In Amylin Pharmaceuticals LLC & Anr. vs Assistant Controller of Patents (C.A.(COMM.IPD-PAT) 76/2022), the Delhi High Court upheld the refusal of a patent application for a sustained-release exenatide injection for diabetes. The Court in this appeal case examined whether the claimed invention exhibits an inventive step under Section 2(1)(ja) of the Patents Act, 1970, in the light of Documents D1 to D4 cited by the Controller for rejection of the patent application 1498/DELNP/2011 titled “Sustained release formulations using non-aqueous carriers”. To carry out the inventive step analysis, the Court used the procedure for assessing the inventive step as laid down in the judgment of the Court in Hoffmann-La Roche Ltd. vs Cipla Ltd. [(2016) 65 PTC 1 (Del)].
The Court compared the disclosure and teaching of D1-D4 with the characterising variations of the claimed invention and found that Amylin and AstraZeneca’s claimed formulation was an expected variation of existing prior art and not a truly inventive step, as described in the patent specification. The Court also looked into the Controller’s argument for combining prior art D1 and D2 to arrive at the claimed invention. In this context Court cited ruling of the Court in Bristol-Myers Squibb Holdings Unlimited Company and Others vs BDR Pharmaceuticals International Pvt. Ltd. [2020 SCC OnLine Del 1700]I, wherein it was held that “mosaic of prior arts may be done while claiming obviousness, however the party claiming must be able to demonstrate that how the person of ordinary skill in the art would have been led to combine the relevant components relied from the mosaic of prior art”.
In the present case, the Court found that the PSITA would seek to refer Document D2, D3 and D4 after referring to Document D1 for the reason that D1 disclosed the microspheres of PLGA copolymers and discussed the need for improved PLGA microspheres containing biologically active agents with controlled release profiles. Further, D1 mentioned that “there exists the need for improved PLGA microspheres containing biologically active agents that have controlled release profiles.” Both of these statements would make the PSITA refer to other cited Documents to find a solution. Additionally, D2 disclosed the scope for GLP-1 being long-acting and sustained formulations, which would, along with D1, suggest coming to the present invention. Further, D2, which discussed the burst/lag issues, would teach to refer to other cited documents like D4.
Appellants’ Case
The appellants submitted that document D1 pertained to the microsphere delivery systems in which the microspheres include blended PLGA copolymers and a biologically active agent. The appellants contended that documents D2 and D3 did not talk about a non-aqueous carrier, and the subject application had a non-aqueous carrier, which was not present in documents D1 to D4. The appellants submitted that fatty acid, in the main claim of the subject application, was not mentioned in D1 to D4. They argued that the respondent failed to take into consideration that Dl recites fatty acids such as oleic acid, which can be used in the preparation of injectables. Since oleic acid is a fatty acid, it is a long-chain triglyceride and thus, Dl taught away from the specific use of medium-chain triglycerides (i.e., C6 to C12) in a carrier.
The appellants also referred to Paragraph No. [0062] of D2 and argued that Exenatide was not mentioned in D1. The appellants contended that in the impugned order, the respondent had not considered and failed to appreciate the detailed submissions in respect of objections raised in the hearing under Sections 2(l)(ja) and 3(d) of the Act, in the post-hearing written submissions and the amended set of claims as filed along with the post-hearing written submissions made. The appellants also argued that the respondent was not justified in holding that the amended Claims 1 to 19 did not fulfil the requirements of Section 2(l)(ja) of the Act, i.e., lack inventive step, and that they also fell under Section 3(d) of the Act. The appellants further contended that the respondent had not provided reasoning for rejecting the patent under Section 2(1)(j) of the Act.
Respondent Controller’s Reply
The respondent Controller maintained that the present invention did not involve an inventive step, considering the prior art documents D1 to D4, as the pharmacokinetic profile, storage, and in vivo stability of exenatide had already been disclosed in the cited prior art documents. According to the respondent, the claims related to a new form of known active substance, i.e., exenatide, with no improved therapeutic efficacy, would be considered the same substance. The pharmaceutical active ingredient exenatide, which was used for the treatment of Diabetes Mellitus Type 2, was known from the prior art document D3.
The respondent stated that the claims in question were characterised by the formulation comprising a non-aqueous carrier comprising triglycerides of C6 to C12 fatty acids, and microspheres comprising a PLGA polymer having dispersed therein 1% to 10% (w/w) of exenatide as an active pharmaceutical ingredient and 0.1% to 5% (w/w) sugar. The respondent submitted that the claimed formulation was obvious and lacked an inventive step when compared to prior art D1-D4 involving microsphere delivery and sugar stabilisers. As per the respondent, it was obvious to PSITA at the time the invention was made to utilise pre-mixed formulations comprising the active pharmaceutical ingredient Exenatide and the stability agent sugar, as taught by document D2, in microsphere delivery systems taught by document D1.
Document D2 disclosed a premixed formulation having dispersed therein about 5% (w/w) as mentioned in Paragraph No. [0053], Exenatide as an active pharmaceutical ingredient as mentioned in Paragraph No. [0013] and sucrose as mentioned in Paragraph No. [0087]. The respondent contended that it would have been obvious to PSITA at the time of the invention to combine the pre-mixed formulation of document D2 with the invention of document D1 to arrive at the claimed invention without undue experimentation for the purpose of developing a more stable injectable formulation that has a higher rate of patient compliance due to the pre-mixed nature of the formulation.
Court’s Analysis and Findings
Subject Invention
The subject invention relates to formulations comprising microspheres containing active pharmaceutical ingredients, wherein the microspheres are suspended in a non-aqueous pharmaceutically acceptable carrier. The formulations are one-component injectable microsphere formulations that do not require the patient to mix them with a pharmaceutically acceptable carrier prior to injection. The claimed carrier consists of one or more triglycerides, which comprise C6 to C12 fatty acids; and microspheres, which consist essentially of a PLGA polymer having dispersed therein about 1% to 10% (w/w) exenatide and about 0.1% to 5% (w/w) of a sugar. The ratio of lactide: glycolide in the polymer under Claim 1 is about 70:30 to 30:70, or about 1:1.
The inventor claimed that the formulations had advantages over two-component formulations, including the long shelf-life of the composition in the carrier and sustained release of the active pharmaceutical ingredient. As a one-component injectable microsphere formulation, it offered ease of use for patients and did not require the practitioner to mix it with the carrier before injection. In other words, the first problem that the subject invention solved was that these formulations provided therapeutic amounts of active pharmaceutical ingredients over an extended period of time from a single injection, thereby eliminating the need for daily injections, and the second problem it solved was to overcome the significant burst release of injectable microsphere formulations following injection, thereby avoiding any deleterious side effects.
Prior Art Cited by the Respondent Controller
The respondent Controller rejected the patent application as the claimed invention did not involve an inventive step under Section 2(l)(ja) of the Act in view of cited prior art documents: US 2004/0224030 (“D1”), US 2008/0146490 (“D2”), JAIN R A et al: “Controlled release of drugs from injectable in situ formed biodegradable PLGA microspheres: effect of various formulation variables”, European Journal of Pharmaceutics And Biopharmaceutics, Vol. 50, No. 2,01.09.2000, (“D3”) and WO 2005/102293 (“D4”).
On Prior Art US 2004/0224030 (D1)
D1 pertains to the microsphere delivery systems in which the microspheres include blended PLGA copolymers and a biologically active agent. The delivery of a biologically active agent to a specific in vivo location can be achieved by administering the microspheres in a pharmaceutical composition. The purpose of the non-aqueous carrier, i.e., oil, is so that it does not solubilise the polymer(s) that form the microspheres. Non-aqueous carrier will not solubilise Exenatide or other water-soluble therapeutic peptides or proteins. The Court found that Paragraph No. [0068] of D1 suggested the use of sterile, fixed oils; however, it suggested employing synthetic mono- or diglycerides.
The statement “In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium” could reasonably be understood as suggesting the use of triglyceride oils, as fixed oils in ordinary usage refer to fats/oils whose principal constituents are triglycerides. The next line of the paragraph added specific examples in the fixed‑oil domain, while not replacing the baseline understanding that fixed oils are predominantly triglyceride oils in natural form. Therefore, the “teaching away” argument of the appellant would not apply here. The Court cited Astrazeneca AB and Another vs Torrent Pharmaceuticals Ltd. [2020 SCC OnLine Del 1446], wherein it was held that merely because there is teaching towards one solution (ethoxy) rather than another (methoxy) does not mean there is “teaching away” from the latter.
Similarly, in Fresenius Kabi Oncology Limited vs Glaxo Group Limited & Anr. [2013 SCC Online IPAB], the Intellectual Property Appellate Board held that “if a prior art reference teaches two alternative methods to reach the same result, while indicating that one method gives better result than other, and the alternative carries several disadvantages, the person skilled in the art would read the statements neutrally in such a way that he would neither picking out the “teaching towards” statement nor seeking out the “teaching away” statement.” In view of this precedent, the Court ruled that in the present case, the oils mentioned in Paragraph No. [0068] of D1 would also include the specified oils mentioned in the Complete Specification under the headings “summary and “carrier”.
Additionally, D1 specifically disclosed the oleic acid in Paragraph No. [0068], which is a C18 fatty acid, and the shortest chain length amongst the mixtures of compositions cited in 29 different forms of excipients, which are esters made from C16 acids. Therefore, in the light of the above reasoning, it would be obvious for PSITA to use the triglyceride fatty acid of carbon chain lengths ranging from 6 to 12, which was claimed under Claim 1 of the Subject Application. Therefore, the submission of the Appellants that Dl was silent regarding any non-aqueous carrier comprising triglycerides, much less the carbon range as set out in Claim 1, could not be accepted.
This clearly means D1 was relevant for the analysis of inventive step. Moreover, the examples in D1 were examples of microspheres present in the formulation at a concentration of 10 mg/ml as claimed in the application. Dl also disclosed a manufactured formulation for injection consisting essentially of a suspension of:
(i) a pharmaceutically acceptable carrier which consists essentially of one or more triglycerides of CIS fatty acids;
(ii) microspheres consisting essentially of a PLGA polymer; and
(iii) wherein the ratio of lactide: glycolide in the polymer is about 1:1.
On Prior Art US 2008/0146490 (“D2”)
The Court found that the Paragraph Nos. [0013] and [0015] of D2 disclosed Exenatide and Paragraph No. [0087] of D2, and the sucrose, trehalose, lactose, etc. In the complete specification, the subject invention disclosed the different types of sugars:
“The sugar may be, e.g., glucose, dextrose, galactose, maltose, fructose, mannose, sucrose, lactose, trehalose, raffinose, acarbose, glycol, glycerol, erythritol, threitol, arabitol, ribitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol, mannitol, xylitol, or a combination of two or more thereof. In one embodiment, the sugar is sucrose.” This according to the Court means that D2 discloses formulation precursors (preformulations) for the in situ generation compositions for the controlled release of active agents such as Glucagon-like-peptide-1 (GLP-1) and / or analogues thereof, “native GLP-1” indicates human GLP-l(7-37) and / or human GLP-l(7-36) amide and the terms “Liraglutide”, ‘‘a C-1131”, ‘’AVE-010”, and “Exenatide’’ are used to indicate the respective actives.
The formulations may include from 0.1% to 10% of Exenatide. Paragraph No. [0087] of D2 also taught that exenatide and/or its analogues dissolved in lipid formulations gain stability (both storage and in vivo) with such stabilising additives as sugars. Further, Paragraph No. [0099] also disclosed that said formulations may be stored for at least six months at room or refrigerator temperature, without phase separation.
On Prior Art Document JAIN R A et al (D3)
The Court found that Document D3, in its abstract, disclosed a novel in situ method for preparing injectable biodegradable PLGA microspheres for the controlled delivery of drugs and for the formulation of a stable dispersion of PLGA microparticles. D3 also disclosed an injectable dispersion of microspheres comprising a drug and PLGA in a continuous phase consisting of triacetin, PEG400 and Miglyol as claimed in the application.
On Prior Art WO 2005/102293 (D4)
The Court found that D4 disclosed that the compositions are preferably formulated for injection and for the controlled release of the active compound into the body. Further, D4 disclosed exendin-4 at several places, which was nothing but Exenatide. The Complete Specification of the subject invention stated that Exenatide has the same meaning and amino acid sequence as exendin-4.
On a mosaic of prior art
Since the rejection order of the respondent referred to the combined reading of D1-D4, the Court looked into the ruling of the Court in Bristol-Myers Squibb Holdings Unlimited Company and Others v. BDR Pharmaceuticals International Pvt. Ltd. [2020 SCC OnLine Del 1700], wherein it was held that a mosaic of prior arts may be done while claiming obviousness. However, the party claiming that must be able to demonstrate how the person of ordinary skill in the art would have been led to combine the relevant components derived from the mosaic of prior art.
To find whether PSITA would seek to refer to Document D2, D3 and D4 after referring to Document D1, the Court referred to the phrase in Paragraph No. [0002] of D1, which disclosed the microspheres of PLGA copolymers and discussed the need for improved PLGA microspheres containing biologically active agents that have controlled release profiles. Further, the statement therein that “there exists the need for improved PLGA microspheres containing biologically active agents that have controlled release profiles” would prompt the PSITA to refer to the other cited Documents to find a solution.
Additionally, the discussion under Paragraph No. [0014] of D2 that disclosed the scope for GLP-1 being long-acting and sustained formulations, which would, along with D1, suggest coming to the present invention. Moreover, Paragraph No. [0018] of D2, which discussed the burst/lag issues, would teach PISITA to refer to other cited documents, such as D4. Looking at the above facts, the Court concluded that, in the present case, it would have been obvious to PSITA to arrive at the present invention, which utilised pre-mixed formulations comprising the active pharmaceutical ingredient Exenatide and the stability agent sugar, as taught by D2 in microsphere delivery systems taught by Dl.
The Court concluded that the respondent Controller had rightly held that the claimed invention under the Subject Application was obvious and did not involve an inventive step under Section 2(l)(ja) of the Act in the light of the prior art documents D1 to D4, and no inventive step could be acknowledged.
Court’s Decision
In view of the above, the subject application of the appellant could not be termed as an invention under Section 2(1)(j) of the Act. The Court held that the learned Controller rightly refused the application under Section 2(1)(j) of the Act and that no interference was required. The appeal filed by ‘Amylin and AstraZeneca’ was dismissed by the Court.
Concluding Remarks
This decision would serve as a landmark for the patent office in understanding how the ‘Hoffmann test’ for assessing inventive step should be applied and under what circumstances a mosaic of documents is permissible for assessing inventive step as required under section 2(1)(j). In this case, the Court also clarified why the ‘teaching away’ argument of the appellant would not apply, citing the ruling of the Court in the ‘Astrazeneca AB’ case and the ruling of IPAB in the ‘Fresenius Kabi’ case.
Author: DPS Parmar
First Published by: Mondaq here