Celator’s Patent Upheld against Post-Grant Oppositions filed by Cipla and Mylan

Kan and Krishme successfully represents patentee in landmark post-grant opposition against Indian pharmaceutical companies:

Introduction

The Indian Patent Office (IPO) has upheld Indian Patent No. 315447 in favor of Celator Pharmaceuticals Inc., dismissing post-grant oppositions filed by Cipla Ltd. and Mylan Laboratories Ltd. This landmark ruling affirms the strength of Celator’s patent covering its novel lyophilized gel-phase liposomal composition encapsulating daunorubicin and cytarabine.

Kan and Krishme’s Mr. Sharad Vadehra (Managing Partner), Ms. Shikha Baiswar (Senior Partner), and Ms. Reena M.P. Singh (Partner), represented Celator Pharmaceuticals in the post-grant opposition proceedings and successfully secured this outcome after rigorous written and oral advocacy. The 172-page order can be found here.

Facts

Celator Pharmaceuticals Inc. filed patent application no. 4087/DELNP/2014 for a novel lyophilized gel-phase liposomal composition encapsulating two therapeutic agents i.e., cytarabine and daunorubicin, wherein gel-phase liposomes exhibit a melting phase temperature (Tc) of at least 37°C without internal cryoprotectant. The patent was granted on July 3, 2019.

Two leading Indian pharmaceutical companies Cipla Ltd. (Opponent 1) and Mylan Laboratories Ltd. (Opponent 2) filed post-grant opposition on the following grounds:

Ground I: Section 25 (2)(b) – Lack of Novelty due to prior publication
Ground II: Section 25 (2)(d) – Prior public use/Prior knowledge
Ground III: Section 25(2)(e) – Obviousness/lack of inventive step
Ground IV: Section 25(2)(f) – Not an invention (3d and 3e)
Ground V: Section 25(2)(g) – Insufficiency of Disclosure
Ground VI: Section 25(2)(h) – Non-compliance with Section 8

Cipla and Mylan relied on various prior art documents including published patent applications, clinical studies, and scientific literature (D1 to D5 and O1 to O7 respectively).

After receipt of the notice of the post-grant oppositions, our team at Kan and Krishme filed a detailed statement and evidence on behalf of Celator Pharmaceuticals to contest the oppositions. Oral hearings were conducted on June 21, 2024, with all parties provided an opportunity to present their arguments.

Opponents’ Submissions

Anticipation and Prior Publication – The Opponents cited D1 (a clinical study of CPX-351), and O1 (WO2006055903) respectively to establish that the claimed invention was anticipated. They contended that D1 and O1 discloses lyophilized liposomal formulation with similar components and characteristics, in absence of internal cryoprotectant.

Lack of Inventive Step – The Opponents argued that cited documents D1 to D5 and O1 to O7 rendered the invention obvious. They mentioned that these documents already taught lyophilized formulations with similar liposomal compositions. According to them, combining known elements from these documents would have been within the routine capability of a skilled person.

Section 3(d) –New Form of a Known Substance – The Opponents argued that invention was a new form of a known substance without enhanced therapeutic efficacy. They submitted that the lipid components and drug ratios were already known from prior art (e.g., CPX-351). Further, no experimental data had been provided to show significantly enhanced therapeutic efficacy over known formulations.
Section 3(e) – Mere Admixture – The Opponents asserted that claimed invention is a substance obtained by mere admixture resulting only in the aggregation of properties of the components without any synergistic effect.

Insufficiency of Disclosure – The Opponents contended that the patent lacks sufficient disclosure in complete specification that a person skilled in the art would be unable to perform the invention across its full breadth without undue experimentation.

Arguments by the Patentee

Represented by Mr. Sharad Vadehra, Ms. Shikha Baiswar and Ms. Reena MP Singh of Kan and Krishme

Anticipation and Prior Publication – The patented lyophilized gel-phase liposomal composition is prepared with daunorubicin and cytarabine in the absence of any internal cryoprotectant. Since each and every feature of the claimed invention is not disclosed in the cited document D1 or O1, the claimed invention is novel and not anticipated by prior publication or prior claiming.

Lack of Inventive Step – The Opponents failed to define the “person skilled in the art”. Further, by applying the 5-step inventive step test¹, Opponents failed to show how cited references would motivate a skilled person to arrive at the claimed invention. Further, none of the cited prior art teach or suggest lyophilizing the liposomes with substantially no internal cryoprotectant and maintaining mean diameter, and drugs are retained in the liposomes following reconstitution in a pharmaceutical carrier. It was emphasized that unexpected technical effect of the patent is that a liposomal formulation of daunorubicin and cytarabine is provided which is able to safely and synergistically treat cancer, in particular acute myeloid leukaemia (AML), even after it has been stored for a long period. This inventive concept cannot be derived from any of the cited prior arts.

Section 3(d) – Mere New Form of Known Substance – The invention relates to a novel lyophilized gel-phase liposomal composition. Further, as per DS Biopharma Limited v. The Controller of Patents and Designs And Anr.,² Section 3(d) requires opponent/Controller to:
1. Identify the “known substance”.
2. Prove that the claimed invention is a “new form” of it.

No such identification was done. Further, enhanced stability, size retention, and drug encapsulation after long storage establish enhanced efficacy (supported by data in Examples 2 & 3 of complete specification and additional data also submitted in the form of declaration) of lyophilized gel-phase liposomal composition. Relying on Novozymes vs. Assistant Controller of Patents,³ it was argued that efficacy under 3(d) is not restricted to therapeutic efficacy alone, it may include stability or functional improvement. It was argued that claimed invention improves efficacy via enhanced stability and drug retention. Thus, the claims fall outside the scope of Section 3(d).

Section 3(e) – Mere Admixture – Relying on British Celanese Ltd., v. Courtaulds Ltd.,⁴ it was argued that Section 3(e) is not applicable to the claimed invention because: “The claimed invention is a synergistic composition i.e. lyophilized gel-phase liposomal Composition characterized by both structural and functional features. Further, the individual components are added in specific ranges or concentrations which resulted in unexpected advantages of the end product i.e., long term stability of the liposomal composition. Further, it maintains liposomal integrity, drug ratio, and size after lyophilization and reconstitution. Thus, claimed composition is not a mere “admixture” but shows the synergy and unexpected technical advancement.”

Sufficiency of disclosure: It was argued that it is not necessary to exemplify all the embodiments and the best method to perform the invention is sufficiently disclosed. Further, detailed support of the embodiments was provided in the complete specification and working examples.

Controller’s Finding

Despite the Opposition Board’s recommendation for revocation, the Controller adopted a different view, noting that the Opponents failed to identify the Person Skilled in the Art (PSITA) and did not establish how such PSITA would be motivated to combine the cited prior art to arrive at the claimed invention. The Opponents merely stated that the invention constitutes a new form of a known substance but failed to identify the specific known substance. They could neither establish that the claimed composition is a mere admixture nor substantiate their allegation of insufficiency of disclosure. In contrast, the Patentee, through Kan and Krishme’s representatives, effectively demonstrated that a PSITA would not be motivated to arrive at the present invention and provided clear evidence, through examples in the specification and supporting data, that the invention has inventive step, exhibits enhanced efficacy, has synergistic effect and sufficiently disclosed in the specification:

Anticipation and Prior Publication – The Controller of Patents held that neither O1 nor D1 clearly and unambiguously discloses all the essential features of the claimed invention in a single enabling disclosure. Thus, claims as granted meet the requirements of novelty.

Lack of Inventive Step – The claimed invention represents a significant and non-obvious advancement over the prior art references D1 – D5 and O1-O7. None of these documents disclose or suggest the critical technical features of the patent, namely the lyophilization of liposomal pharmaceutical compositions in the substantial absence of internal cryoprotectants, while maintaining drug stability and therapeutic efficacy. Experimental data, particularly from Examples 2 and 3, substantiate the claimed advantages, showing minimal drug leakage and consistent maintenance of the synergistic 1:5 daunorubicin/cytarabine ratio, even after extended storage periods. This ensures effective treatment of AML upon reconstitution, a result that would not have been expected by a person skilled in the art at the priority date. The invention thus meets the legal criteria for inventive step.

Section 3(d) – Mere New Form of Known Substance – The claimed invention is not merely a new form of a known substance but a novel lyophilized gel-phase liposomal composition characterized by specific membrane properties that preserve liposome integrity during lyophilization and reconstitution. Unlike prior art, present invention effectively prevents drug leakage and liposomal size increase. This represents an unpredictable and significant technical advancement. The data as presented, confirm the stability and efficacy of the composition for up to nine months, clearly demonstrating enhanced therapeutic efficacy. Thus, claimed invention does not fall under the purview of Section 3(d) of the Act.

Section 3(e) – Mere Admixture – The claimed invention is a synergistic composition wherein the components interact in specifically defined ranges to achieve unexpected advantages, including long-term stability, retention of encapsulated drugs, and maintenance of liposome size post-reconstitution. The data provided supports the stability and synergistic behavior of the composition.

Sufficiency of disclosure – The specification includes detailed descriptions, working examples, and the best method known to the Applicant for performing the invention. Thus, this ground of opposition is without merit.

Conclusion

The IPO’s decision in favor of Celator Pharmaceuticals, Inc. marks an important precedent in Indian Patent Law particularly with respect to complex pharmaceutical matters. It highlights the importance of an optimistic approach to evaluate novelty, inventive step, and patentability that considers not only structural differences but also functional advantages.

This ruling reinforces that novelty must be assessed based on single enabling disclosure. Further, inventive step is not merely about individual elements; their combination should results in unexpected properties/effects. It also clarifies that the requirement of enhanced efficacy under Section 3(d) may be interpreted more broadly than just therapeutic action and the improvements in stability and overall effectiveness of the composition can also satisfy the requirement of Section 3(d).

Further, there has long been a perception, especially among international applicants, that in technically complex matters, outcomes may tilt in favor of Indian opponents, especially well-established pharma companies. This case firmly defies that assumption. This ruling proves that strong patents can and will survive rigorous scrutiny when supported by sound science and compelling advocacy.