The judgment issued by the Madras High Court in the patent dispute between Amgen and Intas has determined that the invention related to the lyophilisation of Romiplostim meets the criteria for inventiveness. Furthermore, the Court concluded that the claimed invention was not subject to exclusion from patent protection under Sections 3(d) or 3(e) of the Patents Act, 1970. Setting aside the order of the Controller, the Court directed patent application No. 5857/CHENP/2008 to proceed for grant, subject to the following amendments to independent claims 1 and 9:
- A lyophilized therapeutic peptibody composition comprising a buffer, a bulking agent, a stabilizing agent, and a surfactant; wherein said pH buffering agent is 10 mM histidine and wherein the pH is 5.0; wherein said bulking agent is 4% w/v mannitol; wherein said stabilizing agent is 2% w/v sucrose;
wherein said surfactant is 0.004% w/v polysorbate-20; wherein said therapeutic peptibody comprises a structure set out in Formula V
Formula V: [F¹-(L¹)e-P1-(L2)f-P2]-(L1)c-WSPd wherein: F1 is an Fc domain attached at the Nterminus of -L1-P1-L2-P2;
P1 and P2 consist of peptides with the amino acid sequence of SEQ ID NO.459 of Table 6; L1 and L2 are each independently linkers; e and d are each 0; and e and f are each independently 0 or 1.
9. A method for making a lyophilized therapeutic peptibody comprising the steps of:
a) preparing a solution of a buffer, a bulking agent, a stabilizing agent, and a
surfactant; wherein said pH buffering agent is 10mM histidine and pH is 5.0;
wherein said bulking agent is 4% w/v mannitol; wherein said stabilizing agent is 2% w/v sucrose; and wherein said surfactant is 0.004% w/v polysorbate-20; and
b) lyophilizing said therapeutic peptibody solution; wherein said therapeutic peptibody comprises a structure set out in Formula V
Formula V: [F1-(L1)e-P1-(L2)f- (L1)c-WSPd wherein: F1 is an Fc domain attached at the Nterminus of -L'-P'-L2-P2; P1 and P2 consist of peptides with the amino acid sequence of SEQ ID NO.459 of Table 6; L1 and L2 are each independently linkers; c and d are each 0; and e and f are each independently 0 or 1. (amendments emphasized in bold font)
Factual Matrix
During the prosecution of the application at the Patent Office, Amgen amended their claims to focus on Formula V, which covered 52 slight variations of the central medicine part. On July 18, 2016, a pre-grant representation was filed by Intas Pharmaceuticals Limited under Sections 25(1)(e) (obviousness), 25(1)(f) (not an invention), and 25(1)(g) (insufficiency). After hearings, the Assistant Controller rejected the application on March 31, 2023, for the reasons: (a) Amgen claimed using known methods not allowed under Section 3(d); (b) being simple mixes without synergistic effects not patentable under Section 3(e); (c) being an invention not patentable under Section 2(1)(ja) in view of existing prior arts D1–D6; (d) ground of insufficiency under Section 10(4). Amgen filed an appeal against the rejection.
Subject Invention
The subject invention relates to Romiplostim, a thrombopoietin receptor agonist (TPO-RA) peptibody that stimulates platelet production. This medicine is useful to cure a condition called immune thrombocytopenic purpura (ITP). Romiplostim is made from living sources. It is known that this drug is liable to break down or clump together during storage and transportation. To resolve this stability issue, Amgen developed a way to freeze-dry this medicine. This process is calledlyophilization. This process turns the claimed medicine into a stable powder that is easier to store, ship, and mix with water for use later. This formulation is marketed as Nplate. Amgen described a specific dry mix of the main medicine, romiplostim, structured as Formula V, which shows that the mix remains stable. The claimed formulations improved romiplostim's stability by combining it with four specific excipients at defined concentrations.
Issues Before the Court
The Court looked into the reasons for refusal and examined the following four key questions:
- Reuse of old process: Whether Amgen's method for making the dry mix just reuses an old, known process without adding anything new? (Section 3(d)).
- Mere admixture: Whether the dry mix is simply a blend of known ingredients that do not work together in a special way to create a synergistic effect? (Section 3(e)).
- Obvious: Whether a person skilled in the art (PSITA) would find this mix obvious in view of the teaching in prior arts D1–D5? (Section 2(1)(ja)).
- Insufficiency: Whether Amgen's description fully and clearly describes the invention with the experimental data and disclosures in the complete specification sufficiently to enable a PSITA of average skill and knowledge in India to carry out the process of preparing the composition of independent claim 1 by adopting the method of independent claim 9 in respect of the remaining 51 peptide mimetics in Table 6. (Section 10(4)).
Respondent 1's Reasons for Rejection under Section 3(d)
The first respondent submitted that the active ingredient in the claimed invention is a known peptibody, and lyophilization is also a known technique for increasing the shelf-life of protein formulations. The first respondent submitted further that all the excipients of the claimed invention are present in the cited prior arts, which also relate to protein formulations. Therefore, the method claim of the claimed invention (claim 9) is a mere use of a known process and falls within the scope of Section 3(d) of the Patents Act. Additionally, respondent 1 argued that in the absence of comparative data relating to pre-lyophilization and post-lyophilization stability, synergy has not been established. Respondent 1 maintained that Claim 9 (The method for preparing and drying the mix with specific additives and amounts) was just using the old freeze-drying process, which is not allowed under Section 3(d).
Amgen's Argument on Section 3(d) Rejection
Amgen contended that the application of Section 3(d) by the Controller was misplaced, as the method for preparing the lyophilized peptibody was not a mere use of a known lyophilization process. The appellant submitted that none of the cited prior arts relate to the lyophilization of the therapeutic peptibody comprising the structure of Formula V. Additionally, the appellant contended that lyophilized formulations were prepared by adding specific excipients in specific concentrations to the active ingredient/peptibody.
Court's Findings and Decision on Section 3(d)
The Court examined claim 9 and disagreed with Respondent 1 on the applicability of Section 3(d). The Court found that no prior art showed exactly how to dry the claimed medicine with specific additives in these amounts. The Court observed that "I find that D4 does disclose a therapeutic peptibody of the structure of Formula V." Additionally, prior art D4 mentioned freeze-drying vaguely, saying compositions "may be in dried powder, such as lyophilized form," but gave no steps or details. The Court also found that prior art D5 described drying a different substance but lacked method steps. Referring to column 19 of D4, the Court observed that lyophilization is referred to in the following terms:
".... The compositions may be prepared in liquid form, or may be in dried powder, such as lyophilized form.
The Court observed that the use of excipients was also referred to in column 19 of D4, and ingredients like sucrose are referred to, but the process of lyophilizing the therapeutic peptibody was not recited therein. D5 discloses a lyophilized composition of IL-12 by use of excipients, but it does not describe the method of lyophilizing the therapeutic peptibody of Formula V. In fact, D5 contains only composition claims and no method claims. The Court also found that independent claim 9 recited the use of specific excipients of specific excipient categories, such as buffering agent (at a specific pH), bulking agent, stabilising agent and surfactant, specific concentrations. The Court concluded that the process described in independent claim 9 cannot be characterised as the mere use of a known process. Consequently, the rejection under Section 3(d) of the Patents Act was not sustainable.
Respondent 1's Reasons for Rejection under Section 3(e)
The respondent submitted that comparative pre-lyophilization and post-lyophilization data were required to prove claimed synergy under Section 3(e). Respondent 1 submitted that Amgen's medicine mix was a simple blend, as they didn't provide data to prove synergy by comparing the mix before and after drying to prove better stability.
Amgen's Argument on Section 3(e) Rejection
Amgen argued that the claimed composition exhibited synergy between the peptibody and excipients. The appellant submitted that this was proved by Tables 40 and 41 in the specification, which clearly demonstrated enhanced stability.
Court's Findings and Decision on Section 3(e) Rejection
The Court examined the provisions under Section 3(e) and observed that Section 3(e) doesn't always require before-and-after drying data. The purpose of the inbuilt synergy in Section 3(e) is to show that the ingredients interact to produce a result greater than their individual effects. Amgen's tests given in Tables 39–41 were sufficient to meet the requirements of this Section. The Court rejected the Controller's reasoning that before-and-after drying data was required by observing that Section 3(e) doesn't always require before-and-after drying data. On the argument of respondent 1 that different amounts made the data weak, the Court ruled that the tests' purpose was to show synergy (polysorbate-20's effect on clumping), not to compare amounts.
The Court further observed that, unlike prior art D3, which aimed to increase substance concentration, Amgen's goal was stability, so before-and-after drying data was not needed. The Court ruled that for purposes of establishing synergy, it is sufficient if the appellant demonstrates interaction between the ingredients and, consequently, that the composition is more than the sum of its parts. Data relating to pre-lyophilization and post-lyophilization is not relevant for the purpose of Section 3(e), and the conclusion that the claimed invention is excluded from protection under Section 3(e) on that account was rejected as untenable. The Court found clear synergy in this case and set aside the Section 3(e) rejection.
Respondant1 reasoning on section 2(1)(ja) Rejection
The respondent submitted that the claimed medicine mix was obvious based on prior arts D1-D5. Respondent 1 and Respondent 2 (Intas) reasoned that it was obvious by combining D4 and D5.
Amgen's Argument on Section 2(1)(ja) Rejection
Amgen contended that its medicine mix was unique, and the tests disclosed in the specification showed the ingredients teamed up to prevent spoiling and clumping. Picking the right additives and amounts was a creative challenge. Amgen argued that narrowing their claims to focus on Formula V, which covered 52 slight variations of the main medicine part, was making their claim non-obvious when compared with the cited prior art. Amgen argued that D5 deals with the lyophilization of IL-12, which is a distinct family of protein. Amgen further submitted that choosing the claimed additives and exact amounts for this medicine is not obvious.
Court Findings and Decision
The Court examined the requirement of Section 2(1)(ja) and noted that inventive step is a feature that makes the invention not obvious to a person skilled in the art (PSITA). PSITA, according to the Court, would be an average medicine-making expert with common knowledge but no extraordinary creativity. The Court went on to examine the cited prior art and found that D1 is an Amgen patent which works on a different binder, and it did not mention this medicine or drying; D2 is an Amgen patent on modified proteins which described combining parts for longer life but not drying; D3 discussed drying to increase concentration, not stability. According to the Court, PSITA will not look for obviousness of the claimed invention in these documents, either alone or together.
D4 is another Amgen patent which refers in general to the use of excipients and mentions ingredients like sucrose, dextrose and calcium phosphate. Amgen agreed that it refers to the preparation of the composition in dried powder such as lyophilized form, but it does not provide any further information with regard to lyophilization or deal with categories of excipient, such as stabilisers, buffering agents, bulking agents and surfactants. Moreover, it does not deal with or specify the appropriate concentrations of the peptibody and excipients. The Court concluded that a non-inventive PSITA with knowledge of D4 cannot arrive at the claimed invention either solely on the basis of D4 or D1 to D4.
According to the Court, D5 is directed at formulations for IL-12, including in lyophilized form. Amgen argued that D5 describes drying a different substance, such as IL-12, which is a paired helper for cancer, whereas romiplostim, the medicine of the claimed invention, is a fused piece for platelets. Amgen argued that the Controller applied a combination of the D4 and D5 to prove obviousness even when D4 didn't suggest looking at D5. The Court found that scientific literature showed 6-16 options for each additive type, making selection a complex puzzle with thousands of combinations. No standard recipe exists, and a common clumping preventer (polysorbate-80) differed from Amgen's choice (polysorbate-20).
The Court concluded that choosing specific additives and specified amounts for this medicine does not make it obvious. The Court also observed that in the absence of any teaching, suggestion or motivation in D4, which would direct PSITA to D5, given the distinct nature of proteins, there is no rational basis to conclude that PSITA, without the benefit of hindsight, would combine the excipients and concentrations indicated in D5 while setting out to prepare a lyophilized formulation of the peptibody of D4. Disagreeing with respondent 1's reasoning, the Court ruled that the said process would not have led PSITA to make a mosaic of D4 and D5 so as to arrive at the claimed invention. The Court concluded that the Section 2(1)(ja) rejection was unsustainable.
Insufficiency under Section 10(4)
Respondent 1's Argument
The respondent 1 contended that pre-lyophilization and post-lyophilization data was not provided. It was also submitted that Formula V of the claimed invention consists of 52 peptide mimetics and that the appellant only provided experimental data relating to an Fc-TMP peptibody corresponding to a dimeric form of SEQ ID No.1017. The respondent submitted that in their application, especially when it could apply to 52 variations, but Amgen only tested one.
Amgen's Argument
Amgen contended that the patent application fully and clearly describes the invention, including the best method known, so others can recreate it as its disclosed Formula V covered 52 variations of the medicine's core part.
Court Findings and Decision
To examine the sufficiency requirement, the Court look into the description and found that in the absence of guidance in the complete specification, given the varying characteristics of amino acid sequences and the complexities of arriving at a lyophilized peptibody formulation, the experimental data and disclosures in the complete specification were not sufficient to enable a PSITA of average skill and knowledge in India to carry out the process of preparing the composition of independent claim 1 by adopting the method of independent claim 9 in respect of the remaining 51 peptide mimetics in Table 6. The Court concluded that the requirements of Section 10 of the Patents Act are only partly satisfied. As a corollary, it is necessary to curtail the width of the monopoly claim in independent claims 1 and 9.
Final Words of the Court
Setting aside the order dated March 31, 2023, the Court directed the Controller to grant the patent subject to independent claims 1 and 9 being modified in the manner set out. The Court concluded that the claimed invention satisfies all requirements of Section 2(1)(j), including Section 2(1)(ja), and Section 10 of the Patents Act. The Court also concluded that the claimed invention is not excluded from protection under Section 3(d) or 3(e) of the Act.
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