Unipharm Successfully Opposes Novartis Patent for Panobinostat Lactate Salts

PanobinostatThis ruling relates to an opposition against a patent application by Novartis for Panobinostat  which is a hydroxamic acid  that acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor).  On 23 February 2015 the drug received FDA accelerated approval for use in patients with multiple malignancies, and on 28 August 2015 it was approved by the European Medicines Agency for the same use.

The Opposer claimed that the drug was described in the Applicant’s earlier published PCT application and was thus both anticipated (known) and obvious. The Commissioner rejected the anticipation claim but accepted that in light of the earlier publication, it was obvious and lacked an inventive step.

Due to the ruling being rather interesting but only available in Hebrew, and since these Israeli rulings can and do have an effect on validity of corresponding patents elsewhere, I have translated the decision in full. At the end I have made some general comments.

Background

NovartisNovartis AG filed Israel Patent Application Number 195087 titled “ANHYDROUS LACTATE SALTS OF ANHYDROXY-3-[4-[[[2-(2-METHYL-1HINDOL-3 YL)ETHYL]AMINO]METHYL] PHENYL] – 2E-2-PROPENAMIDE AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME” as a national phase of PCT/US2007/070558 that was filed on 7 June 2006 and claims priority from US 60/804523 and US 60/869993, two US provisional patent applications filed in June and December 2006 respectively. The Israel national phase entry was submitted on 3 November 2008 and, on allowance, published for opposition purposes on 31 October 2012.

UnipharmUnipharm opposed the application on 3 January 2013. Subsequently, on 26 June 2013, Novartis requested to correct the application and, since neither Unipharm nor anyone else opposed this, the application was corrected and this ruling concerns an opposition to the amended application.

The parties submitted their claims and evidence and a hearing was held before the Commissioner of Patents and Trademarks, Asa Kling on 24 February 2016. The Opposer’s Summary was submitted on 24 August 2016 and the Applicant’s summary was received on 30 November 2016. The Opposer responded to this on 20 December 2016.

The Application claims salts of the material mentioned in the title, and known as panobinostat which is a histone deacetylase (HDAC) inhibitor used to treat cancerous growths.

The Application describes and demonstrates 21 panobinostat salts, including the hydrochloride, the lactate, the matate, oxalate, tartrate, acetate, benzoate, citrate, fumarate, gentisate, mallate, melonate, oxalate, phosphate, propionate, sulphate, and the sodium, potassium calcium and zinc saccinates. The original Application included 49 claims for the various salts. However, on 28 June 2011 during examination of the Application, the claim-set was restricted to 14 claims directed to the lactate.

The claim-set includes two independent claims. Claim 1 is for the anhydrous lactate and claims 2-6 depend on claim 1. Claim 2 is for the stoichiometric anhydrous lactate salt and claims 3-5 claim the DL, L and D variants. Claim 6 relates to a therapeutic preparation of at least one of claims 1-5, a carrier, solvent, or pharmaceutically acceptable support material. Claim 7 is for the monohydrated lactate and claims 8-14 are for dependent claims that are similar to claims 2-6.

The Parties’ Claims and Evidence

The Opposer submitted their evidence as an affidavit of Zebulun Tomer. The Applicant submitted their evidence as an affidavit by Dr Michael Mutz and this evidence was not countered.

Zebulun Tomer submitted WO/2002/022577, which is another (earlier) Novartis application.

Dr Mutz submitted the following documents:

  • M.Berge et al., Pharmaceutical Salts, J. PHARM. SCI., vol. 66 (1977) (“Berge”);
  • L. Gould,Salt selection for basic drugs, Int. J. of Pharm., 33, 201-217, (1986) (“Gould”);
  • Pfannkuch, H. Rettig, and P.H. Stahl, “Biological Effects of the Drug Salt Form” inHandbook of Pharmaceutical Salts – Properties, Selection, and Use, P.H. Stahl and C.G. Wermuth, Eds. (2002), pp. 129 (“Stahl”);
  • A.Stephenson et al., Physical stability of salts of weak bases in the solid-state, J. Pharm. Sci., Vol. 100, No. 5, 1607-1617 (2010) (“Stephenson”).

Novartis applied for the Opposition to be thrown out and Unipharm requested certainly sections of Mutz’ affidavit be deleted. In interim rulings from May 2015 https://blog.ipfactor.co.il/2014/06/16/novartis-attempts-to-get-unipharms-opposition-to-il-195087-thrown-out/and July 2015, these applications were rejected.

Both witnesses were cross-examined in the February 2014 hearing.

The Opposer’s Claims

prior artThe Opposer alleges that the active ingredient was known at the priority date due to earlier publication of the WO/2002/022577 case which claimed the material in claim 26 thereof. The publication date was 30 August 2001, i.e. six years before the priority date. The Opposer alleges that this application describes, demonstrates and claims the specific product. (Claim 27 of IL 154574 is equivalent to claim 26 of the PCT application and the pharmaceutical preparation and equivalent pharmacological salts are claimed in claims 38 and 42 thereof. IL 154574 published for Opposition purposes on 17 February 2010 which is after the priority date, and was registered and is in force in Israel.

The Opposer adds that on page 18 of the ‘577 application, the lactate salt is specifically mentioned. Furthermore, on page 74 thereof, preparation of five lactates of pharmacologically equivalent analogues are given. The Opposer alleges that the term ‘dissolved’ that appears on Page 74 of the ‘577 application shows that the lactates were put into liquid solvents and dissolved to produce stock solutions as described. The lactate salts were dissolved in dimethylsulfoxide (DMSO), an organic solvent used for screening. Consequently, the Opposer claims that this is a case of double patenting and the national phase of the ‘577 PCT application already protects this invention.

The Opposer adds that creating a salt of a specific formulation is a standard procedure in the pharmaceutical industry. The Opposer alleges that where the solubility of the formulation is low, one creates a salt that has increased solubility. This requires defining the pKa of the ionizable formulation, i.e. the groups that provide the counter-ion. Subsequently to choose the appropriate salt, one acts according to the rule-of-thumb that there should be at least three units between the pKa of the ionizable formulation and that of the counter-ion.

The opposer claims that there is a method for scanning salts using a microplate as described in Bastin R.J. et al., Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical Entities, Org. Pro. Res. & Dev., 4, 427-435, (2000).

The method described in the Application is the same as that of the microplate. They allege that Dr Mutz cannot deny their allegation that the method is similar to the microplate method since he wasn’t involved in the Applicant’s experimentation.

polymorphsThe Opposer further alleges that the lactate salt is commonly used in the pharmaceutical industry.  They allege that of necessity, persons of the art would obtain the monohydrate when preparing the lactate and the anhydrous lactate would then necessarily appear. They allege that the Application does not explain how the anhydrous salt will precipitate out of an aqueous solution. Consequently, the anhydrous lactate is not an invention, but, at best, a non-patentable discovery. Furthermore, the Opposer claims that the ‘577 published application anticipates not just the lactate but also both polymorphs, since preparation of the salt will certainly result in both isotopes forming.

The Opposer alleges that the only example in the Application that demonstrates obtaining the anhydrous lactate salt without seeding is where a wet filter cake is achieved that is essentially the monohydrate and only after heating to 50 under vacuum does the anhydrate crystal appear. Therefore, where the Opposer claims that the anhydrous crystal was surprisingly found in the aqueous environment is simply wrong.

The Opposer also alleges that the monohydrate lactate is not a stable polymorph and so there was no justification is claiming this. Furthermore the specification does not define this form. [MF – presumably this is not metastable either…]

The Opposer further alleges that the restriction to only the lactate out of the original 21 salts mentioned, does not indicate that the lactate has the optimal properties. Opposer claims that the hydrochloride is actually the preferable salt. The Opposer claims that contrary to that stated in the Application, the Applicant did not show that the hydrochloride failed in laboratory tests.  Furthermore, even if the hydrochloride did indeed fail in the laboratory testing, testing the utility of the lactate is the technical requirement that persons of the art would be expected to undertake.

Furthermore, the Opposer alleges that the tables on pages 22 and 23 of the Application indicate that other salts and their solutions showed similar stability to that of the lactate. Consequently, the disproportionation, i.e. the breakdown of the salt into a free base and an acidic counter-ion is pH dependent, see Stephenson page 1610, right hand column, referenced by the Applicant, which according to Tomer, is trivial and peripheral.

In this regard, based on Stephenson, the Opposer claims that there is only the slightest likelihood of disproportionation. Furthermore, Tomer alleges that in his attempts to create the salt, the salts are obtained with varying pH that is independent of the pHmax. The Opposer claims that the Applicant is actively prevented from appending an affidavit from one of the inventors, but chose to file an expert opinion by someone not involved in the invention and who is not an expert in histone deacetylase (HDAC).

The Main Claims of the Applicant

needle in haystack The Applicant alleges that the ‘577 application claimed a range of HDAC inhibitors. The publication included a general Markush claim (formula 1) and secondary formulae 1a-1f, where panobinostat is but one of the 265 claimed formulations. The Applicant claims that the ‘577 application does not even hint that panobinostat has preferable properties to other formulations described in the Application. The other formulations were indicated as being important of effective. They also claimed that of all the formulations in the ‘577 application, only five reached the stage of in vivo effectiveness testing and panobinostat was not one of them (see page 74 of the ‘577 publication).

Consequently, the Applicant considers that the present Application is a later application for a specific formulation out of many formulations described in the ‘577 application. Thus the ‘577 publication is at worst a ‘dominating patent’ and is not an example of double patenting.

The Applicant claims that the ‘577 publication does not teach the method of preparing the panobinostat lactate. Rather, the ‘577 publication teaches clearly that precipitated crystal of panobinostat lactate were not fabricated but only a stock solution intended for injection into a vein (page 74 of ‘577). With reference to the list of salts on page 18 of ‘577, the applicant alleges that this is a standard list of salts that is included in all applications of this type and does not teach the method of preparing a specific salt.

The Applicant further notes that a known use of lactic acid is as a useful pharmaceutical additive for intravenous injection into living organizations to regulate the acidity, but this does not teach oral medication using the solid salt. The Applicant claims that using lactate salts to prepare solid salts of the active ingredient is not something usual, and that there are no drugs today that use the salt for this purpose.

The Applicant alleges that the claims that the selection of a pharmaceutical salt suitable for certain formulations is a complex process that is unpredictable and requires investment in research and many resources.

The Applicant claims that panobinostat is a ‘zwitterion’ that includes acidic substitutes (hydroximate group) and also basic substitutes (secondary amines and the indol group). The claim that zwitterions can create both acidic and basic salts, and also ‘self salting’. They further claim that unlike self salting, using a counter-ion, whether acidic or basic, creates a competition between ‘internal’ salting and ‘external’ salting using the acidic or basic counter-ion. Consequently, to develop a salt into a material requires considering both acidic and basic salts and the thermodynamic and kinetic preferences of the external salt over the internal one.

In developing the invention, they considered tens of acidic and basic salts in different crystallization conditions, solutions and general conditions. They claim that this research did not focus on salts in the usual usage of the term, i.e. compounds of cations and anions, but also partially ionic compounds (partial protonation). Consequently, the definition of salt in the application includes all ‘salts’ resulting for reacting the active ingredient with an acid or base, and not just ionic compounds.

The applicant considers that protonation in the application is measured by the chemical offset of the benzyl protonation Hbz (see page 14 of application). Full protonation in the specification gives an Hbz of about 4.22, which is obtained the hydrochloride having a pKa of -6. The mesilate having a pKa of -1.2 and the sulfate having a pKa of -3.

The Applicant claims that since the lactate has a pKa of 3.86, persons of the art would not suspect that there would be full protonation and an Hbz of about 4.18, similar to that obtained using strong acids such as HCl, and not like other weak acids having only partial protonation.

Furthermore, the Applicant considers that preparing lactic acid, which, as stated above, is a weak acid, has a tremendous advantage in that unlike strong acids, lactic acid does not accelerate the breakup of the active ingredient. Furthermore, the pHmax of panobinostat (the pH of maximum solubility) is 3, and the pH of the saturated solution is of panobinostat lactate is about 6.5, which is similar to the pH in the damp micro-environment, i.e. the water surrounding the pill – see Stephenson page 1608 , right hand column. The Applicant claims that when the pH exceeds the pHmax the basic salt is expected to disproportionate and return to the acid and fee form. So the stability of the lactate salt was surprising.

The Applicant claims that in the first stages of the research, the monohydrate salt was the first crystalline form they succeeded in synthesizing. They succeeded in first creating the anhydrous salt in an aqueous solution by seeding with the monohydrate crystals. This result is surprising since in an aqueous environment, precipitation of the anhydrous crystal is unexpected. [MF – as a chemist (sort of) but not a pharmacist, I concur that this is unexpected. I would use the term unbelievable. ]

The Applicant claimed that Example 18 of the Application is an example of the preparation of the anhydrate from an aqueous environment. Contrary to the Opposer’s claim that short heating of the wet filter cake I the workup is what caused the monohydrate to convert into the anhydrate, the Oppose claims that since the anhydrate form has low miscibility compared to the monohydrate, it would preferentially precipitate out of solution and the wet cake could not include the monohydrate. Similarly the heating could not have caused the transition from one form to another, and the thermal behaviour of the two forms indicates that there is no transition from one to the other.

The Applicant claims that when preparing the lactate salt, average persons of the art would not expect to first obtain the monohydrate and then the anhydrate, and what surprisingly caused the fabrication of the anhydrate was a change in the process for preparing the materials. In their opinion, there is no simple transition from the monohydrate to the anhydrate. To convert from one form to another requires a complex and non-obvious process. One has to dissolve the monohydrate in water with lactic acid whilst heating, and then seed with the anhydrate, to stir for 19 hours with further heating and then to stir for further hours. This product is filtered to obtain the wet filter cake and then dried under vacuum at 50ºC to obtain anhydrate (example 20 of the Application).

Furthermore, the Applicant claims that surprisingly, the anhydrate has a lower solubility (3.7 mg per ml) than does the monohydrate (6.4 mg per ml) which implies that the anhydrate is the stabler form.

Contrary to the Opposer’s claims that the monohydrate is not a stable polymorph, the Opposer claims that one can see from the data in the Application (table 23 page 47) that the monohydrate remains stable at high temperatures in damp conditions.

Contrary to the Opposer’s claims that the anhydrate is only obtained by seeding with anhydrate (which makes it not novel), Example 18 shows how the anhydrate may be obtained without seeding with anhydrate.

The Applicant claims that paragraph 27 of the application that in most cases the anhydrate is not converted into the monohydrate but in an equilibration experiment, the monohydrate slowly converts to the anhydrate but this has nothing to do with the process described in Example 18 where the anhydrate precipitates first from the wet cake.

The Applicant claims that the dissolved salt cannot be an anhydrate or a monohydrate. The Application specifically claims that the lactate salt is sold and contrary to the Opposer’s assertion, salts in liquid form are not claimed.

Interlocutory Request to Submit a Summation Response

The Applicant filed a preliminary request to respond to the Opposer’s summation response, claiming that the Opposer was using his summing up to insert new factual and legal matters.

After the Commissioner Asa Kling reviewed the Application, the evidence, and the summary, he rejected this request. In essence the Objector related to that chemical offset of the protonated benzene of the lactate salt. The Applicant related to this in the Application and in their response, they connected it to the protonation measurements of various salts discussed in the Specification on pages 26-30. In their counter response the Opposer alleged that this value was not actually surprising since that the malate had a similar pKa, i.e. a similar chemical offset. Since in their response, the Applicant explicitly related to the chemical offset discussed in the specification, they cannot now prevent the Opposer from responding to this in their summary on the basis of new matter.

Furthermore, in their Summary Response, the Opposer responded to the claims raised by the Opposer in their response. Although the Applicant alleged that this was a widening of their opposition, after examination, the Commissioner did not consider this to be case.

Furthermore, in pages 3 and 4 of their summary response, the Opposer raised legal arguments regarding how Israeli and foreign case-law that was cited by the Applicant should be interpreted. There is no reason to refuse this on the grounds of introducing new subject matter.

Therefore the Commissioner rejected the new matter complaint.

The Ruling

burden of proofThe burden of proof during Opposition procedures, including establishing inventive step (non-obviousness for our American readers) in the eyes of ordinary persons of the art is on the shoulders of the Applicant.  See 665/84 Sanofi ltd. vs. Unipharm Ltd p.d. 41(4) 729 section 5 of the Decision, Appeal 645-06013 Unipharm vs. Lilly Icos, 26 January 2014, and Opposition to IL 143977 Unipharm vs. Astra Zeneca AB, 29 July 2007. So if an Opposer manages to cast doubt on the patentability of an application, the applicant will have to overcome this.

In this instance, the Opposition is based on allegations of lack of novelty and inventive step which are required by Sections 4 and 5 of the Israel Patent Law 1967.

Novelty

Section 4 of the Israel Patent Law 1967 states that absolute novelty is required, both in Israel and elsewhere:

An invention is deemed new if it was not published, in Israel or abroad, before the application date—

(1) by written, visual, audible or any other description, in a manner that enables a skilled person to make it according to the particulars of the description;

(2) by exploitation or exhibition, in a manner that enables a skilled person to make it according to the particulars thus made known.

noveltyTo cancel the Novelty of an Application a single piece of prior art has to fully describe the elements of the invention in a manner that enables persons of the art to make the invention. See Appeal 345/87 Hughes Aircraft vs. State of Israel p.d. 44(4) 45 (page 105 of the ruling).

The first rule is that to prove novelty destroying prior publication one has to identify a single document that describes the invention in its entirely and it is not sufficient to create a mosaic of different documents to create a general picture.

Hughes also states that:

A general description is insufficient to remove novelty if it is not enabling and does not provide enough signposts leading to the invention of the patent.

The ‘577 publication relates to hydroxymate derivatives that are useful as deacetylase inhibitors. The ‘577 publication is intended for treating malignant illnesses. The publication describes and claims a number of formulations by Markush claims [MF – these are typically broad chemistry claims for lists of molecules or chemicals having similar active groups and thus expected to demonstrate similar chemical or pharmaceutical behaviour], including that referred to as formula 1e, and panobinostat is one of the formulations that is included in formula 1e and is claimed in the ‘577 publication. The publication also claims the ‘pharmaceutically acceptable salt thereof’.

On page 18 of ‘577 there is a list of pharmaceutically acceptable salts which can be used to prepare the formulations claimed and these include the lactate. Furthermore, on page 74 a method of preparing lactates of five formulations to provide stock solutions is described. Two of these are listed in formula 1e.

Claim 26 is as follows:

“A compound of claim 16 selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide [–  א.ק.  CMD 2], N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide [– א.ק.  CMD 1] and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide [AK – panobinostat], or a
pharmaceutically acceptable salt thereof.”

Page 74 explains how the five lactate salts are synthesized:

“Lactate salts of N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl-2E-2-propenamide (CMD1), N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (CMD2), N-hydroxy-3-[4-[[[2-(5-methoxy-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (CMD3), N-hydroxy-3-[4-[[[2-(5-fluoro-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (CMD4), N-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (CMD5) having a purity of higher than 95% are dissolved in pure dimethylsulfoxide (DMSO) to create a stock solution.”

The Opposer considers that the ‘577 publication anticipates the invention, and there is no doubt that it predates the priority date of the present application.

Although the ‘577 does not disclose the monohydrate and anhydrate salts of  panobinostat  lactate, it does state that lactates are pharmaceutically acceptable forms of the claimed molecules, but it does not describe the process of fabricating the salt and that one can obtain these polymorphs, or indeed that they are a possibility.

In 4867/92 Sanitovsky vs. Tams ltd et al, p.d. 50(2), 509 it was established that a lack of novelty or anticipation can occur due to a piece of prior art that includes the core of the invention:

On one hand, the defense of a patent includes not just that described in the claims, but also the core of the invention [MF – what the British case-law refers to as the pith and marrow in a somewhat odd mixed metaphor] (section 49). On the other hand one can claim a lack of novelty when accused of infringement (section 4) not just when a piece of prior art describes all the elements of the invention, but also then the prior discloses the core of the invention.

This determination in re Sanitovsky is known as ‘inherent anticipation’ and is discussed in the US case-law in re Lewmar Marine Ind. V. Barient, Inc. 827, F.2d 744 (1987). As the Us Case Law determines, a piece of prior art can anticipate an invention if it describes the core of the invention, where a missing element js inherently expected by persons of the art:

“Under the doctrine of inherent anticipation, a prior art reference that does not expressly disclose a particular element of a claimed invention may nevertheless anticipate “if that missing characteristic is necessarily present, or inherent, in the single anticipating reference.” Schering Corp. v. Geneva Pharms., 339 F.3d 1373, 1377 (Fed. Cir. 2003). “In general, a limitation or the entire invention is inherent and in the public domain if it is the natural result flowing from the explicit disclosure of the prior art.””

re Valeant Int’l (Barbados) SRL v. Watson Pharms., Inc., 2011 U.S. Dist. LEXIS 128742 (S.D. Fla. Nov. 7, 2011, henceforth – ” re Valeant” .

Also:

“We have repeatedly held that [n]ewly discovered results of known processes directed to the same purpose are not patentable because such results are inherent.” Bristol-Myers Squibb, 246 F.3d at 1376. As we stated in Cruciferous Sprout, 301 F.3d at 1350, “[i]t matters not that those of ordinary skill heretofore may not have recognized the[] inherent characteristics of the [prior art].”

In re Montgomery, 677 F.3d 1375, 1379-1380 (Fed. Cir. 2012)/

In re Valeant it was ruled that the result must by certain and not just a possible outcome:

Moreover, the result flowing from the explicit disclosure must invariably happen. As the Federal Circuit has stated, “[i]nherency . . . may not be established by probabilities or possibilities. The mere fact that a certain thing may result from a given set of circumstances is not sufficient.” In re Robertson, 169 F.3d 743, 745 (Fed. Cir. 1999) (internal quotations omitted) (emphasis added). Cases dealing with inherent anticipation look to whether the purported inherent production of the claimed compound “faithfully followed” the prior art example being relied upon. Glaxo, Inc. v. Novopharm Ltd., 830 F. Supp. 871, 876 (E.D.N.C. 1993), aff’d, 52 F.3d 1043 (Fed. Cir. 1995). A prior art example inherently anticipates a claimed compound only if the claimed compound is “invariably” produced when one follows the example. Id. at 874.

In the British case-law, there is a kind of anticipation if something is an outcome of the specification teaching knowledge that inescapably leads to expected results – anticipation by disclosure.

“It may be helpful at this point to highlight the similarities and the distinctions between the case for anticipation by use, which I have rejected, and the case for anticipation by disclosure, which I have accepted. In both cases no one was aware that the acid metabolite was being made. In the case of anticipation by use, however, the acts relied upon conveyed no information which would have enabled anyone work the invention, i.e. to make the acid metabolite…. Anticipation by disclosure, on the other hand, relies upon the communication to the public of information which enables it to do an act having the inevitable consequence of making the acid metabolite. The terfenadine specification teaches that the ingestion of terfenadine will produce a chemical reaction in the body and for the purposes of working the invention in this form, this is a sufficient description of the making of the acid metabolite. Under that description the acid metabolite was part of the state of the art.”

Merrell Dow Pharmaceuticals Inc. v. HN Norton & Co. Ltd. [1995] UKHL 14 (26 October 1995).

Similar to the US courts, the British courts established that for a result to be novelty destroying it has to be a certain outcome:

“But the infringement must be not merely a possible or even likely consequence of performing the invention disclosed by the prior disclosure. It must be necessarily entailed. If there is more than one possible consequence, one cannot say that performing the disclosed invention will infringe. The flag has not been planted on the patented invention, although a person performing the invention disclosed by the prior art may carry it there by accident or (if he is aware of the patented invention) by design. Indeed, it may be obvious to do so.”

Synthon BV v. Smithkline Beecham plc [2005] UKHL 59 (20 October 2005).

In a similar way, Appeal 8806/06 Smithkline Beecham PLC vs. Unipharm 18 May 2011 determined that the salt of a known formulation claimed in the earlier patent is not novelty destroying for a different salt claimed in a later patent.

The 228 patent relates to salts of the TZD familt. Example 30 of the 228 patent describes a process for creating Roziglitazone (page 38 of the 228 patent) and the claims of the 228 patent claim Roziglitazone in claim 12 (pages 41-43). However, as the Court of First Instance determined, and it is the case, the Roziglitazone Maleate is not mentioned in the 228 patent. It is not superfluous in this regard to refer to the Appellant’s expert witness, Professor Breuyer, who writes in a large font that the ‘228 patent does not explicitly describe the Roziglitazone Maleate (paragraph 9 of the Opinion from 26 Feb 2004. It is necessary to relate to his testimony in the Court of First Instance that the Roziglitazone Maleate itself is a new material.

The way to achieve the monohydrate and anhydrous salts discussed in this patent is not mentioned in the ‘577 publication. The ‘577 publication describes in general how the lactate salt is pharmaceutically acceptable and how the lactate is obtained for five compounds. One cannot learn from the ‘577 publication that the using panobinostat-lactate with certainly lead to these polymorphs and this is not inherent.

Inventive Step

Section 5 defines inventive Step (Non-Obviousness) as follows:

An inventive step is a step which does not, to an average skilled person, appear obvious in the light of information published before the application date in ways said in section 4.

inventiveIn contrast to the novelty requirement discussed above, that can only be destroyed by one publication disclosing the invention, in Hughes it is established that to destroy inventiveness it is legitimate to cobble together a number of publications to create a general picture when considering whether or not there is an inventive step:

The basic question of inventive step is determined by considering the total professional knowledge in the relevant field, and to do so it is legitimate to join different publications into a general picture Appeal 3314/77 [1] page 209. However, one must always bear in mind that the joining together of the disparate documents must be obvious to persons of the art at the date in question; for if it requires an inventiveness to do so, particularly where scattered crumbs of knowledge are gathered together – the general picture obtained is not obvious and one cannot say that the patent has no inventive step.” –page 111.

See also Sanitovsky pages 515-516 and Appeal 793/86 Michael Porat vs. Tzamal Modern Medical Equipment, p.d. 44(4) 578, 585.

In this instance, the Applicant claims that persons of the art would not have chosen to concentrate specifically on panobinostat out of the 265 claimed compounds, since at the relevant date there was no indication that this had optimal properties.

 

Selection of panobinostat from the various compounds in the ‘577 Publication

MarkushAs to choosing a specific compound mentioned in a prior publication in a general Markush claim, the US case-law determined a two stage test to consider the question of inventive step in choosing one such compound:

First, the court determines whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or starting points, for further development efforts. Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1359 (Fed. Cir. 2008) (“[P]ost-KSR, a prima facie case of obviousness for a chemical compound still, in general, begins with the reasoned identification of a lead compound.”). A lead compound, as we have explained, is “a compound in the prior art that would be most promising to modify in order to improve upon its … activity and obtain a compound with better activity.” Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007). As such, a lead compound is “a natural choice for further development efforts.” Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009).

Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1292 (Fed. Cir. 2012)). Henceforth re Otsuka.

Furthermore, in re Otsuka it was established that identical or overlap in compounds claimed in a patent and those claimed [MF – presumably described was intended] in an earlier publication does not indicate with certainty that a person of the art would choose such a compound. Rather, first one has to indicate some motivation that the earlier publication would have resulted in a person of he art choosing the compound:

“In determining whether a chemist would have selected a prior art compound as a lead, the analysis is guided by evidence of the compound’s pertinent properties. See Eli Lilly, 471 F.3d at 1378; In re Lalu, 747 F.2d 703, 707 (Fed. Cir. 1984). Such properties may include positive attributes such as activity and potency, Altana, 566 F.3d at 1008; Eli Lilly, 471 F.3d at 1379; Yamanouchi, 231 F.3d at 1345; adverse effects such as toxicity, Takeda, 492 F.3d at 1358, and other relevant characteristics in evidence, see Eisai, 533 F.3d at 1358 (considering a prior art compound’s lipophilicity and low molecular weight); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1363 (Fed. Cir. 2007) (considering the “strength, solubility, and other known chemical characteristics” of a prior art salt-forming acid). Absent a reason or motivation based on such prior art evidence, mere structural similarity between a prior art compound and the claimed compound does not inform the lead compound selection.”

The second state in Otsuka is whether an average person of the art would have a motivation to change or adapt the chosen preparation such that he would have reason to believe that the change would lead to the desired results.

The second inquiry in the analysis is whether the prior art would have supplied one of ordinary skill in the art with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success. Takeda, 492 F.3d at 1357 (“[I]n cases involving new chemical compounds, it remains necessary to identify some reason that would have led a chemist to modify a known compound in a particular manner to establish prima facie obviousness of a new claimed compound.”); Pfizer, 480 F.3d at 1361 (“[T]he challenger of the patent [must] show by clear and convincing evidence that a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success in doing so.”); Dillon, 919 F.2d at 692.”

The two-stage test proposed in Otsuka is one of the tests for determining inventive step which is known as the ‘obvious to try’ test. The ‘obvious to try’ test considers if at the relevant time, average persons of the art would conduct tests in the manner conducted by the Applicants, on the assumption that there is a certain likelihood of success.
The ‘obvious to try’ test has been applied in the Israel Case-law. For example in the Opposition to Il 136532 G.D. Searle vs. Tarima Israel Medical Products ltd. from 28 February 2008; Opposition to IL136294 Teva vs. Pharmacia & Upjohn AB 30 September 2014   , IL153109 – Teva and Unipharm vs. Merck & Co Inc, 5 August 2010, and on Appeal in 6837/12 Mercke & Co Inc. vs. Teva and Unipharm from 28 March 2013  Which upheld the 35096-09-10 rejection of the Appeal against the Commissioner of Patents . Supreme Court Judge Neal Handel accepted the application of the ‘obvious to try’ test for determining inventive step:

In this regard, one should ask if the publications that post-date Lunar 1 and 2 had something to push the average person of the art away from the solution such that it ceases to be obvious. If that is the question, it seems that the Commissioner has ruled:

“In light of that stated previously, it would have been obvious for an average person of the art to try out the suggestions in the Lunar publications, even if these publications are not unequivocal regarding the effect of the dosages on the side effects.

An answer to the question posed by the Supreme Court in the previous decisions is given by applying the two stage test proposed in Otsuka whereby, in this instance, the first stage is to test if average persons of the art would choose panobinostat out of the compounds claimed in the ‘577 publication.

Dr Muz confirmed that the CMD 1 and CMD 2 molecules were amongst those passed on for in-vivo testing as indicated by Applicant and as described on page 74 of the ‘577 application itself:

  1. Please confirm that CMD1 and CMD2 are of the 5 compounds that suits for biological activity in 577, that would be page 75, example 1.
  2. Yes.

Page 36 lines 14-17 of the Protocol from the 24 Feb hearing.

Dr Mutz acknowledged that panobinostat was specifically claimed in the ‘577 publication, in claim 26, which also claimed the CMD-1 and CMD-2.

  1. Please confirm that Panobinostat is specifically claimed in claim 26 to 577 together with CMD1 and CMD2?
  2. Yes.
  3. Q. And also in claims 34, 38 and 40?
  4. Claims?
  5. Q. 38, 34, 40.
  6. Yes.

Protocol from 24 Feb 2016, page 36 lines 18-24.

Dr Mutz also acknowledged that panobinostat was defined as one of the important compounds on page 17 of the ‘577 :

  1. and Panobinostat is defined here as one of the important compounds in 577?
  2. important compounds of formula 1e, yeah.”

Protocol from 24 Feb 2016, page 35 lines 16-18.

Furthermore, Dr Mutz acknowledged that the CMD-1 and CMD-2 compounds are zwitterions like  panobinostat.

Q.  Ok, thank you. In paragraph 18 you mentioned the term “zwitterion” and please take a look again at the board and confirm that Panobinostat and CMD1 and also CMD2 are all zwitterions?

A.  Yes.

Protocol from 24 Feb 2016, page 45 lines 5-9.

In light of this, the Commissioner is inclined to accept the Opposer’s claim that the Applicant had a motivation to choose Panobinostat with reasonable likelihood of success. As the Applicant himself and their expert witness have admitted, 2 of the five compounds tested were in the same ‘Formula 1e’ group as Panobinostat, were claimed together and were indicated as being the important compounds in that formula.

Therefore it appears to have been reasonable for a person of the art to have selected Panobinostat as a preferred compound for testing and he would have had reason to believe that Panobinostat would lead to desired results.

Choice of the Lactate Salt

Having ruled that there was a motivation to choose Panobinostat from the various compounds listed in the ‘577 publication, the Commissioner went on to consider whether the average person of the art would have selected lactic acid for making the salt.

There is no doubt that converting specific desired compounds into salts is desirable. The problems and costs involved would not have been insurmountable obstacles to this desire. For example, Berge teaches that conversion to a salt is widespread, despite the development of a specific pharmaceutically acceptable salt is complicated and may have unanticipated effects:

“The chemical, biological, physical, and economic characteristics of medicinal agents can be manipulated and, hence, often optimized by conversion to a salt form. Choosing the appropriate salt, however, can be a very difficult task, since each salt imparts unique properties to the parent compound.”

Berge goes on to indicate the impossibility of prophecying the influence of a specific salt on all the ingredients of the formulation.

“Unfortunately, there is no reliable way of predicting the influence of a particular salt species on the behavior of the parent compound.”

See also, the Stahl and Gould publicaitons, the US rulings such as Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1366 (Fed. Cir. 2007), Sanofi-Synthelabo v. Apotex, Inc., 492 F. Supp. 2d 353 (S.D.N.Y. 2007); Pfizer Inc. v. Synthon Holdings BV, 2006 U.S. Dist. LEXIS 63063 (M.D.N.C. Aug. 31, 2006).

The question is, given the difficulty with developing salts, would it have been obvious to an average person of the art to try to use the lactate in a similar manner to that described in the Application, with a reasonable likelihood of success?

The Applicant claims that the choice of the lactate salt was counter-intuitive and that the guiding rules for selecting an appropriate salt would teach away from the lactate.

rule of thumbThe Commissioner disagrees with the Applicant. Despite there being some rules-of-thumb for selecting salts that do not indicate the lactate, the Commissioner considers that in this instance, and following the teachings in the ‘577 publication, persons of the art would have a motivation to try the lactate salt as a possibility for Panobinostat.

Gould (page 209 left column) teaches that a salt with a low pKa generally gives a low pHmax in solution. Thus the solubility thereof is higher:

“If we consider physiological pH, a low pKa for a conjugate acid of high aqueous solubility, would appear to give the best change of obtaining the lowest pHmax and the highest aqueous salt solubility.”

Additionally, Stephenson (page 1610 right column) teaches that where the pH of a saturated solution is higher than the pHmax, there is a risk of disproportionation:

“When the microenvironmental pH exceeds the salt’s pHmax, the disproportionation reaction becomes “spontaneous” having a net negative free energy.”

FarydakThe pKa of the lactate is 3.85 and that of the saturated solution is Panobinostat lactate varies over the range of 5.65 to 6.8 (see Tomer’s testimony from the 24 Feb 2016 hearing, column 14 lines 17-18. The pHmax of Panobinostat is about 3 – paragraph 11 of the prescription information for Farydak which the Applicant manufactures from Panobinostat lactate. Submission of this document at the hearing was allowed in the interim ruling of 24 Feb 2016. Therefore in light of these values and the Gould and Stephenson publications, the Application claims that persons of the art would not choose the lactate due to its high pKa.

Despite the rule-of-thumb proposed by Gould that was cited by the Applicant, the Commissioner concludes that in the circumstances, persons of the art would have motivation to specifically choose the lactate.

Gould (Page 203 left column) teaches that due to the optimal properties, persons of the art will first try the hydrochloride. However, if the hydrochloride is shown to be inappropriate, persons of the art will test the efficacy of other salts:

“Because of simple availability and physiological reasons, the monoprotic hydrochlorides have been by far the most frequent (~40%) choice of the available anionic salt-forming species. Thus, there is clear precedent, and an overwhelming argument on many grounds to immediately progress to the hydrochloride salt and evaluate other forms only if problems with the hydrochloride emerge.

Gould (page 204 left column) teaches that the strength of the hydrochloride salt often causes a lowering of the pH of the solution. This lowering is liable to adversely effect dosages and the coating of the pill and to cause increased hygroscopy which adversely affects stability.

“With hydrochloride salts there is frequently an ‘overkill’ on acid strength, which leads to a very low pH for an aqueous solution (Nudelman et al., 1974) of the salt. This can limit the utility of hydrochloride salts in certain parenteral dosage forms, or lead to packaging incompatibilities with pharmaceutical metal containers (aerosols).

Other problems frequently arise as the result of the polar nature of hydrochloride salts. Their high hydrophilic nature… leads to water vapour sorption (hygroscopicity) which on occasion, may be excessive.”

thumb ruleConsequently, according to Gould, despite the hydrochloride salt being indicated by the rule-of-thumb, this is only an indication. The Applicant himself claims that the hydrochloride did not produce optimal results. Since this was the case, Gould would expect persons of the art to test other salts.

On page 18 of the ‘577 publication, the lactate salts are indicated as being pharmacologically acceptable forms of the claimed formulations:

“The compounds described above are often used in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, when appropriate, pharmaceutically acceptable base addition salts and acid addition salts, for example, metal salts, such as alkali and alkaline earth metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts, and sulfonate salts. Acid addition salts include inorganic acid addition salts such as hydrochloride, sulfate and phosphate, and organic acid addition salts such as alkyl sulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrate and lactate.”

Furthermore, on page 74 thereof, it is indicated that lactates of compounds 1-5 were prepared, and two of these share the formula 1e Markush group with panobinostat and are thus analogous to Panobinostat. The parties disagree as to the purpose that the ‘577 publication had to create the lactates. Under cross-examination, Dr Mutz testified that he had not participated in the test described in the ‘577 publication and cannot rule out the possibility that the lactate salt was solid during the testing.

Dr Mutz:               If I read this in the overall context my interpretation that this was done in solution but I have not done this experiment.

Commissioner:       also you cannot exclude that the starting point was solid?

Dr Mutz:                Yes.”

The burden of proof during Oppositions lies with the Applicant. In this instance, the Applicant could have produced evidence [in the form of Affidavits from the experimenters that show that the lactates obtained in the ‘577 publication were not crystallized and that there was a special reason for lactates of compounds 1and 2 being fabricated] that there was indeed no motivation to fabricate the panobinostat lactate] and didn’t, thus they failed to show that this wasn’t an obvious selection.

Furthermore, in the Gould paper, a drug called preylamine was mentioned as an example of an orally administered lactate salt. This provides further support that the use of lactate salts for orally administered drugs was known.

There was thus a motivation to try the lactate as a pharmacologically acceptable salt of Panobinostat.

Advantages and surprising results of using the lactate salt

The Applicant claims that the stability of the anyhydrate form of Panobinostat  lactate was surprising. This surprising determination which expresses itself in unexpected results is claimed by the Applicant as being an inventive step.

The question of something being surprisingly found to be the case is one of the tests of inventive step that is listed in Hughes Aircraft page 114:

An additional supporting test for inventive step is the reaction from the relevant people of the art. If the invention is surprising and is considered a game changer by persons of the art, it will be difficult to consider it as being self-evident.

For example, regarding IL 85096 to the Wellcome Foundation from 22 January 1993, on page 73 of the decision it is stated explicitly that proof of an unexpected advantage can be considered as an inventive step.

It will be noted that one cannot merely point out any and all advantages as providing an inventive step. If the advantage is predictable it may be insufficient to establish an inventive step. Furthermore, an expected advantage cannot be used to determine that an invention is not self-evident. As ruled in Hughes (page 114) this is a supporting test that, though inconclusive, can be indicative that there is indeed no inventive step. For example, in re Pfizer, it is stated that a surprising advantage discovered in an invention will not overcome a completely certain lack of inventiveness.

“Alternatively, we hold that even if Pfizer showed that amlodipine besylate exhibits unexpectedly superior results, this secondary consideration does not overcome the strong showing of obviousness in this case. Although secondary considerations must be taken into account, they do not necessarily control the obviousness conclusion. Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 768 (Fed. Cir. 1988). Here, the record establishes such a strong case of obviousness that Pfizer’s alleged unexpectedly superior results are ultimately insufficient.”

The Applicant claims that in development of the panobinostat salt, other compounds that are not pharmacologically acceptable and which are not used in commercial formulations were tested. For example, the gentisate [MF, this is the 2,5-dihydroxybenzoate (any salt of ester of gentisic acid)], malonate, exalate and propionate. The Applicant considers that the lactate is similarly exotic and the discovery that the anhydtrate salt was stable was quite surprising.

This discovery could indeed have been surprising, but in light of all of the above, this would not be sufficient to provide an inventive step in this instance. This decision is reached in light of Berge which indicates that lactates were used from the 1970s, and generally received FDA approval (table 1 in Berge). This makes it unlikely that the Applicant’s claim that selection of the lactate was inventive and that the advantages of so-doing were a surprise.

In light of the above, the Commissioner of Patents rules that the Applicant has not provided convincing evidence of an inventive step.

Double Patenting

The Opposer claims that in light of issued IL 154574 which is the national phase entry into Israel of the ‘577 PCT, issuing this application as a patent would be to give two patents for the same invention, which is a situation considered double patenting. This issue was discussed at length in the IL 203972 Novartis decision (published 2 Dec 2014). Since the Commissioner has ruled that there is no inventive step, the issue of double patenting is moot. He does, however note that there is no overlap between the claims of IL 154574 and those of the present invention. The IL 154574 claims panobinostat itself, whereas the present application claims the monohydrate and anhydrate polymorphs of the lactate salt thereof. Consequently, were the claims to be otherwise patentable, it does not seem that double patenting would be grounds of refusal.

The patent application is refused.

The Opposer may request costs in line with the guidelines in circular MN 80.

COMMENT

So once again, Unipharm™ goes forth to slay a pharmaceutical patent.  I was particularly unimpressed with the argument that “With reference the list of salts on page 18 of ‘577, the applicant alleges that this is a standard list of salts that is included in all applications of this type and does not teach the method of preparing a specific salt.” Good drafting does involve cutting and pasting lists and boiler-plate text but it cannot be done with impunity so that the Applicant can dismiss things stated as being the case, as not disclosed and subsequently claimed as being novel and inventive. Companies like Novartis should be thinking ahead when drafting applications and should be checking their own published art before filing new cases. This is elementary. It is what quality control is for.

In general, those working for the drug development industry will see this ruling as pro-generics and the generic industry will see Novartis as trying to protect the same invention twice, and accuse them of evergreening and other disreputable things.

Adi LevitPersonally, I was impressed with Zebulun Tomer and his pet litigator, Adi Levit. The pair are remarkably successfully oppose or invalidate patent applications and patents have been killing a block-buster drug a year. When the term ordinary persons of the art comes up in considering obviousness,

 

Tomers

I wonder are the Tomer family ordinary pharmacists or exceptionally bright and capable ones?

I am not a pharmacist. However, I did a special paper in chemistry in high school which was certainly higher than the five point chemistry matriculation that I tutored my daughter in last year. I then went on to study materials, which is at least related. Unlike his predecessor, Dr Meir Noam, who was a chemist, the current commissioner is neither a PhD nor a chemist, and I am also impressed with his obvious grasp of the material.

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