1 This suit involves two patents which claim processes for the manufacture of bortezomib, a drug used for the treatment of multiple myeloma and mantle cell lymphoma. The plaintiffs allege that the defendant infringed their patents by, inter alia, supplying bortezomib to hospitals in Singapore. ¹ The defendant denies infringing the plaintiffs’ patents and further contends that the patents are invalid for lack of novelty, lack of inventive step and insufficiency of particulars. The defendants also counterclaim for the partial and/or full revocation of the patents. ² For the reasons I set out hereunder, I find one of the patents to be valid but not infringed and the other patent invalid for lack of inventive step.

2 The two patents in question are Singapore Publication No. SG 151322 (“SG 322”) and Singapore Application No. SG 10201600029P (“SG 29P”, (collectively with SG 322, the “Patents”)). SG 322 purports to teach the use of an ether solvent with low miscibility in water during the synthesis of bortezomib. More specifically, it claims to improve the Matteson Homologation process by performing the first step of the reaction process in a coordinating ether solvent of low miscibility with water. SG 29P purports to teach the use of convergent synthesis for the large-scale manufacture of bortezomib.

3 The first plaintiff is a company incorporated in the State of Delaware, United States of America. ³ It is the registered proprietor of the Patents. ⁴ The second plaintiff is a Singapore-incorporated company, which is alleged to be an exclusive licensee of the first plaintiff in respect of the Patents and the distributor of the “brand-name” bortezomib drug, Velcade, in Singapore (the “Product”). ⁵

4 The defendant is a Singapore-registered partnership. ⁶ It carries on business in, inter alia, the wholesale and distribution of pharmaceutical products, controlled drugs, medical devices and health supplements. ⁷ The defendant represents and distributes pharmaceutical products made by several pharmaceutical manufacturers globally, including Dr Reddy’s Laboratories Limited (“DRL”). ⁸ In February 2018, the defendant applied to the Health Sciences Authority (“HSA”) for approval to import, market and distribute a generic version of bortezomib, “MYBORTE POWDER FOR SOLUTION FOR INJECTION 3.5MG/VIAL”, which is manufactured by DRL (see [12] below). ⁹ On 5 July 2019, the HSA approved its registration under Registration No. SIN15736P. ¹⁰

5 I will go into greater technical detail in my judgment. However, at this juncture, it suffices to provide a simple description of the Patents and the context in which the claimed processes are employed. The claimed processes relate to the manufacture of bortezomib, which is an international, non-proprietary name for a cancer drug used in the treatment of multiple myeloma and mantle cell lymphoma. ¹¹ Parties do not dispute that the chemical compound itself, bortezomib, is not protected by patent in Singapore. ¹² It is therefore agreed that drugs using bortezomib as an active pharmaceutical ingredient may be sold without infringing any product patent in Singapore. In other words, the matters of contention between parties are in relation to process patents pertaining to the manufacture of bortezomib. Bortezomib is a type of boronic acid (ie, a compound related to boric acid in which one of the three hydroxyl groups is replaced by an alkyl or aryl group). ¹³ It was developed in the mid-1990s and was approved for medical use in the United States in 2003 and in Europe in 2004. ¹⁴ The general process to synthesise bortezomib is to synthesise a number of organic chemical molecules, which are called intermediates. ¹⁵ Being a known organic compound, there are a number of ways to synthesise bortezomib and its intermediates.

6 SG 322 relates to the method of making a boronic ester compound by employing an improved asymmetric Matteson homologation protocol. ¹⁶ The Matteson homologation protocol is a chemical process that synthesises a boronic ester compound by using zinc chloride as a catalyst. ¹⁷ Zinc chloride is also a Lewis Acid (see [36] below). Broadly, in simplified terms, the reaction sequence includes two steps: the first step is the synthesis of the boron “ate” complex 2 which is an intermediate product; and the second step involves contacting the boron “ate” complex 2 with a Lewis acid to generate the boronic ester. SG 322 consists of 56 claims, of which 39 have been put in issue in the present case. In other words, only 39 claims are relied on by the plaintiffs. The table annexed at Annex 1 sets out the 39 asserted claims in full, according to the patent specification filed with the Intellectual Property Office of Singapore on 24 March 2005. ¹⁸ SG 322 was granted on 31 July 2012.

7 Out of the asserted claims for SG 322, it is undisputed that only claims 1, 20, 31, 32, 33, 38, 48 and 52 are independent claims. ¹⁹ The rest of the asserted claims in SG 322 are dependent claims. ²⁰

8 SG 29P consists of 10 claims, of which 5 have been asserted by the plaintiffs in the present case. The table annexed at Annex 1 sets out the 5 claims in full, according to the patent specification filed with the Intellectual Property Office of Singapore on 24 March 2005. ²¹ SG29P was granted on 19 February 2018.

9 For SG 29P, there is no serious contention that the sole independent claim is claim 1. ²² The rest of the asserted claims are claims 2–4, and 6, which are dependent claims. ²³

10 I will discuss the Patents in greater detail below.

11 Before I proceed to set out parties’ respective cases on the Patents, I provide the background and context to these proceedings.

12 On or around July 2019, the first plaintiff discovered that the defendant had obtained registration under the Health Products Act (Cap 122D) (“HPA”) for the following therapeutic product (the “Alleged Infringing Product”): ²⁴

The Alleged Infringing Product’s registration shows that it contains bortezomib as its active ingredient. ²⁵ The Patents claim processes for the manufacture of bortezomib. ²⁶

13 On 11 July 2019, the first plaintiff issued a letter of demand to the defendant through its solicitors, Mirandah Law LLP (“Mirandah”). ²⁷ Upon receipt of the letter dated 11 July 2019, the defendant referred the matter to DRL. DRL engaged Eldan Law LLP (“Eldan”) to respond to the letter. Subsequently, Eldan sent a letter dated 15 July 2019 to inform Mirandah that it was acting for DRL. ²⁸ It followed up with a letter dated 24 July 2019 to state that DRL did not use water immiscible ether solvents such as methyl tert-butyl ether (“MTBE”) (which is subject of the plaintiffs’ SG 322) to manufacture the Alleged Infringing Product and further that DRL’s manufacturing process for the Alleged Infringing Product was not a large-scale process as required by SG 29P. ²⁹ Mirandah responded on 30 July 2019 to inform that they had been instructed to commence legal proceedings and asked if Eldan had been instructed to accept service. ³⁰ Eldan responded with, inter alia, an offer to disclose details of DRL’s manufacturing process. ³¹ On 2 August 2019, Mirandah wrote to seek clarification on whether Eldan had instructions to accept service on behalf of the defendant. On the same day, Ravindran Associates LLP wrote to Mirandah on behalf of the defendant to deny the relevance of, inter alia, the Patents in respect of the Alleged Infringing Product. It appears that the letters had crossed. There was other correspondence between parties in the lead up to the commencement of the suit, but it is not necessary to set it out in full here. It suffices to mention that Eldan had been re-appointed to act for the defendant by 27 August 2019. ³²

14 The first plaintiff commenced the present suit on 19 August 2019. The second plaintiff was later joined as party to the suit on 12 November 2019. By parties’ consent, the claim in HC/S 817/2019 proceeded on a bifurcated basis. ³³ This judgment therefore deals only with the determination of liability issues covered at the trial.

15 The originating summons HC/OS 1034/2019 was commenced on 19 August 2019 by the first plaintiff against the defendant. The first plaintiff sought, inter alia, “a declaration that [the defendant’s] declaration(s) made under regulation 23(2) of the Health Products (Therapeutic Products) Regulations 2016 contains a statement that is false or misleading in a material particular or omits to disclose any matter that is material to its application(s) for registration of its therapeutic product”. ³⁴ The defendant took the position that only product patents in respect of bortezomib needed to be declared and there was no need to declare the existence of the Patents which are process patents relating to the manufacture of bortezomib. On 23 October 2019, I held that there was a material omission of the Patents in the defendant’s declarations in respect of the Alleged Infringing Product. I granted the prayer sought.

16 On 21 November 2019, the defendant filed a notice of appeal (CA/CA 221/2019) against the decision on the basis that process patents need not be declared to the HSA. My full reasons for my decision to grant the declaration sought by the first plaintiff are set out in Millennium Pharmaceuticals, Inc v Zyfas Medical Co (sued as a firm) [2020] SGHC 28. The declaration was confined to the defendant’s omission to disclose a matter that was material to its application in its declaration(s) made under regulation 23(2) of the Health Products (Therapeutic Products) Regulations 2016 (“HPTPR”) (at [10]), being the failure to mention the existing process patents (ie, the Patents) in respect of the Alleged Infringing Product in its application (at [26]). On 27 August 2020, the Court of Appeal upheld the decision below and dismissed the defendant’s appeal. It held in Zyfas Medical Co (sued as a firm) v Millennium Pharmaceuticals, Inc [2020] 2 SLR 1044 at [42] that the proper procedure was for the defendant to have declared the existence of the Patents under regulation 23(2)(a) of the HPTPR, and thereafter declare that the Patents would not be infringed by the doing of the acts for which the registration of the Alleged Infringing Product was sought pursuant to regulation 23(3)(b)(ii) of the HPTPR.

17 Following my decision in HC/OS 1034/2019, the plaintiffs applied to the HSA to suspend the registration of the Alleged Infringing Product on 29 November 2019. The HSA did not accede to the application to suspend the registration of the Alleged Infringing Product. After the decision was upheld in CA/CA 221/2019, the plaintiffs applied to the HSA to cancel the registration of the Alleged Infringing Product. The HSA did not exercise its discretion pursuant to regulation 24(1)(a)(ii) of the HPTPR to cancel the registration of the Alleged Infringing Product.

18 On 19 March 2021, the plaintiffs filed HC/OS 264/2021 for leave to be granted to them to apply for, inter alia, a quashing order to quash the decision of the HSA dated 21 December 2020, in which the HSA refused to suspend or cancel the registration of the Alleged Infringing Product under s 37(1) of the HPA and/or regulation 24(1)(a)(ii) of the HPTPR. Alternatively, the plaintiffs sought a mandatory order enjoining the HSA to exercise its powers under s 37(1) of the HPA to suspend the registration of the Alleged Infringing Product until the final determination of the present suit. At the hearing on 16 August 2021, the parties made their respective submissions before me. I reserved judgment. Prior to the delivery of my judgment, the HSA cancelled the registration of the Alleged Infringing Product on 27 August 2021.

19 On 29 January 2020, the plaintiffs filed HC/SUM 430/2020 (“SUM 430”) to seek an interlocutory injunction to prevent the defendant from performing any of the acts for which it obtained the registration of the Alleged Infringing Product, including its distribution, until the conclusion of the present suit. ³⁵ In addition, the first plaintiff filed HC/SUM 437/2020 on the same day, which sought in substance the same relief as in SUM 430, except “until the conclusion of CA/CA 211/2019”. ³⁶ I heard parties on these applications on 16 March 2020. On 2 April 2020, I ordered that, inter alia, the defendant be restrained from performing any of the acts for which registration of the Alleged Infringing Product had been obtained under Therapeutic Product Registration No. SIN15736P until the conclusion of the present suit, save that the defendant was not restrained from supplying 2,183 vials of the Alleged Infringing Product pursuant to GPOR 17519. ³⁷ GPOR 17519 was the tender awarded by the group procurement arm of the National Healthcare Group, National University Health System and Singapore Health Services (“ALPS”) to the defendant in early November 2019 for the supply of bortezomib to public hospitals in Singapore from March 2020 to November 2020.

20 Being dissatisfied with my decision, the plaintiffs sought leave to appeal against my decision on SUM 430 (see [19] above) in HC/SUM 1716/2020 on 9 April 2020. The plaintiffs later filed HC/SUM 2121/2020 on 29 May 2020 to seek an interlocutory injunction restraining the defendant from performing any of the acts for which registration of the Alleged Infringing Product was obtained under Therapeutic Product Registration No. SIN15736P pending the conclusion of the plaintiffs’ appeal against the decision in SUM 430, or in the event that their application for leave to appeal in HC/SUM 1716/2020 is dismissed, the conclusion of any application to the Court of Appeal for leave to appeal the decision in SUM 430. ³⁸ At the hearing on 9 June 2020, parties presented their arguments for HC/SUM 1716/2020 (ie, the application for leave to appeal against SUM 430) and HC/SUM 2121/2020 (ie, the application for an interim injunction pending the conclusion of HC/SUM 1716/2020 or the conclusion of any application to the Court of Appeal for leave to appeal against SUM 430). I dismissed the plaintiffs’ leave application and their summons for an interim injunction. The plaintiffs then applied to the Court of Appeal in CA/OS 18/2020 for leave to appeal against SUM 430 on 22 June 2020. The Court of Appeal dismissed the application for leave to appeal on 21 July 2020.

21 At the close of the trial on 27 October 2021, parties consented to discharge the interim injunction which was granted in SUM 430 on 2 April 2020. ³⁹

22 On 12 June 2020, the defendant applied in HC/SUM 2368/2020 to strike out the present action pursuant to O 18 rr 19(1)(a) and (d) of the Rules of Court 2014 (the “ROC”). The defendant cited as its basis the plaintiffs’ failure to provide the Particulars of Infringement pursuant to O 87A r 2(2) of the ROC. Just prior to the hearing fixed on 15 July 2020, the plaintiffs filed an application for leave to amend their Statement of Claim in HC/SUM 2850/2020. In the circumstances, I made no order on the prayer seeking to strike out the action but ordered costs against the plaintiffs in favour of the defendant. ⁴⁰

23 I turn now to the present suit before me.

24 The Patents disclose the large-scale synthesis of boronic acid and ester compounds for the production of bortezomib, a cancer drug for treating multiple myeloma and mantle cell lymphoma. The difference between the two Patents resides in the part of the synthetic process that each claims. ⁴¹ SG 322 mainly teaches the reaction sequence to generate the boronic ester compound bearing Formula (I) (see [58(a)]) by involving the use of water-immiscible ether solvent in the Matteson homologation reaction for use in the manufacture of bortezomib. ⁴² SG 29P, on the other hand, purports to teach the use of the “convergent synthesis” process for the large-scale manufacture of bortezomib. ⁴³

25 Given the highly technical nature of the subject-matter in the Patents, I directed that the parties provide a primer containing their respective positions on the key concepts such as the person skilled in the art, common general knowledge and the state of the art, and a glossary of the relevant technical terms (the “Primer”) (see [110] below). ⁴⁴ In this section, I distil the pertinent technical background to the Patents based on the Primer and the expert reports proved by the parties’ experts (see [106(a)] and [107(a)] below).

26 The Patents concern the field of pharmaceutical process chemistry. ⁴⁵ Pharmaceutical process chemistry is a field bridging medicinal chemistry and the industrial and commercial production of medicines. The main purpose of pharmaceutical process chemistry is the scaling up of the process for the production of specific drugs and active pharmaceutical ingredients (“APIs”). ⁴⁶ It therefore has the following features: (a) selection of inexpensive and easily available starting materials; (b) utilisation of inexpensive catalysts and/or reagents and solvents; (c) establishment of robust and speedy procedures for producing drug candidates and APIs with high quality; (d) development of methods to produce drug candidates and APIs in an economical, convenient, and efficient manner; (e) avoidance of dangerous procedures and hazardous reagents; (f) selection of safer and environmentally friendly processes; and (g) reduction of wastes. ⁴⁷ Generally, pharmaceutical process chemistry involves the employment of known, but conscientiously chosen and optimised synthetic methods and reagents to produce specific drugs and APIs – it may not involve the discovery of new chemical reactions. ⁴⁸

27 To recapitulate, the Patents claim chemical processes which produce bortezomib. For a better grasp of the Patents, it would be useful to first define the various terms used to describe the components involved in a chemical reaction.

28 A chemical compound is any substance composed of identical molecules consisting of atoms of two or more chemical elements held together by chemical bonds. An organic compound consists of a relatively unreactive backbone, and one or several functional groups. ⁴⁹ A functional group is a substituent or moiety in a molecule that causes the molecule’s characteristic chemical reactions. ⁵⁰

29 A reactant is a substance that is consumed in the course of a chemical reaction, and it is also known as a reagent. ⁵¹ A reaction intermediate or an intermediate is a molecular entity that is formed from the reactants but is consumed in further reactions. In the hypothetical example below, A and B are reactants, ‘X’ is a reaction intermediate and ‘Y’ is a final product: ⁵²

30 A catalyst is a substance that speeds up a chemical reaction, or lowers the temperature or pressure needed to start one, without itself being consumed during the reaction. An example of a catalyst is a Lewis acid (see [36] below). A coordinating ether solvent is a solvent that is capable of coordinating the Lewis acid and solvating the ionic components of the reaction. ⁵³

31 Bortezomib is a type of boronic acid. To understand the context in which the Patents teach processes to synthesise bortezomib, it is important to understand the basic structure of boronic acid. In the Primer, the plaintiffs define boronic acid as a compound related to boric acid in which one of the three hydroxyl groups is replaced by an alkyl or aryl group. ⁵⁴ A hydroxyl group is a functional group denoted by the chemical formula −OH and composed of one oxygen atom covalently bonded to one hydrogen atom. ⁵⁵ An alkyl group is derived from an alkane by the removal of one hydrogen atom from a carbon atom. ⁵⁶ In organic chemistry, an alkane is a hydrocarbon, which in other words consists of hydrogen and carbon atoms only, arranged in a tree structure. ⁵⁷ For instance, the alkyl group of methane (denoted by the chemical formula CH4) is methyl (denoted by the chemical formula CH3). ⁵⁸ An aryl group is a functional group derived from a simple aromatic ring compound where one hydrogen atom is removed from the ring. ⁵⁹ For example, a simple aryl group is phenyl (denoted by the chemical formula C6H5), a group derived from benzene (denoted by the chemical formula C6H6). The defendant has defined boronic acid as “compounds having the structure RB(OH)2”. ⁶⁰ While the parties have defined boronic acid slightly differently in the Primer, the definitions are common in respect of the chemical structure of boronic acid: ⁶¹

32 Boronic acids also act as Lewis acids, with the unique capability of forming reversible covalent complexes with substances such as sugars, amino acids, hydroxamic acids. Given their unique characteristics, boronic acids are used extensively in organic chemistry as chemical building blocks and intermediates in various organic reactions.

33 The annotated diagram below depicts the components of bortezomib: the two hydroxyl groups circled by the dotted lines and the replacement group with the dashed line. The boron atom is denoted by “B”.

34 In the context of bortezomib, the “ate” complex refers to a specific type of complex formed during the synthesis of the active ingredient, bortezomib. Specifically, it refers to the complex formed between boronic acid and an organometallic reagent, typically a lithium or magnesium compound, which is used to create the boronate ester intermediate in the synthesis of bortezomib. ⁶² It is a complex which is formed by the rearrangement of boron compounds in the presence of Lewis acid. ⁶³ These boron compounds can be represented in the form of Formula (II), ⁶⁴ as (IIa) or (IIb), ⁶⁵ and as the compound of Formula (XV). ⁶⁶ This complex allows for the transfer of the boronic acid moiety to the organometallic reagent, which is necessary to form the boronate ester intermediate. Without this complex, the reaction may not proceed effectively, leading to lower yields or incomplete reaction. The “ate” complex is therefore a critical component of the synthesis of bortezomib, allowing for the efficient formation of the boronate ester intermediate.

35 Furthermore, the formation and stability of the “ate” complex is dependent on several factors, such as the nature of the boronic acid and the organometallic reagent, as well as the reaction conditions. As a result, optimizing the conditions for the formation of this complex is important for the efficient synthesis of bortezomib. ⁶⁷

36 A Lewis acid is a molecular entity and chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. ⁶⁸ A Lewis base is any species that has a filled orbital containing an electron pair which is not involved in bonding but may form a dative bond with a Lewis acid to form a Lewis adduct because it can donate its lone pair of electrons. ⁶⁹ In a Lewis adduct, the Lewis acid and base share an electron pair furnished by the Lewis base, forming a dative bond. ⁷⁰ This is depicted in the diagram below.

A dative bond is also known as a coordinate, coordination or dipolar bond, and it is a bond formed upon interaction between molecular species where one serves as a donor and the other an acceptor of the electron pair to be shared. ⁷¹ Its analogy as a “type” of covalent bond stems from it sharing a common electron pair between two atoms; although dative bonds have significant polarity, lesser strength and greater length. ⁷² A covalent bond is a region of relatively high electron density between nuclei of atoms which arises from inter alia the sharing of electrons. ⁷³

37 For the purposes of the present suit, it would be useful to note that zinc chloride (ZnCl2) is a Lewis acid. ⁷⁴

38 A nucleofuge group, otherwise known as a nucleofugic group, is a functional group that is capable of leaving a molecule during a chemical reaction by accepting a pair of electrons. It departs from a substrate with a pair of electrons, forming a new species, while the substrate undergoes a transformation. ⁷⁵ In the synthesis of bortezomib, a nucleofuge is used in the formation of the boronic acid or boronate ester moiety. For instance, a suitable nucleofugic group is attached to a boron-containing intermediate, and upon reaction with the desired nucleophile, the nucleofugic group leaves the molecule, enabling the formation of the boronic acid or boronate ester functional group. ⁷⁶

39 The proteasome is a multisubunit enzyme complex that plays a central role in the regulation of proteins that control cell-cycle progression and apoptosis (cell death), and has therefore become an important target for anticancer therapy. ⁷⁷

40 A coordinating solvent or a coordinating co-solvent refers to a solvent that is capable of coordinating the Lewis acid and solvating the ionic components of the reaction. ⁷⁸ A co-solvent is a solvent added to another primary solvent to modify the solubility of the reaction components. ⁷⁹

41 A coordinating ether solvent is an organic solvent that contains one or more ether functional groups, such as dimethyl ether, diethyl ether, or tetrahydrofuran (“THF”). ⁸⁰ These solvents are commonly used in coordination chemistry and organometallic chemistry, as they have the ability to coordinate with metal ions and facilitate their solubility in organic solvents. ⁸¹

42 Homologation is the chemical process through which some boronic acid esters compounds (ie, the class of intermediates in the synthesis of bortezomib (see [58] below)) are synthesised. In organic chemistry, a homologation reaction is any chemical reaction that converts the reactant into the next member of the homologous series, which is a group of compounds that differ by a constant unit, generally a methylene (–CH2–) group. ⁸²

43 The Matteson homologation protocol is an organic chemistry reaction used to extend a carbon chain by one carbon atom, while also introducing a functional group, typically an alkene or alkyne. ⁸³ The reaction involves the use of a homologating agent, which contains a halogen atom, and a nucleophile, typically an organometallic reagent such as an alkyl lithium or magnesium compound. ⁸⁴ In the manufacture of bortezomib, the Matteson homologation protocol introduces an additional carbon atom to the boronate ester intermediate, which is a key step in the synthesis of bortezomib. Specifically, the protocol involves the use of a Lewis acid catalyst, which facilitates the reaction between the boronate ester intermediate and the homologating agent. The Lewis acid catalyst may be a metal halide such as zinc chloride, which coordinates with the boronate ester intermediate and activates it towards reaction with the homologating agent. The resulting product is an extended carbon chain with a new functional group, which can be further manipulated to obtain the desired final product, bortezomib. ⁸⁵

44 In 1983, Professor Donald S. Matteson (“Prof Matteson”) reported his studies on the synthesis of (+)-pinanediol (αS)-α-chloro-α-phenylmethane boronate by using zinc chloride as a Lewis acid catalyst in an academic article titled “Epimerization of α-Chloro Boronic Esters by Lithium and Zinc Chlorides” (“Matteson and Erdik”). ⁸⁶ Prof Matteson recorded his findings that the epimerisation of (+)-pinanediol (αS)-α-chloro-α-phenylmethane boronate was catalysed by lithium chloride (denoted by chemical formula LiCl) in the solvent THF. THF is an organic compound with the formula (CH2)4O, and in the case of moisture-sensitive reactions, anhydrous THF may be used. ⁸⁷ Epimerisation creates an undesirable compound that reduces product purity (see [52] below). ⁸⁸ Prof Matteson observed that the rate of epimerisation is greatly increased by reagents which promote the ionisation of lithium chloride, including water and dimethyl sulfoxide. ⁸⁹ The active catalyst is thus the free chloride ion (Cl-). Prof Matteson further explained that zinc chloride (being a direct substitute for lithium chloride) also catalysed the epimerisation. ⁹⁰ In summary, the Matteson homologation reaction may be split into two stages, and the synthetic reaction sequence is shown below.

45 Step 1 involves the synthesis of the boron “ate” complex (ie, an intermediate in the synthesis of bortezomib), while step 2 involves contacting the resultant boron “ate” complex with a Lewis acid (contacting step) to generate the desired product. The yield of the desired product was accompanied with a 6% rate of the unwanted epimerised product (see [249] below). In the subsequent studies, Matteson and Erdik identified excess lithium chloride (LiCl) to be the reason for the rate of epimerisation observed, and further noted that the presence of a small amount of water led to the higher ionisation of lithium chloride (in other words, an increased formation of Li+ ions and Cl- ions). As a consequence, the rate of epimerisation increased significantly. The diagram below illustrates the epimerisation process.

46 The known problem (or limitation) of the Matteson homologation process is therefore epimerisation, which introduces an undesired by-product. The coordinating solvent, THF, with even small amounts of water, promotes the ionisation of LiCl, and the Cl- ions. This in turn causes the epimerisation of the desired product to form the undesired by-product that is the impurity (or the epimer). Moisture in the THF is likely introduced by the Lewis acid catalyst, zinc chloride (ZnCl2), itself. Zinc chloride is a highly hygroscopic compound (ie, it absorbs moisture from its surroundings) and drying it is difficult and resource-intensive, especially when a large amount of the Lewis acid is to be dried. To illustrate the magnitude of the known problem of epimerisation, Matteson and Erdik recorded that 11mg of water in 10ml of THF doubled the rate of epimerisation. ⁹¹ Resultantly, the yield of the desired product falls.

47 Deprotection is a chemical process in which a protecting group is removed from a functional group in a molecule, restoring the original reactivity of that functional group. Protecting groups are temporary modifications made to a molecule to prevent undesirable side reactions during a multi-step synthesis. ⁹² In the synthesis of bortezomib, deprotection is a critical step. Bortezomib contains an N-terminal pyrazinoic acid moiety and a C-terminal boronic acid group. ⁹³ During synthesis, the boronic acid group is often protected as a boronate ester to prevent unwanted side reactions. Deprotection of the boronate ester is necessary to obtain the active boronic acid form of bortezomib. ⁹⁴

48 Ionisation is the process by which an atom or molecule acquires a net electric charge by gaining or losing one or more electrons, thus forming an ion. In the context of the manufacture of bortezomib, ionisation may be utilised during the analytical stages to monitor the quality and purity of the intermediates and the final product. Ionisation is employed in various analytical techniques such as mass spectrometry, to identify and characterise molecules by altering their charge states and subsequently detecting their masses.

49 Linear synthesis is a chemical synthesis process in which a series of linear transformation reactions are used to convert a reactant or some reactants into a product or multiple products. ⁹⁵ This synthesis process includes the longest route for the production of the target product. ⁹⁶

50 Convergent synthesis is a chemical synthesis process in which pieces of the desired product are made by a set of reactions, and the pieces are combined with each other via another set of reactions. ⁹⁷ This type of synthesis process is different from linear synthesis because this process involves parallel reactions rather than linear transformations. ⁹⁸ This process features in SG 29P.

51 Diastereomeric ratio is a term used in chemistry to describe the relative amounts of different diastereomers in a mixture. ⁹⁹ Diastereomers are stereoisomers that are not mirror images of each other (or non-superimposable stereoisomers) and have different physical and chemical properties. ¹⁰⁰ Such physical and chemical properties include melting point, boiling point and solubility. The diastereomeric ratio is usually expressed as the ratio of the concentration of one diastereomer to the concentration of the other diastereomer in a mixture. ¹⁰¹ For example, if a mixture contains 60% of diastereomer A and 40% of diastereomer B, the diastereomeric ratio of A:B is 3:2. ¹⁰² By measuring the diastereomeric ratio, pharmaceutical chemists can determine the purity and quality of drug compounds, optimise the production processes for chiral drugs and monitor the stability and degradation of chiral drug compounds during storage or in biological systems. ¹⁰³

52 Epimerisation is a process in which there is an interconversion of one epimer to another epimer (ie, the configuration of a stereocenter is changed from one enantiomer to another). ¹⁰⁴ An epimer is one of a pair of diastereomers, each of which have opposite configuration at only one stereogenic centre out of at least two. In the context of the Matteson homologation protocol, epimerisation can occur during the reaction of the chiral starting material with reagents such as THF in the presence of a Lewis acid catalyst (eg, zinc chloride). ¹⁰⁵ During the Matteson homologation reaction, the chiral starting material is converted to a new chiral intermediate, which is then used to synthesise the boronic ester intermediate for bortezomib. If the reaction conditions are not carefully controlled, however, the chiral intermediate can undergo epimerisation, leading to the formation of undesired stereoisomers and reducing the yield and purity of the desired product. ¹⁰⁶

53 Hygroscopic refers to a substance’s tendency to absorb moisture from the environment. ¹⁰⁷ Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption or adsorption from the surrounding environment, which is usually at normal or room temperature. ¹⁰⁸ In the context of the manufacture of bortezomib, hygroscopic materials may be used to control moisture levels in the reaction environment to ensure the stability and effectiveness of the final product. ¹⁰⁹

54 Miscibility is the ability of two or more substances to mix together and form a homogeneous solution without phase separation. ¹¹⁰ If two substances are miscible, they are also completely soluble in one another irrespective of the order of introduction. For example, THF and water are miscible. ¹¹¹

55 Scalability is the ability of a process or system to handle a growing amount of work or accommodate larger production volumes without compromising efficiency, performance or quality. ¹¹²

56 Stereochemical erosion is the loss of stereochemical information, such as chirality or geometry, during a chemical reaction or process, leading to a mixture of stereoisomers. Stereochemical erosion is an important consideration in the synthesis of chiral compounds, particularly in pharmaceuticals, where stereoisomers can have different biological activities. Stereochemical erosion must be minimised during bortezomib synthesis to maintain the desired stereochemistry of the final product, which directly affects its therapeutic efficacy. ¹¹³

57 It is common ground that there are a number of ways to synthesise bortezomib.

58 Bortezomib is made by synthesising a series of intermediates. The following intermediates are relevant to the present suit: ¹¹⁴

(a) The first intermediate is (3aS,4S,6S,7aR)-2-((S)-1-chloro-3-methylbutyl)-3a,5,5-trimethyl-hexahyfro-4,6-methanobenzo[d][1,3,2]dioxaborole. This compound is referred to as Formula (I) in the Patents and “BZM-2” in DRL’s process.

(b) The second intermediate is 4-lsobutyl-2,9,9-trimethyl-3,5-dioxa-4-bora-trioyclo[6.1,1.02.6],decane. This is referred to as Formula (III) in the Patents and “BZM-1” in DRL’s process.

(c) The third intermediate is 1,1,1-trimethyl-N-((R)-3-methyl-l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo [d][1,3,2]dioxaborol-2-yl)butyl)-N-(trlmethylsilyl), silanamine. This compound is referred to as Formula (VIII) in the Patents and “BZM-3” in DRL’s process.

(d) The fourth intermediate is 3-Methyl-l-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo [6.1.1.02.6] dec-4-yl, butyl amine trifluoroacetate. This compound is an acid addition salt referred to as Formula (VII) or (XVIII) in the Patents and “BZM-4” in DRL’s process.

(e) The fifth intermediate is (S)-3-Phenyl-2-[(pyrazine-2-carbonyl)-amino], propionic acid. This compound is called Formula (XIXa) in the Patents and “BZM-8” in DRL’s process.

(f) The sixth intermediate is Pyrazine-2-carboxylic acid {1-[3-methyl-1(2,9,9-trimethyl-3,5-dioxa-4-boratricyclo [6.1.1.02.6]dec-4-yl), butyl carbamoyl]-2-phenyl-ethyl)-amide. This compound is referred to as Formula (XXIII) in the Patents and “BZM-9” in DRL’s process.

59 The general proposition is that the right of action for patent infringement is reserved for the proprietor of the patent, with certain statutory exceptions for persons other than the proprietor. In this case, the relevant provision is s 74 of the Patents Act (Cap 221) (the “Patents Act”), which provides that an exclusive licensee of a patent may commence proceedings for its infringement. I reproduce the material parts of s 74 of the Patents Act:

60 Correspondingly, the definition of an exclusive licensee is set out in s 2(1) of the Patents Act, which I reproduce in full:

61 To determine whether a party is an exclusive licensee, the Court must assess all the evidence put before it. Generally, the decision will depend on the contract that governs the party’s status as an exclusive licensee. In the case of Oxford Nanopore Technologies Ltd v. Pacific Biosciences of California Inc [2017] EWHC 3190 (Pat) (“Oxford Nanopore”), the English High Court has summarised some relevant principles to aid in the determination of whether a licence is exclusive (at [44]). The relevant portion of the decision in Oxford Nanopore is reproduced below:

62 The cases referred to in the extract above at [61] are Dendron GmbH v University of California (No 3) [2004] EWHC 1163 (Ch), Courtauld's Application [1956] RPC 208 and Illumina Inc and others v Premaitha Health PLC and another [2017] EWHC 2930 (Pat).

63 Later in this judgment (see [115]–[122] below), I analyse the issue of the second plaintiff’s standing as an exclusive licensee with these propositions (at [61] above) in mind.

64 Section 80(1) of the Patents Act sets out the grounds on which the validity of a patent can be undermined. Of particular relevance to the present case is the following ground: the invention is not a patentable invention (s 80(1)(a)). The applicable legal principles are elaborated on below.

65 Before moving to the substantive question proper, the claims asserted in a patent should first be properly interpreted. Claim construction is an integral exercise to dealing with issues relating to the validity and infringement of a patent. It involves determining the substance of the claim, which in turn clarifies the scope of protection of the invention: IIa Technologies Pte Ltd v Element Six Technologies Ltd [2023] 1 SLR 987 (“Element Six”) at [62]; Sunseap Group Pte Ltd and others v Sun Electric Pte Ltd [2019] 1 SLR 645 (“Sunseap”) at [68]; First Currency Choice Pte Ltd v Main-Line Corporate Holdings Ltd and another appeal [2008] 1 SLR(R) 335 (“First Currency”) at [23]. In other words, claim construction seeks to answer the question: what does the patentee claim monopoly rights over? Section 113(1) of the Patents Act states as follows:

In First Currency, the Court of Appeal held that the claims themselves are the principal determinant in ascertaining the true construction of a patent specification (at [23]). It explained that the description and other parts of the specification play an assisting role in the construction of the claims (ibid). The claims and the description are to be read together and construed contextually (ibid). As the background of the words used in the claims may be affected or defined by what is said in the body of the patent specification, the claims should not be viewed independently, but construed as part of the whole specification (First Currency at [24], citing Rosedale Associated Manufactures Ld v Carlton Tyre Saving Coy Ld [1960] RPC 59 at 69). That said, it is impermissible to “put a gloss on or expand the claims” by relying on a statement in the specification (ibid). If the claims have an ordinary and plain meaning, then reliance ought not to be placed on the language used in the body of the specification so as to make them mean something different (First Currency at [24], relying on Electric & Musical Industries v Lissen Ld (1938) 56 RPC 23 at 57). The Court of Appeal therefore endorsed the “purposive construction” approach to the claims to determine the essential features of an invention, which are protected by the patent (First Currency at [25]).

66 Another facet of claim construction pertains to the relationship between independent and dependent claims. The Court of Appeal in Sunseap held that “once the defendant succeeds in establishing that all the independent claims in a patent are invalid, the dependent claims must necessarily fall away and the patent as a whole must be regarded as invalid” [emphasis added] (Sunseap at [70]). The Sunseap approach contends that the invalidity of the underlying independent claim necessarily undermines the foundation of the dependent claims. In Element Six, the Court of Appeal deemed it unnecessary to rule on the correctness of the observation in Sunseap and left this to be considered at a later juncture (at [240]). The approach in Element Six involved an assessment of the sole independent claim asserted and the resolution of the remaining dependent claims asserted was on the basis that they all “refer back to [claim 1]” (ie, the independent claim) (Element Six at [29] and [239]). As the Court of Appeal has left open the question in Element Six, I would have ordinarily also considered the issue of validity on a claim-by-claim basis (Element Six at [236]) in addition to applying the general rule in Sunseap that a patent should be revoked if all the independent claims in the patent have been found to be invalid (see Sunseap at [70]). However, as the parties have run their respective cases on the premise that all other asserted claims are contingent on the validity of the first independent claim in SG 322 and SG 29P respectively (see [148], [162] and [184] below), I will engage only with the arguments specific to claim 1 of SG 322 and claim 1 of SG 29P.

67 Having set out the approach taken for claim construction, the next aspect to consider is the theoretical perspective through which the construction is conducted. It is envisaged that the notional person through whose eyes the claim must be construed is one who is a reasonable person skilled in the art. The Court in Element Six affirmed that the person skilled in the art is concerned with the subject-matter of the patent, which should be determined with reference to the words in the patent specification (at [69] and [72]). The distinction is that the person skilled in the art is imbued with certain knowledge and assumptions that one attributes to that particular audience. Courts have considered the purposive interpretation of the claims to be able to adequately balance the rights of the patentee and those of third parties: Element Six at [79]; Lee Tat Cheng v Maka GPS Technologies Pte Ltd [2018] 1 SLR 856 (“Lee Tat Cheng (CA)”) at [41]; First Currency at [26]; FE Global Electronics Pte Ltd v Trek Technology (Singapore) Pte Ltd [2006] 1 SLR(R) 874 (“Trek Technology (CA)”) at [14]. Who the person skilled in the art is depends on the technology and patented invention. He should be taken to be the workman or technician who is aware of everything encompassed in the state of the art and who has the skill to make routine workshop developments, but not to exercise inventive ingenuity or think laterally (Element Six at [67]; First Currency at [28], citing with approval Pfizer Ltd’s Patent [2001] FSR 16 at [62]–[63]). Despite the lack of ingenuity, the person skilled in the art is equipped with a reasonable degree of intelligence and with a wish to make the directions in the patent work (Element Six at [69], citing Zipher Ltd v Markem Systems Ltd and another [2008] EWHC 1379 (Pat) at [366] with approval; see also Ng Kok Cheng v Chua Say Tiong [2001] 2 SLR(R) 326 (“Ng Kok Cheng”) at [21], which cited with approval McGhan Medical UK v Nagor Case No 1999 1720 (28 February 2001) at [23]–[24]). Further, the person skilled in the art would possess common general knowledge of the subject matter in question: Element Six at [67] and [69]; First Currency at [28].

68 Common general knowledge is information which, at the relevant date, is common knowledge in the art to which the alleged invention relates, so as to be known to duly qualified persons engaged in that art: Element Six at [63]. It features in the analysis of the validity of the patent in various ways. When determining whether the patented invention is novel or contains an inventive step, the person skilled in the art employs his common general knowledge to interpret prior art, amongst other purposes: Element Six at [64]. Interpreting the prior art is crucial to determining what information is conveyed to the person skilled in the art at the priority date of the patent in suit or the date on which the piece of prior art (such as a book or journal) was published and whether that information renders the invention obvious and/or anticipates the invention. However, the disclosure does not form part of the common general knowledge merely because it is widely read or circulated – rather, it must be shown that it is generally known and regarded as a good basis for further action by the bulk of those who are engaged in the particular art to which the disclosure relates: Element Six at [74]. In the contexts of claim construction and sufficiency, however, the person skilled in the art mainly directs his common general knowledge towards the interpretation of the patent claims and the working of the invention disclosed therein: Element Six at [64].

69 Section 80(1) of the Patents Act sets out the grounds on which a patent may be revoked for lack of validity. Of particular relevance to the present case are the following grounds: the invention is not a patentable invention (s 80(1)(a)); and the specification of the patent does not disclose the invention clearly and completely for it to be performed by a person skilled in the art (s 80(1)(c)).

70 Whether the invention is patentable rests on the statutorily-defined requirements in s 13(1) of the Patents Act. The requirements for an invention to be patentable are listed below:

(a) The invention must be new (s 13(1)(a)) (the “novelty requirement”).

(b) The invention must involve an inventive step (s 13(1)(b)) (the “inventive step requirement”).

(c) The invention must be capable of industrial application (s 13(1)(c)).

71 In the present case, only the requirements of novelty and inventive step are put in issue.

72 Parties agree on the applicable law on the novelty requirement. The law on novelty is set out in s 14 of the Patents Act. Section 14(1) provides that “[a]n invention shall be taken to be new if it does not form part of the state of the art”. Section 14(2) sets out the definition of the “state of the art”:

73 The principles that govern the inquiry on what constitutes the state of the art for the purposes of assessing patentability are well established. Section 14(2) makes it clear that the state of the art is assessed on a worldwide basis with no geographical or territorial limits: Rohm and Haas Electronic Materials CMP Holdings, Inc (formerly known as Rodel Holdings, Inc) v NexPlanar Corp and another [2018] 5 SLR 180 (“Rohm”) at [46]. It comprises “all matter” made available to the public before the priority date: ibid. The modality of “[being] made available” may be through “written or oral” disclosure, “use”, or “in any other way”. The priority date is the date of the filing of the application (s 17(1) Patents Act), but the patentee may depart from the default position by claiming that the priority date of the invention takes reference from the date of filing of an earlier patent application or applications (s 17(2) Patents Act). This has the effect of limiting the state of the art to what it was at that earlier date: Element Six at [59]. Section 14(3) provides that the “state of the art” may also include matter contained in a patent application that was published on or after the priority date of the invention, provided that: (a) that matter was contained in that patent application at the time when it was filed, as well as when it was published; and (b) the priority date of that patent application is earlier than that of the patented invention. While the scope of the state of the art is broad, there must be “clear and satisfactory evidence” that the prior disclosure and/or use did in fact take place: Main-Line Corporate Holdings Ltd v United Overseas Bank Ltd and another (First Currency Choice Pte Ltd, third party) [2007] 1 SLR(R) 1021 (“Main-Line”) at [55].

74 Once the prior disclosure or prior art is identified, the next step is to determine whether the claimed invention was anticipated by the prior disclosure or prior art: Lee Tat Cheng v Maka GPS Technologies Pte Ltd [2018] 3 SLR 1334 (“Lee Tat Cheng (HC)”) at [76]–[77]; Rohm at [58].

75 Whether the claimed invention was anticipated turns on more than merely the prior publication identifying the subject matter of the claim in the later patent. Anticipation requires “enabling disclosure”: see Merck & Co Inc v Pharmaforte Singapore Pte Ltd [2000] 2 SLR(R) 708 (“Merck”) at [38]. To meet the threshold of “enabling disclosure” means that an invention would be anticipated by the prior art if the teachings disclosed in it are sufficiently clear and complete to allow the person skilled in the art to make the claimed invention. The information or teachings disclosed in the prior art may be explicit or implicit: Research in Motion v Inpro [2006] RPC 517 at [128] (see generally Terrell on the Law of Patents (Colin Birss gen ed) (Sweet & Maxwell, 19th Ed, 2022) (“Terrell”) at paras 11.68–11.71). The disclosure should be “so clear” that a person skilled in the art following those directions “must inevitably produce something [ie, a product or a process] that would, if the patentee’s patent were valid, infringe the patentee’s claim”: ASM Technology Singapore Pte Ltd v Towa Corp [2018] 1 SLR 211 at [59]; Mühlbauer AG v Manufacturing Integration Technology Ltd [2010] 2 SLR 724 (“Mühlbauer”) at [17]. This inquiry in relation to disclosure has been framed as the “reverse infringement” test in Dien Ghin Electronic (S) Pte Ltd v Khek Tai Ting (trading as Soon Heng Digitax) [2011] 3 SLR 227 (per Chan Seng Onn J (as he then was) at [30]) and the “would it infringe” test in Lee Tat Cheng (HC) (per George Wei J at [81]). It would not suffice if the disclosure in the prior art is a “near miss” (see Main-Line at [63]) or merely reveals “something close or similar” to the claimed invention (see Lee Tat Cheng (HC) at [80]). Put another way, a disclosure which does not enable the person skilled in the art to perform the claimed invention is not anticipatory (see Rohm at [61]). In construing whether a piece of art has anticipated the claimed invention, where the prior art is a patent application, this prior art must be construed as at the date of its publication and not on the date that it was filed: Mühlbauer at [18].

76 The burden is on the party challenging the novelty of a granted patent to adduce evidence of a prior disclosure that led to the claimed invention forming part of the state of the art: Rohm at [49]; Martek Biosciences Corp v Cargill International Trading Pte Ltd [2012] 2 SLR 482 at [44].

77 Finally, there exists a rule against “mosaicking” the pieces of the prior art in the assessment of the novelty requirement. This is to say that it is impermissible to assemble all the pieces of prior art together into a “mosaic” and then to compare the claimed invention against this “mosaic”. The claimed invention should only be compared against each individual piece of prior art to determine whether it was anticipated by each piece of prior art, unless the prior art expressly directs the reader to another piece of prior art: Trek Technology (CA) at [38]; Rohm at [62], Mühlbauer at [18].

78 In summary, the novelty requirement is dealt with in the following manner (Rohm at [63]):

(a) Determine the relevant state of the art.

(b) Interpret the prior art material from the perspective of the person skilled in the art at the date the material entered the prior art and without use of hindsight or mosaicking, and consider what each piece of prior art disclosed.

(c) Interpret the scope of the claimed invention from the perspective of the person skilled in the art and by reference to the patent specification.

(d) Compare the prior art against the claimed invention and determine whether the prior art anticipated the claimed invention.

79 The applicable law on inventive step is well-established. Section 15 defines an inventive step as one that “is not obvious to a person skilled in the art”, having regard to the relevant state of the art. This is termed an inquiry for obviousness. An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art as at the priority date of the invention: Element Six at [60]. When considering the issue of obviousness, it is assumed that the invention is novel and differs in some identifiable respect from the prior art. The key question then is whether these differences constitute steps that would have been obvious: Element Six at [60].

80 The state of the art in the obviousness inquiry is a subset of the state of the art in the novelty inquiry. Although both inquiries concern themselves with the construction of the relevant state of the art, the relevant state of the art for the inventive step requirement is the same state of the art for the novelty requirement, except that unpublished patent applications which have a priority date earlier than that of the invention in question are disregarded (see s 15 read with ss 14(2) and 14(3) of the Patents Act; Terrell at para 12.41; Ng-Loy at para 30.2.49). Quite apart from the content of the relevant state of art in the assessments of novelty and inventive step, the manner in which the relevant state of the art is treated in the inquiries differs as well. Unlike in the assessment of novelty, “mosaicking” is permissible in the assessment of obviousness as long as the “mosaic” can be put together by an unimaginative man with no inventive capacity: Mühlbauer at [93], citing Technograph Printed Circuits Ltd v Mills & Rockley (Electronics) Ltd [1972] RPC 346 (“Technograph”) at 355). The notional skilled person assesses the obviousness of an invention by reference to the whole of the state of the art relevant to the invention, using his common general knowledge.

81 The Court of Appeal in First Currency set out the four-step test to determine whether an alleged invention involves an inventive step (at [41]–[42]). The four steps, which were derived from Windsurfing International Inc v Tabur Marine (Great Britain) Ltd [1985] RPC 59 at 73–74 (“Windsurfing”), are as follows:

(a) Identify the inventive concept embodied in the claim, or construe it: Mühlbauer at [22]. A purposive approach is taken to claim construction: Mühlbauer at [22]–[24]. The purposive approach asks: what would the hypothetical person skilled in the art have understood the patentee to mean by choosing to use the word/phrase (the cause of the dispute) in the claim at the time of the patent application? (Lee Tat Cheng (CA) at [41(c)]).

(b) Identify (i) the notional person skilled in the art (ie, skilled but unimaginative addressee in the art at the priority date) and (ii) impute to him what was, at that date, common general knowledge in the art in question. The skilled but unimaginative addressee is only a “diligent researcher” and may be entitled to disregard a piece of prior art that he did not know of and was not likely to know of or pay attention to: First Currency at [38]–[41].

(c) Identify what, if any, differences exist between the matter cited as forming part of the “state of the art” and the inventive concept of the claim or the claim as construed.

(d) Whether, viewed without any knowledge of the alleged invention in the claim, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention. This involves comparing the invention against the whole of the state of the art comprising all relevant pieces of prior art, and may involve “mosaicking”.

82 The inquiry in [81(d)] above is grounded in a holistic, multi-factorial assessment of factors relevant to obviousness. The English courts have acknowledged that the question of obviousness is necessarily fact-dependent: Conor Medsystems Inc v Angiotech Pharmaceuticals Inc [2008] UKHL 49; [2008] 4 All ER 621 (“Conor”) at [42] and Actavis Group PTC EHF and others v ICOS Corporation and another [2019] UKSC 15 (“Actavis”) at [63]. Lord Hoffmann expressed his view on the holistic approach to the obviousness inquiry in Conor:

83 The list of factors above (see [82]) was illustrative and not exhaustive: Actavis at [63]. The English Supreme Court set out a non-exhaustive list of considerations as follows: (i) whether at the priority date something had been ‘obvious to try’; (ii) the routine nature of the research and any established practice of following such research through to a particular point; (iii) the burden and cost of the research programme; (iv) the necessity for and the nature of the value judgments which the team of persons skilled in the art would have in the course of a testing programme; (v) the existence of alternative or multiple paths of research; (vi) the motive of the person skilled in the art; (vii) the fact that the results of research which the inventor actually carried out were unexpected or surprising; (viii) hindsight, which included knowledge of the invention, must not be used; (ix) whether a feature of a claimed invention was an added benefit in a context in which the claimed innovation was obvious for another purpose; and (x) the nature of the invention (Actavis at [65]–[74]).

84 I set out the law on the relevant consideration which arises in the present case: whether the inventive step is “obvious to try” to a person skilled in the art who is in possession of the cited prior art.

85 In Lee Tat Cheng (HC) at [133] and Rohm at [121(d)], our courts have endorsed the formulation of the “obvious to try” factor as outlined by Lord Hoffmann in Conor at [42], approving Diplock LJ in Johns Manville Corp’s Patent [1967] RPC 479 (“Johns Manville Corp’s Patent”) at 493. In Johns Manville Corp’s Patent, Diplock LJ stated that “the notion of something being obvious to try was useful only in a case in which there was a fair expectation of success” (at 493). In other words, if the prior art teaches many paths one of which might lead to the solution, the obvious thing to do will be to try all those paths: Lee Tat Cheng (HC) at [133]. A decision to try a particular path, with no fair expectation of success, is inventive: Lee Tat Cheng (HC) at [133]. Although not relevant in our case, more recently, Lord Hodge in Actavis considered that the general approach to the “obvious to try” consideration did not preclude a finding of obviousness in a case where there is no particular expectation as to the result of a routine test or experiment (at [65]). The relevant extract from Actavis is reproduced below (at [65]):

86 Inventiveness may be present even if the gap between the invention and what existed in the prior art is small; a Lilliputian step is no less significant: First Currency at [54]. However, a step which is in substance a “mere workshop improvement” or “workshop variation of existing prior art” is not an inventive step: ASM Assembly Automation Ltd v Aurigin Technology Pte Ltd and others [2010] 1 SLR 1 at [55]. Whilst the court is often assisted in the assessment of obviousness by experts, the ultimate decision on non-obviousness is one of fact, impression and judgment, and one which only the court can make: Lee Tat Cheng (HC) at [126].

87 I illustrate next the law on technical prejudice as it has developed in the UK as the plaintiffs have relied on this factor.

88 The obviousness inquiry may feature a prejudice in overcoming the preconceptions of the skilled person in a particular field: Terrell at para 12-97. In one of the seminal cases on the concept, Jacob J in Union Carbide Corp v BP Chemicals [1998] RPC 1 at [25] explained that “[i]nvention can lie in finding out that that which those in the art thought ought not be done, ought to be done”. The learned authors in Terrell considered that the prejudice may be a general one, and the invention a more specific answer to it: Terrell at para 12-99. In Dyson Appliances Ltd v Hoover Ltd [2001] RPC 26; [2001] IP & T 1 (“Dyson”), the claimant and the defendant were companies in the business of manufacturing and distributing domestic vacuum appliances. The claimant was the patent proprietor of a patent that enabled it to manufacture vacuum cleaning appliances that did not require the user either to empty or replace dust-collecting bags. Its vacuum cleaning appliances depended upon use being made of cyclonic separation to deposit dirt from laden air that had been sucked through the apparatus from a location that required cleaning. The defendant later manufactured a vacuum cleaning appliance, which operated without bags and made use of three cyclone separation units to separate dust from the ambient air sucked in by the machine. The claimant alleged that certain claims of the patent had been infringed by the defendant, while the defendant claimed that the patent was invalid on the grounds of lack of novelty, obviousness and insufficiency. In considering that the patent was non-obvious, Michael Fysh QC sitting in the Chancery Division (Patents Court) of England and Wales held that there had been a prejudice in favour of bags within the industry, and no evidence of technical problems with the use of those bags (at [156]). Furthermore, the court considered that there was no motive or reason for stepping away from the prior art in the direction of the claims (at [159]). In the discussion of technical prejudice that the person skilled in the art would have to overcome, the court considered that the “negative aspects of knowledge” – in this case the mindset within the vacuum cleaner industry that no notional person skilled in the art would consider the viability of purifying dirt-laden air from a vacuum cleaning operation (other than through using a bag or a bag and a final filter) – “would at least have caused the addressee to regard modification to any of these prior art proposals with considerable reserve if not overt skepticism” (at [156]). The claim in Dyson was narrower than a machine that was bag-free, but it was a specific combination of an invention which overcame a relevant defect: Terrell at para 12-99. The decision was upheld by the English Court of Appeal in Dyson Appliances Ltd v Hoover Ltd [2001] EWCA Civ 1440.

89 It is also necessary to note the distinction between technical prejudice and commercial prejudice. In Cipla Ltd v Glaxo Group [2004] EWHC 477 (Pat) at [30], Pumfrey J held:

It is clear from the holding above that the prejudice alleged by the patent proprietor must be one that is technical in nature, rather than merely commercial. The technical prejudice must also be sufficiently widespread to be regarded as commonly shared. However, it is not necessary for the patent to explain why the prejudice is wrong or provide a scientific explanation of how the invention works to overcome it. Indeed, in Synthon BV v Teva Pharmaceutical Industries Ltd [2015] EWHC 1395 (Pat), Birss J did not accept that “much [could] be made of the fact that the patent did not expressly assert that this or that element in the disclosure was surprising or difficult” (at [115]), because it was ultimately an assertion that either bears out in the assessment of the prior art, or it does not. It suffices that the patent specification sets out properly the invention (at [115]). Having set out the law on technical prejudice, I will consider the issue as it arises in the present case below (see [213]–[219]).

90 Section 25(4) of the Patents Act requires, in the making of a patent application, that the specification of the application “disclose the invention in a manner which is clear and complete for the invention to be performed by a person skilled in the art”. As I stated at [69], insufficiency of disclosure is a ground for the revocation of a patent.

91 Following the decision in Element Six, insufficiency arising from uncertainty is recognised as a ground of insufficiency in addition to classical insufficiency. Classical insufficiency is where the patent specification was not clear and complete enough to enable the person skilled in the art to perform the invention across the whole breadth of the claim(s) without an undue burden. Insufficiency resulting from uncertainty is concerned with whether the person skilled in the art knew how to determine whether a particular product or process was within the scope of the claimed invention even after employing his common general knowledge and the normal claim construction process. The assessment of sufficiency proceeded in two steps: the first involved identifying the invention and deciding what it claimed to enable the person skilled in the art to do; and the second step asked whether the specification enabled him to do it: Element Six at [105]. Regardless of whether the invention pertained to a product or a process, the patent specification had to enable the invention to be performed by the person skilled in the art over the full breadth of the monopoly claimed for the purposes of the sufficiency requirement in ss 25(4) and 80(1)(c) of the Patents Act: Element Six at [108].

92 The concept of infringement is defined in s 66(1) of the Patents Act, which reads:

93 Given that the defendant is the distributor of DRL’s Alleged Infringing Product (rather than its manufacturer per se), s 66(1)(c) of the Patents Act contains the relevant limb of patent infringement for the present case.

94 The prevailing law on s 68(1) of the Patents Act is trite. Generally, the burden of proof is on the plaintiff to show that the defendant has done one or more of the prohibited acts referred to in s 66(1) of the Patents Act. However, there may be a reversal of this burden of proof if s 68(1) of the Patents Act is engaged.

95 Section 68 of the Patents Act reads as follows:

96 The test is therefore summarised as follows:

(a) If the patent concerns a new product, then the burden of proving that the product is not made by the process shall be on the alleged infringer.

(b) If the patent does not concern a new product, the following must be shown:

(i) a substantial likelihood exists that the product is made by the process; and

(ii) the proprietor of the patent has been unable through reasonable efforts to determine the process actually used.

97  According to the High Court in Merck & Co Inc v Pharmaforte Singapore Pte Ltd [1999] 3 SLR(R) 1072 (“Merck”) (at [55]–[57]), “new product” includes anything not known in the state of the art, including improvements. Bortezomib is known in the state of the art. The plaintiffs in the present case therefore rely on the second limb of the test in s 68 of the Patents Act (see [96(b)]).

98 I move to the parties’ cases in these proceedings.

99 It bears mention that there are several factual and legal areas which parties are broadly aligned on. There is no contention that the first plaintiff is the proprietor on record for the Patents and thus has standing to bring this action. ¹¹⁵ It is not in dispute that the defendant had indeed imported the Alleged Infringing Product into Singapore and supplied the Alleged Infringing Product to public hospitals pursuant to the tender awarded (ie, GPOR 17519). ¹¹⁶

100 The plaintiffs allege that DRL’s manufacturing process for the Alleged Infringing Product (ie, a generic version of bortezomib) has infringed the asserted claims of the Patents, which set out the manufacturing process for bortezomib. The defendant tendered a bid for GPOR 17519 with the Alleged Infringing Product and fulfilled the bid it was awarded by supplying the Alleged Infringing Product to the relevant public hospitals. Thus, the defendant has infringed the Patents, pursuant to s 66(1)(c) of the Patents Act, by inter alia, disposing of, offering to dispose of and importing the Alleged Infringing Product that was obtained directly by means of the process protected by the Patents. ¹¹⁷

101 The key arguments underpinning the plaintiffs’ position are as follows:

(a) The second plaintiff has standing in the present action for patent infringement. It is the exclusive distributor of the Product in Singapore. By virtue of s 2 of the Patents Act, which “allows an exclusive right to be given ‘in respect of any right in respect of the invention’”, ¹¹⁸ the plaintiffs argue that such right should also include an exclusive distribution right, and therefore, as an exclusive distributor, the second plaintiff has locus standi in the present proceedings.

(b) The manufacturing process adopted by DRL infringes the asserted claims in the Patents. Pursuant to s 66(1)(c) of the Patents Act, the defendant has infringed the Patents.

(i) For SG 322, the plaintiffs allege that they have shown that there has been a reversal of the burden of proof such that the defendant now bears the burden of showing that DRL’s process is not using the taught process. The plaintiffs contend that there is a substantial likelihood that the intermediate boronic ester compound within the manufacturing process undertaken by DRL is made by the patented process in SG 322 and they have undertaken reasonable efforts to determine DRL’s process. Thus, the burden of proof shifts from the plaintiffs to the defendant under s 68(1) of the Patents Act. The defendant has not discharged its evidentiary burden in showing that the intermediate compound was not made by the process taught in SG 322. ¹¹⁹

(ii) For SG 29P, the plaintiffs contend that the process taught in the asserted claims of SG 29P “falls on all fours” with the corresponding part of DRL’s process. ¹²⁰ Further, the plaintiffs argue that claim 1 of SG 29P is not restricted to large-scale processes (contrary to what the defendant asserts) because there is no wording in the claim itself to suggest that the process taught is subject to such a restriction. ¹²¹

(A) The specification of the patent does not support the defendant’s position that the ambit of SG 29P is limited to large-scale processes only. ¹²²

(B) In any case, the plaintiffs’ expert, Prof Chiba Shunsuke (“Prof Chiba”), has shown that a process which can be performed on a large-scale can be applied to synthesise lower amounts of the same end-product. However, the inverse – translating a small-scale process to a large-scale one – does not hold with the same level of ease. ¹²³

(C) In particular, the last part of the schematic representation of DRL’s manufacturing process, where the compounds referred to as “BZM-4” and “BZM-8” are coupled to synthesise the compound referred to as “BZM-9” and the final product (ie, bortezomib) is exactly the same as the process disclosed in the asserted claims of SG 29P. ¹²⁴

(c) The Patents are valid and subsisting at all material times.

(i) In SG 322, the core inventive concept is “the use of an ether solvent of low miscibility with water in the contacting step at particular proportions”. ¹²⁵ This is novel and inventive.

(A) The defendant’s submission that the use of Lewis acid to promote the rearrangement of the boron “ate” complex, ie, the Matteson homologation reaction is known in International Publication No. WO 96/13266 (“WO 266”), US Patent No. 5,780,454 (“US 454”) and US Patent No. 4,525,309 (“US 309”) is misconceived. The teaching of SG 322 seeks to improve the Matteson homologation process “for the large-scale production of boronic ester and acid compounds”. ¹²⁶

(B) Furthermore, an application of the test in Windsurfing shows that “the differences between the inventive concept of SG 322 and US 309 as well as the common general knowledge of the material time would not be obvious to the person skilled in the art”. ¹²⁷

(ii) In SG 29P, the core inventive concept is “the convergent coupling of [two compounds] to produce [another compound], which is deprotected to form [bortezomib]”. ¹²⁸

(A) In response to the defendant’s argument that the removal of “large-scale” from claim 1 of SG 29P results in added subject matter, the plaintiffs contend that the patent description for SG 29P contains several statements and examples which show that the process taught in SG 29P can be carried out regardless of scale. ¹²⁹

(B) The defendant also challenged the validity of SG 29P regarding added subject matter – the patent description discloses a six-step process, but claim 1 of SG 29P discloses a process with only the last two steps of the six-step process. The plaintiffs’ response is that SG 29P, whether as originally filed or later after grant, has always only referred to those two steps. Even the parent of SG 29P, the 763 Patent, had only contained the two steps. The parent is typically the first non-provisional patent application submitted for a new invention. Thus, it is wrong of the defendant to allege that the steps had been removed in SG 29P. Additionally, Mr Lim Teck Yeow (“Mr Lim”) testified that there was sufficient support in the patent description filed for claim 1 of SG 29P which shows the two steps being disclosed independent of any preceding steps. ¹³⁰

102 Therefore, the following remedies are sought in the present suit: ¹³¹

(a) For the first plaintiff:

(i) A declaration that the act(s) authorised by the registration of the Alleged Infringing Product infringes the Patents.

(ii) An injunction to restrain the defendant from infringing the Patents.

(b) For the plaintiffs:

(i) An order for the delivery up or destruction upon oath of all infringing articles or any article in which that Alleged Infringing Product is inextricably comprised, in the defendant’s possession, power, custody or control.

(ii) An inquiry as to damages or alternatively, at the plaintiffs’ option, an account of profits and an order for payment of all sums due, with interest.

103 The defendant denies all allegations of its infringement of the Patents. It raises the following arguments against the plaintiffs’ case:

(a) The second plaintiff does not have standing in the present proceedings. ¹³² Section 74 of the Patents Act enables the holder of an exclusive licence under a patent to have the same rights as a proprietor of a patent to bring proceedings in respect of an infringement. Section 75 of the Patents Act sets out certain limitations to the exclusive licensee’s right to recover damages and other financial relief if the exclusive licence is not registered. ¹³³ The defendant submits that the second plaintiff was not an exclusive licensee, and did not register any document establishing that relationship. ¹³⁴ It relies on the concessions made by the second plaintiff’s Ms Ho King Siew (“Ms Ho”) and emphasises the absence of any documentation evidencing its status as an exclusive licensee. ¹³⁵ Given that the second plaintiff was not an exclusive licensee, its claims must be dismissed with costs. ¹³⁶

(b) The Patents are not valid and/or are not infringed by DRL’s manufacturing process of the generic version of bortezomib, ie, the Alleged Infringing Product.

(i) For SG 332, there is no infringement because it teaches the use of an ether solvent having low miscibility with water. The defendant argues that it has shown that DRL’s manufacturing process utilises THF, which is a water-miscible ether solvent. ¹³⁷ The defendant points to its willingness to have the plaintiffs visit the manufacturing facilities used by DRL to verify its position, and emphasises that the plaintiffs declined to take up this offer. ¹³⁸ Further, the defendant counter-claims for the revocation of claims 1, 9–14, 20, 25, 26, 28, 30–35, 38, 41–44, 48 and 52 because their basis is neither novel nor inventive. ¹³⁹ Claims 12–20 of SG 322 should be revoked because of a manifest and evident error in these claims. ¹⁴⁰

(ii) For SG 29P, there is no infringement because DRL’s manufacturing process is not a large-scale process. It is therefore not covered by the claims in SG 29P. ¹⁴¹ The defendant counter-claims for the revocation of SG 29P in its entirety because the convergent synthesis process in the context of manufacturing bortezomib (ie, the main process which is the subject of SG 29P) is neither new nor inventive. ¹⁴² Another basis for the revocation of SG 29P is that the claims as granted in SG 29P contain added subject matter over the claims as filed. ¹⁴³ The final ground relied on for the revocation of SG 29P is that claim 1 is unsupported by the description of the invention. ¹⁴⁴

104 In the Primer, the defendant states its reliance on the following 15 documents as prior art in challenging the validity of the Patents:

(a) Donald S. Matteson and Debesh Majumdar, “a-Chloro Boronic Esters from Homologation of Boronic Esters”, Journal of the American Chemical Society (1980) Vol 102, pp 7588-7590 (“Matteson and Majumdar”);

(b) Donald S. Matteson and Rabul Ray, “Directed Chiral Synthesis with Pinanediol Boronic Esters”, Journal of the American Chemical Society (1980) Vol 102, pp 7590-7591 (“Matteson and Ray”);

(c) Donald S. Matterson et. al., “Boronic Ester Homologation with 99% Chiral Selectivity and Its Use in Syntheses of the Insect Pheromones (3S,4S)-4-Methyl-3-heptanol and exo-Brevicomin”, Journal of the American Chemical Society (1983) 105, pp 2077-2078 (“Matteson 1983”);

(d) US Patent No. 4,537,773 dated 27 August 1985 (“US 773”);

(e) US Patent No. 4,845,079 dated 4 July 1989 (“US 079”);

(f) WO 266, filed with application number PCT/US95/14117, dated 9 May 1996;

(g) US 454 dated 14 July 1998 (see [5] above);

(h) Laurence Carmes et. al., “Homologation of Boronic Esters with (Dialkoxymethyl)lithiums. Asymmetric Synthesis of a-Alkoxy Boronic Esters”, Journal of Organic Chemistry (2000), Vol 65, pp 5403-5408 (“Carmes”);

(i)  US 309 dated 25 June 1985 (see [101(c)(i)(A)] above);

(j) Sara Wu et. al., “Degradation Pathways of a Peptide Boronic Acid Derivative, 2-Pyz-(CO)-Phe-Leu-B(OH)2”, Journal of Pharmaceutical Science (2000), Vol. 89, Issue 6, pp 758-765 (“Wu”);

(k) WO 03/033506, filed as PCT/JP02/10450, dated 24 April 2003 (“WO 506”);

(l) WO 03/033507, filed as PCT/JP02/10451, dated 24 April 2003 (“WO 507”);

(m) US Package Insert for Velcade, Bortezomib for Injection;

(n) Announcement of commercialisation and development between Millenium Pharmaceuticals and Ortho Biotech; and

(o) Center for Drug Evaluation & Research, US Chemistry Review Application No. 21-602.

105 As the defendant does not ultimately employ all of the materials listed at [104] above in its arguments against the validity of the Patents, I will address only the materials on which the defendant has structured its objections for the validity of the Patents.

106 At the trial, the plaintiffs led evidence from the following witnesses:

(a) Prof Chiba is the expert witness appointed by the plaintiffs for this suit for his expertise in pharmaceutical chemistry. He is a tenured Professor of Chemistry in the Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, of the Nanyang Technological University and obtained a PhD from the Department of Chemistry in the University of Tokyo in 2006. ¹⁴⁵ Dr Chiba has expertise in synthetic organic chemistry and catalysis, and has published over 100 peer-reviewed papers. ¹⁴⁶ He provided the following affidavits of evidence-in-chief (“AEIC”):

(b) Ms Ho King Siew is the legal director of the second plaintiff. Her AEIC is dated 9 September 2021 (“Ms Ho’s AEIC”).

(c) Mr Lim Teck Yeow is the plaintiffs’ expert witness on issues of intellectual property law, with an established practice in patent prosecution specifically. He filed an AEIC dated 11 October 2021 (“Mr Lim’s AEIC”).

107 The defendant led evidence from the following witnesses:

(a) Dr Charles William Johannes (“Dr Johannes”) is the defendant’s expert witness on pharmaceutical chemistry. He is the Vice President of the Exploratory Chemistry department at FOG Pharmaceuticals, Inc and holds a PhD in Organic Chemistry from Boston College in 1998. ¹⁴⁷ Prior to his present appointment, Dr Johannes was Head of Organic Chemistry at the Institute of Chemical and Engineering Sciences in A*STAR. ¹⁴⁸ Dr Johannes is familiar with product compounds related to bortezomib such as epoxocin and eponemycin and was named an inventor in a patent teaching their preparation. ¹⁴⁹ The following AEICs were filed:

(i) AEIC of Dr Johannes dated 9 September 2021 (“Dr Johannes’ 1st AEIC”) containing his expert opinion dated 15 August 2021 (“Dr Johannes’ Expert Report”); and

(ii) AEIC of Dr Johannes dated 14 September 2021 (“Dr Johannes’ 2nd AEIC”) containing his reply to Prof Chiba’s Expert Report (“Dr Johannes’ Second Expert Report”).

(b) Ms Julia binte Johari (“Ms Johari”) is a partner of the defendant. She is in charge of the defendant’s regulatory matters in Singapore and Malaysia, including filling and obtaining approval for registrations of the pharmaceutical and health products that the defendant distributes. Ms Johari’s AEIC dated 16 August 2021 (“Ms Johari’s AEIC”) contains her averments that she had checked for the HSA registrations of bortezomib in Singapore.

(c) Mr Mohamed Tahir (“Mr Tahir”) is the managing partner of the defendant. He is in charge of business development, sales, tenders, liaison with suppliers, principals and customers. Mr Tahir’s AEIC dated 16 August 2021 (“Mr Tahir’s AEIC”) details, inter alia, the process through which the Alleged Infringing Product came to be registered in Singapore and the checks conducted by the defendant prior to its registration.

(d) Mr Manda Amarendhar (“Mr Amarendhar”) is the lead “QbD” (or “Quality by Design”) in DRL. He is a chemist by training and was part of the research and development team in DRL that developed the process for manufacturing the Alleged Infringing Product. Mr Amarendhar’s AEIC dated 16 August 2021 contains his evidence on how the Alleged Infringing Product is produced and manufactured by DRL.

(e) Mr Sunil Kumar Mishra (“Mr Mishra”) is an intellectual property management specialist in DRL. He is a chemist by training and is a registered patent agent in India. Mr Mishra is in charge of patent related activities in DRL, such as patent filing and prosecution.

108 The parties agreed to the appointment of a court assessor, Professor Paul Sharratt (“Prof Sharatt”), to assist the court in its review of the technical evidence. This is provided for under s 10A(1) of the Supreme Court Judicature Act (Cap 322) and O 33 r 4 of the ROC, where the court may appoint one or more assessor to assist the court in dealing with a matter in which the assessor has skill and experience within a trial. Prof Sharratt is a Professor at the Singapore Institute of Technology and holds a PhD in Reaction Engineering from the University of Manchester Institute of Science and Technology. He has worked in areas related to chemical and pharmaceutical process development.

109 In our jurisprudence, there has not been any pronouncement on the role of the court assessor in cases featuring intellectual property disputes. I found Heerey J’s statements on the role of a court assessor in Genetic Institute Inc v Kirin-Amgen Inc (No 2) (1997) 149 ALR 247 at 250 useful:

As parties have not put this in issue, I will not say anything further on this save that the role of the court assessor in the present suit is limited to assisting the court in understanding and analysing the technical aspects of the parties’ cases. Ultimately, the court bears the responsibility of arriving at a reasoned outcome on the application of the law as it stands to the facts of the case.

110 Following the decision of the Court of Appeal in Element Six, I asked parties to provide their further submissions on the issue of sufficiency, the requisite technical background to the present matter in a technical primer (ie, the Primer) and a summary of their positions on the asserted claims in the Patents vis-à-vis validity and infringement. These further submissions and materials, which were confined to evidence already led in the trial, were placed before the court on 5 May 2023.

111 I distil the issues for determination as follows:

(a) Whether the second plaintiff has standing to commence the present proceedings against the defendant.

(b) Whether the Patents (ie, SG 322 and SG 29P) are valid patents.

(c) Whether the Patents (ie, SG 322 and SG 29P) have been infringed by the defendant’s registered use of the Alleged Infringing Product pursuant to reg 24(1) of the HPTPR. Alternatively, whether the defendant’s participation in the tender for the supply of bortezomib to public hospitals in Singapore from March to November 2020 (ie, GPOR 17519) and the defendant’s award of the tender to supply 2,183 vials of bortezomib under GPOR 17519 constitute acts infringing the asserted claims in the Patents.

112 The issue in [111(c)] is assessed in respect of whether the Patents have been infringed by DRL’s manufacturing process of the Alleged Infringing Product.

113 For the issue of patent validity, the following sub-issues will be addressed:

(a) Whether the invention is patentable. In the present case, the following two requirements are pertinent:

(i) The invention must be new.

(ii) The invention must involve an inventive step.

114 For the issue of patent infringement, I will also consider whether the plaintiff has successfully invoked s 68 of the Patents Act to reverse the burden of proof.

115 I first address the preliminary question of whether the second plaintiff has standing in the present suit (see [59]–[61] above). I answer this question in the negative.

116 The second plaintiff claims to have standing on the basis that it is an exclusive licensee (pursuant to s 74(1) of the Patents Act). The crux of the second plaintiff’s case is that it is an exclusive distributor of the Product in Singapore and that an exclusive distributor falls within the statutory definition of an “exclusive licensee” in s 2(1) of the Patents Act. In particular, s 2(1) of the Patents Act states that an exclusive licence means “a licence from the proprietor of … a patent conferring on the licensee … any right in respect of the invention to which the patent … relates…” [emphasis added]. The second plaintiff submits that such a right also encompasses the right of distribution of a product protected by a process patent. ¹⁵⁰ In short, the second plaintiff seeks a broad interpretation of the statutory term “exclusive licensee” and contends that the issue turns on a question of law rather than fact.

117 Conversely, the defendant argues that the plaintiffs have not adduced evidence to show that the second plaintiff is the exclusive licence holder of the Patents. In particular, the plaintiffs’ Ms Ho testified unambiguously under cross-examination that the second plaintiff is not the exclusive licensee of the Patents. ¹⁵¹ The defendant also points to s 41(4) of the Patents Act, which provides that a licence may be granted under a patent “for working the invention which is the subject of the patent or the application”.

118 In my judgment, the second plaintiff does not have standing in the present suit. In coming to this decision, it is not necessary for me to decide on the issue of whether an exclusive distributor of a patent falls within the meaning of a statutory exclusive licensee in s 2(1) of the Patents Act. Rather, the plaintiff’s case on standing fails on the facts.

119 There is simply no evidence before me to show me the scope of the second plaintiff’s rights in Singapore. The second plaintiff alleges that it holds an exclusive right to distribute the product produced by the first plaintiff’s patented process under an exclusive licence conferred upon Janssen Products LP (“Janssen”) by the first plaintiff. It is alleged that Janssen is the second plaintiff’s affiliate company. ¹⁵² Early on in the proceedings, in the second plaintiff’s Statement of Claim dated 26 August 2020, the second plaintiff had pleaded that it “is and was at all the material times the exclusive licensee of the [first plaintiff] in respect of the [P]atents and the distribution of bortezomib in Singapore. ¹⁵³ Similarly, in Ms Ho’s Affidavit of Evidence-in-Chief, she states that the “[second plaintiff] is … the distributor / supplier of the brand-name bortezomib, Velcade, and is presently the only distributor of bortezomib in Singapore”. ¹⁵⁴ In the Defence dated 7 July 2021, the defendant put the plaintiffs to strict proof that the second plaintiff was, indeed, an exclusive licensee. However, the plaintiffs have not even produced the agreement between Janssen and the first plaintiff governing the alleged exclusive license (with the alleged right to sub-license), much less the second plaintiff’s distributorship agreement(s) with Janssen to discharge their burden of proving the assertion. This is so, notwithstanding the clear relevance of the distributorship agreement(s) in the Court’s assessment of whether the second plaintiff was an exclusive licensee. Therefore, even if I accept the plaintiffs’ interpretation of s 2(1) of the Patents Act, ie, that an exclusive distributor constitutes a statutory exclusive licensee, there is no evidence to prove the nature and content of the rights that Janssen allegedly holds in respect of the Patents (and therefore the rights it is capable of granting in relation to the Patent). This in itself is fatal. Moreover, the plaintiffs have not produced any documentary evidence that the second plaintiff dealt exclusively with the inventions to which the Patents relate.

120 Grasping at straws, the second plaintiff’s Ms Ho could only refer to a result from the HSA Information Search of the product “VELCADE 3.5mg FOR INJECTION”. ¹⁵⁵ However, the information provided by the search result is sparse. It merely states that the second plaintiff is a “Registrant” of this product, with an “Approval Date” on 15 March 2005 and that its status remains “Active”. In effect, it only shows that the second plaintiff is a distributor of the product. However, it does not reveal what rights of distributorship are attributed to the second plaintiff, and much less whether these rights would confer the second plaintiff legal standing as an exclusive licensee. This does not advance the second plaintiff’s case on its standing.

121 Further, it is significant that Ms Ho agreed that the omission to produce any documentary evidence meant that the second plaintiff was not an exclusive licensee of the first plaintiff. Although it is ultimately a question of fact whether the entity is an exclusive licensee, the answers given by Ms Ho in cross-examination buttress my conclusion. At the trial, Ms Ho responded in the following manner: ¹⁵⁶

Following that line of questioning, I queried about the reason for which the second plaintiff was joined in the present suit; Ms Ho answered that “it was purely on the basis that [their] business was impacted”. ¹⁵⁷ This is plainly insufficient to show that the second plaintiff was an exclusive licensee.

122 More significantly, the court is not to award damages to an exclusive licensee or order that it be given an account of profits if the licence is not registered within the period of six months beginning with its date unless the court is satisfied that it was not practicable to register the transaction, instrument or event before the end of that period and that it was registered as soon as practicable thereafter: s 75 of the Patents Act. The plaintiffs therefore face yet another hurdle in their position as the second plaintiff has not been registered as an exclusive licensee. Here, the issue of damages accruing to the second plaintiff does not arise because their claims are dismissed for the reasons I set out below (see [204]–[219] and [288]). Even if the plaintiffs were successful in their claims, the second plaintiff cannot be awarded damages or granted an order for an account of profits for the alleged infringement of the Patents as the exclusive licence they assert was not registered.

123 I begin by identifying the reasonable person skilled in the art (“person skilled in the art”) to whom the Patents are addressed (ie, the notional person through whose eyes the claims in the Patents should be construed). The relevant legal principles have been set out above (see [67]–[68]).

124 The plaintiffs submit that the person skilled in the art is one who would be aware of the state of the art in process chemistry and, in particular, the synthesis of organic compounds. The skilled person would hold a graduate degree in chemistry (either a Masters of Science or a Doctor of Philosophy (“PhD”)) and at least five years of experience in organic synthesis in an academic laboratory. ¹⁵⁸ The defendant posits that the person skilled in the art would be a person who is theoretically and technically competent in the design and development of synthetic procedures for the synthesis and production of drug compounds with a PhD degree in synthetic organic chemistry and having at least five years of laboratory experience in synthesis of organic compounds or a person who has a Bachelor’s or Master’s degree in synthetic organic chemistry with at least 10 years of laboratory experience in synthesis of organic compounds. Although there are some differences between the identity of the notional person skilled in the art put forth by the parties, the core qualities of the person skilled in the art include knowledge of process chemistry (in particular, in the synthesis of organic compounds) and at least five years of laboratory experience and a graduate degree in the field. ¹⁵⁹ It suffices to proceed on this basis.

125 In this connection, I observe that parties have not made any challenge as to the lack of qualifications or partiality against the other party’s expert and the court assessor, Prof Sharratt. The more crucial point is that the parties diverge on the common general knowledge purportedly held by the person skilled in the art. I address this in the next section.

126 I have set out the definition of common general knowledge (see [68] above). There is some consensus between the parties as to what constitutes the common general knowledge purportedly held by the person skilled in the art. According to the parties, the common general knowledge would include first-hand experience in the performance of literature search, the planning and execution of multistep synthetic reaction sequences, the purification and characterisation of products in a laboratory setting, as well as knowledge of the issues involved in the synthesis of products at a medium-to-large scale. ¹⁶⁰ The notional person skilled in the art (see [67] above) would also be aware of the literature in standard textbooks relating to organic chemistry. ¹⁶¹ Parties’ experts agree that the person skilled in the art would have the necessary common general knowledge of synthesising bortezomib and related organic compounds. ¹⁶²

127 Where the parties are not in agreement on whether the material forms part of the common general knowledge, the following summarises the parties’ positions on what it considers form part of common general knowledge:

(a) The defendant claims the following to form part of the common general knowledge:

(i) The use of zinc chloride as a Lewis acid, often under anhydrous conditions. ¹⁶³

(ii) The conduct of experiments relating to organometallic compounds (which are highly reactive) at cold temperature (-100 to -78C) and to then warm the reaction up to various warmer temperature ranges to ensure selectivity (enantiomeric or diastereoselective) and/or control exothermic reactions. ¹⁶⁴

(b) The plaintiffs claim the following forms part of the common general knowledge:

(i) The issues relating to scalability. ¹⁶⁵

(ii) The particular issues involved in the synthesis of products at a medium-to-large scale. ¹⁶⁶

(iii) Epimerisation is caused by even trace quantities of water as well as excess zinc chloride. ¹⁶⁷

128 At this juncture, I pause to make the observation that parties’ cases on common general knowledge appear to be inconsistent. The common general knowledge outlined by Prof Chiba in his reports has been broadly stated with only a few specific areas falling within its specified scope. However, the plaintiffs’ position on common general knowledge in the Primer includes all the literature and prior filed patents relied on by the defendant to dispute the validity of the Patents. ¹⁶⁸ Yet in the Primer the plaintiffs also take the view that the literature and prior patents relied on by the defendant to dispute validity do not form part of the state of the art in the novelty inquiry and the obviousness inquiry.

129 In my judgment, the position taken by the plaintiffs is untenable. The plaintiffs acknowledge that the materials form part of the common general knowledge, but contend that they do not form part of the state of the art in the novelty inquiry and the obviousness inquiry. Their position sits uncomfortably because the state of the art has a broad reach, extending to any information that has been publicly disclosed (see [73] above). The defendant has similarly adopted a broad position in its expert reports by Dr Johannes, and only takes a more granular approach to the matters forming part of common general knowledge in the Primer.

130 For the present purposes of setting out the relevant common general knowledge, I default to the broad definitions of common general knowledge provided by the parties’ experts at [126] above. This includes also the specific literature and prior patents listed in the Primer at [24]–[58] and [104] above. On this basis, it is not meaningful for the plaintiffs’ expert to contend that the literature and prior patents listed in the Primer form part of common general knowledge but do not fall within the state of the art for the novelty inquiry and the obviousness inquiry.

131 SG 322 relates to the method of making a boronic acid ester of compound Formula (I) and its use in the preparation of bortezomib. It seeks to overcome and solve the known problem of epimerisation (see [45]–[46] above). SG 322 teaches the use of an ether solvent that has low miscibility with water, such as methyl tert-butyl ether (ie, MTBE). Miscibility is the property of two substances to mix in all proportions (that is, to fully dissolve in each other at any concentration), forming a homogeneous mixture (a solution). The plaintiffs are asserting claims 1–7, 9–17, 20–26, 28, 30–35, 38, 41–46, 48 and 52 of SG 322 as being infringed. ¹⁶⁹

132 The diagram below depicts the improved Matteson homologation process taught under SG 322 (see [133]). ¹⁷⁰ Based on the teaching of SG 322, the first plaintiff performs the first step of the reaction (formation of “ate” complex I) in a coordinating ether solvent that has low miscibility with water (ie, MTBE). This solvent, when compared by volume, is the major constituent of the reaction mixture (at least 70% volume per volume (“v/v”)); and the water miscible ether solvent is either completely eliminated or used in a low volume (less than 20% v/v). This ensures that the first intermediate (ie, the boron “ate” complex) remained in the organic layer that had a majority of an ether solvent with low miscibility with water. ¹⁷¹

133 Subsequently, at the second step involving the addition of the Lewis acid catalyst (ie, zinc chloride), the molecular re-arrangement occurs in the MTBE layer and the by-product lithium chloride is unable to significantly ionise (owing to the absence of water). Although THF is used as a solvent for zinc chloride to transfer it to the reaction mixture during the second step (also the contacting step), the use of MTBE in the first step as constituting the majority of the reaction mixture renders the amount of THF introduced in the second step incapable of effecting significant epimerisation. This reduces, or eliminates entirely, the epimerisation. ¹⁷²

134 Paragraph [001] of SG 322’s specification states that the “invention relates to the synthesis of boronic ester and acid compounds”. ¹⁷³ In particular, it states that the invention relates to “large-scale synthetic processes for the preparation of boronic ester and acid compounds by Lewis acid promoted rearrangement of boron “ate” complexes”.

135 As part of the “Background of the Invention”, paragraph [007] states that US 309 describes an improved procedure for the homologation of boronic esters by rearrangement of the intermediate boron “ate” complex in the presence of a Lewis acid catalyst. Paragraph [007] describes US 309 as reporting the use of the Lewis acid to promote the rearrangement reaction and to minimise epimerisation at the alpha-carbon atom. It is also noted that US 309 recorded that “[r]igorous exclusion of water and careful control of Lewis acid stoichiometry are required for optimum results”. However, SG 322 claims that “[t]hese features [in US 309] render the reaction difficult to perform successfully on a production scale”, and limit the availability of pharmaceutically important boronic ester and acid compounds, such as bortezomib. There was consequently “a need in the art for improved methods for the large-scale production of boronic ester and acid compounds”.

136 Paragraph [008] states that the invention provides “improved synthetic processes for the large-scale production of boronic ester and acid compounds”, which “offer increased yield and purity, increased throughput, and greater ease of handling as compared to prior art methods”. Specifically, regardless of the scale of production, the products (such as chiral boronic ester and acid compounds including alpha-aminoboronic ester and acid compounds) are produced with “very high chemical and stereochemical purity”.

137 Paragraph [025] describes the core inventive concept of SG 322 – that “the requirement for scrupulously dry equipment, solvents, and reagents that characterized previously described procedures for the Lewis acid promoted rearrangement of boron “ate” complexes can be obviated by use of an ether solvent that has low miscibility with water”. [emphasis added] By contrast, as paragraph [028] states, previously reported processes for Lewis acid-promoted rearrangement of boron “ate” complexes employed THF, which is an ether solvent that is fully miscible with water – the limitation was therefore that a “failure to employ rigorously dried equipment, solvents and reagents … results in a dramatic reduction in the diastereomeric ratio” and rendered it costly and difficult to scale. Thus, as paragraph [029] outlines, SG 322 seeks to resolve the epimerisation at the alpha-carbon centre from the exposure of alpha-haloboronic ester products to free halide ion (as reported in Matteson and Erdik). As epimerisation is thought to occur during concentration of the reaction mixture, SG 322 “remove[s] the [THF] and exchange[s] it for a water-immiscible solvent” per paragraph [029].

138 The specific requirements of the ether solvent (see [137] above) are as follows:

(a) Preferably, the solubility of water in the ether solvent is less than about 5% w/w, and more preferably less than about 2% w/w. In various embodiments, ether solvent that has low miscibility with water constitutes at least about 70%, 80%, 85%, 90%, or 95% v/v of the reaction mixture (paragraph [030]).

(b) The ether solvent preferably is one that is suitable for routine use in large-scale production. The term “large-scale” refers to a reaction that utilises at least about five moles of at least one starting material. Preferably, a large-scale process utilises at least about 10, 20, 50, or 100 moles of at least one starting material (paragraph [031]).

(c) For purposes of the invention, the term “ether” refers to any of a class of chemical compounds characterised in having an oxygen atom attached to two carbon atoms. An “ether solvent” is an ether compound that exists in liquid form at the desired reaction temperature and is capable of dissolving the starting material(s) and/ or product(s) of the reaction. Non-limiting examples of ether solvents suitable for use in the process of the invention include MTBE (paragraph [032]).

(d) In one embodiment, the reaction mixture further comprises a coordinating co-solvent or a coordinating solvent, which refers to “a solvent that is capable of coordinating the Lewis acid and solvating the ionic components of the reaction” (paragraph [033]).

(e) In some embodiments, the reaction mixture comprises at least about 5% or 10% v/v of a coordinating co-solvent (paragraph [034]).

139 Claim 1 claims a process for preparing a boronic ester compound of Formula (I) comprising: (a) the provision of at least five moles of a boron “ate” complex of Formula (II); and (b) “contacting the boron “ate” complex of Formula (II) with a Lewis acid under conditions that afford the boronic ester compound of Formula (I)” (the “Contacting Step”). The crux of claim 1 is that it teaches the composition of the reaction mixture in which the Contacting Step is carried out. Claim 1(b) states that such a reaction mixture comprises:

140 The general definition of “ether solvent” within SG 322 is set out at [138(c)] above. ¹⁷⁴ In claim 1(b)(i), the ether solvent that has low miscibility with water is sufficiently coordinating that a coordinating co-solvent is not necessary. In claim 1(b)(ii), the reaction mixture further comprises a coordinating co-solvent. A “coordinating co-solvent” or “coordinating solvent” are interchangeable terms referring to a solvent that is capable of coordinating the Lewis acid and solvating the ionic components of the reaction. ¹⁷⁵ On either one of the taught compositions of the reaction mixture, the solubility of water of the ether solvent with low miscibility with water is less than 5% w/w and the ether solvent constitutes at least 70% v/v of the reaction mixture.

141 As the defendant’s case on novelty rests on claim 1 of SG 322 (with the other asserted claims contingent on claim 1), ¹⁷⁶ I deal only with the arguments and evidence raised in respect of claim 1.

142 I begin first by identifying the state of the art relevant to the novelty requirement on the priority date of SG 322.

143 Parties are sharply divided on what constitutes the relevant state of the art for SG 322. The plaintiffs deny the relevance of the following materials listed below and take the position that they do not form the state of the art in relation to the large-scale manufacture of bortezomib:

(a) US 309 discloses the use of a suitable solvent medium for the Matteson homologation protocol, such as THF, diethyl ether, petroleum ether “or the like”, for the preparation of the compound of Formula (I). ¹⁷⁷ US 309 was first filed on 25 June 1985, and it was available to the public before the priority date of SG 322 on 24 March 2005. The plaintiffs claim that US 309 is not relevant as the disclosure of borate complexes in US 309 does not anticipate the use of an ether solvent of low miscibility with water. ¹⁷⁸ The defendant contends that US 309 forms part of the state of the art and notes that the patent itself states that it teaches an improved form of Matteson homologation. ¹⁷⁹ The defendant argues that the teachings disclosed in US 309 would enable the person skilled in the art to deduce that other water-immiscible ether solvents, such as MTBE, may be used as alternative solvents in the process. ¹⁸⁰ Therefore, according to the defendant, claim 1 of SG 322 would not satisfy the novelty requirement. ¹⁸¹ Conversely, the plaintiffs aver that US 309 only teaches the Matteson homologation reaction, whereas the teaching in claim 1 of SG 322 seeks to improve the Matteson homologation process. ¹⁸²

(b) WO 266 dated 9 May 1996 is the international patent disclosing bortezomib (see [5] above). ¹⁸³ The defendant uses WO 266 as evidence that all the elements in claim 1 for the synthesis of bortezomib are known. The reagents/reactants employed to make bortezomib, the reaction process (the Matteson homologation process) and the end product (ie, bortezomib) are disclosed. ¹⁸⁴ The plaintiffs have not addressed whether WO 266 anticipates the inventive concept of claim 1 of SG 322 in their written submissions. For completeness, I consider also the evidence led by the plaintiffs on this. In Prof Chiba’s First Expert Report, whether WO 266 anticipates claim 1 of SG 322 is also not addressed.

(c) US 454 dated 14 July 1998 is the US patent disclosing bortezomib (see [5] above). It belongs to the same patent family as WO 266. ¹⁸⁵ The arguments made by the defendant in respect of US 454 are the same as WO 266 (see [(b)] above). ¹⁸⁶

144 I disagree with the plaintiffs that the materials referred to by the defendant (see [143] above) in challenging the validity of SG 322 do not form part of the state of the art for the novelty requirement. In this connection, as I considered above at [128], the plaintiffs take an unworkable position in respect of common general knowledge and the state of the art. If it were the case that the plaintiffs have conceded that the literature and prior patents stated in the Primer formed part of the common general knowledge, it cannot be that the literature and prior patents do not form part of the prior art relevant to novelty. Given the broader parameters of what the state of the art constitutes (ie, all uses or disclosures that were made available to the public at the priority date are to be treated as relevant prior art), the materials which form part of the common general knowledge must necessarily form part of the state of the art.

145 The only argument, in substance, raised by the plaintiffs in refutation of the materials forming part of the state of the art is that they lacked relevance to the “large-scale production of bortezomib”. This is misguided. In my view, the plaintiffs’ submission is contrivedly narrow – the materials are relevant and form part of the state of the art at the priority date of SG 322 because they pertain to the manufacture of bortezomib and its analogous compounds, and the reported limitations based on the experimental processes described. This should also be seen in light of the plaintiffs’ position in the Primer that the pieces of literature form part of the common general knowledge for the novelty requirement for claims in SG 322. More crucially, SG 322’s specification itself contains reference to, inter alia, WO 266, US 454 and US 309. ¹⁸⁷ Thus, the materials relied on by the defendant as forming part of the state of the art for the assessment of novelty of SG 322 (at [143] above) must be included as prior art relevant to the inquiry.

146 In any event, flowing from my analysis below at [147]–[159], while the relevant literature and prior patents form part of the state of the art relevant to the novelty inquiry for SG 322, they do not anticipate the claimed invention in the asserted claims of SG 322.

147 Before I proceed with my assessment of whether the prior art anticipates claim 1 of SG 322, I summarise briefly the parties’ positions on this. The plaintiffs assert that there is no prior art that discloses all of the inventive concept of SG 322. ¹⁸⁸ Further, the plaintiffs submit that the novelty of SG 322 ought to be assessed with reference to the “core inventive concept” which is the use of an ether solvent of low miscibility with water, and in which water’s solubility is less than 5% w/w, at a proportion of at least 70% of the reaction mixture. ¹⁸⁹ The defendant on the other hand argues that US 309, WO 266 and US 454 anticipate claim 1 of SG 322. ¹⁹⁰

148 I proceed to examine whether any of the individual matter in the state of the art anticipated the claimed invention in claim 1 of SG 322 for the novelty requirement, before turning to the inventive step requirement. If claim 1 is found to be valid, then the rest of the asserted claims in SG 322 are valid as well. This is on the basis that the parties’ cases on the validity of SG 322 (in respect of novelty and inventive step) is that the remaining claims in SG 322 are premised on the claimed invention in claim 1, which is “the use of an ether solvent of low miscibility with water”. ¹⁹¹

149 The defendant submits that WO 266 discloses all the elements in claim 1 for the synthesis of bortezomib. These elements include the reagents utilised in the manufacture of bortezomib and the Matteson homologation process. ¹⁹² It acknowledges, however, that the use of an ether solvent with low miscibility with water in the Matteson homologation process is not taught in WO 266. ¹⁹³ The defendant makes the same argument for US 454. ¹⁹⁴ The plaintiffs have not responded to this argument in their submissions.

150 In my view, however, WO 266 and US 454, which are product patents for bortezomib, did not disclose any information which would enable the person skilled in the art to derive from them individually the use of an ether solvent of low miscibility with water, or the use of an ether solvent of low miscibility with water and a coordinating solvent in the proportions taught in claim 1. Indeed, the defendant concedes that the use of an ether solvent which has low miscibility with water is not taught by either WO 266 or US 454. Anticipation by WO 266 and US 454 of claim 1 of SG 322 requires enabling disclosure, in that the person skilled in the art may arrive at the claimed invention in claim 1 from the information disclosed in WO 266 and US 454 individually. I therefore conclude that WO 266 and US 454 do not anticipate claim 1 of SG 322.

151 The defendant also relies on US 309 to show that it concerns an improved form of Matteson homologation and that it teaches that “among the solvents that have been found to be useful are included … [THF] … and the like”, which anticipates claim 1 of SG 322. ¹⁹⁵

152 US 309, first filed on 25 June 1985, describes an improved procedure for the homologation of boronic esters by the rearrangement of the intermediate boron “ate” complex in the presence of a Lewis acid catalyst. ¹⁹⁶ US 309 discloses the use of both water miscible ether solvents such as THF and water immiscible ether solvents such as diethyl ether or petroleum ether “and the like” for the Matteson reaction. ¹⁹⁷ As part of the “Description of the Invention”, US 309 states: ¹⁹⁸

US 309 records a substantial improvement over the process, which is shown by the data on yields and diastereoselectivities as follows: ¹⁹⁹

153 The defendant submits that the phrase “and the like” in US 309 teaches that similar kinds of ether solvents can be used. ²⁰⁰ It contends that there is no doubt that THF and MTBE are substitutable solvents and Dr Johannes avers that the person skilled in the art would consider other solvents that are suitable candidates that can be used in the synthesis of bortezomib. ²⁰¹ Further, there was enabling disclosure of diethyl ether, which is a water immiscible ether solvent, which in the defendant’s submission leaves no doubt that other water immiscible ether solvents like MTBE may be used as an alternate solvent. Dr Johannes opines that the use of the ether solvent that has low miscibility with water (or the mixture of the ether solvent that has low miscibility with water and an ether solvent that “has miscibility with water” [ie, with higher miscibility with water]) was “well known”. ²⁰² In this regard, he avers that the prior art achieved desired yield and purity by using the Matteson homologation protocol. US 309 discloses the use of a suitable solvent medium for the Matteson homologation protocol including THF, diethyl ether, petroleum ether, “or the like”. ²⁰³

154 According to Prof Chiba, however, claim 1 is the process for preparing a boronic ester compound of Formula (I) by employing the “improved” Matteson homologation protocol for the large-scale synthesis of bortezomib. The use of an ether solvent that has low miscibility with water (ie, MTBE) as a major component of the reaction mixture during formation of the “ate” complex II (ie, the first intermediate) fulfils the novelty requirement as this is an improvement to the Matteson homologation protocol. This allows the use of moist zinc chloride as a Lewis acid during the Contacting Step without significant epimerisation, which reduces the creation of undesirable compounds that reduce product purity. Prof Chiba therefore concludes that the claimed invention provides an effective process for synthesising the compound of Formula (I). On this claimed invention, Prof Chiba avers that the process ultimately generates products of desired chemical and stereochemical purity, even on a large-scale production – claim 1 is therefore novel.

155 In my view, the prior disclosure of the use of diethyl ether or petroleum ether (which are ether solvents that have low miscibility in water) does not fully anticipate claim 1 of SG 322. The teachings disclosed in US 309 in respect of the use of specific ether solvents with low miscibility with water, namely, diethyl ether and petroleum ether, do not enable the person skilled in the art to distil from it the use of a mixture of an ether solvent with low miscibility with water and a coordinating co-solvent in the proportions taught in claim 1 that would maintain the reaction yield even with the presence of high levels of moisture. However, the teaching in US 309 of the use of ether solvents with low miscibility with water as a coordinating solvent serves as enabling disclosure for the person skilled in the art to arrive at the claimed invention in claim 1(b)(i). Indeed, Prof Chiba acknowledged under cross-examination that the phrase “and the like” in US 309 refers to “other ether solvent(s)”. The pertinent portion of his evidence is reproduced below: ²⁰⁴

Prof Chiba agrees that the reference to “and the like” in US 309 included ether solvents with low miscibility in water, such as MTBE. This is the teaching in claim 1(b)(i) of SG 322. US 309 has therefore clearly anticipated the use of an ether solvent with low miscibility in water in the reaction taught. In this regard, it is apparent that US 309 anticipates claim 1(b)(i) of SG 322.

156 The plaintiffs’ objection against Dr Johannes’ argument that the patent is invalid through the use of MTBE not being novel is that it does not appreciate the actual mechanism behind the invention of SG 322. ²⁰⁵ SG 322 teaches the use of solvents in certain proportions in the reaction mixture that maintains reaction yield even if there are high levels of moisture in the system. I observe that Dr Johannes characterises claim 1 of SG 322 as teaching a choice of a solvent that works for the reaction rather than teaching a method of utilising a solvent in specific proportions (at least 70% v/v of the reaction mixture) to cope with high moisture levels in the system. ²⁰⁶ The latter formulation more accurately depicts the teaching in claim 1(b) of SG 322. Dr Johannes’ criticism on the lack of novelty of claim 1 of SG 322 is therefore limited to claim 1(b)(i). US 309 teaches the use of ether solvents with low water miscibility and the person skilled in the art may extrapolate that an ether solvent with low water miscibility would be suitable as a coordinating solvent with reasonable yield.

157 That being said, however, claim 1(b)(ii) teaches the use of a mixture of (a) an ether solvent that has low miscibility with water and (b) a coordinating co-solvent provided that the ether solvent that has low miscibility with water constitutes at least 70% v/v of the reaction mixture. I agree with the plaintiffs’ argument on novelty with respect to claim 1(b)(ii) vis-à-vis US 309. Based on the patent description at paragraph [033], SG 322 highlights that the performance of MTBE leaves room for improvement and that “[h]indered ether solvents, such as [MTBE], are poorly co-ordinating and preferably are used with a coordinating co-solvent”. ²⁰⁷ Claim 1(b)(ii) introduced the use of a “coordinating co-solvent” to the reaction mixture in order to resolve the poorly coordinating nature of MTBE on its own.

158 In my view, US 309 itself does not teach the use of the mixture identified in claim 1(b)(ii), much less explain the rationale for the introduction of such a mixture. That much is clear on the face of the patent specification and the claims of US 309. It does not suffice that US 309 is “merely close or similar” to the teachings of SG 322 – there is still a gap in that the use of a mix of an ether solvent with low miscibility with water and a coordinating co-solvent would not result from the person skilled in the art following the directions of the teachings of US 309 as it does not teach the use of an ether solvent of low miscibility with water with another coordinating co-solvent in the proportions taught in claim 1. Thus, US 309 does not anticipate claim 1(b)(ii).

159 Claim 1(b)(ii) is therefore not anticipated by prior art. As I have analysed above at [155], however, claim 1(b)(i) is anticipated by US 309.

160 Turning to the inventiveness of SG 322, the defendant submits that THF and MTBE are substitutable Lewis basic solvents which may be used in the synthesis of bortezomib. It contends that the difference in US 309 and SG 322 is that MTBE is not directly mentioned in US 309, but the use of water-immiscible MTBE in place of water-miscible THF is obvious. ²⁰⁸

161 For the obviousness inquiry, the defendant relies mainly on US 309. ²⁰⁹ It also refers to WO 266 and US 454. ²¹⁰ I have accepted above at [143] and [144] that these patents form part of the state of the art for novelty. As US 309 was published earlier than the priority date of the invention in SG 322, it also forms part of the state of the art for obviousness (see [79] above).

162 As the defendant’s case on obviousness rests on claim 1 of SG 322 (with the other asserted claims contingent on claim 1), ²¹¹ I deal only with the arguments and evidence raised in respect of claim 1. I will consider whether the prior art the defendant relies on at [161] above renders claim 1 of SG 322 obvious.

163 The plaintiffs contend that claim 1 of SG 322 frames the epimerisation problem differently from US 309. US 309 frames the problem in terms of the amount of zinc chloride utilised in the reaction. They therefore argue that the inventive concept in claim 1 of SG 322 is not obvious. ²¹² The plaintiffs also allege that although US 309 reveals the use of an ether solvent of low miscibility with water, it does not describe any particular conditions for the reaction. ²¹³ For SG 322, however, the plaintiffs state that the step at which the boron “ate” complex contacts the Lewis acid in the “improved” Matteson homologation protocol has to occur under very specific conditions to avoid affecting the purity of the product due to epimerisation. ²¹⁴

164 In my view, claim 1 of SG 322 is non-obvious in so far as it pertains to claim 1(b)(ii). As I alluded to above, Claim 1(b)(i) teaches the use of a coordinating ether solvent that has low miscibility with water (for eg, MTBE) while claim 1(b)(ii) teaches the use of an ether solvent that has low miscibility with water and a coordinating co-solvent, wherein the ether solvent constitutes at least 70% v/v of the reaction mixture (see Annex 1).

165 I agree with Prof Chiba that US 309 does not disclose the core inventive concept taught by claim 1 of SG 322.

166 On the one hand, the use of a single water-immiscible ether solvent (ie, MTBE) instead of THF is an obvious thing to try given that THF belongs to the same family of solvents (ie, it is an ether solvent). The person skilled in the art would have a fair expectation of success with the use of an ether solvent with low miscibility with water as a solvent in the synthesis of bortezomib. He would also have been aware of the need to reduce moisture-levels in the reaction based on prior literature indicating the higher levels of epimerisation with the presence of moisture and thus the choice of a solvent with low water-miscibility would have been a sensible option. Taken together with the prior art of US 309 that identifies a range of both water-miscible and water-immiscible solvents which serve their purpose in other Matteson homologation reactions, and the mention of “diethyl ether, petroleum ether, or the like”, the person skilled in the art was more than likely to consider MTBE as a possible solvent. This would amount to a substantial inroad to the inventiveness of claim 1(b)(i), which describes only the use of an ether solvent with low miscibility with water.

167 That being said, there is nothing in US 309 that would allow the diligent person skilled in the art with the common general knowledge of the time to consider the mixture of an ether solvent with low miscibility with water and a coordinating solvent, in the proportions as outlined in claim 1(b)(ii).

168 Finally, I deal with the defendant’s submission that if claim 1(b)(i) lacks novelty and/or inventive step then the entire of claim 1 is invalid because the core inventive concept is the use of a water-immiscible ether solvent. ²¹⁵ This is a question of claim construction. Given that the use of an ether solvent of low miscibility with water is linked by the conjunction “or” to the mixture of an ether solvent with low miscibility with water and a coordinating solvent, the plain meaning of the words conveys that the two are disjunctive and teach a method that may be utilised independent of the other. It is incorrect to say that claim 1 only teaches the use of an ether solvent with low miscibility with water as it is apparent on the face of the text of claim 1 that the mixture of an ether solvent with low miscibility with water and a coordinating solvent in the proportions of claim 1 is presented as a distinct reaction mixture in which the promoted Lewis acid rearrangement may occur.

169 I therefore find claim 1 of SG 322 valid. Having found claim 1(b)(ii) to be novel and non-obvious, the other asserted claims contingent on claim 1(b)(ii) are found to be novel and non-obvious as well. Based on my discussion above at [155] and [166], I find that claim 1(b)(i) lacks novelty and inventive step.

170 I begin by summarising the parties’ respective cases on the alleged insufficiency in claim 12 of SG 322.

171 The defendant argues that there is a clear and obvious error in Claim 12 of SG 322 which renders it ambiguous, and the first plaintiff ought to have rectified it as soon as it became aware of the error and “in any event, before [the] trial”. ²¹⁶ The defendant contends that there is a manifest error in claim 12 that gives rise to insufficiency in two ways: ²¹⁷

(a) The manifest error in claim 12 ipso facto renders claim 12 invalid because it refers to a non–existent claim 7(d). The language of claim 12 is clear and unambiguous, and the patentee could have applied to correct that error but did not do so.

(b) The uncorrected error gives rise to uncertainty and consequently, claim 12 (and its dependent claims 13 to 19) are liable to be invalidated for insufficiency.

172 The plaintiffs instead submit that it is an obvious error that could be readily corrected by the person skilled in the art when in the process of making the invention. They rely on the High Court’s holding in Ng Kok Cheng that an error in the specification would not render the patent invalid provided it is an error that a person skilled in the art can at once observe and correct (at [87] and [91]). The reference to “claim 7(d)” in claim 12 is an obvious typographical error for which the person skilled in the art would not have difficulty identifying the correction. ²¹⁸ The plaintiffs argue that there can be no confusion that the reference to claim 7(d) was instead meant to be to claim 11(d) for the following reasons: (a) there is no claim 7(d) in SG 322; (b) in the claims preceding claim 12 in SG 322, reference to groups R4 and R5 is only made in claims 1 and 11; and (c) in the claims preceding claim 12 in SG 322, only claim 11 has a sub-paragraph (d). ²¹⁹

173 As a preliminary issue as to the scope of the sufficiency argument, I agree with the plaintiffs’ objection that the dependent claims 15 to 19 ought to be excluded from the assessment as they were not put in issue in the defendant’s Particulars of Objection. Although the defendant has indicated in its further submissions dated 5 May 2023 that it would be applying to amend the Particulars of Objection to include claims 15 to 19 in the challenges on insufficiency, ²²⁰ it has not done so till date. This suffices to remove claims 15 to 19 from the assessment of sufficiency.

174 I turn to the substance of the sufficiency argument. Claim 12 is reproduced below:

175 In Ng Kok Cheng, the court held that for there to be enabling disclosure, it was sufficient that a person skilled in the art would find the wording of the specification sufficient to enable him to make the invention, even if the specification did not state every single step that had to be followed in order to make the invention (at [49]). This did not require absolute clarity and completeness (Ng Kok Cheng at [49]). The court also accepted that the error could be readily corrected by the person skilled in the art when in the process of making the invention (Ng Kok Cheng at [91]).

176 In the present case, it is apparent on the face of SG 322 that the reference to “claim 7(d)” in claim 12 is an error that may be corrected by the person skilled in the art with reference to SG 322 as a whole, enabling him to perform the invention without an undue burden with reference to “claim 11(d)”. Claim 11 is reproduced below for discussion:

This is because only claim 11 contains reference to groups R4 and R5 and includes a sub-paragraph (d) in the claims preceding claim 12. Although the defendant makes much of its characterisation that the person skilled in the art would need to engage in guesswork and speculation to arrive at the reference to claim 11(d) from the error in claim 12, ²²¹ I disagree with the defendant’s argument on this. I note also that no evidence was provided by Dr Johannes on this point. As the Court of Appeal held in Element Six, the test for whether there was sufficient clarity is whether the person skilled in the art is left unclear as to how to determine whether a particular process remains within the scope of the claim even after drawing upon his common general knowledge or applying the typical claim construction process (at [131]). With the present claim 12, the application of the typical claim construction process (see [65] above) which involves reference to the rest of SG 322, assists the person skilled in the art to arrive at the conclusion that claim 12 must have referred to claim 11(d). There is otherwise no claim 7(d), and the reference to the chiral moiety of both R4 and R5 is to be found in claim 11(d). It would have been clear to a person skilled in the art to arrive at this conclusion by situating claim 12 in relation to claim 11(d) of SG 322 in his exercise of the purposive interpretation of the claim.

177 I therefore find that claim 12 (and the dependent claims 13 to 14) is not invalid for lack of sufficiency.

178  To recapitulate, the asserted claims in SG 29P are claims 1, 2–4 and 6 where claim 1 is the sole independent claim.

179 The plaintiffs take the position that the core inventive concept of SG 29P is the convergent coupling of the compounds of Formulas (XVIII) and (XIXa) (corresponding to the compounds referred to as BZM-4 and BZM-8 respectively in DRL’s process) to produce a compound of Formula (XXIII), which is deprotected to form a compound of Formula (XIV) (bortezomib). ²²² This process is termed convergent synthesis. ²²³

180 The defendant does not dispute that claim 1 of SG 29P claims a two-step convergent process for the synthesis of bortezomib. ²²⁴ Rather, it disputes the validity of claim 1 of SG 29P (and indeed SG 29P as a whole) on the basis that the invention claimed is neither novel nor inventive. ²²⁵

181 The background of the invention in SG 29P, and thus the patent specification of SG 29P, substantially mirrors that of SG 322. I have outlined the salient aspects above at [134]–[138].

182 Claim 1 relates to synthesis of a compound of Formula (XIV) (ie, bortezomib) by coupling a compound of Formula (XVIII) or an acid addition salt thereof with a compound of Formula (XIXa), wherein X is a leaving group, to form a compound of Formula (XXIII), and deprotecting the boronic acid moiety to form a compound of Formula (XIV) (ie, bortezomib) or a boronic acid anhydride thereof. ²²⁶

183 The defendant relies on the following materials as part of the state of the art for the novelty inquiry for SG 29P: ²²⁷

(a) International Publication No. WO 03/033506, filed as PCT/JP02/10450, dated 24 April 2003 (“WO 506”) is a Japanese patent relating to aminoboronic acid derivatives. It discloses the convergent synthesis of compounds having the phenylalanine amino group. ²²⁸ I analyse this below at [186]–[195].

(b) International Publication No. WO 03/033507, filed as PCT/JP02/10451, dated 24 April 2003 (“WO 507”) is a patent with a priority date of 12 October 2001. I analyse whether WO 507 anticipates claim 1 of SG 29P below at [196]–[201].

(c) US 079 teaches the use of convergent synthesis process for the synthesis of peptides. ²²⁹ I analyse whether US 079 anticipates claim 1 of SG 29P below at [203].

184 The plaintiffs argue that claim 1 of SG 29P is novel and teaches an inventive step. The core inventive concept of SG 29P is the convergent coupling of the compounds of Formula (XXIII), which is deprotected to form a compound of Formula (XIV) (ie, bortezomib) (ie, convergent synthesis). ²³⁰

185 It is relevant at this juncture to explain how convergent synthesis features in SG 29P. This develops the general definition of convergent synthesis which was set out earlier in this judgment (see [50] above). The plaintiffs rely on the side-by-side comparison between the process at claims 45 to 51 of SG 322 and DRL’s process, prepared by the defendant’s Mr Amarendhar, to illustrate the difference between linear synthesis (process taught in claims 45 to 51 of SG 322) and convergent synthesis (DRL’s process). ²³¹