In a recent decision[1] dated 20 December 2023, the Single Judge of the Madras High Court while adjudicating an appeal against the refusal of Patent Application no. 7096/CHENP/2015, titled ‘2,2–Difluoropropionamide Derivatives of Bardoxolone Methyl, Polymorphic Forms and Methods of Use Thereof’; set aside the Controller’s refusal order dated 18 September 2020 in so far as the compound claims 1-6 are concerned and directed that the said claims may proceed to grant. The Court held that claims 1-6 are inventive and do not fall foul of Section 3(d) of the Patents Act, 1970 (‘Act’). The Court however, upheld the refusal of the composition claim 7, as being hit by Section 3(e) of the Act, for lack of synergy between the ingredients.
The Court held that the claimed invention which relates to polymorphic forms of a parent compound (RTA-408), that was made known to the public after the priority date of the claimed invention; does not qualify as a ‘known substance’ for purposes of Section 3(d) of the Act.
The Court also analysed the scope of polymorphic forms under Section 3(d) of the Act and held that the claimed polymorphic forms are not polymorphs of the compounds in the cited prior art documents owing to structural variation in the chemical composition.
On the aspect of inventive step, the Court held that the refusal order contains no reasons as to why a person skilled in the art would pick out the compound TX-63682 from the 100+ compounds disclosed in the cited prior art document D3 and arrive at RTA-408 by adding a methyl substituent in position 4a especially when there are many other compounds in D3 with a lower IC50 value. The Court held that a person skilled in the art could not have arrived at the claimed invention from D3 without the benefit of hindsight and the resultant recognition of TX-63682 as a structural analogue. The Court also held that the Controller failed to discuss the other claimed technical advancements such as ARE activation, increased expression of nrf2 target genes and its relevance in assessing inventive step.
Facts
The Appellant (Mr. Tony Mon George on behalf of ABBVIE Inc.) asserted that the claimed invention is in respect of two polymorphic forms, Forms A and B, of a compound called RTA-408 and compositions comprising the polymorphic forms with a pharmaceutically acceptable carrier. It was argued that the two polymorphic forms exhibit technical advancement over the existing knowledge in as much as they exhibit greater stability and are solvent-free, and exhibit superior anti-inflammatory, anti-oxidative and anti-proliferative properties. It was also pointed out that the publication date in respect of the RTA-408 patent was 31st October 2013, which is after the priority date of the claimed invention is 24 April 2013.
Section 3(d)
The Court held Section 3(d) is not applicable as the parent compound RTA-408 does not constitute a ‘known substance’, since it was published after the priority date of the claimed invention.
The Court then considered the issue as to whether the claimed polymorphic forms qualify as new forms of either 402-38 or TX 63682, as asserted by the Controller.
The Court observed that when a substance takes two or more crystalline forms with identical chemical composition as the said substance, the crystalline forms are referred to as polymorphic forms. Applying the same to the facts of the matter, the Court held that as between the compound 402-38 and the claimed invention, the admitted position is that the claimed invention contains additional fluorine atoms. Therefore, the chemical composition is different, and the claimed invention cannot be construed as polymorphic forms of 402-38. With respect to the compound TX-63682, the Court observed that the structure of the claimed invention contains di-methyl substitution and thus structurally differs from TX-63682. Accordingly, the Court held that despite the structural similarities between the claimed invention and TX-63682 or 402-38, the claimed invention cannot be considered as polymorphic forms of TX 63682 or 402-38.
Section 2(1)(ja) - Inventive step
The Appellant asserted that the claims are made for two polymorphic forms of RTA-408, each of which is identified by the distinct X-ray powder diffraction pattern comprising distinct peaks and melting points. In addition to the technical advancement that are common to the claimed invention and RTA-408, the additional properties claimed for the polymorphic forms were enhanced stability and solvent-free nature thereby reducing toxicity.
The Controller assailed inventive step of the claimed invention by asserting that the IC50 value of TX-63682 is lower and, therefore, TX-63682 has greater potency as regards suppression of IFN-y induced NO production. As regards stability and being solvent-free, the Controller contended that the said properties are inherent characteristics of the crystalline forms of any compound.
The Controller’s reasoning and the Court’s determination on inventive step, are summarized as follows:
The Controller held that prior art documents D1, D2 and the compound of the claimed invention have anti-inflammatory activity. The Court while concurring to the factual position, held that D1 does not qualify as prior art and, therefore, cannot form the basis of either novelty or obviousness analysis.
The Controller held that the anti-inflammatory activity of TX 63682, as measured by the IC50 value in prior art document D3, is greater than that of the claimed invention. Further, it would be obvious to a person skilled in the art to add a methyl group to TX 63682, which would lead to the claimed invention. Furthermore, the additional activity in other assays cannot be regarded as an advancement. The Court noted that D3 is an invention relating to more than 100 compounds and that TX-63682 is one of the compounds forming the subject of D3. The IC50 values of these compounds vary considerably and many compounds of prior art D3, such as TX-63522, TX-63558, TX-63811, TX- 63914, TX-63925, TX-63928 and TX-63929, have a lower IC50 value than TX-63682. The Court also noted that the complete specification of D3 contains comparisons between the IC50 values of the compounds forming the subject of D3 invention and RTA 402. Therefore, the Court held that there is no basis to establish why a person skilled in the art would pick out the compound TX-63682 from the 100+ compounds in D3 and arrive at RTA-408 by adding a methyl substituent in position 4a especially when there are many other compounds in D3 with a lower IC50 value, without the benefit of hindsight.
The Controller held that the x-ray diffraction pattern is an inherent property of each crystalline compound, and the crystalline non-solvate form cannot be treated as a new entity. The Controller also held that the polymorphic forms of a compound can be discovered without inventive merit. The Court held these conclusions to be untenable because RTA 408 is not a known substance and, therefore, the polymorphic forms thereof cannot be treated as obvious. The Court held that polymorphic forms are also entitled to a patent provided there is clear identification and enablement. In the instant case, the Court held that each polymorphic form is identified by the distinct x-ray powder diffraction pattern and melting point in the claims and the methods of production of Forms A and B are also fairly described in the complete specification.
Conclusion
This decision by the Madras High Court highlights a nuance of applying Section 3(d) in so far as the ‘known substance’ based exclusion under the said provision, is concerned. The Delhi High Court, in DS Biopharma Limited v. The Controller of Patents and Designs 2022/DHC/3563, unequivocally established the importance of identifying the ‘known substance’ and the ‘known efficacy’, in determining applicability of Section 3(d). It is easily deducible that ‘known substance’ means a substance that is ‘known’ or in other words published or made available to the public before the claimed invention. Merely because the claimed invention is a polymorph of a compound that is previously patented, does not automatically render the compound a ‘known substance’, unless the compound is published before the priority date of the claimed invention.
The Court also touched upon the aspect of ever-greening under Section 3(d) in cases of subsequent polymorphic patents of already granted product patents; specifically observing that the term of the polymorphic patent in the instant appeal exceeds the product patent by only one year. It is stated that irrespective of the term of such polymorphic patents, if such patents can demonstrate inventive step (in addition to novelty and industrial applicability) and are able to overcome Section 3(d), whether by asserting non-applicability of 3(d) or by demonstrating enhanced efficacy of the polymorphic forms; they are liable to be granted under the scheme of the Patents Act, 1970.
[The author is a Partner in IPR practice at Lakshmikumaran & Sridharan Attorneys]
[1] (T) CMA (PT) No. 150 of 2023
