GSK’s patent on lapatinib ditosylate revoked by IPAB

GSK’s granted patent IN221171 (‘171) on lapatinib ditosylate (marketed as Tykerb), a tyrosine kinase inhibitor for treating breast cancer, was revoked by IPAB by its order of 27th July, 2013.

A revocation application was filed by Fresenius Kabi Oncology Limited. The patent is revoked on ground of non-compliance with S.3d alone on basis of no proof of enhanced therapeutic efficacy vis-a-vis lapatinib di-HCl salt (known compound). Still IPAB discusses the grounds of obviousness and non-compliance with S.8 in detail as it considers these grounds important.

Section 3d

IPAB very straight forwardly failed the test of section 3d for the ‘171 patent. Taking precedent of Novartis Glivec case, it was held that there was no enhancement in therapeutic efficacy of the ditosylate salt as compared to the di-HCl salt and thus “the patent deserves to be revoked”. The only enhancement w.r.t the di-HCl salts was the increase in moisture absorption property and the increase in stability which are physico-chemical properties.

Next IPAB discussed the grounds of obviousness and Section 8, though it considers that non-compliance with Section 3d itself revokes the patent.

Obviousness

GSK’s basic patent (IN221017) on lapatinib was cited as prior art (D1) in view of three other prior art documents D2 to D4. It was argued that D1 describes a list of acid addition salts which exemplify 19 acid addition salts among which p-toluene sulphonic acid salts were one of them and even one Example 29 is a tosylate salt.

It was held that at the time of invention of ‘171 patent, the inventors knew that the HCl salts of lapatinib were hygroscopic and thus having stability issues (described in background section of the ‘171 patent). D3 and D4 are non-patent basic literature articles describing selection of salts and pharmaceutical salts respectively. D2 is a prior patent WO 98/25920 disclosing tosylate salts of 3-pyridoxyl alkylene azetidine-2-yl compound and that these are less hygroscopic, more crystalline, more stable, have a higher melting point and are readily purifiable as compared to hydrochloride salts. It was argued that D3 discloses that aryl groups are said to minimize hygroscopicity as opposed to the poorly stable hydrochloride and sulphate salts which teaches towards tosylate or ditosylate salt with reasonable expectation of success in combination with D1, D2 and D4. D2 further teaches tosylate salts to sorb less moisture, are more stable and crystalline.

IPAB clarified that the skilled person in obviousness analysis in Indian law is the person skilled in the art (Ms. SITA) rather than the person having ordinary skill in the art (PHOSITA) as used in US law, in reply to the Respondent’s citing of US case laws and description of skilled person as PHOSITA. IPAB held that the skilled person (Ms. SITA) would know at the time of the invention of the problem of the hygroscopicity and stability of HCl salts and it would be obvious to try for her to select ditosylate salt as taught by D1 in view of D2 to D4. IPAB further held that whether D2 belonged to another class of compounds (read analgesics) would be immaterial. IPAB asserts that:

“Salt selection especially if there is a wide range is not a matter of routine, according to the respondent. Even if we accept this as correct, it does not help the respondent. Ex D is about salt selection and it shows that aryl groups present a hydrophobic barrier to minimize hygroscopicity. The Person Skilled in the Art would look at Ex.C  and find that the tosylate salt of such 3-pyridoxyl alkylene azetidine-2-yl compound shows exactly the same qualities that the persons in this field are looking for in relation to Lapotinib. She knows that tosylate compound is a preferred compound from Ex B and that it can be prepared by Procedure D. She is not a dullard she can do experiments with skill. She is more likely to think “Let me try a tosylate first. If it demonstrates the same improvements as it has in Ex-C then I need not search further.” She would have tried a tosylate with a reasonable expectation of success.”

                                                                              Ex D = D3, Ex C = D2 and Ex B = D1

IPAB finally held that if the salt selection were to be made from a vast variety of salts by testing each compound with no clue available, then selection of one particular salt is not easy but in this case the clue is provided by D2 to D4 which makes the invention obvious.

Section 8

IPAB rejects the ground of Section 8 in the absence of pleading and proof of violation. IPAB stated that:

“It is not enough to merely reproduce the language of the section. A S.8 violation has severe consequences and the case for it has to be made out. The facts have to be pleaded and the applicant must state how the particular undisclosed application was for the same or substantially the same invention. It is also not enough to just file the documents along with an affidavit. The least that the deponent shall state is how each application mentioned therein is for the same or substantially the same invention”

On another note, IPAB stressed the importance of compliance with S. 8 in a number of ways as shown below. In the opening sentence under the S. 8 heading itself, IPAB states that

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”.

Further excerpts of IPAB are as below:

“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.”

In view of what is stated in the Ayyangar Committee Report, we are of the opinion if in any of the foreign offices the patentee had made a division or was required to make a division, in respect of the same or substantially the same invention or had amended or was required to amend in respect of the same invention or substantially the same invention such information regarding division or amendment would also be information required to be furnished under Section 8.”

Patentees must comply with S.8 (1) provision however inconvenient it is.”

Fresenius Kabi also filed revocation petition against GSK’s basic patent IN 221017 claiming Markush structure encompassing lapatinib and pharmaceutically acceptable salts (discussed as D1 hereinabove) on grounds of obviousness, non-compliance with S.3d and S.8. This revocation petition however was dismissed by IPAB. We would discuss this in detail in an upcoming article.

About the Author: Ms. Meenakshi Khurana, Patent Attorney at Khurana & Khurana and can be reached at: Meenakshi@khuranaandkhurana.com

Follow us on Twitter: @KnKIPLaw.

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