In a recent case, Takeda Pharmaceutical Co Ltd. vs Controller of Patents and Designs and Ors. [IPDPTA/119/2023], brought before the Calcutta High Court, the Appellant sought to set aside the order passed by the Controller concerning the refusal of the Appellant’s application number 3939/KOLNP/2010, entitled “Phosphorous Derivatives as Kinase Inhibitors”. The refusal was based on the grounds of lack of inventive step under Section 2(1)(ja), patent ineligibility under Section 3(d), and insufficiency of disclosure under Section 10(4) of the Patents Act, 1970.

The subject application disclosed a new pharmaceutical compound, Brigatinib, purported to be effective in treating protein kinase associated diseases such as cancer. Brigatinib was claimed to exhibit improved selectivity in inhibiting anaplastic lymphoma kinase (ALK), while significantly reducing inhibition of other kinases such as the insulin receptor (Ins-R). Ins-R inhibition is considered clinically undesirable due to its association with insulin resistance and related metabolic disorders. By preferentially targeting ALK and minimizing off-target interactions with Ins-R, the application asserted that Brigatinib involved a technical advancement and provided enhanced therapeutic efficacy.

Notably, the originally filed claims covered a broad Markush structure covering a group of compounds, including Brigatinib. The complete specification included experimental data for a few such compounds (not for Brigatinib itself), with inhibitory activity expressed via IC50 values. During the course of prosecution, the claims were amended to cover only Brigatinib. After the hearing, the applicant submitted additional experimental data highlighting Brigatinib’s improved selectivity for ALK over Ins-R, in support of the narrowed claims.

Despite these submissions, the Controller refused the application on the following grounds of:

• Obviousness: The Controller held that the claimed compound, Brigatinib, differed from the known compound, TAE-684, only by the substitution of a sulfonyl group with a phosphoryl group. This substitution was considered obvious to a person skilled in the art (PSITA) in view of bioisosterism teachings in the cited prior arts.
• Lack of Adequate Data to Support the Claim of Technical Advancement and Enhancement of Efficacy:  The Controller held that the claimed technical advancement of Brigatinib improving ALK selectivity was not supported by the as-filed specification. It was observed that while the specification included IC50 data for some kinase inhibitors, Brigatinib itself was not among those compounds. Because Brigatinib’s specific efficacy data was provided only in the post-hearing submissions, the Controller inferred that the Appellant had not recognized the compound’s technical advantage at the time of filing, and, therefore, the additional data was not taken on record.
• Insufficiency of Disclosure: The Controller noted that the specification merely described a process for the preparation of Brigatinib and did not include any evidence demonstrating the compound’s ALK inhibitory activity. This, the Controller reasoned, was inadequate to support a product claim directed to a pharmaceutical compound.

The Appellant challenged the impugned order before the Calcutta High Court, arguing that:

• The Controller’s analysis of inventive step was affected by hindsight bias. It was contended that the Controller first identified the structural similarity between Brigatinib and compounds known in the prior art, and then a rationale was constructed retroactively, without explaining why a PSITA would have found the substitution obvious.
• The Controller erred in disregarding the additional experimental data and affidavits submitted post-hearing, which demonstrated improved selectivity of Brigatinib for ALK over Ins-R, technical advancement and enhanced therapeutic efficacy.
• The additional data was within the scope of the as-filed disclosure and did not present any new or additional features of the claimed invention.
• The Controller failed to appreciate that even a single functional group substitution can result in significant alterations in a compound’s properties. It was argued that cited prior art references discussed bioisosterism in the context of herbicidal compounds, not therapeutics. It was, thus, emphasized that the possibility of such substitutions leading to selective kinase inhibition was not taught or suggested in the cited prior arts.
• The order lacked reasoning and was in violation of the principles of natural justice.

In response, the Controller maintained that the Appellant had failed to furnish evidence of technical advancement and enhanced efficacy possessed by Brigatinib.

The Court allowed the appeal and set aside the impugned order. The key observations of the Court included the following:

• On Obviousness: Placing reliance on F. Hoffmann-La Roche Ltd. vs Cipla Ltd. [2015 SCC OnLine Del 13619] and Bristol-Myers Squibb Holdings Ireland Unlimited Company vs BDR Pharmaceuticals International Pvt. Ltd. [2020 SCC OnLine Del 1700], the Court found that the Controller had failed to properly assess the evidence and submissions of the Appellant. The Court concurred with the submissions of the Appellant that mere structural similarity between claimed compound and known compound does not render an invention obvious, and any such conclusion must be supported by a clear rationale explaining why the compounds are structurally similar and how the teachings of the prior art would have led a PSITA to the claimed invention.
• On Technical Advancement and Enhancement in Therapeutic Efficacy: The Court observed that the specification disclosed the effectiveness of few exemplified compounds using IC50 values, and additional data demonstrated Brigatinib’s increased selectivity for ALK over Ins-R using IC50 values, which consequently resulted in improved therapeutic efficacy. The Court alluded that submissions made “during the process of hearing before passing the impugned order” ought to be allowed and considered by the Controller. The Court underscored that there is no statutory bar under the Patents Act, 1970, against filing additional documents after the filing of patent claims. Emphasizing that developing a pharmaceutical drug is an inherently lengthy process, the Court held that data submitted post-filing to substantiate technical effect and therapeutic efficacy must be duly considered.
• On Sufficiency of Disclosure: The Court found the Controller’s reasoning on sufficiency of disclosure to be contradictory. The Controller acknowledged that the specification disclosed a process for the preparation of Brigatinib, yet refused to recognize that the requirements of Section 10(4) were fulfilled. Noting that Brigatinib had been selected from a class of compounds originally claimed as a Markush structure during the prosecution of the application, the Court stressed that when dealing with a novel compound, the requirement of sufficiency of disclosure is met when the structure of the compound and the method of its preparation are disclosed. The Court remarked that the presence or absence of data to demonstrate technical effect relevant for assessment of inventive step and therapeutic efficacy to overcome patent ineligibility under Section 3(d), should not be conflated with the disclosure requirements under Section 10(4). Additionally, the Court observed that no objection regarding insufficiency had been raised in the First Examination Report, and that it was only after the pre-grant opponent raised the objection, that the Controller, applying hindsight, refused the application on this ground. The Court also remarked that the Controller had disregarded the fact that corresponding patent applications had been granted in other jurisdictions without any objection concerning insufficiency of disclosure.
• On Disregarded Evidence of Industrial Acclaim and Global Recognition: The Court noted that the invention had been granted patent protection in over fifty countries, and that the legal standards for assessing inventive step are largely consistent across jurisdictions, therefore, the same should have been given weightage. The Court also observed that the Controller failed to consider evidence demonstrating Brigatinib’s technical advancement and industry recognition which included:
  • US FDA approval of Brigatinib as a front-line therapy for ALK-positive metastatic non-small cell lung cancer, attributed to its superior progression-free survival outcomes;
  • articles published in peer-reviewed journals highlighting the comparative advantages of Brigatinib over existing drugs; and
  • expert affidavits

In view of the foregoing, the Court set aside the refusal order and remanded the matter to the Patent Office for fresh consideration upon consideration all materials on record.