment of IOP but also a reduction in the side effects of either or both components. He added that this document clearly nullifies the contentions of the Respondent vide claims 2 and 3 of its 695 patent.
55. The learned counsel for applicant relied upon the following case laws:
T 0757/89 October 1990:: Technical Boards of Appeal of the European Patent Office,
"In Decision T 21/81 (OJ EPO 1983, pages 15-21), it is stated that "if, having regard to the state of the art, something falling within the terms of a claim would have been obvious to a person skilled in the art, because the combined teachings of the prior art documents could be expected to produce an advantageous effect, such claim lacks inventive step, regardless of the fact that an extra effect (possibly unforeseen) is obtained". In the Board's view, in the present case, although there is evidence of synergy between the two etching processes and of an etching enhancement in the case of conducting samples, both such extra effects are simply an extension of the effect which would in any event be expected by the skilled reader of document Dl, namely an increased etching rate." [Page 9 Paragraph 3]
56. The learned counsel for applicant submitted that obviousness of the patent has to be determined in combination of the prior art, if in combination the prior arts teach all the advantages taught in the patent the same will not be patentable on ground of lack of inventive step. The teachings of D2 as well as D4 clearly indicate that a combination would result in increased treatment or additive effect in addition to reduced side effects. The counsel submitted that if there has been a clear cut case of motivation, just because of the fact that one more effect is found, or one more advantage is found, the invention would still be called obvious. In the present matter, it was obvious that a combination of a prostaglandin analog and a beta blocker, specifically Timolol, would result in an additive enhanced effect. This motivation with a reasonable expectation of success is sufficient to render the '695 patent obvious and devoid of inventive merit.
57. In T 0393/01 July 2004 Boards of Appeal of the European Patent Office, it was held
"Indeed, according to established case law of the board of appeal (see eg T 296/87, OJ EPO 1990, 195), enhanced effects cannot be adduced as evidence of inventive step if they emerge from obvious tests. Since, in the present case, tests with the combination of "triazine" and IPC were obvious in view of the task at hand, discovery of a synergistic effect exhibited by such a combination cannot be regarded as an indication of inventive step. Accordingly, in the absence of any evidence to the contrary, the Board concludes that, even without the teaching of document (6), the synergetic effect cannot represent an inventive step since the prior art points towards the claimed combination." [121 Paragraph 8 ]
The learned counsel for applicant submitted that higher level of interaction between two components, such that there is synergy between the two. In the present matter however, there happens to be no synergy, as there is no direct interaction between the two components. It was submitted that routine experiments such as the testing of compatibility of two actives, arise from obvious steps. It was stated that prior art had set a clear cut path in the direction of combination of Bimatoprost and Timolol, such that the enhanced treatment or reduced side effects of the same were relatively expected in light of routine laboratory protocol. This case law too states that such routine protocol does not amount to an invention, even if there is synergy between the actives and a better result, as such synergy and result is expected and is a result of plain and simple trial and error.
58. In Ciyla Ltd. & Ors v Glaxo Group Ltd. [20041 EWHC 477 (Pat) (19 March 2004)
“95. In his report, Dr Crompton had described Ventide as an irrational product. He accepted under cross-examination that its use in an attempt to improve compliance was not irrational. To use combination products for such a purpose had been sussested by others. For example. Puffin (1988) is a report of a paper delivered at a conference. Included is a report of the ensuing discussion, during which Dr Barnes is reported as having said 'If you have to make compromises, you should think about giving combinations of inhaled steroids and beta agonists. The patients will take the drug because they set immediate symptom relief, but the important thins is you actually set the useful drug into the patients.'
96. Finally, Dr Crompton was himself a co-author of a paper, McDonald & al (1988) 'Evaluation of the combination Inhaler of salbutamol and beclomethasone dipropionate in the management of asthma' Current Medical Research and Opinion ll;2:ll6. It is necessary only to consider the Introduction and a concluding paragraph.
'Many asthmatics require regular therapy with an inhaled receptor agonist and an inhaled corticosteroid to achieve control of their symptoms. The use of these two agents affords relief of bronchospasm, suppression of inflammation and hyper-reactivity and prevention of adrenoceptor tolerance. Salbutamol and beclamethasone dipropionate are frequently used concomitantly and a combination inhaler of the two has now been developed. This form of treatment may aid patient compliance since it is recognized that compliance decreases as the number of different medications increases. Two studies have shown that the combination inhaler is as effective as the same two agents from different inlzalers.
This study was designed to compare the clinical effects of regular inhalations of salbutamol and beclomethasone dipropionate used simultaneously from a combination inhaler with regular inhalations of the same agents used sequentially from separate inhalers. An attempt was also made to assess patient compliance.
103. In the light of the whole of the evidence, I think this series of answers contains the right approach. The combination was an obvious combination, as a combination. It was not obvious that it would be safe, or that it would represent any advance on what had gone before. Whether this would be the case depended won the outcome of clinical trials which was not foreseeable, although it was a reasonable prediction for the skilled man having regard to the known properties of salmeterol (which was part of the common general knowledge at the date) and any steroid previously used for prophylactic therapy that the combination would be both safe and efficacious. Any skilled person would find fluticasone propionate in looking for w-to-the-date members of the class of steroids as candidates for incorporation in his new Ventide. A. good reason for such a combination is the need to ensure compliance. The 'prejudice' discussed at such length above was, in fact, a doubt relating to questions that could onh be resolved by clinical trial. This extends to such matters as the significance of the long-acting effects of salmeterol. The skilled man would understand this: and accordingly the combination was entirely obvious in the light of the prior manufacture, use and sale of Ventide and the publication, of the various data associated with that preparation.
104. That salmeterol would be the. obvious substitution for salbutamol follows from the most basic consideration, that a drug that only needs to be taken twice a day will encourage compliance. That this was the case appears to be the universal message of the evidence. It is also Glaxo's Internal view of the justification for the product:
Fixed combinations have been used before eg. Salbutamol/beclomethasone dipropionate (Ventide) and have received a very mixed reception from the medical profession. However the problem of compliance, particularly with inhaled steroids, has lead [sic] clinicians to recently re-appraise the need for such products in selected patients. A fixed combination treatment of salmeterol with beclomethasone dipropionate (BDP) or salmeterol with fluticasone propionate will fulfil such a need by combining a long lasting bronchodllator with a steroid in a twice-daily treatment.' (October 1989)
Unless these extracts contain some inventive insight at the priority date, the patent must be Invalid, because I consider that the problem of compliance has, on the evidence, always been a problem.
111.1 confess that absent any strong prejudice against regular therapy with ft-agonists 1 would consider that this was, in fact, sufficient to make the invention of the patent in suit obvious, but manifestly the case is stronger on the footing of the Ventide prior use.
112. In the result the invention of the patent in suit is obvious. The claimants' case is, in my view, overwhelmingly strong. This is a decision arrived at on what 1 believe to be a conventional approach, and I have not felt. It necessary to examine the effect of the interesting decision of the Privy Council inAncare New Zealand Limited's Patent [2003] RFC 8 (page 139). Had I considered that scientific opinion was wholly out of accord with what was being done in the market, it would have been necessary to do so. I do not read this case as throwing any doubt on the proposition that invention may lie in overcoming a prejudice in the art.”
The learned counsel for applicant contended that the subject matter of this case was similar to the matter at hand. However, as may be noted, the Court was pleased to hold that the combination was obvious whether or not the combination was formulated with some amount of clinical trial. The fact that the combination was obvious clearly flows from this case. The counsel argued that the fact that this case held the combination to be obvious due to the fact that most combinations are formulated to ensure patient compliance, i.e. enhanced treatment, reduced dosage. It is a similar contention of the Respondents in the matter at hand. It was further stated that this case was applicable to the arguments on enablement as well wherein there was no whisper in the specification of known combinations.
59. In T 0355/97 :Boards of Appeal of the European Patent Office it was held that the burden of proof is on party that alleges it.
"However, according to the jurisprudence of the Boards of Appeal, each of the parties to the proceedings carries the burden of proof for the facts it alleges (see e.g. decision T 270/90, OJ EPO 1993, 725, point 2.1). If a party, whose arguments rest on these alleged facts, is unable to discharge its onus of proof, it loses thereby. In the present case, the Respondent alleges the fact that the claimed invention improves the performance index of the preparation process without loss of selectivity. Therefore, the burden of proof for that fact rests upon him. The unverifiable statement in the specification of the patent in suit on page 2, lines 45 to 51, that the performance index is improved without loss of selectivity referred to by the Respondent as proof for the alleged fact, is devoid of any corroborating evidence. In the absence of evidence, however, the Respondent has not discharged the burden of proof which is upon him, with the consequence that his unsubstantiated allegation is not to be taken into account by the Board."
"To conclude, in the Board's judgement, the evidence on file neither demonstrate properly that the purported advantages of the claimed invention, i.e. the improvement of the performance index without loss of selectivity, have successfully been achieved nor that they are due to the pretreatment of the sulfuric acid with hydrogen peroxide, i.e. the solution proposed by the patent in suit."
"According to the jurisprudence of the Boards of Appeal, alleged but unsupported advantages cannot be taken into consideration in respect of the determination of the problem underlying the claimed invention (see e.g. decision T 20/81, OJ EPO 1982, 217, point 3, last paragraph of the reasons). Since in the present case. the alleged advantages, i.e. improvement of the performance index without loss of selectivity, lack the required adequate support, the technical problem as defined in point 2.3 above needs reformulation. In view of the teaching of the closest prior art document (9), the objective problem underlying the patent in suit can only be seen in providing merely a further method for preparing 4-aminophenol."
"The Board concludes from the above that the state of the art gives the person skilled in the art a concrete hint on how to solve the objective problem underlying the patent in suit as defined in point 2.6 above, namely by using in the preparation process known from document (9) a sulfuric acid which was treated with hydrogen peroxide, thereby arriving at the claimed process. In the Board's judgment, to follow the avenue indicated in the state of the art is obvious without involving any Inventive ingenuity. For these reasons, in the Board's judgment, the subject-matter of claim 1 represents an obvious solution to the problem underlying the patent in suit and does not Involve an inventive step. Since a decision can only be taken on a request as a whole, none of the farther dependent claims need to be examined."
The learned counsel for applicant argued that the burden of proof lies on the party that alleges it, such that the patent goes with a piece of evidence to ensure that the claims are in accordance with the specification. The counsel contended that the Respondents should have provided valid and substantial data to actually indicate the effect that is claimed is actually present. For example, the claims discuss that there are reduced side effects. However, no experiment is provided to substantiate the same. It is also suggested by this decision that alleged unsupported advantages cannot be taken into account. This, according to the Applicant, ought to apply to the present matter as well, wherein there is no indication of such advantage. Lastly, the decision also discusses the issue of an obvious solution to the problem. The Applicant states that the problem at that point of time was the fact that Bimatoprost was in effect a highly effective hypotensive, wherein its use was hampered by the presence of side effects i.e. hyperemia which were more than its counterpart Latanoprost. In such a situation, prior art taught that side effects could be reduced with the use of combination of another active with a complementary mechanism of action, such that this amounted to an obvious solution to the problem. It was also taught in prior art that such combinations would lead to enhanced treatment by means of the same complementarity.
60. In T 0073/0 : Boards of Appeal of the European Patent Office
"It is undisputable that combinations of additives were currently used and had to be used at the priority date of the patent in suit in order to improve the characteristics of diesel fuels (see e.g. document (6) page 13 "Conclusions"). Such additives, being necessarily present as a mixture with the diesel fuel, were nevertheless not expected to behave differently because of a possible reciprocal negative influence. On the contrary they were expected to provide in the mixture the effect for which they were used."
"As explained in point 1.3.5 it was obvious for the skilled person to try a commercially available diesel fuel additive containing the copolymers of the patent in suit in order to improve the lubricity of low sulphur diesel fuels. Therefore, it was also obvious to try such a polymer, which was known bv itself to
have also additional effects, e.g. as cold-flow improver, in combination with further desirable additives for diesel fuels and. thus to look for commercial products already containing such combinations. In the light of the teaching of the prior art, the skilled person would thus have tried also the commercially available additive Keroflux 3243 and thus a combination of additive as used in the patent in suit with the expectation not only of improving the coldflow properties of the diesel fuel, but also of improving its lubricity. The fact that such a specific combination could provide a greater increase in lubricity than the copolymers when used alone amounts in the Board's judgement only to the discovery of further properties of a known product which would have been obviously used, as explained above, for its known characteristics."
The learned counsel submitted that combination of known components and discovery of any property does not provide inventive merit to an invention and the same shall not be patentable as it does not add anything to me existing knowledge. As in the case discussed in the decision, the patent in suit too pertains to a combination of known components with known properties that is a product of routine experimentation. Such act is deemed obvious and thereby non-inventive.
61. The counsel submitted that in light of the arguments and contentions presented, case laws discussed and documents cited, the Applicant thereby stated that the 212695 patent was obvious and devoid of inventive merit.
Respondents reply
62. Mr Praveen explained the working of eye and the mode of the action of drug through power point presentation.The learned counsel admitted that
1. Prostaglandins are highly effective ocular hypotensive agents.
2. US 5688819 D1 discloses bimatoprost (certain cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyi compounds as ocular hypotensives).
3. Timolol maleate is a non-selective beta adrenergic blocking agent which is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
4. The hypotensive lipids and timolol maleate, when used alone, are effective in treating ocular hypertension. (Page 5 of the complete specification).
63. The learned counsel submitted that the clinical use of prostaglandins in managing increased intraocular pressure has been limited by side effects such as (conjunctiva!) hyperemia and foreign-body sensation. Timolol maleate when used to control ocular hypertension may have one or more side-effects such as headache, fatigue, chest pain and can have disadvantageous effects on the cardiovascular, digestive, immunologic and digestive systems.
64. According to the cousel the claimed invention provides compositions which are surprisingly effective in treating ocular hypertension and reducing die number and/or frequency and/or severity of unwanted side effects caused by die bimatoprost component, relative to prior art compositions and methods.The compositions provide enhanced treatment of ocular hypertension, for example, enhanced reduction in intraocular pressure, relative to applying a similar composition including either the timolol component or the hypotensive lipid component, but not both.
65. The learned counsel submitted that the invention relates to compositions comprising a timolol component and a hypotensive lipid component (bimatoprost, pharmaceutically acceptable salts thereof and mixtures thereof) with each of the component being present in an amount effective to reduce ocular hypertension when applied to a hypertensive eye.He submitted that that the compositions may also contain excipients like vehicle, buffers, preservatives, antioxidants, tonicity adjusters, chelating agents, stabilizers, surfactants and one or more other conventionally used components. The preferred amount of the hypotensive lipid component is in a range of about 0.00001 to about 0.1 (w/v), more preferably about 0.0001 to about 0.01 (w/v) and the preferred amount of timolol employed is in a range of about 0.001 (w/v) to about 1.0 (w/v), more preferably from about 0.01 to about 0.2 (w/v) or about 0.25 or about 0.5 (w/v).
66. The learned counsel submitted that Composition in general given at page 21 of the complete specification is reproduced below.
Ingredients
|
Amount (w/v)
|
Timolol component
|
About 0.001-1
|
Hypotensive lipid component
|
About 0,00005-1
|
Preservative
|
0-0.10
|
Vehicle
|
0-40
|
Tonicity Adjuster
|
0-10
|
Buffer
|
0.01-10
|
pH adjustor
|
q.s pH 4.5-7.5
|
antioxidant
|
As needed
|
surfactant
|
As needed
|
Purified water
|
As needed
|
67. According to the learned counsel the comparative example on page 22 of the complete specification compares 4 compositions namely:
a. Composition 1 comprising bimatoprost (0.001% w/v) but not timolol (bimatoprost only composition)
b. Composition 2 comprising timolol (0.05% w/v) but not bimatoprost (timilol only compostion)
c. Composition 3 comprising both timolol (0.005% w/v) and bimatoprost (0.001% w/v) (combination)
d. Composition 4 comprising neither timolol nor bimatoprost
68. The learned counsel submitted that these compositions were administered to conscious cynomolgus monkeys. The combination (using relatively low doses of timolol) was found to be more effective than either bimatoprost only or timolol only composition in lowering intraocular pressure.
69. Referring to Para 15 of respondents expert Prof. Orest Olejnik's declaration the learned counsel submitted that the combination of bimatoprost and timolol as claimed in IN 212695 has an additive effect, increasing aqueous humor outflow and decreasing aqueous humor production, thereby reducing intraocular pressure inside the eye more than timolol or bimatoprost monotherapy and is non-inferior in lowering intraocular pressure compared to concurrent administration of bimatoprost and timolol. .Additionally, the Respondents along with their counter statement filed as Exhibits R-l and R-2 declarations of Dr. June Chen (one of the inventors), that were filed in the corresponding US proceedings to support this. The same declarations have also been relied upon by the Respondent's expert witnesses Dr. Orest Olejnik in his affidavit submitted vide M.P. No. 63 of 2012.
70. According to the learned counsel the first affidavit of Dr. June Chen had carried out safety and efficacy studies using a fixed combination of bimatoprost and timolol, serial administration of bimatoprost and timolol and bimatoprost monotherapy which can be tabulated as herein below:
Drug
Administered
|
Administration
|
Reported
Hyperemia
| |
Concurren t
|
0.03 (w/v) of
Bimatoprost
|
Once daily
|
25.6
|
0.5 (w/v)of
Timolol
|
Twice daily
| ||
Combination
|
0.03 (w/v) of
Bimatoprost and
0.05 (w/v) of
Timolol
|
Once daily
|
19.6
|
Monotherapy
|
0.03 (w/v) of
Bimatoprost
|
Once daily
|
He submitted that the key finding of the studies in para 9 of this affidavit clearly states that the incidence of conjunctival hyperemia was surprisingly lower in the combination administration group (19.3%) relative to the concurrent administration group (25.6%) and the said reduction of adverse events or side effects in particular conjunctival hyperemia was unexpected and could not have beenanticipated.Referring to the second affidavit of Dr. June Chen (Exhibit R2 of the counters statement) the counsel submitted that Dr Chen describes two twelve months, multicentre, double masked, randomized three arms study, involving approximately one diousand human patients, conducted over a period of one year.
0.5 (w/v)
timolol
|
0.03 (w/v)
bimatoprost
|
0.5 (w/v) timolol and
0.03 (w/v) bimatoprost
| |
Administered
|
Twice daily
|
Once daily
|
Once daily
|
Conjunctival
hyperemia
|
8.7
|
43.4
|
25.7
|
Eyelid
pigmentation
|
0.4
|
9.1
|
3.2
|
71. According to the learned counsel in view of these affidavits of Dr. Chen the following has been established:
a. Treatment with bimatoprost alone gives rise to ocular hyperemia and eyelid pigmentation (Blepheral hyperpigmentation)
b. Timolol alone also gives rise to ocular hyperemia and eyelid pigmentation
c. A person of ordinary skill in the art would have expected an additive increase in the incidence of ocular hyperemia and eyelid pigmentation upon combining bimatoprost and timolol as compared to bimatoprost monotherapy.
d. In contrast, the invention claimed in IN '695 v^hich comprises a combination of bimatoprost and timolol shows reduction in ocular hyperemia and eyelid pigmentation relative to bimatoprost monotherapy (evident from Dr. June Chen's second affidavit- Exhibit R2 of counter statement) and shows a reduction in ocular hyperemia relative to die concurrent use of bimatoprost and timolol (evident from Dr. June Chen's first affidavit- Exhibit Rl of counter statement). It is important to note that the concentration of bimatoprost and timolol in die fixed combination is the same as die concentration of bimatoprost in bimatoprost monotherapy and die concentration of bimatoprost and timolol in concurrent therapy. The reduction in ocular hyperemia and eyelid pigmentation using the fixed combination as compared to bimatoprost monotherapy and bimatoprost and timolol concurrent therapy is therefore anunexpected result.
e. Additionally, bimatoprost was administered once daily and timolol was administered twice daily, in concurrent administration as also in monotiierapy whereas according to die present studies the composition of bimatoprost and timolol was administered once daily. The efficacy of concurrent administration with the dosing regimen referred to above is comparable to that of combination therapy as is evident from the first affidavit of Dr. June Chen (Exhibit R1). In other words, it can easily be inferred that as combination therapy is administered once a day, it clearly has superior efficacy as compared to bimatoprost and timolol concurrent therapy wherein timolol is administered twice a day. Further, the combination shows reduced adverse events as compared to bimatoprost monotherapy or concurrent administration.
Post filing data
72. The learned counsel submitted that post-filing data can be relied upon by the Patentee to establish their case. Reliance is placed on the following:
· Genetics Institute, LLC. Vs. Novartis Vaccines And Diagnostics (655 F.3d 1291) in para 14 die Court held that
"our law is equally clear that every property of a claimed compound need not be fully recognised as of the filing date of the patent application to be relevant to nonobviousness. Knoll P harm. Co. v. Teva Phams. USA, Inc., 367 F.3d 1381, 1385 (Fed. Czr. 2004) ('There is no requirement that an invention's properties and advantages were fully known before the patent application was filed, or that the patent application contains all of the work done in studying the invention, in order for that work to be introduced into evidence in response to litigation attack.''). For those reasons, we have held that evidence of unexpected results may be used to rebut a case of prima facie obviousness even if that evidence was obtained after the patent's filing or issue date. Id. ("Evidence [of unexpected results] developed after the patent grant is not excluded from consideration, for understanding of the full range of an invention is not always achieved at the time of filing the patent application."); In re Khelghatian, 53 CCPA 1441, 364 F.2d 870, 876 (1966) (holding the claimed invention non obvious in view of post-filing evidence of an unexpected property not disclosed in the specification, while noting that the evidence "[wa]s directed to that which 'would inherently flow' from what was originally disclosed".
· Knoll Pba-fmaceuticsils Company, Inc. Vs. Teva Phatmaceuticals USA, Inc. [367 F.3d 1381) in para 138 the Court held that
"Evidence developed after the patent grant is not excluded from consideration, for understanding of the full range of an invention is not always achieved at the time of filing the patent application. It is not improper to obtain additional support consistent with the patented invention, to respond to litigation attacks on validity. There is no requirement that an invention's properties and advantages were fully known before the patent application was filed, or that the patent application contains all of the work done in studying the invention, in order for that work to be introduced into evidence in response to litigation attack. Nor is it improper to conduct additional experiments and provide later-obtained data in support of patent validity."
Thus the affidavits of Dr. June Chen, which were filed after the instant application had been filed, should be taken into consideration by the Hon’ble IPAB.
OBVIOUSNESS
73. The learned counsel for the Respondent dealt with prior art documents relied upon by the Applicant and also the relevance of the said documents for the purpose of determining obviousness as follows:
D1. US 5688819
The learned counsel submitted that US 5688819 (hereinafter referred to as US '819) is an admitted prior art on page 4 para 5 of IN '695.The equivalent of US’819, which is WO 97/30710, was cited by the Controller during the prosecution of IN '695. US '819 is the basic patent that discloses bimatoprost having an IUPAC name of cyclopentane-N-ethyl heptenamide-5-cis-2-(3a-hydroxy-5-phenyl-l-trans-pentenyl)-3,5-dihydroxy, (la, 2(3, 3a, 5a).and it recognize that some prostaglandins are highly effective ocular hypotensive agents which are ideally suited for long term medical management of glaucoma. [Col. 2, lines 9 and 10] .The isopropyl ester of PGF2α has been shown to have greater hypotensive potency than the parent compound.[ Col. 2, lines 34]. It also recognizes that the use of prostaglandins in the management of conditions associated -with increased ocular pressure, e.g. glaucoma, is greatly limited by intraocular side effects such as conjunctival hyperemia. .[ Col. 2]. It also recognizes that certain cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyi compounds wherein the carboxylic acid group is replaced by a non-acidic substituent have pronounced effects on smooth muscle and are potent ocular hypotensive agents. In certain instances they may be significantly more potent than their respective parent compounds and, in the case of glaucoma surprisingly, cause no or significantly lower ocular surfaces hyperemia than parent compounds.
The learned counsel submitted that US '819 provides a number of compounds (possibly thousands). To prepare a composition a person skilled in the art would need to narrow down the number of possible compounds which can be done by looking into the experimental data, for example as that provided in table 1 and table 2, which provide data on ocular hypertension using several different compounds taken in dogs as well as data on ocular hyperemia.There is no experimental data provided in this document for bimatoprost. Thus one of skill in the art would not choose bimatoprost.
According to the counsel US '819 does not teach that as a general principle, the amides are always more potent than the corresponding carboxylic acids. Instead, US '819 states that "such compounds, in certain instances, may be significantly more potent, than their respective parent compounds. Example 3 is an amide of the carboxylic acid of example 1, and example 3 does not appear to have an improved potency or reduced hyperemia as compared to example 1. Thus, US '819 does not allege that improved potency of an amide over a carboxylic acid is a general principle.Further, none of the compounds disclosed in the examples relate to bimatoprost. It is unclear why one would have chosen bimatoprost out of thousands of compounds disclosed in Dl and which is not even exemplified in any of the examples.
D2. Diestelhotst M et aL,
The learned counsel submitted that the objective of this study was to determine the "effective concentration" of latanoprost (0.001 or 0.005) to be used in fixed combination with timolol 0.5 for the effective treatment of open angle glaucoma.The objective of the combination was patient compliance and was never to determine or reduce the adverse effects caused by latanoprost or timolol.This study compared two fixed combination of latanoprost and timolol. While in one combination tile concentration of latanoprost was 0.001 ; it was 0.005 in the second combination. Timolol was used at a concentration of 0.5 in both the combinations.
74. In respect of the averment of the Applicant that latanoprost can be replaced with bimatoprost in the fixed dose combinations disclosed in D2 the learned counsel submitted that bimatoprost is not an obvious replacement of latanoprost. The two drugs are very different and 'the same is apparent from the following:
(a) Bimatoprost is a prostamide and not a prostaglandin ester like latanoprost. The cousel submitted following articles in support of this.
In Woodward et aL, The Pharmacology of Bimatoprost (Lumigan@), Surv Ophthalmol 2001, May; 45 (Suppi 4): S337- S345 (Submitted vide M.P No. 14/2013 filed by the Respondent) it is stated that
"Bimatoprost (Lumigan) is one compound in a new class of highly efficacious ocular hypotensive agents, bimatoprost is pharmacologically unique and appears to mimic the prostamides. Prostamides are the newest members of the fatty acid amide family, which includes anandamide, oleamide and palmitylethanolamide…..” [Volume V,Page 52 Column 1, lines 1-7]
(b) Bimatoprost is not a prodrug while latanoprost is a prodrug. This fact is supported by the disclosure in the following;
Louis B Cantor, Bimatoprost: A Member of a New Class of Agents, the Prostamides, for Glaucoma Management, Exp. Opin. Invest. Drugs (2001) 10(4): 721-731 (Abstract enclosed as Exhibit XA1 with the reply to the counter statement. Complete document submitted by the Respondent during the hearing)
"Bimatoprost is not a prodrug. It does not need to be metabolized to exhibit bioactivity. However, radioligand binding assays using bimatoprost as a competitior have demonstrated that bimatoprost has no meaningful affinity for previously described classes of membrane receptors, ion channel or transporters [44]. Most importnantly, bimatoprost has no relevant affinity for adrenergic, cholinergic, prostaglandin or cannabinoid receptors”. [Page 724, column 1, lines 3-10]
Woodward et a/. The Pharmacology of Bimatoprost (Lumigan@), Surv Ophthalmol 2001, May; 45 (Suppi 4): S337- S345 (Submitted vide M.P No. 14/2013 filed by the Respondent)
"Bimatoprost appears to exert its effects on intraocular pressure by virtues of its inherent pha'macological activity as aprostamide. It does not need to be converted to a free acid metabolite in the eye to exert its pharmacological activity and no free acid was detected at the site of action in the eye. Thus it is not a prodrug." , [Volume V, Page 59, column 2, para 3, lines 10-16]
Martin B Wax, Prostaglandin Analogues: What we know Today, Clinical Opthalmic Practice 20:1, 2002, Pages 30-32
"The isopropyi ester ofPGF,^ was therefore a prodrug..... Finally, they "hit a home run" by saturating the double bond between carbons 13 and 14 on the omega side chain, which created a product that was potent and efficacious, more stable and lacked irritating effects and significant byperemia, This product was latanoprost." [Volume V, page 61, columns 2 and 3, line 9 Onwards]
"Allergan claims that bimatoprost works by binding to a novel site called prostamide receptor, and that the agent is not a prodrug because it is not significantly hydrolyyd inside the eye to its free acidfom. " [Volume V, Page 62, Column 3, Para 2, line 1onwards]
(c) Bimatoprost does not act on the same receptors as latanoprost. This fact is supported by the disclosure in the following;
· Louis B Cantor, Bimatoprost: A Member of a New Class of Agents, the Prostamides, for Glaucoma Management, Exp. Opin. Invest. Drugs (2001) 10(4): 721-731 (Abstract enclosed as Exhibit XA1 with the reply to the counter statement. Complete document submitted by the Respondent during the hearing)
"However, radioligand binding assays using bimatoprost as a competitior have demonstrated that bimatoprost has no meaningful affinity for previously described classes of membrane receptors, ion channel or transporters [44]. Most importnantly, bimatoprost has no relevant affinity for adrenergic, chollnergic, prostaglandin or cannabinoid receptors.[Page 724, column 1, para 1, lines 5-10]
"Thus, the prostamides display unique pharmacological activity, and the pharmacological profile of bimatoprost in biological assays in vitro suggests that bimatoprost and related prostamides activate novel receptor(s) that have not jet been identified.” [Page 724, column 1, para 2, lines 8-13]
· Woodward et al., The Pharmacology of Bimatoprost (LumiganTM), Surv Ophthalmol 2001, May; 45 (Suppl 4): S337 – S345 (Submitted vide M.P. No.14/2013 filed by the Respondent)
"Bimatoprost is pharmacologically unique and does not exert its effects by stimulating any known receptor subtype." [Volume V, Page 59, column 2, para 3, lines 2-4]
· US 5352708 (Submitted as Exhibit R3 with the counter statement)
"[r]eplacement of the CO OH [carboxylic acid] by a diverse variety of substituents resulted in potent ocular hypotensive agents, despite the inability of these a-sents to bifid to prostaaoid receptors or elicit Ca2+ second message as shown above." [Volume IIA, Page 246, column 13, para 2]
· Woodward et al, Prostamides (Prostaglandin-Ethanolamides) and Their Pharmacology, British Journal od Pharmacology (2008) 153, 410-419
“Prostamide F2α and bimatoprost effects appear independent of prostanoid FP receptor activation, according to a litany ofagonist studies." [Volume IIA, Page 252, abstract, lines 5-6]
"An exhaustive series of against studies using prostamide F2a and bimatoprost have provided much evidence that their effects cannot be readily attributed to prostanoid FP receptor stimulation. In 2007, the first selective prostamide antagonist was reported, which provided further evidence for the prostamide receptor as a distinct entity" [Volume IIA, Page 253, column 1, para 2, lines 6-12]
"Neutral PGF2a analogues were known to exert little or no agonist activity in PGF2a -sensitive preparations... Replacement of the charged carboxylate group by a –CONH2, group reduced activity at FP receptors by more than two orders of magnitude....... What is more important, however, was an absence of meaningful agonist activity at prostanoid FP receptors." [Volume IIA, Page 254, column 1, para 2, line 3 onwards]
“All of these prostamides exhibited no meaningful activity at prostanoid receptors including the FP receptors. None were FP receptors antagonists.” [Volume IIA, Page 255, column 2, para 2, lines 10-13]
· Martin B Wax, Prostaglandin Analogues: What we Know Today, Clinical Ophthalmic Practice 20:1, 2002, Pages 30-32
"Allergan claims that bimatoprost works by binding to a novel site called prostamide receptor, and that the agent is not a prodrug because it is not significantly bydroly^ed inside the eye to its free acid form." [Volume V, Page 62, Column 3, Para 2, line 1 onwards]
75. According to the learned counsel the structural similarities between bimatoprost and latanoprost are overemphasized. Bimatoprost is a prostamide .while latanoprost is a prostaglandin. There is a double bond in the lower chain of bimatoprost that is not present in latanoprost. Double bonds are important to prostaglandin activity. For example the difference between PGF1α and PGF2α the natural versions of different classes of prostaglandins is a single double bond.
76. According to the learned counsel attributing structural similarities between bimatoprost and latanoprost does not translate into similar and expected pharmacological and/or therapeutic effects. Small differences in chemical structure often result in radical differences in pharmacology and therapeutic effects. There are numerous examples where structural analogues may have the same basic structural scaffold, but result in unexpected activities:
a. P. Genton et al- Exhibit R5 of the counter statement: Piracetam and levetiracetam have close structural similarities but their pharmacological and clinical profiles are very different.
b. C.W Wemiuth- Exhibit R6 of the counter statement: Closely related tricyclic isoxazole derivatives with modest changes to chemical structure have shown very different activity profiles.
c. The oc-adrenergic agonists, apraclonidine and brimonidine, have a similar structural scaffold, yet their respective therapeutic activities in treating glaucoma and side-effect profiles are very different. R. L Gross- Exhibit R7 of the counter statement: Whereas apraclonidine and brimonidine both decrease aqueous humor production, brimonidine increases uveoscleral outflow. Moreover, brimonidine has a significantly higher potency and reduced side-effects compared to apraclonidine.
According to the learned counsel there are many chemical compounds that are as close structurally to latanoprost as bimatoprost and there is no reason why one of skill in the art would have considered bimatoprost alone as the best compound for modification of a latanoprost composition.
D3 WO 97/30710
In respect WO 97/30710 D3 (Exhibit E of the revocation) the learned counsel submitted that it belongs to the same patent family as US 5688819 and therefore has already been dealt with in these written submissions. It was also cited by the Controller during the prosecution of IN212695
D4 US 4952581
The learned counsel submitted that US’581 was cited by the Controller during the prosecution of IN 212695. It discloses' a composition for treating ocular hypertension comprising an effective intraocular pressure reducing amount of a mixture of an adrenergic blocking agent and a prostaglandin or prostaglandin derivative m an ophthalmically compatible carrier.It disclosed that a combination drug or a drug regimen that acts by decreasing aqueous humor secretion, such as an adrenergic blocking agent and a prostaglandin would be ideal, provided the adrenergic blocking agent can be shown not to block the ocular hypotensive effects of prostaglandins. According to the counsel the teaching of this document was therefore to select an adrenergic blocking agent to be used along with the prostaglandin that does not block the ocular hypertensive effects of prostaglandins (col. 2 lines 44-50).
The learned counsel submitted that US’581 teach lowering of the concentration of individual actives to reduce the side effects (column 1, lines 61-69). In contrast, the concentration of the actives in the commercial product of the Respondent which is covered by the claims of IN '695, is not reduced as compared to the products used in monotherapy, yet the side effects of the bimatoprost component in the combination product are reduced relative to bimatoprost monotherapy. It focuses on reducing the dose of PGF2α-1- isopropyi ester in order to reduce the undesirable side effects of PGF2α -1- isopropyi ester. [col. 7 lines 1-20]. According to the counsel this is clearly a teaching away as the Respondent in their subject patent and also in their commercial product covered by the subject patent have been able to unexpectedly reduce the side effects without reducing the dose of bimatoprost. He refrred to Dr. Chen's second declaration (Exhibit R2 of the counter statement) which shows that in spite of dosage of bimatoprost being the same in bimatoprost monotherapv arm and combination arm, the incidence of side effects was lower in the combination arm.
The learned cunsel submitted that simply reducing drug concentration amounts does not in turn reduce side-effects.According to the counsel the objective in drug formulation or combination drugs is not only to reduce side effects but also to ensure that the said product is pharmacologically effective in treating the disorder.
The learned counsel contended that a clinical evaluation of diclofenac-gentamicin combination eye drops showed an increase in drug related adverse events (W.F.I. Shepherd et al; Ocular Immunol. and Inflamm. 6(1):13-18, 1998- enclosed and exhibited as Exhibit R8 of the counter statement). Similarly combined therapy is also contraindicated where drug-drug interactions could have a propensity to increase undesirable events e.g. the use of ocular non-steroidal anti-inflammatory drugs (NSAIDs) with ocular steroids can cause reduced wound healing.He submitted that NSAIDs can block prostaglandin synthesis which could possibly interfere with the hypotensive effect of prostaglandins (P. Koay; Brit. Jnl. of Ophthalmol. 80:480-485,1996 marked and annexed asEXHIBIT R9 of the counter statement).
The learned counsel contended that person with ordinary skill in the art would actually predict an increase in ocular hyperemia as an outcome in combining hyperemia inducing agents e.g. prostaglandins, specifically bimatoprost with vasodilator, hyperemia inducing drug compounds e.g. (3-blockers, specifically timolol. He added that the process of combining two active anti-glaucoma agents may or may not have the potential for increased activity. Unexpected drug-drug interactions could occur leading to profound effects, e.g. rendering a combination inactive. There is always a potential for drug saturation at the receptor sites which may result in the absence of an enhanced effect. Consequently, it cannot be deemed obvious that drug combinations result in improved therapeutic activity. The same can be said for reducing any adverse events. A combination of two drug moieties could in fact cause increased toxicity due to simultaneous exposure of the patient to two drugs. (Combination Therapies in Ophthalmology, G.A. Peyman and K. Hosseini, Journal of Ophthalmic and Vision Research 6(1):36-46, 2011 marked and annexed as EXHIBIT RI0of the counter statement).The cousel submitted that this document D4 does not teach or suggest bimatoprost or any other prostamide structure. Prostamides such as bimatoprost were known to have very different biological activity than prostaglandins such as PGF2α and thus such a substitution would not have been made.
Exhibit XA1
Lomis B Cantor. Bimatoprost: a member of a new class of agents, the prostamides. for p-laucoma manas-ement..-Exo. Onin. Invest. Drues j'2001) 10(4):721-731- the title as well as Abstract, lines 1-6 (Abstract at Page 466, Convenience file, Volume IIB, Referred to as Cantor)
According to the counsel Cantor teaches the following:
(a) Bimatoprost is a synthetic analog of a newly discovered class of fatty acid amides, called prostamides.
(b) The non-selective beta adrenergic antagonists, such as timolol, remain the most commonly prescribed agents for glaucoma management. However, contraindications to non-selective beta blockers such as cardiac and pulmonary disease, are prevalent in the elderly population most at risk for glaucoma. Moreover, these drugs tend to show reduced efficacy with long-term use.
According to the counsel the focus in Cantor 'article was never to use bimatoprost as a combination therapy but as a replacement monotherapy drug. Studies on page 725 clearly establish that the Cantor article was directed to bimatoprost monotherapy and comparison of bimatoprost was done with timolol alone and latanoprost alone.He submitted that this article talks about bimatoprost being in development as a topical ocular hypotensive agent for the treatment of glaucoma and ocular hypertension (Abstract, lines 1-2).Cantor is not conclusive about the superiority of bimatoprost over latanoprost as it states that though the patients in the bimatoprost group were more likely than patients in the latanoprost group to achieve low target pressures, the difference between the groups did not reach statistical significance. (Page 726, bridging lines between columns 1 and 2).In the concluding lines on page 728 Cantor further states that bimatoprost may be more efficacious than all available medications when it is approved for clinical use and it may set a new standard for IOP lowering.Cantor also with stated that all newly introduced drugs, the full therapeutic profile of bimatoprost will be better understood after long term use of this medication in a large population of patients.Therefore, in essence, Cantor is speculative about the clinical effects of bimatoprost.
According to counsel Cantor was published at a time when bimatoprost was not even available for clinical use. At such an early phase of development of a drug, a person skilled in the art would not be motivated to use that drug in drug combinations as a replacement for some other active ingredient.The counsel submitted that on reading Cantor, a person skilled in the art will not be motivated to form any drug combinations, particularly combinations of bimatoprost with timolol, as bimatoprost has been shown to be much more promising than both latanoprost and timolol.One of skill in the art would further not be motivated to combine bimatoprost with timolol due to its adverse, side effects and because of the fact that non-selective beta blockers like timolol show reduced efficacy with long-term use. He referred From to page 723 of the article and submitted that even if one was to assume that combination therapy is preferred, a person of ordinary skill in the art on reading of this document 'will prefer using betaxolol as opposed to Timolol as betaxolol has a more favorable safety profile.Additionally , due to the higher concentration of 0.03 at which bimatoprost is recommended as opposed to 0.005 of latanoprost, a person skilled in the art would never be motivated to combine bimatoprost with timolol as this would:Reduce the safety profile of the combination drug; and One would expect an increase in adverse effects such as hyperemia.In fact the Cantor article did not even recognize the adverse effects associated with bimatoprost and held under Section 6 tided "safety' and tolerability" that Bimatoprost monotherapy was associated with trace to mild conjunctival hyperemia.
77. In conclusion, the learned counsel argued that a person of ordinary skill in the art will not be motivated to combine bimatoprost with timolol from the teachings of any of the above discussed prior art documents. The state of the art does not motivate one of ordinary skill in the art: 1. To replace latanoprost. 2. To combine bimatoprost with another compound.3. To combine bimatoprost with timolol.4. To combine bimatoprost and timolol in a fixed combination
78. The learned counsel submitted that study by Martin B Wax, Prostaglandin Analogues: What we Know Today, Clinical Ophthalmic Practice 20:1, 2002, [Pages 30-32] it is fund that
“Latanoprost, travoprost and bimatoprost have a similar molecular structure (Fig 1).0ne key difference is that the latter two agents have an unsaturated double bond between carbons 13 and 14 of the omega chain. This largely explains why they are associated with a higher incidence of hyperemia than latamoprost.” [Volume V, Page 61, Column 3, Para 2, Line 1 onwards]
"A reasonable conclusion from these studies is that both bimatoprost and latanoprost work equally well as hypotensive agents. The major difference between them is not efficacy but side effects. In one clinical trial, the incidence ,of hyperemia with bimatoprost was 36 vs. 14.2 for latanoprost" [Volume V, Page. 63, column 2, para 1, lines 4-12]
"All the three PG analogues were prescribed once daily in the evening and have similar peak, reduction in IOP. The key difference between these drugs is their ocular adverse effects. My clinical experience with the newer agents is admittedly limited because I see little utility in prescribing them as long as latanoprost is readily available, bimatoprost and travoprost may be effective agents, but in my view their value in clinical practice is severely limited by the increase in their ocular adverse events." [Volume V, Page 63, Column 2, Para 2, lines 1-15]
The learned counsel contented that in view of this teaching the is skilled person will not replace latoplast with Bimatoprost.
79. The learned counsel contented that in Louis B Cantor, Bimatoprost: A Member of a New Class of Agents, the Prostamides, for Glaucoma Management, Exp. Opin. Invest. Drugs (2001) 10(4): 721-731 it is stated that
"bimatoprost will likely be available for clinical use in 2001 and it has great potential to be superior to all other medications in lOP-lowering efficacy. It is anticipated that bimatoprost will have an important, role in therapy for glaucoma and ocular hypertension" [Abstract, last 4 lines]
"In summary, bimatoprost 0.03 ophthalmic solution once daily has great potential for the management of glaucoma and ocular hypertension, bimatoprost may be more efficacious than all other available medications when it is approved for clinical use and it may set a new standard for IOP lowering" [Page 728, column 2, last para, lines 1-6]
The learned counsel contented that in view of this teaching the skilled person will not combine Bimatoprost with others compounds.
80. The learned counsel contented that in Louis B Cantor it is also discussed that
"The non-selective b-adrenergic antagonist such as timolol, remain the most commonly prescribed agents for glaucoma management. However, contraindications to non-selective beta-blockers, such as cardiac and pulmonary disease, are prevelant in the elderly population most at risk for glaucoma [26]. Rare, serious and potentially fatal cardiopulmonary adverse effects have been associated with the use of non-selective B-blockers [27]. These drugs also tend to show reduced efficacy with long-term use [28]. It has been estimated that half of the patients who receive b-blacker therapy will require an additional medication for IOP control within two years [29]" [Page 723, column 1, para 2, line 3 onwards]
"bimatoprost 0.03% instilled q.d. was superior to timolol 0.5% b.i.d in IOP lowering throughout the day at every study visit" [Page 725, column 2, lines 1-3]
The learned counsel contented that in view of this teaching the skilled person will not combine Bimatoprost with timolol.
81. Referring to US 4952581 where it is discosed that
"This suggests that levobunolol hydrochloride may be a very good candidate for combined therapy since there was a more pronounced reduction of intraocular pressure within one hour after the topical application of 0.5 µg of PGF2α-1- isopropyi ester in eyes that were pretreated with this beta blacker than typically occurs with this dose ofPGF2a-1- isopropyi ester."[Volume IIA, page 110, column 6, last para, lines 7-14]
the learned counsel contented that the skilled person will use levobunolol to combine.Similarly US 5502052, discloses a number of beta blockers that may be used in ophthalmic formulations and he Merck Manual Home Health Handbook, 2009 discloses a number of ocular hypotensive agents that may be used in ophthalmic formulations.
82. The learned counsel submitted that one big advantage of adjunctive/concurrent/serial use of two actives over their combination is greater flexibility of individual actives. Moreover, there may be a number of complications of putting two drugs together in a single bottle which are discussed in detail in the following:
1. Peyman and Hosseird, Combination Therapies in Ophthalmology, Journal of Ophthalmic and Vision Research 6(1): 36-46, 2011,
“However, combination therapy can augment inherent complications of individual interventions, therefore vigilance is required. Complications of combination therapy include potential incompatability among compounds and tissue toxicity.” [Volume IIA, Page 323, Abstract, lines 6- 9]
"Competitive effects occur during combination of drugs which can be positive or negative, depending on whether the drugs have synerg.st.ic or antagonistic effects. Drug displacement interactions are a possibility; this can occur at binding or receptor sites. Alternatively, the combination of drugs can produce a new effect that neither drug produces on its own." [Volume IIA, Page 325, column 1, para 3, lines 2-10]
"It remains almost impossible to predict drug interactions in different locations of an organ or the whole body, as transport and elimination routes and dynamics ca vary greatly depending on ongoing physiological and pathological processes" [Volume IIA, Page 325, column 2, para 3, lines 1-6]
"The challenge becomes even greater when two or more drugs are combines and their combination may cause new physiochemical reactions within the mixture in vitro or within the organ. Such adverse effects may manifest as incompatibility, which is described as preventable or reversible precipitation or insolubility and recognisable as crystals, turbidity or harness." [Volume IIA, Page 326, column 1, para 3, lines 8-15]
"Another possible physiochemical reaction due to combinations of drugs stems from instability, which can @result from hydrolysis and oxidation. The combination of chemical entities can cause degradation products and such products are often unstable chemicals that may be less active or inactive tberapeutically, but more importantly they can become toxic products which are not always visually discernible." [Volume IIA, Page 326, column 2, para 1, lines 1-10]
"Combinations of pharmaceutical compounds may precipitate adverse physical and chemical interactions, both in vitro during mixing and in vivo upon delivery." [Volume IIA, Page 331, column \, para 1, lines 6-9]
2. Finding of Facts and Conclusions of Law, United States District Court for the Eastern District of Texas Marshall Division in Civil action Nos. 2:09-cv~97, 2:09-cv-348 TJW, 2:10-cv-200 TJW, 2:10-cv-344 TJW
“24. Although there are many individual medications available, for many patients, one glaucoma medication is not enough to treat their disease effectively. (D.I. 238, Trial Tr. Day 1 (AM) at 54:22-55:17 (\Vhitcup).) for patients whose glaucoma cannot be effectively controlled with a single drug, the most common form of treatment is the serial or concomitant administration of two or more different medications, provided in two or more separate bottles, at least several minutes apart to prevent one of the drops from washing the other out. (D.I. 238,Trial Tr. Day 1 (AM) at 55:1-56:2; 56:14-57:16 (Whitcup).)
25. This type of treatment is referred to by various terms, including adjunctive, concomitant, or serial therapy, and the combination of the products is considered “unfized” because the amount the patient gets of each drug at any particular time is dependent on the treatment regimen prescribed by the doctor and or whether the patient properly administers the drugs. (D.I. 239, trial Tr. Day 1 (PM) at 64:10-66:3 (Batoosinsh).) By contrast, a 'fixed combination'^ combines two glaucoma drugs in the same bottle. (D.I.240, Trial Tr. Day 2 (AM) at 17:21-18:3 (Tanna).) It is "fixed" because the patient gets the same amount of each
drug each time a drop of the combination is delivered to the eye. (D.I. 239, Trial Tr. Day 1 (PM) at 64:10-24 (Batoosingh).)
26. There are advantages to using unfixed combinations over fixed combinations. For example, if a patient needs a smaller dose of one medication, a physician can prescribe a smaller dose of that medication without modifying the dose of the other. Unfixed combinations thus give physicians wide flexibility in treatment options. (D.I. 239, Trial Tr. Day 1 (PM) at 64:10-20 (Batoosingh); D.I. 240, Trial Tr. Day 2 (AM) at 132:14--i33:3 (Tanna); D.I. 242, TrialTr. Day 3 (AM} at 79:7-18 (Noecker).)
27. Serial or concomitant administration of two drugs is different than administering them in a fixed combination. (D.I. 238, Trial Tr. Day 1 (AM) at 56:14-57:19 (Whitcup).) When two ophthalmic products are used together in a concomitant regimen, they do not interact in a patients eye. The human eye maintains only a small volume of liquid, approximately 10 microliters, on its outer surface. 'Eye-drops (about 35-40 microliters) are absorbed or drain away quickly through the eye's drainage ducts. (Id.; D.I. 242, Trial Tr. Day 3 (AM) at 64:24-65:3 (Noecker) ("And then the biggest problem is the window of delivery. It's there, you blink a bunch, and the eye is gone. So you have about a minute to get this right and get it into the eye. So if you're a little slow out of the gate, it's gone."').) Thus, under recommended dosing, which requires administration of drugs in an adjunctive regimen at least five minutes apart, the second administered drug given as part of an adjunctive regimen would not interact with the first administered drug. (D.I. 238, Trial Tr. Day 1 (Afvl) at 57:13-16 (Whitcup).)”
OBVIOUSNESS
83. The counsel for the Respondent relied on the following cases laws: On questions of oviousness
Apotex Inc. v. Sanofi-Synthelabo Canada Inc., & Ors. - [2008] 3 S.C.R. 265, 2008 SCC 61
"However, a possibility of finding the invention is not enough. The invention must be self-evident from the prior art and common general knowledge in order to satisfy the "obvious to try" test." [Para 85]
Brimonidine Patent Litigation vs. Exela Pharmsci Inc. & Ors.- (643 F.3d 1366)
"The district court found that one of ordinary skill in the art would not have *1374 turned to CMC as a solubility enhancer. In response, Apotex presents two arguments. First, it points out that Alphagan® and Refresh Tears®, which contains CMC, were routinely prescribed together. This fact alone does not establish that it would have been obvious to combine the two in a single formulation. Two ingredients might be therapeutically effective when used separately as part of an overall treatment regimen, yet be incompatible or ineffective when combined in a single solution." [Page 7]
"Where "the problem is known, die possible approaches to solving the problem are known and finite, and the solution is predictable through use of a known option," a solution that is obvious to try may indeed be obvious." [Page 8]
"Apotex's "obvious to try" arguments, based on KSR, are unavailing in light of the district court's factual findings. The district court found that the solutions that Allergan identified and eventually claimed would not have been an "anticipated success". See Rolls-Royce, PLC vs. United Techs. Corp. 603 F.3d 1325, 1339 (Fed. Cir. 2010). The court found that one of ordinary skill would not have been expected to disregard those roadblocks. Because the court's findings are well supported, we do not agree with Apotex that the trial court's conclusion as to the "obvious to try" issue must be overturned."[ Page 9]
The General Tire & Rubber Company v. The Firestone Tyre And Rubber Company Limited and Others- [1972] R.P.C. 457- page 497
"Obvious is, after all, a much-used word and it does not seem to use that there is any need to go beyond the primary dictionary meaning of "very plain".
"When head (f) is invoked it is, of course, as previously indicated, for whoever seeks revocation of a patent to show that the alleged inventive step was obvious to a normally skilled addressee in the art."
Janssen Pharmaceutica N.V. & Amr. Vs. Mylan Pharmaceuticals, Inc. - 456 F. Supp. 2d 644;
It is not enough for a party seeking to defeat a patent on obviousness grounds to merely identify each element of the invention, in the prior art. Id. at 986. This can be done for nearly all inventions. Id. Instead, aprima facie case of obviousness requires the party to "explain the reasons one of ordinary skill in the art would have been motivated to select the references and to combine them to render the claimed invention obvious". [Page 8]
"In examining the prior art to see what it teaches a person of ordinary skill, references cannot be read in isolation. Instead, they must be read in light of what they fairly teach IN COMBINATION WITH THE PRIOR ART AS A WHOLE. Mylan and DRL cannot pick and choose among the prior art references.: [Page 16]
Unexpected results
84. The counsel for the Respondent relied on the following cases laws: On questions of unexpected results
Janssen Pharmaceurica N.V. & Anr. Vs. Mylan Pharmaceuticals, Inc. - 456 F. Supp. 2d 644;
"g. Unexpected Results
The final relevant secondary consideration is unexpected results. Unexpected superior properties of an invention [**74] support the conclusion that the invention was not obvious to one of ordinary skill in the art." [Page 22]
MOTIVATION
85. The counsel for the Respondent relied on the following cases laws: On questions of motivation
Imiogenetics, N.V. Vs. Abbott Laboratories (512 F.3d 1363)-page 13
"The district court was nevertheless correct that knowledge of a problem and motivation to solve it are entirely different from motivation to combine particular references to reach die particular claimed method. Innogenetics, slip op. at 14 ("A generalized motivation to develop a method is not the kind of motivation required by the patent laws.")"
Janssen Pharmaceutica N.V. & Anr. Vs. Mylan Pharmaceuticals, Inc. - 456 F. Supp. 2d 644;
"As stated earlier, when applying the "motivation-suggestion-teaching" test, the Court must ask whether die person of ordinary skill in the art in 1985, "motivated by the general problem facing the inventor would have been led to make the combination recited in the claims." Page 9
HINDSIGHT
86. The counsel for the Respondent relied on the following cases laws: On questions of hindsight
Janssen Pharmaceutica N.V. & Anr. Vs. Mylan Pharmaceuticals, Inc. - 456 F. Supp. 2d 644;
"Almost any invention, no matter how nonobvious at the time, will appear obvious when looking backward from the solution. It is for that reason that "[c]are must be taken to avoid hindsight reconstruction by using 'the patent in suit as a guide through the maze of prior art references, combining the right references in die right way so as to achieve the result of the claims in suit." [Page 14]
PERSON OF ORDINARY SKILL IN THE ART
87. The counsel for the Respondent relied on the following cases laws: On questions of person of ordinary skill in the art
Janssen Phamiaceutica N.V. & Anr. Vs. Mylan Pharmaceuticals, Inc. - 456 F. Supp.
"While the person having ordinary skill knows all of the prior arts, he or she is neither a genius nor an innovator. “A person of ordinary skill in the art is also presumed to be one who thinks along the line of conventional wisdom in the art and is not one who undertakes to innovate, whether by patient, and often expensive, systematic research or by extraordinary insights, it makes no difference which.” [Page 7]
88. According to the respondent bimatoprost is not a PGF2α analog. It is a prostamide. He contended that there is no teaching or suggestion to substitute latanoprost with bimatoprost. If we see structure of PGF2α [also known as Dinoprost]
Dinoprost or PGF2α.
We find it is similar to Structure of Latanoprost and Bimatoprost reproduced below.
Latanoprost [Isopropyl ester of PGF2α]
Bimatoprost [Ethanolamide of PGF2α ]
We also find PGF2α [also known as Dinoprost] analogs include Latanoprost, Bimatoprost, Travoprost, and Carboprost. In US‘819 we find Latanoprost has been referred as isopropyl ester of PGF2α [Col 2. line 34] which was known since 1987. US‘819 discloses bimatoprost as one of the thirteen preferred compounds [col.7 line 44-46]. US ‘708 also disclose same prostaglandin derivativs as US‘819 including bimatoprost as potent ocular hypotensive agents. US ‘581 teaches use of Timolo and PGF2α -1-isopropyl ester [Latanoprost] combination. Diestelhorst M. et alalso in introduction stated Timlol is traditionally as treatment of choice and act by reducing the aqueous humor production. It is also stated that ‘Recently, latanoprost a prostaglandin PG F2α analog,’….. ‘Latanoprost is a prostaglandin analogue (more specifically an analogue of prostaglandin F2α that works by increasing the outflow of aqueous fluid from the eyes (through the uvealsclearal tract).’This is exactly same what has been stated in specification of 695 [page 7 line 3-6] for bimatoprost and timolol combination.
“The combination of a timolol component and a hypotensive lipid component is believed to provide both a decrease in rate of aqueous humor production and an increased aqueous humor outflow.”
Bimatoprost (prostaglandin–ethanolamide). [Known since 1997] is analogue of structurally related prostaglandin F2α that reduces IOP by increasing the outflow of aqueous humour through the trabecular meshwork (pressure-sensitive) and uveoscleral (pressure-insensitive) routes. If we see Cantor (2001) it says ‘Bimatoprost a synthetic analog of endogenous prostamide’ and ‘it mimics the endogenous prostamides by lowering the intraocular presure’. Lumigan Label also under the head ‘Mechanism of action’ states ‘Bimatoprost is a prostamide, a synthetic structural analog of prostaglandin’. Therefore both are known to be prostaglandin (PG) F2α analogue widely recognized in the treatment of glaucoma. Latanoprost is sold as Xalatan and Bimatoprost as Lumigan.
89. We do not agree with the respondent that ‘no comparison was required as Latanoprost is different from Bimatoprost and a comparison of combinations comprising the two would be akin to comparing apples to oranges as we find both are ‘oranges’ Bimatoprost [akin to seedless orange] better than latanprost [akin to orange with seeds] to lower the IOP. We found that two drugs Bimatoprost and Latanoprost were closely related in that they are both (1) ocular hypotensive lipid having the same pharmacological properties (2) derivatives of the same prostaglandin analogs where the carboxylic acid group is replaced by a non-acidic substituent (3) from the same family of substances and (4) lower the IOP efficiently in patients with glaucoma or ocular hypertension when used as monotherapy.
90. In US ‘581 we find that a composition comprising an effective intraocular pressure reducing amount of a mixture of an adrenergic blocking agent and a prostaglandin or prostaglandin derivative is discosed in general for treating ocular hypertension. The perferred beta blocker is Timolol maletae and preferred prostaglandin is PGF2α or a PGF2α derivative PGF2α -1-isopropyl ester [Col 5 line 2-9]. If we see Diestelhorst M. et al (1998) "Comparison of two fixed combinations of latanoprost and timolol in open angle glaucoma” in introduction we find trend in the glaucoma shifted from monotherapy to serial separate bottle to fixed combination (one bottle). The final shift was preferred for the two drugs which were known to have additive effect in view of having ‘complementary mechanism of action’ [ie latanoprost and timolol in this study] and the fixed combination was preferred ‘to optimize the convenience and the patient compliance’. US‘819 discloses bimatoprost as one of the thirteen preferred compounds and such compounds “in case of glaucoma surprisingly cause no or significantly lower ocular surface hyperemia than the parent compounds” [col 3 line 11-18].
91. This being the case Ms Psita would find these drugs closely related, and would therefore access Diestelhorst M. et al when formulating combination of Timolol and Bimatoprost. She would be led to believe by teachings of Diestelhorst that Bimatoprost like Latanoprost may produce same result if not better. This is also confirmed by the specification where inventor stated that
“Without wishing to limit the invention to any particular theory or mode of operation, it is believed that the present compositions and methods take advantage of the different modes of action of the Timolol component and the hypotensive lipid component.” (Page 6, last paragraph)
And as we have found that mode of action of bimatoprost is also complimentary to timolol like latanoprost thus giving additive results.This has been confirmed by the respondent expert Dr. Orest Olejnik when he stated in in para 15
‘the combination of bimatoprost and timolol as claimed in IN 212695 has an additive effect, increasing aqueous humor outflow and decreasing aqueous humor production, thereby reducing intraocular pressure inside the eye more than timolol or bimatoprost monotherapy and is non-inferior in lowering intraocular pressure compared to concurrent administration of bimatoprost and timolol.’
92. Claim1 as worded refers to ‘blend’ and it was known and expected that a blend combination would result in enhanced reduction in intraocular pressure as both the drugs were known toachieve this result through the different modes of action. The claimed blend combination of Timolol component with Bimatoprost component did produce additive results on expected lines. Canter teaches Bimatoprost is better than Timolol and latnoprost. Ms Psita has a sucessful combination of Timolol with Lantoprost in Diestelhorst (1998) before her and she knew the trend is to go for fix combination ‘to optimize the convenience and the patient compliance’. US ,819 and Cantor teaches Bimatoprost is better. So choosing a better altlernative/substitute from the known alternative from the prior art to obtain the known results would not go beyond what may be normally expected from Ms.Psita. In this case Psita would adopt a conservative approach when choosing the combination to reduce IOP where the effect of change is not difficult to predict. Thus in a attempt to find the most appropriate alternative Ms Psita in the given circumstances is expected to pick the the alternative which has proven to be suitable for same use. Bimatoprost uncontested at the priority date of the impunged patent was better than other known Hypotensive lipids.Therfore, the choice of bimatoprost in claim 1 and 12 to replace of latanoprst in Diestelhorst is obvious use of a material generally available in the market and suitable for purpose.
93. The learned counsel for the respondent conteded that it would not have been predictable to replace Latanoprost with bimatoproprost in view of there difference in mechanism of action.We have Diestelhorst before us a successful combination of Timolol and Latnoprost. US ,819 and Cantor teaches Bimatoprost is better. Obviousness does not require absolute predictiblity of success. All that is required is a reasonable expectation of success. Even this argument of the respondent is insufficient to tip the scales of patentability where the invention as whole otherwise appeared obvious in view of teachings US,819, US‘581, Canter and Diestelhorst M. et al . As a result the claimed invention is therefor obvious .The revocation petition therefore succeed on this ground.
94. Mr. Praveen Anand the counsel for the respondent submitted that on 27th February 2013 Respondent No. 1 filed an amended set of claims for specified amount and preferred amount of the two components. The counsel submitted that said amendments were made by way of an explanation and disclaimer and do not enlarge the scope of the claims originally granted. The respondent relied on the later study by Chen (inventor) in 2008 for a particlualr amount of the two components to prove the claimed striking advantages such as reduced side effects. We have said in earlier order No.161/2003 that post filling evidence cannot be considered for obviousness analysis. We are not considering this evidence. Even otherwise, the evidence of non-obviousness in any case must match with the scope of the claims. We find the claims 1 and 20 as granted are not limited to the specific concentration of timolol component and bimatoprost component. Both the claims requires the presence of timolol component and bimatoprost component in an amount effective to reduce ocular hypertension (to the extent not specified) when applied to a hypertensive eye. Even this evidence will not change the position. We find this report and all other documents referred to in para ante are later to the priority date of the invention. We find them as not relavant in determining inventive step. Here we reiterate what we said in IPAB order No.161/2013 “According to our Act, the patent is revoked if the invention is obvious. So the secondary considerations cannot change that.” Therefore the secondary objective evidence is not relenvant in determining non obviousmness as per law. When we have found the claimed invention as obvious, we are not inclined to accept the amendments in claims at last stage of hearing. Moreover, the amended claims are beyond the scope of the claim as granted as no specific amount was claimed in granted compositions claims. Thus those amendment are not allowed under section 59.
95. In the end, the claimed invention is held to be obvious and ground of section 8 violation has been proved. The revocation application is allowed and the grant of Patent No.212695 is set aside. Miscellaneous Petitions 59 of 2011 (for grant of stay) the applicant was disposed of in view of hearing of the main revocation petition M.P. No.25 of 2012 is withdrawn, M.P. No.136 of 2012 (for (waiver of cost) is closed and M.P.Nos.63,64,129, 137 & 138 of 2012 and 14 of 2013 are allowed. No costs.
(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.)
