The Delhi High Court, in Intra-Cellular Therapies, Inc. vs Controller of Patents [C.A.(COMM.IPD-PAT) 24/2023], examined the patentability of pharmaceutical species claims arising from an earlier genus disclosure. The Court considered whether specific deuterated compounds claimed in the application were novel over the applicant’s own earlier patent publications, whether the “multiple selections” argument could preserve novelty, and whether the claimed compounds overcame the bar under Section 3(d) of the Patents Act.

The appeal challenged the refusal of patent application number 201817033732, entitled “Organic Compounds”, which had been refused by the Controller on the grounds of lack of novelty, lack of inventive step and non-patentability under Section 3(d).

In dismissing the appeal, the Court held that where a claimed compound is already covered by the claims of an earlier genus patent, the absence of an explicit individual disclosure does not preserve novelty. The Court further reiterated that improvements in pharmacokinetic properties or metabolic stability, without evidence of enhanced therapeutic efficacy, are insufficient to overcome the exclusion under Section 3(d).

The subject application related to particular deuterated heterocycle-fused gamma-carbolines, in the form of free, pharmaceutically acceptable salt and/or substantially pure form. The claimed compounds were intended for treating disorders involving the 5-HT2A receptor, serotonin transporter (SERT) and dopamine D1/D2 receptor signalling pathways, including schizophrenia, psychosis, anxiety and related disorders. The invention sought to improve the metabolic profile of previously known compounds through selective deuteration while maintaining their pharmacological activity.

The Appellant challenged the Controller’s findings on all three grounds and argued that the impugned order suffered from both substantive and procedural infirmities.

Novelty

The Appellant primarily contended that the Controller had incorrectly assessed novelty by relying upon multiple prior art documents (D1 and D7) instead of evaluating novelty against a single anticipatory disclosure. It was argued that:

• the novelty objection had not been raised during the first hearing notice and was introduced only in the second notice;
• the Controller wrongly treated multiple documents as constituting the closest prior art;
• the European Patent Office had considered the same prior art documents and nevertheless acknowledged novelty of the corresponding claims.

The Appellant further argued that arriving at the claimed compounds from D1 or D7 would require a person skilled in the art (PSITA) to perform multiple independent selections from broad Markush disclosures before reaching the claimed compounds.

The Appellant submitted that D7 broadly disclosed deuteration at several positions but did not specifically teach the particular substitutions eventually claimed. Moreover, subsequent research allegedly demonstrated that other deuterated variants covered by D7 failed to achieve the same advantages as the presently claimed compounds.

Inventive Step

The Appellant argued that:

• the impugned order merely concluded that combining D1 and/or D7 with D4-D6 (which disclosed the ‘principle of using deuterated alternatives of known drugs’) rendered the invention obvious without explaining why a PSITA would combine those teachings;
• the Controller simply reproduced conclusions without identifying any technical teaching leading from the prior art to the claimed invention.

Failure to Consider Experimental Evidence

The Appellant also argued that the Controller ignored significant experimental evidence contained in the complete specification and supporting affidavits.

The Appellant relied upon comparative in vivo studies in mice; pharmacokinetic studies in rats; comparative studies in dogs; and the affidavit of the co-inventor submitted on multiple occasions during prosecution. These experiments allegedly demonstrated reduced metabolism; improved plasma exposure; increased metabolic stability; and favourable pharmacokinetic characteristics when compared with the corresponding non-deuterated compound.

Section 3(d)

The Appellant also challenged the Controller’s application of Section 3(d). It was argued that:

• the Controller never identified the “known substance” against which Section 3(d) was being invoked;
• the Controller conflated the requirements for novelty/inventive step with those applicable under Section 3(d);
• the rejection merely stated that since the compounds lacked novelty, they were also barred under Section 3(d), without undertaking the independent enquiry mandated by law.

Reliance was placed upon decisions in D.S. Biopharma Ltd. and Taiho Pharmaceutical Co. Ltd., wherein the Delhi High Court had held that a valid Section 3(d) objection requires identification of:

• the known substance with known efficacy;
• the basis for treating the claimed invention as its derivative or new form; and
• an objective comparison of therapeutic efficacy.

According to the Appellant, none of these elements were present in the Controller’s analysis.

Court’s Analysis and Findings

Novelty

The Court undertook an independent comparison of the claimed deuterated compounds with the disclosures contained in the cited prior art documents and ultimately concurred with the Controller’s finding that the claims lacked novelty.

• Prior Art D1 Disclosed Formula IV Claimed in the Application

The Court noted that D1 related to substituted heterocycle fused gamma-carbolines intended for the same therapeutic applications as the present invention. Examining Example 1.21 of D1, the Court observed that it disclosed the precise combination of substituents which, upon comparison, corresponded to Formula IV claimed in Claims 4 to 7 of the subject application.

• Prior Art D7 Disclosed Formulae I-III

The Court analysed D7, which also related to deuterated heterocycle fused gamma-carboline compounds intended for substantially the same therapeutic applications. Upon examining the structural formulae and Claim 1 of D7, the Court concluded that the combinations claimed in the subject application as Formulae I-III (Claims 1-3 and 5-10) were likewise encompassed within the earlier disclosure.

• Multiple Independent Selections

Rejecting the Appellant’s contention that the claimed compounds could only be arrived at through multiple selections from D1 or D7, the Court observed that where a compound is “covered” by the claims of an earlier genus patent, it is immaterial whether the compound has also been specifically disclosed.

Section 3(d)

Rather than merely affirming the Controller’s conclusion, the Court undertook its own analysis of the specification and the experimental data relied upon by the Appellant.

• Revisiting the Scope of Section 3(d)

The Court considered the statutory framework of Section 3(d) and reiterated the principles laid down by the Supreme Court in Novartis AG vs Union of India. The Court reiterated that in the context of pharmaceutical inventions:

• “efficacy” means therapeutic efficacy, not merely improved physicochemical or pharmacokinetic properties;
• bioavailability is “one of the pharmacokinetic parameters and not a direct measure of therapeutic efficacy”,
• therefore, whether increased bioavailability enhances therapeutic efficacy “must be specifically claimed and established by research data”.
• The Court Identified Formula Q as the Known Substance

The Appellant had argued before the Court that the Controller had failed to identify the “known substance” against which Section 3(d) was being invoked. However, while undertaking its own analysis, the Court observed that compound Q (disclosed in prior art documents D1 and D7) was ‘admittedly’ a known compound from which the claimed deuterated compounds were derived.

• Detailed Examination of Example 7

Unlike the Controller, the Court carefully analysed Example 7 contained in the specification and noted that Example 7 compared the deuterated compound claimed in Example 2 and the non-deuterated compound Formula Q through in vivo pharmacokinetic studies in dogs following both sublingual administration and subcutaneous administration. The Court noted that the results demonstrated a 72% higher parent-drug AUC following sublingual dosing and altered Q-1A metabolite ratios. The AUC values were calculated to compare the pharmacokinetic behaviour of the two compounds.

The Court accepted that the data suggested that deuteration:

• reduced metabolism;
• produced higher plasma concentrations of the parent compound; and
• improved metabolic stability by inhibiting oxidation of the demethylated metabolite.

However, the Court held that none of these findings, by themselves, demonstrated that patients would experience an improvement in the therapeutic effect of the drug. It merely showed enhanced bioavailability, and “enhanced bioavailability does not, by itself, lead to enhanced therapeutic efficacy”. The Court remarked that there was no research data to show that improved bioavailability translated into a therapeutic effect.

• Co-inventor’s Affidavit

The Court examined the affidavit, which had been disregarded the Controller, on merits. The Court remarked that the affidavit merely reiterated the experimental findings already disclosed in the specification and primarily highlighted improvements in bioavailability, plasma exposure and metabolic stability. Further, the Court observed that the data showed that the deuterated compound and Formula Q had“substantially similar pharmacological activity” and the same did not indicate enhanced therapeutic efficacy. Accordingly, the Court held that the affidavit did not cure the deficiency under Section 3(d).

Inventive Step

Having upheld the Controller’s findings on lack of novelty and non-patentability under Section 3(d), the Court found it unnecessary to undertake an examination of the inventive step objection.

In view of the above findings, the Delhi High Court dismissed the appeal and upheld the Controller’s refusal of the patent application.