Dec 10, 2012 - patent was published in the Patent Office Journal on 4th March 2011 ... Chennai which in turn is represen
THE PATENTS ACT, 1970 (39 of 1970) as amended by
THE PATENTS (AMENDMENT) ACT, 2005 (15 of 2005) (with effect from 1-1-2005)
& THE PATENTS RULES, 2003 as amended by
THE PATENTS (AMENDMENT) RULES, 2006 (with effect from 5-5-2006) In the matter of Post Grant Opposition under The Section 25(2) of The Patents (Amendment) Act 2005 and The Patents Rules 55-A to 63 of The Patents Rules (Amendment) 2006 AND In the matter of Patent bearing the number as 246328 with the Application Number 402/CHENP/2004 filed on 27th February 2004 by SCHERING CORPORATION of Patent Department K-6-1, 1990, 2000 Galloping Hill Road, Kenilworth, New Jersy 07033-0530, USA, a US Corporation AND In the matter of Post-Grant Opposition Filed under Section 25(2) of the Patents Act (as amended) by M/s CIPLA LIMITED, Mumbai Central, MUMBAI -400008, an Indian Company
HEARING HELD ON 06th NOVEMBER 2012 In the presence of Agent for the Patentee
:
Mr. R. PARTHASARTHY of M/s Lakshmi Kumaran & Sridhran, Chennai
Agent for the Opponent
:
Mr. S.MAJUMDAR of M/s S.Majumdar & Co, Kolkata &
Assistant Controller of Patents & Designs :
Mr. T.V. MADHUSUDHAN
DECISION M/s Schering Corporation, Patent Department, K-6-1 1990, 2000 Galloping Hill Road, Kenilworth, New Jersy 07033-0530 USA, a US Corporation, hereinafter shall be referred as ‘Patentee’ throughout this decision have obtained patent right in India, with the patent number 246328, for their invention with the amended title as “An aerosol suspension formulation for inhalation” and the grant of patent was published in the Patent Office Journal on 4th March 2011 under the provisions of the Section 43(2) of the Patents (Amendment) Act 2005, hereinafter shall be referred as ‘Act’ throughout this decision. Patentee is represented by their Attorneys M/s Lakshmi Kumaran & Sridharan of Chennai which in turn is represented by Mr. Parthasarathy who shall be referred as ‘The agent for the Patentee’ throughout this decision. The patent number 246328 was provisionally, that is before grant, was identified with the number as 402/CHENP/2004 with a filing date in India as 27th February 2004 and with a priority date as 28th August 2001. Under the provisions of the Section 25(2) of the Act M/s Cipla Limited, Mumbai Central, Mumbai400008, an Indian Company, hereinafter shall be referred as ‘Opponent’ throughout this decision has filed a Post-Grant Opposition through their Attorneys, M/s S.Majumdar & Co of Kolkata and represented by Mr.S.Majumdar who hereinafter shall be referred as ‘The agent for the Opponent’ throughout this decision, on 19th January 2012 which is within the stipulated period of one year from the date of publication of grant of patent and therefore has been taken on record. Under the provisions of the Rule 56 of the Patents (Amendment) Rules 2006, which shall be referred as ‘Rules’ throughout this decision, an Opposition Board was constituted and the joint recommendations of the Opposition Board was submitted under the provisions of the Sub-rule (4) of the Rule 56 of the Rules. Upon completion of all the requisite formalities as prescribed in the Act and Rules the ‘Hearing’ was offered on the lines of the Rule 62 of the Rules and was held on 6th November 2012. Before proceeding further it is pertinent to reproduce the granted claims and the said granted claims are; 1. An aerosol suspension formulation for inhalation, comprising: an effective amount of mometasone furoate; an effective amount of formoterol; and 1,1,1,2,3,3,3heptaflouropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 micro gram of mometasone furoate to about 12 micro gram of formoterol fumarate to about 50 micro gram of mometasone furoate to about 6 micro gram of formoterol fumarate, wherein the formoterol fumarate flocculates with the mometasone furoate and wherein the formulation is substantially free of carrier. 2. The aerosol suspension formulation for inhalation as claimed in claim 1optionally comprising a surfactant. 3. The aerosol suspension formulation for inhalation as claimed in claim 1wherein the mometasone furoate is present in an amount of about 50 micro gram and the formoterol fumarate is present in an amount of about 6 micro gram. 4. The aerosol suspension formulation for inhalation as claimed in claim 1wherein the mometasone furoate is present in an amount of about 100 micro gram and the formoterol fumarate is present in an amount of about 6 micro gram. 5. The aerosol suspension formulation for inhalation as claimed in claim 1wherein the mometasone furoate is present in an amount of about 50 micro gram and the formoterol fumarate is present in an amount of about 8 micro gram. 6. The aerosol suspension formulation for inhalation as claimed in claim 1wherein the mometasone furoate is present in an amount of about 100 micro gram and the formoterol fumarate is present in an amount of about 8 micro gram. 7. The aerosol suspension formulation for inhalation as claimed in claim 1wherein the mometasone furoate is present in an amount of about 200 micro gram and the formoterol fumarate is present in an amount of about 12 micro gram.
8. The aerosol suspension formulation for inhalation as claimed in claim 1wherein the mometasone furoate is present in an amount of about 400 micro gram and the formoterol fumarate is present in an amount of about 12 micro gram. 9. A process for producing an aerosol suspension formulation for inhalation, said aerosol suspension formulation for inhalation comprising; an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3-heptaflouropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 micro gram of mometasone furoate to about 12 micro gram of formoterol fumarate to about 50 micro gram of mometasone furoate to about 6 micro gram of formoterol fumarate; wherein the formoterol fumarate is flocculated with the mometasone furoate in said aerosol suspension formulation and wherein the formulation is free of bulking agent, comprising the steps of; a) Mixing a dry powder blend of micronized mometasone furoate and formoterol fumarate with a dry powder surfactant to form a uniform mixture; b) Filling said mixture into a metered dose inhaler canister; c) Crimping said canister with a metering valve; and d) Filling said canister with a nonchlorofluorocarbon propellant. 10. The process as claimed in claim 9 wherein the dry powder surfactant is selected from the group consisting of lecithin, stearic acid, palmitic acid, magnesium stearate, magnesium palmitate and magnesium laureate. 11. An aerosol suspension formulation for inhalation, comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3heptaflouropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 micro gram of mometasone furoate to about 12 micro gram of formoterol fumarate to about 50 micro gram of mometasone furoate to about 6 micro gram of formoterol fumarate; wherein the formoterol fumarate flocculates with the mometasone furoate wherein the formulation is free of additional excipient. 12. An aerosol suspension formulation for inhalation, comprising: an effective amount of mometasone furoate; an effective amount of formoterol fumarate; and 1,1,1,2,3,3,3heptaflouropropane; wherein the ratio of mometasone furoate to formoterol fumarate is about 400 micro gram of mometasone furoate to about 12 micro gram of formoterol fumarate to about 50 micro gram of mometasone furoate to about 6 micro gram of formoterol fumarate; wherein the formoterol fumarate flocculates with the mometasone furoate wherein the formulation contains less than 0.1% of an epoxide degradation product of mometasone furoate. Under the provisions of the Section 25(2) of the Act the opposition can be filed on the prescribed grounds but on no other ground. The agent for the opponent has relied on the following grounds namely; a) Section 25(e): that the invention so far as claimed in any claim of the complete specification is obvious and clearly does not involve any inventive step having regard to the matter published as mentioned in clause (b) of the Section 25(2) or having regard to what was used in India before the priority date of the claim: b) Section 25(2)(f): that the subject of any claim of the complete specification is not an invention within the meaning of this Act or is not patentable under this Act: c) Section 25(2)(g): that the complete specification does not sufficiently and clearly describe the invention or the method by which it is to be performed: d) Section 25(2)(h): the patentee has failed to disclose to the Controller the information required by Section 8 or has furnished the information which in any material particular was false to his knowledge. Apart from the granted specification the agent for the Opponent has relied on the following documents namely; 1) Document – D1: A PCT Publication numbered as WO 2000/51591 [Application number: PCT/EP2000/01722] published on 8th September 2000 filed by Novartis for their invention titled as “Combinations of Formoterol and Mometasone Furoate for Asthma”, claiming the priority from GB application having the number 9904919.9 dated 1st March 2000.
2) Document – D2: A PCT Publication numbered as WO 2000/53187 [Application number PCT/SE2000/00417] published on 14th September 2000 filed by Astrazeneca for their invention titled New combination of Formoterol and Mometasone in a pharmaceutical composition for treating respiratory disorders such as Asthma, Rhinitis and COPD” claiming the priority from Sweden application having the number 9900833-6 dated 2nd March 2000. 3) Document – D3: A PCT Publication numbered as WO 1993/11747 [Application number PCT/US1992/10587] published on 24th June 1993 filed by Minnesota Mining and Manufacturing Company for their invention titled “Suspension Aerosol Formulations” claiming priority from three US applications having the numbers 07/809791; 07/810401; 07/878039 dated 18th December 1991, 18th December 1991 and 4th May 1992 respectively. 4) Document – D4: A PCT Application numbered as WO 1996/32151 [Application number PCT/US1996/05006] published on 17th October 1996filed by Glaxo Wellcome Inc for their invention titled “Metered dose Inhaler for Fluticasone Propionate” claiming priority from two US applications having the numbers 08/422111; 08/584859 dated 14th April 1995 and 5th January 1996 respectively wherein both are CIP applications. 5) Document – D5: A US patent numbered as US 6,238,647 B1 granted on 29th May 2001 which was granted to Glaxo Group Limited for their invention titled “Aerosol formulations containing salmeterol xinafoate an anticholinergic agent and tetrafluoroethane” 6) Document – D6: A US patent numbered as US 5,674,860granted on 7th October 1997 which was granted to Astra Aktiebolag for their invention titled “Combination of a Bronchodilator and a steroidal anti-inflamatory drug for the treatment of respiratory disorders”. 7) Document – D7: An Expert Affidavit by Dr.Amrita Bajaj who is at present an Adjunct Professor of Pharmaceutics and H.O.D. Department of Pharmaceutics, SVKM’s Dr Bhanuben Nanavati College of Pharmacy, Vile Parle, Mumbai, India. Document D7 further consists of additional exhibits other than the Documents D1 to D5, and the said Exhibits are; a) Exhibit-A: Photo copies of pages 1694 to 1712 of Remington’s Pharmaceutical Sciences, 18th edition, published by MACK Publishing Company in 1990 and edited by Alfonso R Gennaro related to the topic “Aerosols” b) Exhibit-B: US patent with the patent number 5474759 granted on 12th December 1995 to Schering Corporation for their invention titled “NON-CHLOROFLUROCARBON AEROSOL FORMULATIONS”. The Opponent has filed the Full Written Statement [FWS] on 19th September 2011 before the expiry of the stipulated 12 month period from the date of Grant Publication. After availing one month extension the agent for the Patentee has filed the Reply Statement and no evidences were filed along with the Reply Statement. Under the provisions of the Rule 59 the opponent is restricted to file Reply Evidence in reply strictly confined to matters in the patentee’s evidence. As no evidence has accompanied with reply statement the proceedings under the Rules deemed to have been completed. All the documents were sent to the constituted opposition board to submit its report and the said board had submitted its report on 20th Day of April 2012. With reference to the decision issued by Hon’able IPAB on 3rd August 2012 in the case of M.P.No. 16/2009, 36/2011, 64/2011, 65/2011, 21/2012 and 54/2012 in OA/4/2009/PT/CH; the agent for the Opponent had sought the copy of the report made by the opposition board and therefore the requested copy has been forwarded to both the Opponent and Patentee. I would like to analyze the arguments made against the Section 25(2)(h) during the hearing. The agent for the Opponent has stated that the Patentee has failed to upheld the constitutional validity of the Section 8 of the Act. The agent for the Opponent was referring to Form-3 as filed on 27th February 2004 wherein it is pointed to the disclosure made by the Patentee about
filing an US Application with the application number 10/229855 dated 28/08/2002 and in subsequent to annexure to Form-3 a reference was made to another US Application with the number 11/071078 dated 03/03/2005 and did not file further proceedings about these two applications to the Indian Patent Office which is against the mandatory requirement under the Section 8 of the Act. In support of this the agent for the Opponent has relied on FURTHER PUBLICATIONS THAT WERE FILED ON THE DATE OF HEARING. A publication from USPTO dated 3rd May 2005 was brought to the notice wherein it is stated that the US Application number 10/229855 was abandoned on the applicant’s failure to timely file a proper reply to the office letter mailed on 31 March 2005. Similarly the US Application numbered as 11/071078 was shown as abandoned through one more publication from USPTO dated 10th March 2010. The agent for the opponent submitted further publication from USPTO wherein it is shown about a continuous application filed on 8th December 2009 to 11/071078 filed on 3rd March 2005, now abandoned, which is a continuation of application number 10/229855, filed on 28th August 2002, now abandoned. A further publication from Espacenet was filed at the time of hearing and relied upon by the opponent to prove that there are 38 substantive applications for the family of WO 03020253 (A2) – 2003-03-13 and the date of priority for all the 38 applications is 28th August 2001 which is the Patentee’s application that was granted with the patent number 246328. The agent for the Opponent has stated that the Patentee has failed to update the foreign filing particulars and did not comply with the requirements of the Section 8(1) of the Act. The provisions of the Section 8(1) states that it is mandatory on the part of the applicant seeking the patent right shall file a statement setting out detailed particulars of such application(s) upto the date of grant. In the present instance the date of grant is 4th March 2011. The Patentee has not updated the information regarding the abandonment of two US Applications and filing the continuous applications. Therefore it was argued that the Patentee has failed to provide the details of prosecution that were happened before the date of grant of patent in India thus has not fulfilled the requirements of the Section 8(1) of the Act and on proving this ground beyond the doubt the patent shall be revoked. Now the dispute is whether to take the above publications which were filed on the date of hearing, for which the Patentee has no option to defend, being unprepared, at the time of hearing, on record so as to decide on the fate of the patent in dispute. The detailed procedure on conducting the Post-Grant opposition is clearly and in unambiguous terms laid in the Rules 55-A to 63. The proceedings as mentioned in Rules 57 to 59 provides the freedom to both the Opponent and Patentee from filing FWS to Reply Evidence wherein the patent office does not direct either the Opponent or Patentee on which citations to depend upon but controls the filings with respect to the prescribed time limits. The Rule 60 provides a further chance to either of the parties to file any further evidence, including publications, but this time with the prior approval of the Controller and such leave shall be prayed before the fixation of date of hearing. The sub rule 4 of the Rule 62 specifically provides further chance to either of the parties to file any publications [restricted evidential format] at least 5 days before the date of hearing by serving a copy to the other party. Here the Controller’s permission is not required. In the present instance the Opponent has relied on four publications which were filed on the date of hearing. The Opponent is well aware of the procedure as laid in the Rules and therefore the Opponent has stated that the Opponent has no objection if the Controller decides to give an opportunity to the Patentee to defend the case on the merits of the submitted publications. In support of his submission of the said publications which are need to be considered, the Opponent has relied on the decision issued by the Hon’able Supreme Court of India against the Civil Appeal number 2254 of 1994 that was decided on 28th January 1994 [Billa Jagan Mohan Reddy and Anr Vs Billa Sanjeeva Reddy and Ors]. The Opponent has relied on a portion of the decision which is reproduced as hereunder; “It is settled Law that, if the documents are found to be relevant to decide the real issue in the controversy and when the Court felt that interest of justice requires that the documents may be received, exercising the power under Order 41, Rule 27 CPC ……and consider their effect thereof. When such is the position, when the documents are sought to be produced in
the trial Court, before the arguments are completed, normally they may be received; an opportunity given to prove them and rebuttal if any and their relevance and effect may have , be considered in deciding the issues arose in the controversy.” Hence it was prayed to take the publications on record and if need be an opportunity to the Patentee may be given for rebuttal, if any, and revoke the grant of patent accordingly. The agent for the Patentee has submitted that the publications as filed during the time of hearing shall not be taken on record and the ground of opposition shall be dismissed for the reasons that the said action of the Opponent is against the well stipulated provisions as laid in the Rules 55-A to 63. It was further stated the Sub rule 4 of Rule 62 has clearly laid down on how to rely on the publications, if any, which have been missed out. Further it was argued that the said publications are in public domain spreading since 3rd May 2005 to 10th June 2010. Therefore it is for the reasons known to Opponent on why the Opponent chose to bring those documents to the notice of the Controller only on the date of hearing. This explains the malafide intention of the Opponent to confuse this forum. It was further stated with respect to the decision issued by the Hon’able Supreme Court of India that the Opponent has relied on a portion of the decision that suits him. It was prayed to understand the consequences on which such decision was issued. It was stated by the agent for the Patentee that in the said Supreme Court order it is clear that the documents which were submitted at the time of hearing were need to be obtained from the government authorities on whom there was no control. Hence those documents were not available to the party and hence they could not submit to the Court within the stipulated time and when they the procedure of hearing started taking place. Therefore the Court has decided accordingly. Whereas in the present instance the submitted publications were available and in public domain, therefore getting access to those documents by the Opponent, or even by any person, before the date of hearing is possible. The Patentee, in support of his argument has relied on the following portion of the same decision which is reproduced as herein; “It is clear from its bare reading that the parties or their counsel shall be required to produce all the documentary evidence in their possession or power which they intend to rely on to establish their right along with pleadings or before settlement of the issues. The Court is enjoined under Sub rule (2) to receive such documents provided they are accompanied by an accurate list thereof prepared in the prescribed form. If they are not in the party’s possession or custody, it shall be filed by the party along with an application to condone the delay in filling them. The explanation for delay is not as rigorous as one filed under Section 5 of the Limitation Act. These documents were not in the possession or custody of the appellant, but they have obtained certified copies from the revenue authorities and sought to be produced. It is undoubted that there is a delay in production of the said documents. But the trial Court had stated that the application was filed at the stage of arguments, seeking to produce those documents and sought to rely upon the documents.” It was further stated that the Patentee has not hidden any information in fulfilling the requirements. Abandonment of applications happened in natural manner for the fault of the Patentee and invention was processed for protection by filing continuous application under the provisions of the US Patent Law. Therefore the Patentee feels that the requirements under the Section 8(1) have been met. Therefore it was prayed that the publications as submitted by the Opponent on the date of hearing is illegal as the said publications were in public domain. In addition to that the Form7 that is notice of opposition was filed on 19th September 2011, the date which is beyond the date of availability of the latest date being 10th June 2010. The FWS does not contain any reference of these publications and the ground of opposition under Section 25(2)(h) does not rely on these publications. Therefore it has to be considered as deliberate tactic by the Opponent to divert the attention of the hearing Controller to suit their needs. Now the question before me is on whether taking the publications on record or not. When I look at the guidelines provided under the Rules 55-A to 63 it is very clear on how to proceed in a Post-Grant Opposition by the Opponent, Patentee and the Patent Office as well. Ample
opportunities are given to both the Opponent and the Patentee to rely on any number of documents and evidences, if any. Provisions of the Rules 60 and 62(4) define on what and how to rely on further evidences and publications which are ought to be filed in support of their cause. The entire action ceases from the 4th day prior to the date of hearing and is a closed end system. This sequential cessation of the actions does not permit either of the parties to submit any evidences either by way of publications or other kinds on the date of hearing. Even the plain understanding of the decision issued by the Hon’able Supreme Court of India indicates that the appellant shall not be punished for the actions on which he has no control. As rightly pointed out by the agent for the Patentee the said publications were in public domain even before filing the Post-Grant opposition. The negligence on the part of the Opponent can not become a basis to take the publications on record. As the Opponent could not give any admissible explanation on why he is submitting those publications at the time of hearing it has been decided not to take those documents on record and the present decision does not bear any effect on account of the presence of unrecorded documents in the file. Consequently the Patentee is not asked for providing the rebuttal arguments. The next ground on which the Opponent has relied on is the Section 25(2)(e) wherein the agent for the Opponent has stated that the present invention lacks inventive step and therefore the patent needs to be revoked. The agent for the Opponent has pointed out from the descriptive portion of the specification and from the claims as well that the alleged invention is towards an aerosol suspension formulation for inhalation, and the preparation of the same and that comprising an effective amount of mometasone furoate; an effective amount of formoterol; and 1,1,1,2,3,3,3-heptaflouropropane, a non-CFC propellant, which is also known as HFA 227, wherein the formoterol fumarate flocculates with the mometasone furoate and wherein the formulation is substantially free of carrier. In other words the said formulation absolutely does not contain any carrier. It was further stated that aim of the invention is towards elimination of the use of CFCs in producing the non-toxic formulations that still will be expressing improved stability and compatibility with the medicament and relatively easy to manufacture. Referring to D1 the Opponent has stated that the combination of mometasone furoate and formoterol fumarate is already known and is marketed under trade name “DULERA’. The Indian equivalent of the said application was granted a patent bearing number IN 202350, however it was revoked by the Indian Patent Office on the ground of obviousness/lacking an inventive step, among others. D1 further teaches that it has been surprisingly found that a significant unexpected therapeutic benefit in the treatment of inflammatory obstructive airways can be obtained by combination therapy using formoterol and mometasone furoate. D1 further teaches that the medicament can be administered as an atomizable composition, in solution or dispersion in a propellant, or a nebulizable composition. It further specifies that the inhalable form of the medicament may be an aerosol of both actives in solution or dispersion in a propellant. And the propellants for such use in the aerosol suspensions are chosen from propellants known in the art and preferably include HFA 134A and HFA 227 [1,1,1,2,3,3,3-heptafluoropropane] or mixtures of two or more such halogen substituted hydrocarbons. The suitable unit doses also have been taught by D1. It is disclosed that the dose of formoterol fumarate dihydrate may be from 1 to 72 micro gram, preferably from 1 to 60 micro gram, generally from 3 to 48 micro gram, preferably from 6 to 36 micro gram, especially from 12 to 24 micro gram. A suitable unit dose of mometasone furoate may be from 25 micro gram to 2000 micro gram, for example from 50 micro gram to 1000 micro gram, preferably from 500 micro gram to 800 micro gram, more preferably from 100 micro gram to 500 micro gram, especially from 100 to 400 micro gram, e.g. from 200 to 400 micro gram. D1 further teaches for on demand usage, a dosage unit containing 6 micro gram or 12 micro gram of formoterol and 50 micro gram or 100 micro gram of mometasone furoate is preferred. Therefore it was stated that in view of disclosure of D1that the non-CFC propellants such as HFA 227 and HFA 134a were known to be used in aerosol formulations, in particular formulations containing mometasone furoate and formoterol fumarate with specific doses. D1 also mentions that the aerosol composition may also contain a co-solvent such as ethanol thus making ethanol as an optional component.
The agent for the Opponent has submitted a publication related to “DULERA” wherein the said publication discloses the i) Indications and usage, ii) Dosage and administration, iii) Dosage forms and strengths, iv) Contradictions and v) warnings and precautions with respect to “DULERA”, a traded commodity. According to this document Dulera is a pressurized metered dose inhaler [MDI] that is available in 2 strengths. I) DULERA 100mcg/5 mcg delivers 100 mcg of mometasone furoate and 5 mcg of formoterol fumarate dihydrate per actuation and ii) DULERA 200mcg/5 mcg delivers 200 mcg of mometasone furoate and 5 mcg formoterol fumarate dihydrate per actuation. Further it discloses that DULERA should be used be primed before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray. Under the caption ‘Dosing’ and in Table 1 the maximum recommended daily dose is 400 mcg/20 mcg when previous therapy is related to inhaling of medium dose corticosteroids and 800 mcg/20 mcg when previous therapy is related to inhaling of high dose corticosteroids. Under paragraph 11 of Dulera publication it was stated that “Each Dulera 100 mcg/5 mcg and 200mcg/5 mcg is a hydrofluoroalkane (HFA 227) propelled pressurized metered dose inhaler containing sufficient amount of drug for 60 or 120 inhalations [see How supplied/Storage and Handling (16)]. After priming, each actuation of the inhaler delivers 115 or 225 mcg of mometasone furoate and 5.5 mcg of formoterol fumarate dihydrate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and the inspiration through the delivery system. DULERA also contains anhydrous alcohol as a cosolvent and oleic acid as a surfactant. Hence it was argued that the combination therapy along with the dosages as disclosed in the present invention is known before the date of priority and no inventive step can be acknowledged with respect to the combination of two actives and dosages that need to be fixed. The patent in dispute is silent on the disadvantages of having a carrier or advantages on not having the carrier hence the presence of inventive step cannot be acknowledged. Referring to the cited document D2 the agent for the Opponent has stated that D2 teaches the combination of formoterol and mometasone in a pharmaceutical composition for treating respiratory disorders such as asthma, rhinitis and COPD. D2 further teaches the use of actives in micronized form either dissolved or preferably suspended in a liquid propellant mixture, where the preferred P134a (tetrafluroethane) and P227 (heptafluoropropane) each of which may be used alone or in combination. D2 further teaches the use of one or more surfactants and or one or more excipients, for example ethanol, a lubricant, an antioxidant and or stabilizing agent. Comparing the examples 7 and 8 of D2 with that example 3 of the impugned specification exemplifying formulations containing varying amounts of excipients clearly disclose the use of ethanol, wherein the content of the same varies 1.5 to 2.437 w/w%. Thus based on the impugned specification, formulations substantially free of a carrier can be construed to obtain about 1.5 to 2.437 w/w% of ethanol as the phrase “substantially free of carrier” has not been defined in the specification. Thus, it is stated that the aerosol suspension formulation of mometasone and formoterol containing a non-CFC propellant and being free of a co-solvent is clearly taught by D2. It was pointed out that D3 refers to the use of HFA134a (1,1,1,2-tetrafluoroethane) HFA 227 (1,1,1,2,3,3,3- heptafluoropropane) in lieu of the CFC propellants due to their low toxicity and vapor pressures which render them suitable for use in aerosols. D3 further teaches that the propellant density should be matched to the drug density in order to avoid creaming or settling of the drug. Though D3 does not specifically mention mometasone in the preferred list of drugs but beclomethasone has been mentioned to which group mometasone belongs to. D3 also discloses the use of ethanol and surfactants. D3 also teaches the relation drug density and propellant density so as to reduce the possibilities of the drug to settle or cream. It was further argued with reference to D4 that the said D4 teaches the formulation comprising fluticasone propionate separately or in combination with other active agents interalia respiratory drugs and optionally containing one or more excipients and a fluorocarbon propellant. D4 further asserts that the drug formulations may be free or
substantially free of formulation excipients e.g. surfactants and co-solvents etc. The preferred propellants in D4 are HFA 134a and HFA 227 and the examples of 18-22 of D4 exemplify formulations of fluticasone with only one propellant, namely HFA 227. With reference to D5 the agent for the Opponent has stated that D5 pertains to aerosol formulation for the administration of medicaments by inhalation. It particularly pertains to a formulation comprising particulate salbutamol and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, which formulation is substantially free from surfactant. D5 at column 1 teaches that the most commonly used aerosol propellants for medicaments being propellant 11 CCl3F and or propellant 114 (CF2ClCF2Cl) with propellant 12 (CCl2F2) were found to deplete the stratospheric ozone thus non-CFC propellants were used, with HFA 134a and HFA 227 being the preferred ones. Combination of medicaments is also taught in D5 as evident from lines 10 to 14 at column 4. Column 4, lines 21 to 30 clearly teach that the formulations form weakly flocculated suspensions on standing but, surprisingly, these suspensions have been found to be easily redispersed by mild agitation to provide suspensions with excellent delivery characteristics suitable for use in pressurized inhalers, even after prolonged storage. It further teaches that minimizing and preferably avoiding the use of formulation excipients e.g. surfactants, co-solvents etc in the aerosol formulations has the advantages of being substantially taste and odour free, less irritant and less toxic than convention formulations. It is stated that examples 13 to 16 at column 8 exemplify formulations which contain medicaments viz. salmeterol, salbutamol, beclomethasone and fluticasone along with HFA 227 as propellant. It was argued that by the combined teachings of D1 to D5 the alleged invention of the impugned specification is obvious because formoterol fumarate and mometasone furoate are known compounds and their combination therapy for the lung disorders is known and use of non-CFCs along with their benefits in the preparation of such formulations are known. Prior art clearly teaches the preparations of such formulations either with substantially free of surfactants and or excipients, therefore the alleged invention is obvious and does not require any inventive ingenuity. Referring to lines 50 to 60 of D6 which states “ For administration, the combination is suitably inhaled from a nebulizer, from pressurized metered dose inhaler or as a dry powder from a dry powder inhaler (e.g. as sold under the trade mark Turbuhaler) or from a dry powder inhaler utilizing gelatin, plastic or other capsules, cartridges or blister packs. A diluent or carrier, generally non-toxic and chemically inert to the medicament e.g. lactose, dextran, mannitol or glucose or any additives that will give the medicament a desired taste, can be added to the powdered medicament” …. The aim of D6 is the aim of the Patentee in the selection of non-toxic and chemically inert substance for the performance of the alleged invention. Therefore it is general common knowledge which has been adopted by the Patentee, in other words the problem and solution are obvious and no ingenuity is required to arrive at the Patentee’s invention. Having proven thus it was prayed to revoke the patent. With respect to Exhibit-B of D7 the agent for the Opponent has drawn the attention to the lines 15 to 20 of column 1 of the said Exhibit-B which is reproduced as herein. “The present invention is directed at aerosol formulations which are substantially free of chlorofluorocarbons (CFCs). More specifically, the present invention is directed at formulations substantially free of CFCs and having particular utility in medicinal applications, especially in metered dose pressurized inhalers (MDI’s).” The agent for the Opponent has stated this particular paragraph is the opening paragraph of the present patent which is reproduced as herein. “The present invention is directed to aerosol suspension formulations which are free of chlorofluorocarbons (CFCs). More specifically, the present invention is directed at formulations substantially free of CFCs and having particular utility in medicinal applications, especially in metered dose pressurized inhalers (MDI’s).” Therefore it was stated that aim of both the inventions are the same but the arguments by the Patentee are differing and deviating from the aim of the invention. Further it is referred to lines 16 to 21 of column 2 of Exhibit-B wherein it is stated thus, “Moreover, where the medicament is to be delivered as a solution, the medicament may not be readily soluble in this propellant. The polarity difference between HFA 227 and the previously used CFC
propellants may result in a different delivery of the medicament when HFC 227 replaces a CFC propellant. The medicament may cream, settle or agglomerate in the non-CFC propellant even though this did not occur in the CFC propellant.” Therefore it was argued that the flocculation as projected by the Patentee is the inherent character of using a non-CFC propellant like HFC 227. Hence the flocculation between mometasone furoate and formoterol fumarate is not an inventive idea over this disclosure which was known at least from 1995 onwards. Attention was drawn to lines 59 to 65 of column 6 of the Exhibit-B which states that, “Suitable suspensions may be screened in part by observing several physical properties of the formulation, i.e. the rate of particle agglomeration, the size of the agglomerates and the rate of particulate creaming /settling and comparing these to an acceptable standard. Suitable solutions may be screened by observing the solubility of the medicament over the entire recommended storage temperature range.” And referring to examples 9 to 12 of the Exhibit-B it was shown that in the claimed examples mometasone furoate and HFA 227 are taken in the effective amounts with an optional addition of excipients, surfactants and additives. The claimed examples 10 to 12 show that the excipient need not be present. Therefore it was argued that now to mometasone furoate, a known drug active that formoterol fumarate is to be added and dosage can be made by the person skilled in the art. Therefore it was argued that the Exhibit-B clearly destroys the inventive step of the alleged invention. Having proved thus it was prayed to revoke the patent. Though the agent for the Opponent has filed one more publication from USPTO at the time of hearing i.e. US Patent bearing the number 6068832 granted on 30th May 2000 to Schering Corporation has been taken on record as no objection was raised by the Patentee probably because the Patentee is one and the same for the 832 patent and the present patent which is in dispute. In addition the Patentee had countered the arguments of the Opponent on this document also. Hence it has been decided to consider the arguments put forward based on this 832 patent for the conclusion of this decision. Comparing line 3 onwards in page 14 of the present specification versus summary of the invention as present in column 2 of 832 patent it was stated that the Patentee had already disclosed about the selection and use of ethanol in the preparation of aerosol suspension formulations. Further uses of about 1% ethanol and advantages have been disclosed in 832 patent. The summary of the invention of 832 patent reads thus, “In accordance with the invention, there is provided a particle size-stable pressurized aerosol suspension formulation of mometasone furoate comprising the propellant HFC 227 about 1 to about 10 weight percent ethanol and mometasone furoate in concentrations at least about 1 percent of the ethanol concentration. The formulation can also contain a surfactant. It has been discovered that the formulation of the invention does not exhibit significant particle size changes in the suspended drug. In addition, the densities of the solid and liquid phases are similar, giving a suspension which has a reduced tendency for particle settling; this results in a greatly facilitated rediespersion into a uniform suspension, after the formulation has remained in an undisturbed condition for prolonged periods.” On page 14 of the present patent it is disclosed that “A certain minimum level of ethanol is preferred to provide consistent and predictable delivery of the drug from a metered dose dispenser. The minimum level is about 1 weight percent of the total formulation which results in a marginally acceptable drug delivery. Increased amounts of ethanol generally improve drug delivery characteristics. However to prevent drug crystal growth in the formulation, it is preferred to limit the concentration of ethanol.” Attention was drawn to lines 53 to 61of 832 patent which states that “\in general, drug particle sizes from about 1 to about 5 micrometers are preferred for administration to the lower airway, which particles are smaller than about 0.5 micrometers frequently being exhaled without complete deposition on tissues, while particles larger than about 10 micrometers can exhibit considerable deposition in the mouth and or pharynx and therefore not reach the lower airway. Very large particles cannot pass through a metering valve and will not be reliably dispensed.” Comparing this statement with the disclosure in page 17 of the present patent the agent for the Opponent has stated that the prior art teaches the selection of the particle sizes and effects of the larger particles sizes on the efficacy. The opening
paragraph of page 17 of the present patent reads thus, “In formulations of the present invention which are suitable for treating lower respiratory system disorders such as asthma, at least a substantial portion of the drug is present as suspended particles having respirable sizes e.g. about 0.5 to about 10 micrometers in their largest dimension. In formulations which are suitable for treating upper respiratory system disorders such as rhinitis, some what larger drug particles may be permissible, but the foregoing size range remains preferred. Where the active compound forms a suspension, the particle size should be relatively uniform, with substantially all the particles preferably ranging between about 0.1 to 25 microns, preferably 0.5 to microns, more preferably 1-5 microns. Particles larger than 25 microns may be held up in the oropharyngeal cavity, while particles smaller than about 0.5 micron preferably are not utilized, since they would be more likely to be exhaled and therefore not reach the lungs of the patient.” Therefore it was argued that the floccules and their sizes shall fall within the respirable range as known to the person skilled in the art. The next comparison was made with Formulation C in column 6 of 832 patent with that of Example 3 in page 21 of the present patent. The formulation C of 832 patent is reproduced as herein; Formulation-C of 832 patent HFC 227…………………. 97.336 Ethanol…………………… 2.497 Mometasone furoate…….. 0.127 Oleic Acid………………. 0.011 Mometasone furoate/Ethanol=0.0508 Example – 3 of the present patent Formulation Mometasone Prototype Furoate (Drug:Drug) (%) Ratio A 0.112 (100microg:8microg) B 0.056 (50microg : 6microg) C 0.112 (100microg:8microg) D 0.224 (200microg:12microg) E 0.112 (100microg:8microg) F 0.056 (50microg:6microg) G 0.056 (50microg:6microg) H 0.056 (50microg:6microg) I 0.056 (50microg:6microg) J 0.056 (50microg:6microg) K 0.056 (50microg:6microg) L 0.224 (200microg:12microg) M 0.224
Formoterol Fumarate (%)
Oleic Acid (%)
Ethanol (%)
HFA-227 (%)
0.009
0.001
2.378
97.5
0.007
0
2.437
97.5
0.009
0.011
20368
97.5
0.014
0.011
2.251
97.5
0.009
0
2.379
97.5
0.007
0.001
2.436
97.5
0.007
0.011
2.426
97.5
0.007
0.011
1.500
98.426
0.007
0.011
1.750
98.176
0.007
0
1.500
98.437
0.007
0
1.750
98.187
0.014
0.011
1.500
98.251
0.014
0.011
1.750
98.001
(200microg:12microg) N (200microg:12microg) O (200microg:12microg)
0.224
0.014
0
1.500
98.262
0.224
0.014
0
1.750
98.012
It was argued by the agent for the Opponent that Formulation C is almost similar to the formulation Prototype C and D of Example 3 of the present patent. Also it was argued that the Drug:Drug ratio of Example-3 is never more than 0.5% which is the teaching of D3. Hence it was prayed that Formulations as disclosed in the present patent are not inventive in nature. Explaining further on the effects of temperatures on the aerosol formulations attention is drawn to the lines 31 to 39 at column 6 of 832 patent which states that, “The containers with formulations B,C and D are subjected to a freeze/thaw temperature program, as follows:-20 degree C for 3 days, then room temperature for one day, then 50 degree C for 2 days, then 20 degree C for 4 days, then 50 degree C for 3 days, then -20 degree C for 3 days, then 50 degree C for 3 days and finally room temperature for 1 day. Upon repeating the microscopic examination, no temperature excursion induced changes in particle form or size are observed in any of these formulations.” Hence it was stated that temperature has no significance on the particle form or size of the aerosol formulations. Only formoterol fumarate is to be added to this formulation and since 832 does not teach about the presence of carrier, the dosages can be formulated by a person skilled in the art because the respirable particle sizes are known and upon simple agitation is sufficient if at all need be to obtain uniformity of the formulation. Therefore it was prayed that the alleged invention does not show any technical advancement or any economical significance. On failing to meet the requirements of the Section 2(1)(ja) of the Act the granted patent needs to be revoked.
Denying the above arguments the agent for the Patentee has argued against the cited documents that are filed by the Opponent. It was stated by the Patentee that D1 uses Formoterol fumarate (hereinafter FF) and Mometasone Furoate (hereinafter MF) with HFA 227 AND HFA 134a with ethanol of 2.5% by weight but without lactose. Thus such a formulation essentially uses mixture of two propellants i.e HFA 227 and HFA 134a whereas in the present invention only HFA 227 is used. Furthermore all other examples of D1 use MF and FF along with lactose and hence, D1 does not appreciate an aerosol formulation of MF and FF with HFA 227 with no or substantially free of carrier such as lactose or bulking agents. With respect to the publication as submitted by the Opponent on “DULERA” the agent for the Patentee has stated that this publication no way can destroy the inventive step of the invention of the Patentee because the said publication is a revised print done in the year 2012 which is beyond the date of grant of the patent. The inventive step shall be assessed on the date of priority but not on any later date. Hence the DULERA document is not a relevant document and need not be considered. Regarding D2 it was argued that D2 while disclosing the combination dosage of the two active ingredients fails to disclose that the said two ingredients are flocculated with each other. D2 on page 5 line 27-29 discloses that “ a diliuent or carrier, generally being non-toxic and chemically inert to medicament e.g. lactose, dextran, mannitol or glucose or any additives…..can be added to the powdered medicament….” Thus teaching is, in fact, contrary to what has been claimed in the patent which says that formulation is to be free of a carrier, like lactose taught to be added in D2 and not excluded. Example 7 of D2 uses HFA 134a and Example 8 of D2 uses HFA 227 along with HFA 134a, whereas in the claims of the patent only HFA 227 is used. Therefore D2 does not disclose a formulation with MF,FF, both actives flocculated in claimed amounts, HFA 227 and substantially free of a carrier or bulking agent as claimed in the claims of the patent. It was further stated that the teachings of D1 and D2 together do not motivate a person skilled in the art to arrive at the teachings of the present invention. D1 and D2 failed to
appreciate the importance of using HFA 227 alone. It is submitted that MF is not very compatible with HFA 134a for the formulations of the type addressed in the patent. Also, the density of HFA 134a is less than HFA 227. In order to overcome these issues HFA 227 alone was used to promote an aerosol suspension formulation for inhalation as presently claimed. This became all the more important when MF was predominantly more in amount in the combination of the actives. Hence the inventive step is acknowledged over the combined teachings of D1 and D2. Denying the contents of D3 as inventive step destroying document of the present patent the Patentee has argued that D3 discloses FF but fails to disclose combination of FF with MF. The Opponent’s statement that MF is part of the same group as beclomethasone is a farfetched argument. Furthermore D3 is completely silent on carriers. D3 also does not appreciate the importance of a formulation that contains less than 0.1% of an epoxide degradation product of MF. Arguing that the contents of D4 are irrelevant it was stated that the solution offered in D4 is to overcome the problem of drug adhering to the inner surface of wall of can. Thus the problem addressed in D4 is distinct from the problem addressed in the present patent. D4 fails to disclose that a drug combination of MF and FF is used in aerosol suspension along with propellant HFA 227alone so as to achieve flocculation between MF and FF. D4 also does not address carriers at all. There is no clear teaching as to the fact that the formulations in D4 are substantially free of carriers / bulking agent. D4 also does not talk about a formulation that contains less than 0.1% of an epoxide degradation product of MF. It was stated that none of the documents D1 to D4 teaches the importance of using HFA 227 over HFA 134a. Not agreeing to the understanding of the Opponent on the disclosure of D5 that D5 provides a clear indication to a person skilled in the art to prepare aerosol formulation without the excipients or being substantially free of excipient, it was submitted that there is no specific teaching about combined drug use of MF and FF in the specified amounts in the presence of single propellant such as HFA 227. D5 also does not disclose formulations substantially free of carriers such as lactose or bulking agent. D5 also does not talk about a formulation that contains less than 0.1% of an epoxide degradation product of MF. With reference to the outline of the invention as provided from line 29 onwards in column 2 of D6 which states that “The present invention is based on the concept of a novel combination therapy whereby formoterol (and/or a physiologically acceptable salt and/or solvate thereof) and budesonide are administered simultaneously, sequentially or separately by inhalation”….it was argued that budesonide are not similar and therefore not interchangeable. Further D6 is silent on the presence or absence of carriers. It was concluded with respect to the documents D1 to D6 that the invention must be judged under the provisions of the Section 2(1)(ja) of the Act based what “would have been” obvious at the date of priority and not what “is” obvious today. Therefore it was prayed that the invention is not obvious on the date of priority and hence opposition shall be dismissed. The agent for the Patentee on rebutting the understanding of the Opponent on use of ethanol has referred to the same page 14 of the specification against the disclosure in 832 patent wherein it is continued in the specification of the present patent thus “Experimental data indicate that the ratio of the weight of MF to the weight of ethanol is important in preventing particle size increases. The active ingredients may be put into the containers housing the formulation as follows: the container that houses the medication can be filled with medicine, ethanol and a surfactant in single or multiple steps, preferably in a single step. Similarly, the propellant or mixture or mixture of propellants may be added to the container in the same or multiple steps. The suspensions of the formulations of the present invention contain floccules of the ingredients. A floccule is as aggregation of particles that form a lattice type of structure that resists complete settling. The loose structure of the lattice permits the aggregates to break up easily and distribute readily with a small amount of agitation. More specifically when mometasone is suspended in a propellant, over time the particles of mometasone will tend to flocculate in the center of the suspension. These
particles readily disperse upon agitation or shaking of the metered dose inhaler canister. Surprisingly the addition of formoterol to the suspension did not alter this phenomenon. When the propellant is HFA 227 the formoterol fumarate and MF form floccules in suspension such that the MF and FF are aggregated with each other. When the propellant is HFA 134a the presence of a bulking agent or carrier such as lactose in an amount of about 0.05% to about 0.3% by weights preferred to enhance drug delivery upon actuation of the inhaler. With 134a based formulations, the formoterol, mometasone and lactose have a tendency to sediment to the bottom of the canister because HFA 134a is less dense than HFA 227; thus shaking of the canister to reform the suspension prior to actuation of the meter is preferred for uniform drug delivery. Hence HFA 134a has not been included in claims. Other bulking agents that may be used in HFA 134a suspensions include. For example, mannitol, glucose, sucrose and trehalose.” With respect to the comparison of Formulation C with that of example 3 of the present patent it was argued that Oleic acid is used as surfactant, Ethanol is used as excipient [ETHANOL IS NOT A CARRIER], and HFA-227 is a propellant. The Formulation prototypes B,E, J.K.N and O of example substantially do not contain Oleic Acid at all. The remaining prototypes contain less than 0.011% of oleic acid and therefore all the examples are substantially free of carrier. In the given prototypes of Example-3 the ethanol is used as excipient but not to be construed as carrier. The undersigned has sought the clarification from the agent for the Patentee whether 832 patent teaches the use of any Carrier? The answer provided by the Opponent is that the formulation C of 832 patent does not teach the use of carrier but the claim 1 of 832 patent teaches the use of a carrier because of the word “comprising” is present in the said claim. The claim 1 of 832 patent reads thus: “An aerosol suspension formulation comprising 1,1,1,2,3,3,3-heptafluoropropane about 1 to about 10 weight percent ethanol and micronized mometasone furoate in concentrations at least about 1 percent of the ethanol concentration, the formulation optionally also containing a surfactant.” On the next ground of opposition under the provisions of the Section 25(1)(g) of the Act the agent for the Opponent has stated that the alleged invention is not sufficiently and clearly described by the disclosure in the impugned specification. It is because the specification does not define “substantially free of a carrier” either in the description or in the claims. It was argued that the carrier and or bulking agent has been defined as an inert substance in/on which the active ingredient and excipients are dispersed. However in the response to the First Examination Report [FER] the Patentee has clearly stated that ethanol is the carrier in the present invention and the formulation uses minimal amount of the same which amounts to the formulation being substantially free of a carrier. There are examples in the specification namely example 3 which manifestly outs forth that the amount of ethanol used in the formulation ranges from 1.5 to 20437% w/w. There are no examples in the specification which exemplifies the advantages of using said amount /absence of any amount of ethanol with respect to the improvement in solubility, stability, particle size distribution and so on. Thus the Patentee’s assertions that the formulations of the impugned patent provides desired solubility, stability, low toxicity, exact dosage are completely baseless and unsubstantiated. It is further stated that if the claim is restricted to the use of HFA 227 propellant then the examples ought to have been comparing containing a single propellant whereas the examples as provided in the patent comprises both the propellants viz., HFA 227 & HFA 134a. It was further argued that the impugned patent teaches that the formulations according to the invention are excipient and or surfactant free and no example supports this statement. Further example 8 fails to substantiate the effect of the formulation which the Patentee has claimed in claim 12. Therefore it was prayed that the Patentee has failed to sufficiently and clearly describe the invention and the patent be revoked on this ground.
Denying the arguments made by the Opponent, the agent for the Patentee has stated that the present patent is sufficiently described and enabled so as to enable a skilled person in the art to work the invention. In fact, the best mode of working the invention is also described in various examples stated in the description along with the drawings. It was argued that the term “substantially free of carrier” does not require any specific definition as the skilled person would know what ‘carrier’ means and what ‘substantially free’ means. It was argued that the opponent has stated that “based on impugned specification, formulations substantially free of carrier can be construed to contain about 1.5 to 2.437 w/w% of ethanol….” and argues that “substantially free of carrier” is obvious. It was argued that this statement of Opponent is in contradiction which ought to be rejected in limine. It was stated that ethanol which is used in the present formulation is used as an excipient but not as carrier. The minimum level of ethanol is about 1% of the total formulation which results in a marginally acceptable drug delivery. The next ground of Opposition relied by the agent for the Opponent is that the invention is not an invention or not patentable under the provisions of the Section 25(2)(f) of the Act. The Opponent has stated that the present invention does not satisfy the requirements of the Section 2(1)(ja) of the Act wherein the said Section provides the definition of “Inventive Step”. The arguments are as same as the arguments made under the provisions of the Section 25(2)(e). Hence for the sake of brevity the arguments are not repeated. Not much was discussed over the expert affidavit. In the said affidavit the expert has opined that the expert agrees with the statements made by the Opponent. Expert has opined that it is obvious to replace CFCs with non-CFCs in the formulations when it is known fact that CFCs have adverse effects on the depletion of ozone layer. It was inferred by the expert on plain reading of the present patent that the specification has not defined the phrase “substantially free of carrier” which can be construed that the formulations of the invention does not contain any significant amount of carrier, which seems to be ethanol in the present case. It was also stated that the formulations of the invention are free of excipients as understood from the specification and various examples provided different ingredients and therefore the invention is ambiguous and equivocal. Further the examples refer to the presence of surfactants, if so the formulations can not be excipient free. It was opined that aerosols are known for the treatment of asthma and like diseases wherein the propellants are used to provide the energy necessary to generate a fine aerosol of drug particles suitable for delivery to the lungs. CFCs are approved propellants also HFA 227 and HFA 134a are known nonCFC and commonly used propellants. Hence replacing the known CFCs with known nonCFCs does not require any inventive ingenuity. The agent for the Patentee has not agreed to the opinion as expressed in the affidavit filed by the expert by pointing towards the paragraph 9 of the said evidence wherein the expert says “the formulation does not contain any significant amount of carrier, which seems to be ethanol in the present case…” and argued that the expert had thought that ethanol appears to be carrier in the present case which is untrue. Further it was stated by the Patentee that in paragraph 10 of the said affidavit the expert had concluded that the Patentee’s stand on the invetive step residing in the formulation being excipient free is ambiguous and equivocal, which is untrue because the present invention is related to carrier free formulations but not excipient free formulations. Similarly the expert on the wrong understanding of the invention has stated in the last line of paragraph 10 of the affidavit wherein the percentages as mentioned of ethanol of the inventive formulations as disclosed in the present patent with the phrase “substantially free of a carrier” and hence the expert has concluded that the disclosure is ambiguous and equivocal. It is stressed that ethanol is not the carrier in the present inventive aerosol suspension formulations and hence expert’s opinion is void. Against the understanding of the expert that all the representative examples of the patent mention presence of a surfactant in the formulations, and therefore the formulations claimed cannot be said to be excipient free it was argued by the Patentee that ethanol is the excipient
and Oleic Acid is the surfactant in the present formulations. The expert’s allegation on that all the examples contain surfactant is untrue because with reference to Example 3 [Table as shown before in this decision] wherein Formulation Prototypes [Drug:Drug] B,E,J,K,N and O; of the examples 3,4 and 5 of the specification refers to nil representation of oleic acid which is a surfactant. Therefore it was prayed that the expert evidence is defective in nature and shall not be taken on record or shall not be considered as a destructive evidence for revoking the present patent.
Now let me discuss what the Opposition Board has recommended. With respect to Section 25(2)(e) the following is the reproduction of the recommendation as provided in the report made by the Opposition Board. “It is understood from the chronological order of the cited documents that the problem prior to the present invention is aerosol formulation to be made without additional components which also directs a skilled person towards D3 which achieved the desired stability using HFC 227 as the only propellant without need of any additional components. The closest prior art for the present invention is D5 in which a desirable stability of aerosol formulation having excellent delivery characters suitable for an inhaler (column 4 para 3 and 4) has been achieved by using either surfactant or co-solvent preferably without surfactant. Cited documents D3 teaches the properties of an aerosol formulation comprising a drug and HFC 27 which exhibits substantially no growth in particle size or change in crystal morphology of the drug over a prolonged period is substantially readily redispersible and upon redispersion does not flocculate so quickly as to prevent reproducible dosing of the drug (para 3 last para and claim 1) as well as discloses formulation obtained without the need for additional component (page 5 para 5). A skilled person starting from D5 facing a problem of stability of drug combination (D1 or D2) would try without co-solvent and only HFC 227 (D3). Hence with such problem of stability of combination drugs (D1 or D2), a skilled person would have arrived at the present invention by combining D5 with D3 in which no co-solvent is used which is considered as carrier free by the patentee. In view of the above the subject matter of claims 1-8 is obvious and does not involve in inventive step. Claim 11 relates to an aerosol suspension formulation for inhalation wherein the formulation is free of additional excipients. A skilled person would have arrived at such a formulation by combining D5 with D3 and D1 or D2 as D3 clearly indicates about ‘formulation obtained without the need for additional component (page 5 para 5)’, hence claim 11 is not inventive. Claim 12 relates an aerosol formulation which has no distinct feature other than what is claimed in claim except the formulation contains less than 0.1% of as epoxide degradation products. What is only a result of claim 1 where HFA 227 alone is used as propellant. Hence it would not be inventive. Claim 9 relates to a process for producing an aerosol formulation comprising a step of mixing dry powder components with a dry powder surfactant to form a uniform mixture which is not taught by any of the documents submitted by the opponent. It would not be obvious to the person skilled in the art to use dry powder surfactant to form a uniform mixture. Hence it would be inventive.” With respect to Section 25(2)(f) the following is the reproduction of the recommendation as provided in the report made by the Opposition Board. “It is opined that the claimed subject matter pertains aerosol suspension formulation used in MDI. The process for preparation as disclosed indicates that it is not a mere admixture of the components present in the formulation. Hence it does not fall under the mischief of Section 3(e).”
With respect to Section 25(2)(g) the following is the reproduction of the recommendation as provided in the report made by the Opposition Board. “The opposition board opined that the specification is not sufficiently disclose the invention as i) the comparative data provided in examples 6 and 7 is not fair as a low bulked formulation containing HFA 134a has been compared with “NO” bulked formulation containing HFA 227 to demonstrate the effect of carrier on alleged advantages as stated in the specification, ii) No support is found for the claimed features like ‘free of excipients’, iii) The role of dry powder surfactant used in the formulation is not substantiated, iv) According to the description, subject matter relates to a MDI, contradicting to that the claims relates to a subject matter of aerosol suspension formulation.” With respect to Section 25(2)(h) the following is the reproduction of the recommendation as provided in the report made by the Opposition Board. “Patentee has submitted all foreign filing particulars of the same application up to the date of grant in India under Section 8.” The following is the reproduction of the overall recommendation of the Opposition Board. “Based on the arguments of the patentee and the opponent, it is hereby concluded that the opposition under section 25 (2) (e) and 25(2)(g) can be considered as valid grounds for opposition. The opposition under section 25(2)(f) and 25(2)(h) cannot be considered as valid grounds of opposition. After examining the documents filed by the opponent and patentee u/r 57 to 60 this board of opposition is jointly recommending for “revocation” of the granted patent number 246328.” Let me try to analyze the invention with respect to the granted specification and the scope of the claims as grated thereon. The renumberd page 3 of the granted specification explains the problem to be solved. The following paragraph is the reproduction from page 3 and 4 of the granted specification. “In the 1970’s certain steps were taken to reduce the CFC emission from aerosols. Other propellants, such as hydrocarbons, were used, or the product was delivered in a different manner. Because CFC usage in medicinal applications is relatively low, i.e. less than 1% of total CFC emissions and because of the health benefits associated with metered dose inhalers steps were not taken at that time to restrict the use of CFC propellants in metered dose inhalers. However, continuing and more sophisticated ozone measurements have indicated that earlier restrictions in CFC usage were insufficient and that additional, significant steps should be taken to drastically reduce CFC emissions. Recommendations have been made that CFC production be virtually discontinued. As a result, it may not be possible to continue to use CFC propellants in the intermediate and long term. While some efforts have been made to use non-pressurized metered dose inhalers, many of these devices have not been successful. Some of the performance issues related to these are ; delivery of uniform doses, mechanical complexity, provision of the required doses per unit of an aerosol container, compliance with stringent regulatory standards and difficulty for individuals to utilize because they are bulky and/or cumbersome for patient use, particularly when patient has an acute need for the medication. As a result there is need for CFC-free pressurized aerosol formulations, such as metered dose inhalers, which are substantially free of CFCs. Non-CFC propellant systems must meet several criteria for pressurized metered dose inhalers. They must be non-toxic, stable and non-reactive with the medicament and the other major components in the valve/actuator. One propellant which has been found to be suitable is CF3CHFAF3, also known as HFA 227, HFC 227or 1,1,1,2,3,3,3heptafluoropropane. From hereon forward this propellant will be referred to as HFA 227.However certain physical characteristics, i.e. polarity and solubility of HFA 227 differ from those commonly used CFC propellants. Commonly used surfactants may be insoluble in HFA 227. Moreover, where the medicament is to be delivered as a solution, the medicament may not be readily soluble in the propellant. The polarity difference between
HFA 227 and the previously known CFC propellants may result in different delivery of the medicament when HFA 227 replaces a CFC propellant. The medicament may cream, settle or agglomerate in the non-CFC propeelant even though this did not occur in the CFC propellant. Another such non-chlorofluorocarbon propellant is Hydrofluorocarbon 134a, also known as 1,1,1,2-tetrafluoroethane or HFA 134a. From hereon forward, this propellant will be referred to as HFA 134a.” From the above disclosure the Patentee explains that the use of CFCs is the most preferred in the aerosol formulations because of the advantages associated with CFCs but since the production of CFCs is discontinued there is a need to substitute the CFCs with non CFCs. Then the Patentee identifies non-CFCs and according to the Patentee HFA 227 and HFA 134a are the most suitable non-CFCs but still some problems are associated with such mere replacement. The granted specification further states that “Prior art formulations containing mometasone in combination with HFA 227 in a metered dose inhaler utilize ethanol to suspend the mometasone in a crystalline state in combination with the propellant. These formulations have improved stability over time.” In the above disclosure the Patentee acknowledges that the active moiety [herein it is mometasone] is suspended with the help of ethanol and HFA 227 combination and there is an improvement in stability. No hint is given with respect to the effects due to the presence or absence of the carrier. The granted specification further refers that, “The specific combinations noted above [mometasone+ethanol+HFA227] may not provide the desired solubility, stability, low toxicity, exact dosage, correct particle size (if suspension) and/or compatibility with commonly used valve assemblies of metered dose inhalers. Accordingly there exists a need for CFC free formulations for the treatment of asthma and processes for producing the same that do not suffer from the aforementioned infirmities.” From the above paragraph it is concluded that except improvement in stability the other desired characteristics like solubility, stability, low toxicity, exact dosage, correct particle size (if suspension) and/or compatibility with commonly used valve assemblies of metered dose inhalers are yet to be achieved by using non-CFCs. Nowhere in the granted specification it is mentioned on the advantages or disadvantages or limitations on using two pharmaceutically active ingredients i.e. mometasone furoate and formoterol fumarate together in the claimed aerosol formulation. Probably it is because the problem to be solved by this invention is different from the problem, if any, on the use of combination drugs. In the absence of any such direction it has to be understood that the two active drugs are known and the combination therapy is also known. Then the only point is replacing CFCs with non-CFCs in the combined formulation which is expected to be an extrapolation of such combination but with only one active pharmaceutical moiety. D1 discloses that “It has now surprisingly been found that a significant unexpected therapeutic benefit, particularly a synergistic therapeutic effect, in the treatment of inflammatory or obstructive airways diseases can be obtained by combination therapy using formoterol, in free form or in the form of a salt or solvate thereof and mometasone furoate.” The present patent claims priority from the Patentee’s USA application numbered as 60/315,386 dated 28th August 2001 whereas the International Publication Date of D1 is 8th September 2000. Hence it is concluded that the combination therapy of using mometasone furoate and formoterol fumarate is known.
Further D1 discloses that “An aerosol composition suitable for use as the inhalable form of the medicament may comprise the active ingredient in solution or dispersion in a propellant, which may be chosen from any of the propellants known in the art. Suitable such propellants include hydrocarbons such as n-propane, n-butane or isobutene or mixtures of two or more such hydrocarbons, and halogen substituted hydrocarbons, for example fluorine substituted methanes, ethanes, propanes, butanes, cyclopropanes or cyclobutanes, particularly 1,1,1,2tetrafluoroethane (HFA 134a) and 1,1,1,12,3,3,3-heptafluoropropane (HFA 227) or mixtures of two or more such halogen substituted hydrocarbons. Where the active ingredient is present in suspension in the propellant i.e. where it is present in particulate form dispersed in the propellant, the aerosol composition may also contain a lubricant and a surfactant which may be chosen from those lubricants and surfactants known in the art. Other suitable aerosol compositions include surfactant free or substantially surfactant free aerosol compositions. The aerosol compositions may contain up to about 5% by weight for example 0.002 to 5%, 0.01 to 3%, 0.015 to 2%, 0.5 to 2% or 0.5 to 1% by weight of the active ingredient, based on the weight of the propellant. Where present, the lubricant and surfactant may in an amount up to 5% and 0.5% respectively by weight of the aerosol composition. The aerosol composition may also contain a co-solvent such as ethanol in an amount up to 30% by weight of the composition, particularly for administration from a pressurized metered dose inhalation device.” From the above paragraph and after concluding the combination therapy is known, it can be concluded that the aerosol formulations can be prepared by using non-CFCs i.e HFA 227 and HFA 134a. While responding to this document the agent for the Patentee has argued that D1 teaches the combined use of HFA 227 and HFA 134a whereas the present patent though discloses about the use of both HFA 227 and HFA 134a either individually or in combination the Patentee has claimed only the use of HFA 227 as propellant but not HFA 134a. This argument is not tenable because the invention is exemplified with the use of both the propellants. The examples of the patent are rewritten for the sake of quick understanding which is as follows; Example 1: MF+FF+Lecithin Example 2: MF+FF+Lecithin+HFA 227 Example 3: MF+FF+Oleic Acid+Ethanol+HFA 227 Example 4: MF+FF+Oleic Acid+Ethanol+ HFA 134a Example 5: MF+FF+Oleic Acid+Ethanol+ HFA 227 & HFA 134a [50:50] Example 6 is related to a combination of MF and FF and HFA 227 without bulking agent. Through Example 6 it was proved that the particle sizes and doses are maintained in other words proves the improved and acceptable drug delivery of the two actives. Example 7 is related to a combination of MF and FF and HFA 227 with low bulking agent and the bulking agent is lactose. Through Example 7 it was proved that the particle sizes and doses are maintained in other words proves the improved and acceptable drug delivery of the two actives. Example 8 shows a comparative study on the degradation products between HFA 227 with no bulking agent and HFA 134a with low bulking agent. Examples 9 proves the drug content uniformity in the aerosol formulation comprising MF and FF and HFA 227 with no bulking agent. Examples 10 proves the drug content uniformity in the aerosol formulation comprising MF and FF and HFA 134a with low bulking agent.
On pages 14 and 15 of the granted specification it was described that “When the propellant is HFA 227, the FF and MF form floccules in suspension such that the mometasone and formoterol are aggregated with each other. When the propellant is HFA 134a, the presence of a bulking agent or carrier such as lactose in an amount of about 0.05% to about 0.3% by weight is preferred to enhance the drug delivery upon actuation of the inhaler. With HFA 134a based formulations, the formoterol, mometasone and lactose have a tendency to sediment to the bottom of the canister because HFA 134a is less dense than HFA 227; thus shaking of the canister to re-form the suspension prior to actuation of the meter is preferred for uniform drug delivery. Other bulking agents that may be used in HFA 134a suspensions include, for example, mannitol, glucose, sucrose and trehalose”. It is further stated in page 15 of the granted patent that, “Since HFA 227 and HFA 134a may not be compatible with all elastomeric compounds currently utilized in present aerosol assemblies, it may be necessary to substitute other materials, such as white buna rubber, or to utilize excipients and optionally surfactants which mitigate the adverse effects of HFA 227 or 134a on the valve components”. From the above disclosure it can be concluded that both HFA 227 and HFA 134a are the propellants that can be used according to invention. Though HFA 134a has the disadvantage of settling the active drug it can be overcome by shaking the canister, hence the argument made by the agent for the Patentee that the Patentee has restricted to HFA 227 in the claims is not convincing. Had the Patentee thought the HFA 134a cannot be used in the inventive formulations then the description and claims are not in inconsistent with each other? Use of both HFA 227 and HFA 134a not compatible with valve assemblies is concluded to be a known problem and the solution as discussed in the granted specification is also concluded as known solution and does not have any impact on the alleged invention. Surprisingly in the entire granted specification no comparison has been provided by using a carrier and not using a carrier. As understood the problem to be solved by this patent is the elimination of CFCs from the process of preparing the aerosol suspension formulations. How this problem is related either to the presence or absence of a carrier? The granted specification has no answer for this question. The entire granted specification addresses to the problems associated with using non-CFCs in the making of aerosol suspension formulations. These problems and the solutions were amply discussed in the cited documents filed by the Opponent. None of the documents i.e D1 to D6 and other documents had discussed on the effects of carrier or the problems that may arose in the absence of carrier. Then what is the functional difference between a carrier and a propellant? A carrier in general parlance is defined as are substances that serve as mechanisms to improve the delivery and the effectiveness of drugs. Drug carriers are used in sundry drug delivery systems such as: controlled-release technology to prolong in vivo drug actions; decrease drug metabolism, and reduce drug toxicity. The propellant in general parlance is understood as technically, is the general name for chemicals used to create thrust. A propellant, in other words, is a chemical which is used in the production of energy and pressurized gas that is used to create movement of a fluid or to generate propulsion. By looking at a plain reading on the definitions, both the carrier and propellant are doing the same job. Though there is a difference in applications, it is needless to say that when drug has to be delivered in aerosol suspended form the propellant is the only option for intended use. Therefore in the present formulations the propellant is used for effective delivery. Hence the concept of the Patentee on claiming “substantially free of a carrier” is not understandable in the context of the proposed solution for solving the proposed problem. With respect to the combination therapy and the dosages fixed there is no inventive concept in the impugned patent. Also there is no inventive step in the selection of non-CFCs for the preparation of the aerosol suspension formulation of the patent. There is no inventive concept on selecting HFA 227 and/or HFA 134a from known non-CFCs. There is no inventive concept on the preferential use of HFA
227 over HFA 134a. The claims are inconsistent with that of description as there is no comparative data with respect to the absence or presence of a carrier in the said formulations. The claim 1 either on individual parameters or in its entirety lacks inventive step. Consequently the claims dependent on the claim 1 are not inventive. The sole process claim also in its entirety is not inventive as the said claim does not describe any inventive feature. The descriptive portion of the specification does not throw any light on the carrier itself and hence based on the arguments during the hearing which were made around the presence or absence of a carrier is considered to be insufficiently disclosed. In view of the above conclusion I hereby order that the Patent bearing the number 246328 is revoked. This decision falls within the purview of the Section 117-A of the Act. Dated 10th December 2012
(T.V.MADHUSUDHAN) Assistant Controller of Patents & Designs
