T 1684/16 - Screening for polymorphs

Key points

• Polymorphs are commercially important. Typically, medically active molecules can exist in different solid-state forms (crystal forms) which can have different properties, such as one polymorph having better storage stability (hence, the differences are typically not in the basic medical activity). A patent on a polymorph can be used effectively to extend the patent term because for regulatory reasons, generic companies can not easily use a different polymorph (e.g. “pharmaceutical polymorphs provide an excellent way for a company to further protect a small molecule drug in order to recoup the billions of dollars that go into research and development, thereby enabling further research and development” (link, emphasis added).
• The big obstacle to getting a patent for a polymorph is as of yet T 777/08 (Atorvastatin) holding that as of 1995, screening for polymorphism was routine in the art such that “in the absence of any unexpected property, the mere provision of a crystalline form of a known pharmaceutically active compound cannot be regarded as involving an inventive step”. 
• The present Board: “The fact that the skilled person is taught in the prior art to investigate polymorphs in order to isolate the crystalline form having the most desirable properties is in itself not necessarily sufficient to consider a specific polymorphic form having a certain desired property obvious”.
• The present Board: “The board acknowledges that, in view of their disclosures, D4, D5 and D7 teach the investigation of polymorphs in order to isolate the crystalline form having the most desirable properties. This in itself is not sufficient to deny inventive step, however. Only if the prior art contains a clear pointer that it is the claimed subject-matter that solves this problem or where it at least creates a reasonable expectation that a suggested investigation will be successful, can inventive step be denied. In this case, however, there is no clear pointer in any of D4, D5 or D7 that it is the specific crystalline Form I as defined in claim 1 that is the most stable form. ”
• The present Board: “the decision in T 777/08 is concerned with the arbitrary selection of any crystalline form and considers it obvious that any arbitrary crystalline form has better filterability and drying characteristics than the corresponding amorphous form. This is entirely different from the present case. The present case is NOT about the selection of any crystalline form but about the selection of one specific crystalline form, namely Form I of bosutinib monohydrate. Furthermore, the selection of this specific crystalline form is not arbitrary, but rather this form has unexpected properties, namely an improved stability when compared with the other crystalline forms in D1, D2 and D3.”
• I note that in T 777/08, the “solution as defined in claim 3 of the main request and claim 1 of the auxiliary request relates to a specific polymorph of atorvastatin” namely “form IV of crystalline atorvastatin hydrate”. The technical effect was " shorter filtration and drying times for form IV compared to the amorphous form". In T 777/08, “the appellant further argued that the presence of an inventive step was supported by the fact that a specific polymorph was being claimed rather than crystalline forms in general. The board does not deny that there may be other options for solving the problem posed []. However, an arbitrary selection from a group of equally suitable candidates cannot be viewed as involving an inventive step”.

EPO T 1684/16 -  link

Reasons for the Decision

4.3 Inventive step in view of D1, D2 or D3 as the closest prior art

4.3.1 As set out above, the compound in claim 1 of the first auxiliary request is a specific crystalline form of bosutinib monohydrate ("Form I"). The patent aims to provide methods for preparing this form and pharmaceutical compositions containing this form for the treatment of pancreatic and prostate cancer (paragraph [0001] of the patent).

4.3.2 Closest prior art

D1, D2 and D3 disclose solid/crystalline forms of bosutinib.

In accordance with the parties' submissions, any of D1, D2 and D3 may be regarded as the closest prior art.

In D1, D2 and D3, the products are described as a "light pink solid" having a melting point of 116-120°C in D1 (example 1), a solid having a melting point of 125-128°C in D2 (example 50) and a crystalline solid in D3 (example 45). There is no indication that the crystalline form is obtained in D1 and D2, and no indication of the specific nature of the crystalline form obtained in D3. The distinguishing feature is thus the specific crystalline form of bosutinib monohydrate ("Form I"), as defined in claim 1.

4.3.3 Technical problem

The technical effect associated with the distinguishing feature is a stable crystalline form as shown by D16. Table 1 of D16 in conjunction with figure 1 shows that Form I maintained its appearance, purity, water content and crystallinity after being exposed to a temperature of 70°C and 75 % relative humidity for two weeks (points 9 and 15 of D16). Under the same conditions, the crystalline forms of example 1 of D1 (table 2 and figure 2), example 50 of D2 (table 3 and figure 3) and example 45 of D3 (table 4 and figure 4) changed significantly during stability testing and were hygroscopic (points 8, 16-18 of D16).

For these reasons, the objective technical problem is to provide a form of bosutinib that is more stable. Following the board's decision not to admit the appellant's new allegations of facts and to take D16 into account, this was not challenged by the appellant.

4.3.4 Obviousness

The appellant submitted that the claimed solution was obvious since screening of polymorphs was a routine task as demonstrated by D4, D5 and D7. It submitted that there was a reasonable expectation of success for the skilled person as regards whether Form I of bosutinib monohydrate would maintain its stability in terms of appearance, purity, water content and crystallinity after being exposed to 70°C and 75 % relative humidity for two weeks.

D4 (p. 83055) discloses a flow chart for investigating the need to set acceptance criteria for polymorphism in drug substances and drug products. The chart shows the steps of conducting polymorphism screening on drug substances and characterising the form by X-ray powder diffraction, DSC/thermoanalysis, microscopy and spectroscopy (step 1) and of establishing the different properties (solubility, stability and melting point) of the forms (step 2).

D5 (p. 945, first paragraph) discloses that "Interest in the subject of pharmaceutical solids stems in part from the Food and Drug Administration's (FDA's) drug substance guideline that states "appropriate" analytical procedures should be used to detect polymorphic, hydrated, or amorphous forms of the drug substance. These guidelines suggest the importance of controlling the crystal form of the drug substance. The guideline also states that it is the applicant's responsibility to control the crystal form of the drug substance and, if bioavailability is affected, to demonstrate the suitability of the control methods". D5 (p. 946, paragraph A; figure 1) also refers to a flow chart outlining the investigations of the formation of polymorphs, the analytical tests available for identifying polymorphs and studies of the physical properties of polymorphs.

D7 (abstract) purports to provide rapid screening methods to identify solid forms with enhanced properties. Like D4 and D5, D7 refers to the need for screening to identify polymorphs, but it proposes only a general method for producing and screening them. The last paragraph of point 4.8 of D7 (p. 34) teaches that different polymorphs of a given compound are different in structure and properties and that solubility and stability, inter alia, vary with the polymorphic form.

The board acknowledges that, in view of their disclosures, D4, D5 and D7 teach the investigation of polymorphs in order to isolate the crystalline form having the most desirable properties. This in itself is not sufficient to deny inventive step, however. Only if the prior art contains a clear pointer that it is the claimed subject-matter that solves this problem or where it at least creates a reasonable expectation that a suggested investigation will be successful, can inventive step be denied. In this case, however, there is no clear pointer in any of D4, D5 or D7 that it is the specific crystalline Form I as defined in claim 1 that is the most stable form. There is in particular no teaching in the cited prior art that Form I of bosutinib monohydrate would have maintained its appearance, purity, water content and crystallinity after being exposed to 70°C and 75 % relative humidity for two weeks, in contrast to other crystalline forms.

D4 (p. 83055, first question in point 2) and D5 (figure 1) question whether newly discovered polymorphs have different properties. Therefore, and without there being any indication in D7, it is entirely unpredictable which crystalline form is the most stable one. This unpredictability is confirmed by D18. D18 (p. 3640, right-hand column, first sentence) states that "The problem is further complicated by the possibility of obtaining different solvate forms. One can say that if the formation of polymorphs is a nuisance for crystal engineers, solvate formation can be a nightmare, because it is extremely difficult to predict whether a new species may crystallize from solution with one or more molecules of solvent." (emphasis added by the board). D18 emphasises the difficulty of predicting the formation of solvates, which constitutes an additional factor in the unpredictability taught by D4 and D5. Therefore, the unpredictability of polymorphism screening does not represent a reasonable expectation that the specific crystalline Form I as defined in claim 1 would be the most stable form.

The skilled person, starting from the solid bosutinib disclosed in any one of D1, D2 and D3, would thus have found no incentive in D4, D5 and D7 to prepare Form I of bosutinib monohydrate (which is a solvate) in order to provide a form of bosutinib that is more stable nor could he derive a reasonable expectation that a more stable form of bosutinib would be found as a result of the suggested screening.

The appellant submitted that the solution was obvious in the light of T 777/08; however, the present case differs from the situation at issue in decision T 777/08.

In T 777/08, "the skilled person in the field of pharmaceutical drug development would have been aware of the fact that instances of polymorphism were commonplace in molecules of interest to the pharmaceutical industry, and have known it to be advisable to screen for polymorphs early on in the drug development process. Moreover, he would be familiar with routine methods of screening. Consequently, in the absence of any technical prejudice and in the absence of any unexpected property, the mere provision of a crystalline form of a known pharmaceutically active compound cannot be regarded as involving an inventive step. When starting from the amorphous form of a pharmaceutically active compound as closest prior art, the skilled person would have a clear expectation that a crystalline form thereof would provide a solution to the problem of providing a product having improved filterability and drying characteristics. The arbitrary selection of a specific polymorph from a group of equally suitable candidates cannot be viewed as involving an inventive step" (headnote 1 and 2, emphasis added by the board).

Hence, the decision in T 777/08 is concerned with the arbitrary selection of any crystalline form and considers it obvious that any arbitrary crystalline form has better filterability and drying characteristics than the corresponding amorphous form. This is entirely different from the present case. The present case is NOT about the selection of any crystalline form but about the selection of one specific crystalline form, namely Form I of bosutinib monohydrate. Furthermore, the selection of this specific crystalline form is not arbitrary, but rather this form has unexpected properties, namely an improved stability when compared with the other crystalline forms in D1, D2 and D3.

4.3.5 Based on the above considerations, the board comes to the conclusion that, having regard to the cited prior art, it was not obvious to the skilled person to isolate Form I of bosutinib monohydrate and to arrive at the compound as defined in claim 1 as granted.

Therefore the subject-matter of claim 1 and, by the same token, of all remaining claims of the first auxiliary request involves an inventive step.