Alphapharm Pty Ltd v Gilead Sciences, Inc
[2016] APO 50
•22 July 2016
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Alphapharm Pty Ltd v Gilead Sciences, Inc. [2016] APO 50
Patent Application: 2012296622
Title:Tenofovir alafenamide hemifumarate
Patent Applicant: Gilead Sciences, Inc.
Opponent: Alphapharm Pty Ltd
Delegate: Dr S.D. Barker
Decision Date: 22 July 2016
Hearing Date: 4 May 2016, in Sydney
Catchwords: PATENTS – opposition to the grant of a patent – the invention relates to a hemifumarate salt – the hemifumarate is thermodynamically more stable than the monofumarate – citation reports the formation of the monofumarate – it is inevitable that the hemifumarate would have formed, at least in part – lack of novelty – would not have been a matter of routine to repeat the work of the citation or to alter it to prepare the hemifumarate – no lack of inventive step – opposition succeeds – no award of costs
Representation: Counsel for the applicant: Mr B Caine QC and Mr J Cooke
Patent attorneys for the applicant: Mr M Caine and Mr P Dewar of Davies Collison Cave
Counsel for the opponent: Mr A Fox
Solicitor for the opponent: Dibbs Barker
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2012296622
Title:Tenofovir alafenamide hemifumarate
Patent Applicant: Gilead Sciences, Inc.
Date of Decision: 22 July 2016
DECISION
The opposition succeeds to the following extent:
claims 1, 6, 11, 14, 16, 17, 27 and 29 lack novelty in the light of AU 2001282941.
I allow Gilead Sciences, Inc. a period of two months from the date of this decision to file amendments to the specification.
I make no award of costs.
REASONS FOR DECISION
Patent application number 2012296622 (the present application) was filed on 15 August 2012 under the provisions of the Patent Cooperation Treaty. The applicant is Gilead Sciences, Inc. (Gilead). The application claims priority from application US 61/524,224 (the priority document) which was filed on 16 August 2011. No challenge was raised against the priority claim, and I accept that the priority date for the present application is 16 August 2011.
The application was examined and accepted by the Commissioner, and subsequently opposed under section 59 of the Patents Act 1990 (the Act) by Alphapharm Pty Ltd (Alphapharm). A hearing was held on 4 May 2016 in Sydney to decide the opposition. Gilead was represented by Mr B Caine QC with Mr J Cooke. Alphapharm was represented by Mr A Fox of counsel.
The opposition
The statement of grounds and particulars identified six grounds of opposition: manner of manufacture, novelty, inventive step, utility, sufficiency and clarity. At the hearing, the opposition was limited to the grounds of novelty, manner of manufacture and inventive step.
The parties relied upon evidence by several declarants. Evidence in support consists of declarations by:
Jonathan A V Coates (Coates 1),
Alan D Robertson (Robertson 1) and
Helen Grimes (Grimes).Evidence in answer consists of declarations by:
Alistair George Draffan (Draffan) and
Nair Rodriguez-Hornedo (Rodriguez-Hornedo).Evidence in reply consists of declarations by:
Jonathan A V Coates (Coates 2) and
Alan D Robertson (Robertson 2).I will refer to the relevant parts of the evidence where appropriate.
Standard of proof
A request for examination in relation to the present application was filed on 12 April 2013. As a consequence, the substantive amendments of the Act brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 do not apply to the present patent application. This includes the amendment to subsection 60(3A) that allows the Commissioner to refuse a patent application if satisfied on the balance of probabilities that a ground of opposition has been made out. Instead, the onus in this opposition proceeding lies with the opponent, who must establish the grounds of opposition to the traditional standard. That is, the opposition will only succeed if I am clearly satisfied that the patent, if granted, would not be valid (F Hoffman-La Roche AG v New England Biolabs Inc[1]), or it is "practically certain that the patent to be granted on the specification would have been invalid" (Genetics Institute Inc v Kirin-Amgen Inc[2]). In Aspirating IP Ltd v Vision Systems Ltd[3] Besanko J noted that a lesser standard may apply to the primary facts, but not to the ultimate facts:
"The primary facts are to be established on the balance of probabilities, but the ultimate facts – the facts leading directly to a conclusion of a lack of novelty or a conclusion of obviousness – must be proved to the level of practical certainty. In Austal Ships, Bennett J said (at 423 [12]):
'I can accept that a lower standard may apply to proof of evidence such as whether a document has been published or, indeed, whether a prior art vessel was well-known. I do not accept that it properly applies to the factual question that itself is the test for obviousness or lack of inventive step. Where the factual question is itself the legal test, as set out in s 7(3) of the Act, it seems to me that it should be determined at the higher standard. That means that where there are two opposing expert views that are conclusive on obviousness, both presented bona fide by witnesses of accepted expertise, unless one set of views can be rejected on proper grounds, the legal burden to establish a ground of opposition is not discharged; the court cannot be practically certain that obviousness or lack of inventive step is established.' "
[1] [2000] FCA 283; 50 IPR 305 at [67].
[2] [1999] FCA 742; (1999) 92 FCR 106 at [17].
[3] [2010] FCA 1061 at [35]; 88 IPR 52.
The specification
The specification relates to a compound that is useful as a pharmaceutical agent. The specification ends with 4 Figures and 31 claims. There are three independent claims: claim 1, claim 7 and claim 25.
What is the invention as described
The principles of construction of specifications are well established. The Full Court in Kinabalu Investments Pty Ltd v Barron and Rawson Pty Ltd[4] laid out the principles succinctly:
"When determining the nature and extent of the monopoly claimed, the specification must be read as a whole. But as a whole it is made up of several parts which have different functions. The claims mark out the legal limits of the monopoly granted. The specification describes how to carry out the process claimed and the best method known to the patentee of doing that. Although the claims are construed in the context of the specification as a whole, it is not legitimate to narrow or expand the boundaries of monopoly as fixed by the words of a claim, by adding to those words glosses drawn from other parts of the specification. If a claim is clear and unambiguous, it is not to be varied, qualified or made obscure by statements found in other parts of the document. It is legitimate, however, to refer to the rest of the specification to explain the background of the claims, to ascertain the meaning of technical terms and resolve ambiguities in the construction of the claims. See Flexible Steel Lacing Co v Beltreco Ltd [2000] FCA 890; (2000) 49 IPR 331 at [73] - [75] (Hely J).
Other more specific principles of construction collected in Flexible Steel at [81] are:
• a specification should be given a purposive construction rather than a purely literal one;
• the hypothetical addressee of the specification is the non-inventive person skilled in the art before the priority date;
• the words used in a specification are to be given the meaning the hypothetical addressee would attach to them, both in the light of the addressee’s own general knowledge and in the light of what is disclosed in the body of the specification;
• as a general rule, the terms of the specification should be accorded their ordinary English meaning;
• evidence can be given by experts on the meaning those skilled in the art would give to technical or scientific terms and phrases, and on unusual or special meanings given by such persons to words which might otherwise bear their ordinary meaning;• however, the construction of the specification is for the court, not for the expert. In so far as a view expressed by an expert depends upon a reading of the patent, it cannot carry the day unless the court reads the patent in the same way."[5][4] [2008] FCAFC 178.
[5] [2008] FCAFC 178 at [44] – [45].
Further, I note what Middleton J said in Eli Lilly and Company Limited v Apotex Pty Ltd:[6]
"It is well settled that the Court should, from the outset, approach the task of patent construction with a generous measure of common sense. The Court must place itself in the position of a person skilled in the relevant art, being the subject matter of the patent. From this perspective, the patent is to be read as a whole, in the context of the specification and in light of the prevailing common general knowledge and state of the relevant art at the priority date."
[6] [2013] FCA 214, 100 IPR 451 at [139].
The background to the invention
Tenofovir[7] is a compound that has been used to treat human immunodeficiency virus (HIV) infection or hepatitis B virus (HBV) infection. Tenofovir inhibits the reverse transcriptase enzyme, which is essential for virus replication.
[7] The systematic name for tenofovir is ([[(2R)-1-(6-amino-9H-purin-9-yl)-2-propanyl]oxy]methyl)phosphonic acid.
Tenofovir has been administered as a prodrug (a derivative that is metabolised to the active compound following administration). One such prodrug is tenofovir alafenamide[8] (TA), which is known to form a monofumarate salt (TAF mono). This is described in the specification:
"U.S. Patent Nos. 7,390,791 and 7,803,788 (the content of each of which is incorporated by reference herein in its entirety) describe certain prodrugs of phosphonate nucleotide analogs that are useful in therapy. One such prodrug is
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl]adenine. This compound is also known by the Chemical Abstract name L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purinyl)-1-methylethoxy]methyl] phenoxyphosphinyl]-, 1-methylethyl ester. U.S. Patent Nos. 7,390,791 and 7,803,788 also disclose a monofumarate form of this compound and its preparation method (see, e.g., Example 4)."[9][8] The systematic name for tenofovir alafenamide is 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino][9] AU 2012296622 at page 1.
The structure of TA is:
The aim of the invention
The specification does not state an aim for the invention. However, the specification incorporates by reference the priority document, which discusses TA and at page 1 says:
"Currently there is a need for improved methods for preparing this compound [i.e. TA] … Additionally, it would be beneficial to identify a form of the compound that has improved stability or processability while maintaining a comparable PK and tablet dissolution profile. For example, it would be useful to identify a form of the compound that has improved thermodynamic stability in solution or in the solid state that can be more readily purified, that has superior process reproducibility or content uniformity, or that has higher crystallinity or a higher melting point."[10]
[10] US 61/524,224 at page 1.
The nature of the invention
The specification describes a hemifumarate salt of TA. The ratio of TA to fumaric acid in this salt is 1:0.5. I will refer to the hemifumarate of TA as TAF hemi.
TAF hemi is produced by mixing fumaric acid and TA in a solvent, and allowing it to crystallise in the presence of a seed.[11] This process can use TA as the starting point or a mixture of TA and its other enantiomers:
"The method can be carried out by subjecting a solution comprising: a) a suitable solvent; b) fumaric acid; c) tenofovir alafenamide; and, optionally, d) one or more seeds comprising tenofovir alafenamide hemifumarate, to conditions that provide for the crystallization of fumaric acid and tenofovir alafenamide. The starting solution can contain the single diastereomer of tenofovir alafenamide or a mixture of tenofovir alafenamide and one or more of its other diastereomers (e.g., GS-7339, as described in U.S. Patent No. 7,390,791)."[12]
[11] AU 2012296622 at page 3.
[12] AU 2012296622 at page 6.
It is interesting to note that selective crystallisation of TAF hemi "optionally" involves the use of a seed crystal. In other words, selective crystallisation can be carried out without the use of a seed crystal.
The hemifumarate salt is stated to possess a number of advantages:
"One major advantage of the hemifumarate form of tenofovir alafenamide over the monofumarate form is its exceptional capability to purge GS-7339 (i.e., 9-[(R)-2-[[(R)-[[(S) -1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]
propyl]adenine; described in, e.g., U.S. Patent No. 7,390,791), which is the major diastereomeric impurity in the active pharmaceutical ingredient. Thus, the hemifumarate form of tenofovir alafenamide can be more readily and easily separated from impurities than the monofumarate form. Other major advantages of tenofovir alafenamide hemifumarate over the monofumarate form include improved thermodynamic and chemical stability (including long-term storage stability), superior process reproducibility, superior drug product content uniformity, and a higher melting point."[13][13] AU 2012296622 at page 7.
The uses of TAF hemi are described as the same as those of tenofovir:
"Tenofovir alafenamide hemifumarate is useful in the treatment and/or prophylaxis of one or more viral infections in man or animals, including infections caused by DNA viruses, RNA viruses, herpesviruses (e.g., CMV, HSV 1, HSV 2, VZV), retroviruses, hepadnaviruses (e.g., HBV), papillomavirus, hantavirus, adenoviruses and HIV. U.S. Patent No. 6,043,230 (incorporated by reference herein in its entirety) and other publications describe the antiviral specificity of nucleotide analogs, such as tenofovir disoproxil. Like tenofovir disoproxil, tenofovir alafenamide is another prodrug form of tenofovir, and can be used in the treatment and/or prophylaxis of the same conditions."[14]
[14] AU 2012296622 at page 7.
The examples
Example 1 demonstrates the production of TAF hemi as a component of a mixture. Example 1 reads:
"Tenofovir alafenamide monofumarate solids (5.0 g) and 9-[(R)-2-[[(R)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine (GS-7339) monofumarate solids (0.75 g) were charged into 35 g MTBE at 22°C and the mixture was stirred for 1 hour. A slurry was formed and was dried in a rotary evaporator. 58 g acetonitrile (ACN) was charged into the solids and the mixture was heated to reflux to dissolve the solids. The resulting solution was allowed to cool naturally while agitated. A slurry was formed, and the slurry was further cooled by ice-water-bath. The solids were isolated by filtration and washed with 5 g ACN. The solids were dried in a vacuum oven at 40°C overnight. 5.52 g off-white solids were obtained. The solids were analysed by XRPD and found to contain tenofovir alafenamide monofumarate, GS-7339 monofumarate, and tenofovir alafenamide hemifumarate."
In this Example, TAF hemi forms spontaneously without the need to use a seed crystal. It is not necessary to speculate as to why this happens.
Examples 2 and 3 demonstrate the production of TAF hemi by crystallisation using a seed. The seed is explained in Example 2 as follows:
"Seed crystals (5 g) of the hemifumarate form of tenofovir alafenamide were charged (for example, the mixture can be seeded with tenofovir alafenamide hemifumarate formed in Example 1 or a subsequent production), and the resulting mixture was agitated at 54-60°C for about 30 minutes."
At the hearing I suggested that Example 2 was seeded with crystals of pure TAF hemi, and Example 1 did not explain how to separate the TAF hemi crystals from the other crystals. Gilead submitted that instead the specification should be understood as stating that the mixture of crystals produced by Example 1 was used without separating the TAF hemi. I consider that this is a credible explanation of Example 2, and I will proceed on the understanding that this is what is disclosed.
Overall the Examples show the preparation of TAF hemi by spontaneous crystallisation and by seeding. There is nothing to suggest that these processes are difficult or complex.
Paragraph [0071]
Paragraph [0071] of the specification is particularly significant for this opposition. The paragraph reads, in full:
"Stable form screening of tenofovir alafenamide hemifumarate showed that it is thermodynamically stable in most solvents, such as ACN, toluene, ethyl acetate, methyl tert-butyl ether (MTBE), acetone, THF, and 2-methyl THF. A similar stable form screening of the monofumarate form showed that this form is not thermodynamically stable in the above solvents. When suspended in these solvents, the monofumarate form of tenofovir alafenamide fully converts to the hemifumarate form in THF and 2-methyl THF, and partially converts to the hemifumarate form in ACN, ethyl acetate, MTBE, and acetone, as well as at ambient temperatures."
It is apparent that TAF hemi is thermodynamically more stable than TAF mono in a range of solvents, and that TAF mono spontaneously converts to TAF hemi in these solvents. The conversion is relatively simple, requiring nothing more than stirring a slurry in one of the specified solvents. No special conditions are mentioned. It is noteworthy that there is no need to use a seed crystal.
At the hearing I suggested that paragraph [0071] represents an alternative method of preparing TAF hemi. I was told that this is not correct. While I find this surprising, I accept that the applicant must have a good reason for this statement. I accept that paragraph [0071] is not a method of preparing TAF hemi from TAF mono, but that it is a description of the spontaneous conversion of TAF mono into TAF hemi.
Dr Robertson was of the view that the conversion described in paragraph [0071] was not surprising:
"At that time, I knew that it was possible for monofumarates to convert to hemifumarates in the presence of solvents; this is not surprising."[15]
[15] Robertson 1 at [66].
Professor Rodriguez-Hornedo responded:
"a monofumarate may convert to a hemifumarate, but only under the correct conditions. It is not simply a matter of placing the monofumarate in a solvent. As is apparent from my opinion in Part G.2. the monofumarate may or may not convert to the hemifumarate, depending upon all of the variables discussed. Even where both the monofumarate and hemifumarate exist, if the variables are not correct, the monofumarate will not convert to the hemifumarate. Dr Robertson could not have had an understanding of the required variables without substantial experimentation."[16]
and
"I note that paragraph [0071] provides no information in relation to the other conditions relevant to the thermodynamic stability screening such as, for example, the amount of time that the tenofovir alafenamide hemifumarate was immersed in the solvents, the purity of the API Molecule, the purity of the API Complex and the conditions of stirring."[17]
and concludes
"I further understand from the statement contained in paragraph [0071] that under certain undisclosed conditions (the only known variable being ambient temperature), tenofovir alafenamide monofumarate (i) fully converts to the hemifumarate form in THF and 2-methyl THF, and (ii) partially converts to the hemifumarate form in ACN, ethyl acetate, MTBE and acetone. I note that there is no suggestion of the amount of partial conversion, nor the time taken for that partial conversion."[18]
[16] Rodriguez-Hornedo at [175].
[17] Rodriguez-Hornedo at [267].
[18] Rodriguez-Hornedo at [271].
Professor Rodriguez-Hornedo's evidence is that paragraph [0071] does not contain all the information that would be required to repeat the work. At the hearing I asked Mr Caine whether Professor Rodriguez-Hornedo had overstated the difficulty in working the procedure in paragraph [0071], or whether paragraph [0071] failed to provide important information. Mr Caine did not concede that there was any inaccuracy in paragraph [0071], or agree that Professor Rodriguez‑Hornedo had overstated the difficulties that would be involved in repeating paragraph [0071]. However, if Professor Rodriguez-Hornedo is correct then the specification fails to provide sufficient information in paragraph [0071], but if paragraph [0071] is correct then Professor Rodriguez-Hornedo's evidence should be given less weight.
Professor Rodriguez-Hornedo is an Associate Professor of Pharmaceutical Sciences and Chair of the Pharmaceutical Sciences Graduate Program at the College of Pharmacy, University of Michigan.[19] She is a pharmaceutical scientist with particular expertise in pharmaceutical solid state forms, and has significant expertise in the preparation of solid state forms of active pharmaceutical ingredients and complexes.[20] Professor Rodriguez-Hornedo's experience is extensive, but it does not seem that she has experience with TAF mono or TAF hemi. Professor Rodriguez-Hornedo provides general information about crystallisation and salt formation, and draws generalised conclusions based on specific pieces of information. I do not doubt the accuracy of the general information that Professor Rodriguez-Hornedo provides. The problem lies with her extrapolation of these generalisations to the facts of this case. Professor Rodriguez‑Hornedo agrees that a monofumarate can convert to a hemifumarate if the conditions are right.[21] Paragraph [0071] says that the sole variable is the choice of solvent. It is clear that Professor Rodriguez-Hornedo finds this a surprising conclusion based on her knowledge of other substances. For instance, Professor Rodriguez-Hornedo says that it is hard to predict whether salts will crystallise without actually doing the work:
"even if the DDP team were to attempt to form a salt, they could not predict whether a salt would form"[22]
"Salt (or complex) formation is unpredictable and will only occur with the proper balance of forces of the acid and base molecules in solution."[23]
"In my opinion, it is impossible to tell if this experiment [the formation of a hemifumarate] will work without substantial experimentation."[24]
[19] Rodriguez-Hornedo at [1].
[20] Rodriguez-Hornedo at [4].
[21] Rodriguez-Hornedo at [175].
[22] Rodriguez-Hornedo at [101].
[23] Rodriguez-Hornedo at [118].
[24] Rodriguez-Hornedo at [189].
Paragraph [0071] reports that the applicant has done the work to determine the variables involved in converting TAF mono to TAF hemi, and the variable is the solvent. Professor Rodriguez‑Hornedo has not repeated the process in paragraph [0071], and has not shown it to be inaccurate. In an area where it can be difficult to extrapolate results (as declared by Professor Rodriguez‑Hornedo), then the opinion of Professor Rodriguez‑Hornedo (albeit a well-informed opinion) should be given less weight than the clear and unambiguous language of the specification. I am satisfied that paragraph [0071] should be accepted as correct. I conclude that Professor Rodriguez‑Hornedo has overstated the difficulties, and care must be exercised when considering her evidence.
What does paragraph [0071] disclose?
Having concluded that paragraph [0071] is correct, I need to understand what it means. Clearly paragraph [0071] is a demonstration of a well known effect in chemistry - the thermodynamic product will be preferred in a system that is under thermodynamic control because the thermodynamic product is the lower energy state. Professor Rodriguez‑Hornedo notes the same principle (she refers to it as thermodynamic stability) when discussing the crystallisation of a complex versus crystallisation of an uncomplexed compound.[25] Professor Rodriguez‑Hornedo states that the thermodynamic product will tend to crystallise:
"The most stable form is the less soluble under given conditions."[26]
[25] Rodriguez-Hornedo at G.2.
[26] Rodriguez-Hornedo at [138].
The process in paragraph [0071] apparently involves a small amount of the TAF mono dissolving in the liquid, and then crystallising as the lower energy TAF hemi. This proceeds until an equilibrium is established at either full or partial conversion. It is apparent from paragraph [0071] that this is a facile process.
At the hearing there was a discussion that seemed to suggest that the applicant was able to carry out the conversion of TAF mono to TAF hemi reported in paragraph [0071] because they had already produced TAF hemi. The science behind this suggestion is contained in the evidence of Professor Rodriguez‑Hornedo:
"Finally, I note that there are other possible theoretical explanations for why the monofumarate may have been observed as partially converting to the hemifumarate in paragraph [0071] that would have no bearing on Example 4, such as:
(a)as noted by Dr Coates in Paragraph 43 of his declaration, crystal seeds of polymorph A may sometimes cause polymorph B to convert to polymorph A. Similarly it is possible that where the stability tests of the monofumarate and hemifumarate were carried out in the same labs there may have been a seeding of the lab with hemifumarate. This may have caused partial conversion of the monofumarate in the stability tests that would otherwise not have occurred but for the hemifumarate seeds; or
(b)it is theoretically possible that the monofumarate and/or solvents used in the stability tests were not sufficiently pure. This could be due to, for example, an excess of conformer in the solid phase monofumarate which would change the concentration of conformer in the system. Such a change in conformer concentration could in turn promote the formation of the hemifumarate over monofumarate. This could be a relevant factor where there is only partial conversion.
I reiterate that the above are possible theoretical explanations only."[27]
[27] Rodriguez-Hornedo at [284].
While Professor Rodriguez‑Hornedo advances these as theoretical explanations only, the implication that is intended is that a person who had not previously produced TAF hemi would be unable to produce TAF hemi by the process of paragraph [0071]. This is relevant to the discussion of the ground of novelty, later in my decision. However, there is no basis for this conclusion in the specification, and even Professor Rodriguez‑Hornedo considers it a speculation. I give no weight to this conjecture.
Construction of claim 1
The correct approach to the construction of claims was discussed by Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd:[28]
"the words in a claim should be read through the eyes of the skilled addressee in the context in which they appear … while the claims define the monopoly claimed in the words of the patentee's choosing, the specification should be read as a whole … it is not permissible to read into a claim an additional integer or limitation to vary or qualify the claim by reference to the body of the specification … terms in the claim which are unclear may be defined or clarified by reference to the body of the specification".
[28] [2009] FCAFC 70, 81 IPR 228 at [118] – [120].
Claim 1 is a mere three words:
"Tenofovir alafenamide hemifumarate."
This is the compound TAF hemi. The structure of this compound is well understood, as discussed previously. The claim does not specify the degree of purity of the compound, or whether it is in crystalline or amorphous form, or the nature of any crystals. Gilead submitted that the claim should be understood as encompassing any degree of purity, and both crystalline and non-crystalline forms. I asked whether the claim also extended to solutions of the compound. Gilead's submission was that a solution was not sufficiently ordered to be a complex of TA and fumaric acid. This point requires some careful consideration.
The named compound is a salt of two parts: TA and fumaric acid in the ratio of 1:0.5. The claim is characterised by three things - the two parts TA and fumaric acid, and the ratio of the parts being 1:0.5. The claim does not explicitly refer to any particular degree of purity, which leads me to conclude that the claim includes any degree of purity. When the salt is dissolved in a solvent the two parts are still present, and in the same ratio. In solution the parts no longer have the spatial arrangement that they have in the crystallised form. But is that spatial arrangement necessarily implied by the name of the compound? The answer of course is no. The claim extends to solutions that contain the parts in the 1:0.5 ratio, but not other ratios.
To my mind this conclusion is supported by Gilead's submission at the hearing that the claim includes molten TAF hemi. In the molten state the material no longer has its crystalline form. The ratio of the parts is the same, but the spatial arrangement between the parts is no longer defined by the crystal lattice. If the molten form of TAF hemi is within the scope of the claim then other non-crystalline forms, including solutions, are also within the scope of the claim.
This construction makes sense of claim 6, which is appended to claim 1 but has the qualification that the hemifumarate is a solid.
I conclude that claim 1 is directed to TAF hemi, in any degree of purity, in any crystal form, amorphous form, molten state or dissolved.
Claim 7 is also an independent claim directed to TAF hemi:
"Tenofovir alafenamide hemifumarate, having an X-ray powder diffraction (XRPD) pattern that comprises 2 theta values of 6.9 ± 0.2° and 8.6 ± 0.2°."
Due to the limitation defining the XRPD pattern, claim 7 is necessarily restricted to a crystalline form of TAF hemi.
Claim 18 is directed to the preparation of TAF hemi:
A method for preparing tenofovir alafenamide hemifumarate comprising admixing a) aprotic organic solvent; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate; and crystallizing additional tenofovir alafenamide hemifumarate.
Claim 18 is directed to a process characterised by mixing TA, fumaric acid and an aprotic organic solvent with a seed crystal and allowing crystallisation to take place.
Claim 25 is directed to the preparation of TAF hemi:
"A method for preparing tenofovir alafenamide hemifumarate, comprising the steps of:
admixing a) a solvent comprising water, isopropyl alcohol, acetone, acetonitrile, toluene, ethyl acetate, isopropyl acetate, heptane, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate; and
crystallizing additional tenofovir alafenamide hemifumarate at a temperature from about 0°C to about 70°C."Claim 25 is directed to a method of preparation of the hemifumarate that is characterised by mixing TA, fumaric acid and a solvent (selected from a specified list) with a seed crystal and allowing crystallisation to take place. There is no restriction on the amounts or ratios of the materials that are used.
The person skilled in the art
It is well established that many of the issues in an opposition are answered by reference to the person skilled in the art:
"He is the person to whom the patent is addressed and who must construe it. He is the person whose knowledge will determine whether a patent is novel. He is the person who will judge whether a patent is obvious."[29]
[29] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [70].
However, they are an artificial construct that is used as a tool of analysis, and there is a danger in trying to identify them as an actual person or persons:
"The notional person is not an avatar for expert witnesses whose testimony is accepted by the court. It is a pale shadow of a real person – a tool of analysis which guides the court in determining, by reference to expert and other evidence, whether an invention as claimed does not involve an inventive step."[30]
[30] AstraZeneca AB v Apotex Pty Ltd [2015] HCA 30 at [23].
Our understanding of the person skilled in the art is based on evidence from persons with knowledge of the art as to the things that they know and do, and what they understand to be commonly known and done. In this opposition there are declarations by a number of people. The most important are Dr Robertson, Dr Coates, Dr Draffan and Professor Rodriguez‑Hornedo. Dr Robertson has 30 years experience as a medicinal chemist.[31] Dr Coates has worked as a research scientist in drug discovery and development since 1981.[32] Dr Draffan is a medicinal chemist with experience going back to 1999.[33] Professor Rodriguez-Hornedo has been an Associate Professor of Pharmaceutical Sciences and Chair of the Pharmaceutical Sciences Graduate Program at the College of Pharmacy, University of Michigan since 1994. I consider that all of these declarants are in a position to provide evidence as what the person skilled in the art knew and would have done.
[31] Robertson 1 at [5].
[32] Coates 1 at [2].
[33] Draffan at [4] – [8].
Novelty
It is a requirement of subsection 18(1) of the Act that the invention, so far as claimed in any claim, is novel. Subsection 7(1) states that an invention is taken to be novel unless it is not novel in the light of the prior art:
For the purposes of this Act, an invention is to be taken to be novel when compared with the prior art base unless it is not novel in the light of any one of the following kinds of information, each of which must be considered separately:
(a)prior art information (other than that mentioned in paragraph (c)) made publicly available in a single document or through doing a single act;
(b)prior art information (other than that mentioned in paragraph (c)) made publicly available in 2 or more related documents, or through doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art would treat them as a single source of that information;
(c)prior art information contained in a single specification of the kind mentioned in subparagraph (b)(ii) of the definition of prior art base in Schedule 1.
A citation is part of the prior art base for the purposes of novelty if it was published before the priority date of the claim.
It is well established that the general test for lack of novelty is the reverse infringement test. The classic formulation of this test is that given by Aickin J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd:[34]
"The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement".
[34] [1977] HCA 19 at [20], 137 CLR 228 at 235.
This test is satisfied if the alleged anticipation discloses all the essential features of the invention as claimed (see Nicaro Holdings Pty Ltd v Martin Engineering Co[35]).
[35] (1990) 91 ALR 513 at 517.
Australian courts have often cited with approval the words of the UK Court of Appeal in The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited (the General Tire case)[36]:
"If the prior inventor's publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee's patent, the patentee's claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's patent were valid, would constitute an infringement of the patentee's claim, this circumstance demonstrates that the patentee's claim has in fact been anticipated.
If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way which would not do so, the patentee's claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee's claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented: Flour Oxidizing Co. Ltd. v. Carr & Co. Ltd. (1908) 25 R.P.C. 428 at 457, line 34, approved in B.T.H. Co. Ltd. v. Metropolitan Vickers Electrical Co. Ltd. (1928) 45 R.P.C. 1 at 24, line 1). A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee."
It follows from the General Tire case that where a citation contains a clear instruction to do something, but there is an error in the identification of the product, the ground of lack of novelty is determined based on what is in fact the product, not the erroneous identification. This is analogous to the allowability of an amendment to correct an error in a specification.[37]
[36] [1972] RPC 457 at 485 – 486.
[37] Merck & Co, Inc v Sankyo Co Ltd [1992] FCA 198; 23 IPR 415 at 427, [69]
Alphapharm relied on a single citation to allege lack of novelty: AU 2001282941.
AU 2001282941
AU 2001282941 (D1) was published as international application WO 02/008241 on 31 January 2002. Consequently it is part of the prior art base.
D1 is titled "Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same". One of the preferred embodiments of the invention is TA (which is referred to as GS‑7340), and another preferred embodiment is TAF mono (referred to as GS-7340-2). The key part of D1 is Example 4, which reads:
"Example 4
Preparation of Fumarate Salt of GS-7340GS-7340-02 (V). (Scheme 1) A glass-lined reactor was charged with GS-7340 (IV), (1.294 kg, 2.71 mol), fumaric acid (284 g, 2.44 mol), and acetonitrile (24.6 kg). The mixture was heated to reflux to dissolve the solids, filtered while hot and cooled to 5°C for 16 hours. The product was isolated by filtration, rinsed with acetonitrile (9.2 kg), and dried to 1329 g (V) as a white powder: mp 119.7 – 121.1°C; [α]D20 -41.7° (c 1.0, acetic acid)."
This seems to be a clear reference to the preparation of TAF mono, and not TAF hemi. There is no data presented that shows that the compound is a monofumarate, but it is a reasonable inference based on the amount of fumaric acid used (being nearly a molar equivalent).
Alphapharm submitted that the product would probably contain TAF hemi as well as TAF mono. Dr Robertson stated:
"I noted the lack of molar equivalence between GS-7340 (2.71 mol) and fumaric acid (2.44 mol) on page 33 of D1. D1 at page 33 suggests to me that some of the free base compound may not have formed a salt because insufficient fumaric acid has been added, or that some hemifumarate may have been formed. The results in D1 tell me that the fumarate was still made using these amounts and accordingly, if I picked up D1 and followed its instructions, I would expect to get monofumarate (fumarate)."[38]
[38] Robertson 1 at [72].
I conclude that Dr Robertson is unsure whether TAF hemi would be formed. The evidence of Dr Robertson does not satisfy me that the product of Example 4 of D1 contains TAF hemi.
At the hearing I asked whether the TAF mono would convert to TAF hemi in the way that the present specification explains in paragraph [0071]. Gilead stated that such a conclusion could not be drawn. The evidence of Professor Rodriguez-Hornedo addresses this point:
"I note that Example 4 and the thermodynamic stability testing referred to in paragraph [0071] of the Patent are completely different processes. Example 4 is concerned with making the monofumarate, whereas the thermodynamic stability testing is concerned with determining whether the monofumarate is thermodynamically stable in certain solvents under certain conditions. … my view in relation to Example 4 is that, as at the Relevant Date I would have expected that the example would create the monofumarate of GS-7340 exclusively as:
(a) the example states that it makes the [mono]fumarate salt of GS-7340; and
(b) there is no mention in D1 as to the existence of the hemifumarate of GS-7340 and I would therefore have had no knowledge of its existence."[39]
[39] Rodriguez-Hornedo at [274] – [275].
Professor Rodriguez-Hornedo repeats this:
"Based on the information set out in paragraph [0071]:
(a) I have no knowledge as to whether it is possible for the monofumarate to convert to the hemifumarate over the undefined temperature range and rate of cooling in Example 4; and
(b) I have no knowledge of the other factors relevant to the conversion, such as the length of time that the monofumarate was immersed in the acetonitrile or the extent and nature of stirring."[40]
[40] Rodriguez-Hornedo at [281].
This leads Professor Rodriguez-Hornedo to conclude that Example 4 would not produce any hemifumarate:
"I would have no reason to expect that Example 4 (which is not undertaken at ambient temperature) would either (i) partially make hemifumarate, or (ii) would cause part of the monofumarate to convert to the hemifumarate."[41]
[41] Rodriguez-Hornedo at [283].
As noted previously (at paragraph [36] of this decision) Professor Rodriguez-Hornedo suggests a reason why conversion occurs under the conditions of paragraph [0071] but not under the conditions of Example 4 of D1.[42] It cannot be denied that the authors of D1 thought they had made TAF mono based on the stoichiometry of the reaction. However, the authors were not aware of the thermodynamic stability of TAF mono and TAF hemi (see paragraph [27] above). The characterisation of the product of Example 4 of D1 is by means of the melting point (119.7 – 121.1°C) and the specific rotation ([α]D20 -41.7°). This information does not establish whether the compound is the monofumarate, the hemifumarate, or a mixture. Professor Rodriguez‑Hornedo is strongly of the view that Example 4 of D1 would not behave in the same way as described in paragraph [0071], and supports this view with reasons why the conversion in paragraph [0071] should be rejected. I have already explained why I accept the accuracy of the information in paragraph [0071] in preference to the views of Professor Rodriguez‑Hornedo. When using acetonitrile as the solvent, it is inevitable that the monofumarate would convert, albeit partially, to the hemifumarate.
[42] Rodriguez-Hornedo at [284].
I am satisfied on the basis of paragraph [0071] that it is inevitable that if TAF mono formed in Example 4 of D1 it would convert to the thermodynamically more stable TAF hemi. It is uncertain how much TAF hemi would be formed, but not uncertain that it would be formed.
The next question is the nature of the TAF hemi that is formed, particularly the ratio of TA:fumaric acid and the crystal form (this is relevant to some of the appended claims). It is likely that the product in Example 4 of D1 either crystallises spontaneously in the same way as Example 1 of the present application or crystallises spontaneously in the same way as paragraph [0071] of the present specification. The present application does not suggest that there is any difference in the TAF hemi crystals formed in Example 1 compared to those in paragraph [0071]. On the balance of probabilities, the product formed in Example 1 is the same as that formed in paragraph [0071], and this would be the same as that formed in Example 4 of D1. However, this is an ultimate fact and the question is whether it is practically certain that the ration of TA:fumaric acid and the crystal form of product formed in Example 4 of D1 would be the same as that in the present application. There is room for some doubt due to the widely known existence of polymorphs, for instance. I am not satisfied that it is practically certain that they would be the same. While the TA:fumaric acid ratio in the products formed in Example 1, paragraph [0071] and Example 4 of D1 is undoubtedly about 1:0.5, it is unclear whether it is precisely 0.5 ± 0.1 in the product of Example 4 of D1. It would be necessary to repeat the process of Example 4 to be sure. Similarly, the nature of the crystals, their XRPD and their differential scanning calorimetry (DSC), of the product formed in Example 4 of D1 is not clearly the same as those of the present application.
The compounds of D1 are stated to be intended for use in "therapy or prophylaxis of viral (particularly HIV or hepadnaviral) infections".[43]
[43] D1 at page 7.
Claim 1
Example 4 of D1 discloses TAF hemi. There is no reason to believe that the product in Example 4 of D1 is pure TAF hemi, but there is no requirement in claim 1 for the product to be pure. It is clear that the invention defined by claim 1 lacks novelty in the light of D1.
The claims appended to claim 1
I turn now to consider the claims appended to claim 1.
Claim 2: This claim is directed to a "composition" characterised by a sole component - TAF hemi. It is appended to claim 1, with the additional qualification that the ratio of TA:fumaric acid is 0.5 ± 0.1. As stated above, on the balance of probabilities the product in Example 4 of D1 has this ratio. However, this is not the standard of proof that applies. It is not practically certain that the product of Example 4 of D1 has this ratio. Consequently, it has not been shown that claim 2 lacks novelty.
Claim 3: This claim is appended to claim 2, with the additional qualification that the ratio of TA:fumaric acid is 0.5 ± 0.05. For the reasons noted above it has not been shown that this claim lacks novelty.
Claim 4: This claim is appended to claim 2, with the additional qualification that the ratio of TA:fumaric acid is 0.5 ± 0.01. As noted above, it follows that it has not been shown that this claim lacks novelty.
Claim 5: This claim is appended to claim 2, with the additional qualification that the ratio of TA:fumaric acid is "about" 0.5. In other words, the ratio of TA:fumaric acid is both no more than 0.5 ± 0.1 and about 0.5. Since it has not been shown that the TAF hemi produced in Example 4 of D1 has a ratio of 0.5 ± 0.1, it follows that it has not been shown that this claim lacks novelty.
Claim 6: This claim is appended to claim 1 or any of claims 2 – 5, with the additional qualification that the compound is a solid. The TAF hemi formed in Example 4 of D1 is a solid, so it follows that this claim also lacks novelty by virtue of its dependence upon claim 1.
Claim 9: This claim is appended to claim 1, with the additional qualification that the compound has a DSC endotherm of 131 ± 2°C. Since it has not been shown that the TAF hemi produced in Example 4 of D1 has this DSC endotherm, it follows that it has not been shown that this claim lacks novelty.
Claim 10: This claim is appended to claim 9, with the additional qualification that the endotherm is 131 ± 1°C. Since it has not been shown that the TAF hemi produced in Example 4 of D1 has this value, it follows that it has not been shown that this claim lacks novelty.
Claim 11: This claim is directed to a "pharmaceutical composition" that is relevantly characterised by the hemifumarate of claim 1 and a pharmaceutically acceptable excipient. D1 discloses that the compounds are intended for pharmaceutical use, and makes explicit reference to compositions containing the active compound and a pharmaceutically acceptable excipient.[44] It follows that claim 11 lacks novelty in the light of D1.
[44] D1 at page 7.
Claim 12: This claim is appended to claim 11, with the additional qualification that the composition contains an additional therapeutic agent. The disclosure of D1 does not go into detail about additional therapeutic agents. Consequently it has not been shown that this claim lacks novelty.
Claim 13: This claim is appended to claim 12, with the additional qualification that the additional therapeutic agent is selected from a defined group. It follows from the conclusion in relation to claim 12 that it has not been shown that this claim lacks novelty.
Claim 14: This claim is directed to a method for treating HIV infection by use of the compound, composition or pharmaceutical composition of any of the earlier claims. It is clear from what is said above that D1 discloses treatment of HIV infection, and it follows that claim 14 lacks novelty in the light of D1.
Claim 15: This claim is appended to claim 14, with the additional qualification that the treatment further comprises administering an additional therapeutic agent selected from a defined group. As already noted, D1 does not disclose additional therapeutic agents. It has not been shown that this claim lacks novelty.
Claim 16: This claim is directed to a method for treating HBV infection by use of the compound, composition or pharmaceutical composition of any of claims 1 to 13. D1 refers to the compounds having antiviral activity, and the screening includes anti-HBV activity.[45] It follows that claim 16 lacks novelty in the light of D1.
[45] D1 at claim 16.
Claim 17: This claim is directed to a method for preparing a pharmaceutical composition by combining the hemifumarate or composition of any of the claims with a pharmaceutically acceptable excipient. D1 states that the compounds "optionally are formulated into compositions containing pharmaceutically acceptable excipients".[46] It follows that claim 17 lacks novelty in the light of D1.
[46] D1 at page 7.
Claim 21: This claim is appended to claim 14 or 15, with the additional qualification that the treatment is administered in multiple daily doses. D1 does not set out a dosing regimen. Consequently it has not been shown that this claim lacks novelty.
Claim 22: This claim is appended to claim 14 or 15, with the additional qualification that the treatment is administered in a single daily dose. D1 does not set out a dosing regimen. Consequently it has not been shown that this claim lacks novelty.
Claim 23: This claim is appended to claim 16, with the additional qualification that the treatment is administered in multiple daily doses. D1 does not set out a dosing regimen. Consequently it has not been shown that this claim lacks novelty.
Claim 24: This claim is appended to claim 16, with the additional qualification that the treatment is administered in a single daily dose. D1 does not set out a dosing regimen. Consequently it has not been shown that this claim lacks novelty.
Claim 27: This claim is appended to a range of claims. The claim is broadly in the form of a Swiss claim – for the preparation of a medicament for the treatment of HIV by administration in an effective amount. As stated previously, D1 discloses pharmaceutical compositions and treatment of HIV. It follows that claim 27 lacks novelty to the extent that it is appended to claims that lack novelty.
Claim 28: This claim is appended to claim 27, with the additional qualification that the treatment includes administration of additional therapeutic agents. D1 does not set out specific formulation information. Consequently it has not been shown that this claim lacks novelty.
Claim 29: This claim is appended to a range of claims. The claim is broadly in the form of a Swiss claim – for the preparation of a medicament for the treatment of HBV by administration in an effective amount. As stated previously, D1 discloses pharmaceutical compositions and treatment of HBV. It follows that claim 29 lacks novelty to the extent that it is appended to claims that lack novelty.
Claim 30: This claim is appended to any of claims 27 to 29, with the additional qualification that the medicament is administered in multiple daily doses. As noted, D1 does not include dosing information. Consequently it has not been shown that this claim lacks novelty.
Claim 31: This claim is appended to any of claims 27 to 29, with the additional qualification that the medicament is administered in a single daily dose. As noted, D1 does not include dosing information. Consequently it has not been shown that this claim lacks novelty.
Other independent claims
The other independent claims are novel in the light of D1 for the following reasons.
Claim 7: The TAF hemi claimed in claim 7 is characterised by the XRPD pattern. As noted previously, there is no indication of the XRPD data for the compound of Example 4 of D1. Thus it has not been shown that claim 7 (or the claims dependent on claim 7) lacks novelty.
Claim 18: The method of preparation of TAF hemi claimed in claim 18 includes the use of a seed crystal of TAF hemi. There is no use of a seed crystal in Example 4 of D1. Thus it has not been shown that claim 18 (or the claims dependent on claim 18) lacks novelty.
100. Claim 25: The method of preparation of TAF hemi claimed in claim 25 includes the use of a seed crystal of TAF hemi. There is no use of a seed crystal in Example 4 of D1. Thus it has not been shown that claim 25 (or the claims dependent on claim 25) lacks novelty.
Conclusion
101. I conclude that claims 1, 6, 11, 14, 16, 17, 27 and 29 lack novelty in the light of D1.
Inventive step
102. It is a requirement of subsection 18(1) of the Act that the invention, so far as claimed in any claim, involves an inventive step. Subsection 7(2) states that an invention is taken to involve an inventive step unless it would have been obvious to a person skilled in the art in the light of the common general knowledge, considered alone or together with the prior art:
For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with the information mentioned in subsection (3).
103. Subsection (3) prescribes the information that may be considered as:
The information for the purposes of subsection (2) is:
(a)any single piece of prior art information; or
(b)a combination of any 2 or more pieces of prior art information;
being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood, regarded as relevant and, in the case of information mentioned in paragraph (b), combined as mentioned in that paragraph.
104. Once the common general knowledge and relevant information has been identified, the test for whether an invention is obvious is to ask whether it would have been a matter of routine to proceed to the claimed invention. In Wellcome Foundation Ltd v V.R. Laboratories (Aust.) Pty Ltd[47] Aickin J stated:
[47] [1981] HCA 12 at [45], 148 CLR 262 at 286.
"The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not."
105. An expectation of success is not an additional requirement over and above matters of routine:
"It is difficult to think of a case where an expectation that an experiment might well succeed is not implicit in the characterisation of steps as routine and to be tried as a matter of course."[48]
[48] Generic Health Pty Ltd v Bayer Pharma Aktiengesellschaft [2014] FCAFC 73; 314 ALR 91 at [71].
106. The High Court has also endorsed the use of the well known "Cripps question".[49] The Cripps question and the matter of routine approach are alternative ways of analysing obviousness.[50]
[49] Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; 212 CLR 411 at [53].
[50] Generic Health Pty Ltd v Bayer Pharma Aktiengesellschaft [2014] FCAFC 73; 314 ALR 91 at [71].
107. The opponent argued lack of inventive step in two ways: there is a lack of inventive step in the light of the common general knowledge alone, and secondly there is a lack of inventive step in the light of the common general knowledge together with information in document D1.
The problem
108. The specification does not clearly indicate a problem that it addresses. The basic document, which is incorporated by reference, indicates a problem that is addressed (quoted earlier in this decision). The key points are:
"a form of [TA] that has improved stability or processability … improved thermodynamic stability in solution or in the solid state … more readily purified, that has superior process reproducibility or content uniformity, or that has higher crystallinity or a higher melting point."[51]
[51] US 61/524,224 at page 1.
109. I note that it is not appropriate to take as the starting point information that was known to the applicant but was not either common general knowledge or information available under section 7(3).[52] The problem set out above takes TA as the starting point. As will be explained below, it has not been shown that TA is part of the common general knowledge. However, TA is part of the document D1 that is a section 7(3) document. I conclude that for the purpose of assessing inventive step in the light of D1, the problem should be formulated as a form of TA that has improved stability, improved thermodynamic stability, is more readily purified, has superior process reproducibility, higher crystallinity or higher melting point. However, when assessing inventive step in the light of the common general knowledge alone, the problem should be formulated without reference to TA, such as a form of a compound for the treatment of HIV or HBV that has improved stability, improved thermodynamic stability, is more readily purified, has superior process reproducibility, higher crystallinity or higher melting point.
[52] AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99 at [203].
The common general knowledge
110. Common general knowledge is the background knowledge and experience available to all those working in the relevant art:
"The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge."[53]
[53] Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9 at [115]; (1980) 144 CLR 253 at 292.
111. It is not enough that information is recorded in a document, even one that is widely circulated. It is only part of the common general knowledge when it is generally known and accepted:
"information does not constitute common general knowledge merely because it might be found, for example, in a journal, even if widely read by persons in the art … Reference in this regard is made to the words of Luxmoore J in British Acoustic Films (1936) 53 RPC 221 at 250, cited by Lehane J in Aktiebolaget Hässle v Alphapharm Pty Ltd (1999) 44 IPR 593; [1999] FCA 628 at 605 [39]:
In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art."[54]
[54] Ranbaxy v AstraZeneca [2013] FCA 368; (2013) 101 IPR 11 at [217].
112. Alphapharm submitted that a large range of matters formed part of the common general knowledge in Australia at the priority date. It is not necessary to go through these in detail. It is significant that TA is not one of the things that is asserted to form part of the common general knowledge. Professor Robertson declared that he was aware of tenofovir:
"Before August 2011, I was aware of several treatments for the treatment of HIV (to different degrees). In addition to AZT, I was aware of 3TC (also known as lamivudine) and tenofovir, which was a next generation treatment and an advancement from AZT. I recall tenofovir in particular because it has a prodrug that is interesting called tenofovir disoproxil fumarate which I was interested in because it produces formaldehyde when it is cleaved to the active species and I was concerned that formaldehyde may produce unwanted toxicity to the host cell."[55]
[55] Robertson 1 at [50].
113. Dr Coates was also aware of tenofovir:
"In approximately 2001, I was aware of an NRTI called tenofovir disoproxil fumarate (TDF), which I knew was manufactured by Gilead. Tenofovir may also be referred to as a Nucleotide Reverse Transcriptase Inhibitor (NtRTI)."[56]
[56] Coates 1 at [25].
114. Professor Rodriguez-Hornedo does not comment on whether she was aware of tenofovir or TA. Taken as a whole, the evidence does not suggest to me that tenofovir or TA was generally known by the bulk of those working in the art. I am not satisfied that tenofovir (or prodrug derivatives) was part of the common general knowledge.
Matters of routine
115. The critical issue in this opposition is whether it would have been a matter of routine for a person who was aware of TA, or even the monofumarate of TA, to seek to prepare a hemifumarate of TA as a means of achieving a form that has improved stability, improved thermodynamic stability, is more readily purified, has superior process reproducibility, higher crystallinity or higher melting point. If I accept the evidence of Alphapharm it shows:
i)it was known that fumarate salts could exist as monofumarates or hemifumarates;[57]
[57] Rodriguez-Hornedo at [134].
ii)monofumarates can change to hemifumarates over time;[58]
[58] Robertson 1 at [65].
iii)monofumarates can convert to hemifumarates in the presence of solvents;[59] and
[59] Robertson 1 at [66].
iv)a monofumarate can spontaneously become a hemifumarate.[60]
[60] Robertson 1 at [66].
116. This does not lead to a conclusion that a person who was aware of TAF mono would have considered that a hemifumarate would seem like a desirable alternative. It does not suggest that a person would have had any interest in the hemifumarate of TA. I am not satisfied that it would have been a matter of routine to contemplate preparing the hemifumarate of TA.
117. Given this finding it would not have been a matter of routine for a person to want to prepare the hemifumarate of TA.
Obviousness in the light of the common general knowledge alone
118. TA was not part of the common general knowledge. It would not have been a matter of routine for a person to seek to prepare the hemifumarate of a compound of which they were unaware. Even if TA were part of the common general knowledge, it would not have been a matter of routine to want to prepare the hemifumarate (as stated above). In this situation it has not been shown that claim 1, or any other claim, lacks inventive step in the light of the common general knowledge alone.
Obviousness in the light of D1
119. The threshold question is whether D1 would have been ascertained, understood and regarded as relevant. Ascertained means found or discovered.[61] A document would be ascertained "if it was published in such a manner or form that it could reasonably have been expected to be found by a person skilled in the art".[62] Understood means that a person would have comprehended the information, or "appreciated its meaning or import".[63] Relevant means that a person "will be likely to recognize the document in question as being particularly pertinent to, though it may not specifically solve the problem".[64] Dr Robertson declared that he routinely read "patents that were of interest to me".[65] Dr Robertson recognised that D1 relates to a prodrug of tenofovir, and the monofumarate salt of TA.[66] I am satisfied on the basis of this evidence that D1 would have been ascertained, understood and regarded as relevant to a problem directed at improving on TA.
[61] Commissioner of Patents v Emperor Sports Pty Ltd [2006] FCAFC 26; 67 IPR 488 at [29], [30].
[62] Nippon Kayaku Kabushiki Kaisha and Sankyo Company, Limited v Rohm and Haas Company [1997] APO 40.
[63] Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21; 235 CLR 173 at 219, [132].
[64] Beecham Groups Limited's (Amoxycillin) Application [1980] RPC 261 at 282.
[65] Robertson 1 at [29].
[66] Robertson 1 at [70] – [74].
120. The next question is what a person would have done as a matter of routine in the light of D1. To my mind there are two issues to be considered - first, would it have been a matter of routine to prepare the compound of Example 4 (which in fact is TAF hemi), and second, on the understanding that the compound of Example 4 is TAF mono would it have been a matter to want to prepare TAF hemi as an alternative.
121. There is no indication that the product of Example 4 has improved properties of the type recited in the problem. In relation to the melting point, D1 states the melting point of TA is 117 - 120°C,[67] and the melting point of the product of Example 4 is 119.7 – 121.1°C. It is apparent that the product of Example 4 does not possess an advantage of increased melting point. On the face of D1 there is no motivation to produce the compound of Example 4.
[67] D1 at page 31.
122. Turning to the second issue, the evidence of Dr Robertson shows that it would have been a matter of routine to prepare a hemifumarate of TA if that was desired:
"DibbsBarker asked me what I would do before August 2011 if I was provided with a monofumarate form of a compound and asked to obtain the hemifumarate form. The following is an explanation of the standard steps that I would have taken to obtain a hemifumarate form of a compound from a monofumarate form. First, I would dissolve the monofumarate in water and ensure the pH was adjusted to > 7 (typically around 9) by the use of sodium bicarbonate or similar. This will convert the monofumarate to the free base and it can then be dissolved in an organic solvent such as ethyl acetate and separated from the aqueous solutions. Once separated and collected, the solvent can be removed by evaporation and a pure sample of the free base of the compound would be obtained. The liberated free base compound would then be redissolved in a suitable crystallisation solvent (such as isopropyl alcohol) and 0.5 molar equivalents of fumaric acid would be added and the solutions would be stirred together. The solvent may be evaporated to produce a saturated solution and crystallisation either occurs spontaneously or is encouraged by the addition of a rough surface, such as a seed crystal or a microscopic piece of silica. The crystals would then be collected by filtration and the crystals would likely be the hemifumarate of the compound. Before August 2011, it was common for me to identify, consider and formulate different forms of compounds such as monofumarates and hemifumarates. In my opinion, the chemistry involved to identify and formulate different forms of compounds is typically not advanced and requires only standard techniques and procedures."[68]
[68] Robertson 1 at [68].
"I could also make the hemifumarate salt of GS-7340 by halving the amount of fumaric acid required for the fumarate in D1."[69]
[69] Robertson 1 at [72].
"I would also expect to be able to make the hemifumarate form of GS-7340 by applying the relevant standard techniques described in Section C above."[70]
[70] Robertson 1 at [74].
123. Professor Rodriguez-Hornedo disagrees that it would be routine to prepare a hemifumarate by halving the amount of fumaric acid:
"it is impossible to tell if this experiment will work without substantial experimentation … it is not the case that simply combining the API Molecule and conformer in 1.0:0.5 molar concentrations will assure the formation of a hemifumarate."[71]
[71] Rodriguez-Hornedo at [189].
124. I consider that this evidence as a whole establishes that it would be a matter of routine to approach the task of preparing the hemifumarate by using a ratio of 1:0.5, but there is no certainty that it would work. However, none of this addresses the key question of whether it would have been a matter of routine to want to prepare the hemifumarate. Dr Robertson declared that he routinely prepares salts of pharmaceutical compounds,[72] and hemifumarates are a salt that has been used with other pharmaceutical substances.[73] Dr Coates declared that a monofumarate and hemifumarate should have the same biological activity.[74]
[72] Robertson 2 at [57], [61].
[73] Robertson 1 at [66].
[74] Coates 1 at [51], Coates 2 at [21].
125. I am not satisfied that the evidence establishes that a person reading D1, and its disclosure of a monofumarate on the face of the document, would have considered it desirable to prepare the hemifumarate instead. In this situation it cannot be considered a matter of routine to prepare the hemifumarate. I conclude that it has not been established that any of the claims lack inventive step in the light of D1.
Manner of manufacture
126. It is a requirement of subsection 18(1) of the Act that the invention, so far as claimed in any claim, must be a manner of manufacture within the meaning of section 6 of the Statute of Monopolies. Manner of manufacture is assessed by considering the substance of the invention.[75] In the present case the substance of the invention is the compound TAF hemi.
[75] D'Arcy v Myriad Genetics Inc [2015] HCA 35; 115 IPR 1 at [6], [88].
127. It is well established that the requirement of a manner of manufacture is not satisfied if:
"it is apparent on the face of the specification that the quality of inventiveness necessary for there to be a proper subject of letters patent under the Statute of Monopolies is absent"[76]
[76] NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15; 183 CLR 655 at 664, [9].
128. For instance, a mere discovery is not patentable.[77] Alphapharm submitted that a mere discovery can arise where no inventive step is required in the application of a process to bring about a new product, and relied on Samuel Heap & Son Ltd v Bradford Dyers' Association Ltd[78] (Samuel Heap). Samuel Heap seems to be a case about inventive step, and I do not consider that it assists me in the present case.
[77] National Research Development Corporation v Commissioner of Patents [1959] HCA 67; 102 CLR 252 at 264.
[78] (1929) 46 RPC 254 at 264.
129. The statement of grounds and particulars explains this ground as follows:
"On the face of the specification, the subject matter claimed in each claim of the Opposed Application lacks the necessary quality of inventiveness and/or is not new. The alleged invention is said to be tenofovir alafenamide hemifumarate but it is acknowledged in the specification in paragraph [0071] that tenofovir alafenamide monofumarate spontaneously converts to the hemifumarate form when suspended in a range of solvents including acetonitrile. Paragraph [0002] incorporates by reference US 7,390,791 and US 7,803,788 which disclose, in Example 4, a suspension of tenofovir alafenamide monofumarate in acetonitrile. According to paragraph [0071] such a suspension will spontaneously form tenofovir alafenamide monofumarate [presumably this should be hemifumarate]. Accordingly, the alleged invention as defined in claims 1 – 31 is not a manner of manufacture within the meaning of the Statute of Monopolies."
130. The assertion is that the ground of manner of manufacture is a consequence of a lack of newness. This is explained in a different way in the summary of submissions:
"it is submitted that the alleged invention in the Opposed Application involves no more than more than the recognition, in respect of treatments for which tenofovir alafenamide was known to be suitable (for at least 9 years before the Priority Date), that rather than using the known monofumarate salt of tenofovir alafenamide one could also consider use of the hemifumarate form … recognising either of these matters does not rise so high as to constitute a mere 'discovery'. However, if it be characterised as a discovery, that does not qualify it as patentable subject matter. To 'discover' use of the hemifumarate salt of a known compound, for known uses in its monofumarate form, involves no manner of manufacture within NRDC principles."
131. In other words, the submission is that it would have been obvious to prepare the hemifumarate.
132. The specification does not suggest that the hemifumarate was known, and there is no suggestion that it would have been obvious to prepare the hemifumarate. While paragraph [0071] states that TAF mono converts to TAF hemi, this is something that forms part of the invention and does not mean that it would have been obvious to prepare the hemifumarate. I am not satisfied that it has been established that there is a lack of invention on the face of the specification.
Conclusion
133. Claims 1, 6, 11, 14, 16, 17, 27 and 29 lack novelty in the light of AU 2001282941. This deficiency can be overcome by amendment, so I will allow Gilead an opportunity to file amendments.
Costs
134. The parties submitted that costs should follow the event. I have found that the opposition succeeds on the ground of lack of novelty. However, the ground succeeded for reasons that were not advanced by Alphapharm. In these circumstances it would not be appropriate to award costs in favour of Alphapharm. It is more appropriate to make no award of costs.
Dr S.D. Barker
Delegate of the Commissioner of PatentsANNEX The claims of patent application 2012296622
1. Tenofovir alafenamide hemifumarate.
2. A composition comprising tenofovir alafenamide hemifumarate according to claim 1, wherein the ratio of fumaric acid to tenofovir alafenamide in said composition is 0.5 ± 0.1.
3. The composition of claim 2, wherein the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.05.
4. The composition of claim 2, wherein the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.01.
5. The composition of claim 2, wherein the ratio of fumaric acid to tenofovir alafenamide is about 0.5.
6. The hemifumarate of claim 1 or the composition of any one of claims 2-5, which is a solid.
7. Tenofovir alafenamide hemifumarate, having an X-ray powder diffraction (XRPD) pattern that comprises 2 theta values of 6.9 ± 0.2° and 8.6 ± 0.2°.
8. The hemifumarate of claim 7, wherein the XRPD pattern comprises 2 theta values of 6.9 ± 0.2°, 8.6 ± 0.2°, 11.0 ± 0.2°, 15.9 ± 0.2°, and 20.2 ± 0.2°.
9. The hemifumarate of claim 1 that has a differential scanning calorimetry (DSC) onset endotherm of 131 ± 2 °C.
10. The hemifumarate of claim 9 that has a DSC onset endotherm of 131 ± 1 °C.
11. A pharmaceutical composition comprising the hemifumarate of any one of claims 1 and 6-10 or the composition of any one of claims 2-6 and a pharmaceutically acceptable excipient.
12. The pharmaceutical composition of claim 11, further comprising an additional therapeutic agent.
13. The pharmaceutical composition of claim 12, wherein the additional therapeutic agent is selected from the group consisting of human immunodeficiency virus (HIV) protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
14. A method for treating a human immunodeficiency virus (HIV) infection comprising administering to a subject in need thereof a therapeutically effective amount of the hemifumarate of any one of claims 1 and 6-10 or the composition of any one of claims 2-6 or the pharmaceutical composition of any one of claims 11-13.
15. The method for treating an HIV infection of claim 14, further comprising administering to the subject one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
16. A method for treating a hepatitis B virus (HBV) infection comprising administering to a subject in need thereof a therapeutically effective amount of the hemifumarate of any one of claims 1 and 6-10 or the composition of any one of claims 2-6 or the pharmaceutical composition of any one of claims 11-13.
17. A method for preparing a pharmaceutical composition comprising combining the hemifumarate of any one of claims 1 and 6-10 or the composition of any one of claims 2-6 and a pharmaceutically acceptable excipient to provide the pharmaceutical composition.
18. A method for preparing tenofovir alafenamide hemifumarate comprising admixing a) aprotic organic solvent; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate; and crystallizing additional tenofovir alafenamide hemifumarate.
19. The method of claim 18, wherein the solvent comprises acetonitrile.
20. The method of claim 18 or 19, wherein the solution is subjected to a temperature in the range of from about 0 °C to about 75 °C.
21. The method for treating an HIV infection of claim 14 or 15, wherein the hemifumarate or the composition or the pharmaceutical composition is administered in multiple daily doses.
22. The method for treating an HIV infection of claim 14 or 15, wherein the hemifumarate or the composition or the pharmaceutical composition is administered in a single daily dose.
23. The method for treating an HBV infection of claim 16, wherein the hemifumarate or the composition or the pharmaceutical composition is administered in multiple daily doses.
24. The method for treating an HBV infection of claim 16, wherein the hemifumarate or the composition or the pharmaceutical composition is administered in a single daily dose.
25. A method for preparing tenofovir alafenamide hemifumarate, comprising the steps of: admixing a) a solvent comprising water, isopropyl alcohol, acetone, acetonitrile, toluene, ethyl acetate, isopropyl acetate, heptane, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate; and crystallizing additional tenofovir alafenamide hemifumarate at a temperature from about 0°C to about 70°C.
26. The method of claim 25, wherein the solvent comprises acetonitrile and up to about 50% by volume methylene chloride.
27. Use of the hemifumarate of any one of claims 1 and 6-10 or the composition of any one of claims 2-6 or the pharmaceutical composition of any one of claims 11-13 for the preparation of a medicament for treatment of a human immunodeficiency virus (HIV) infection by administration in an effective amount.
28. The use of claim 27 further comprising administering to the subject one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
29. Use of the hemifumarate of any one of claims 1 and 6-10 or the composition of any one of claims 2-6 or the pharmaceutical composition of any one of claims 11-13 for the preparation of a medicament for treatment of a hepatitis B virus (HBV) by administration in an effective amount.
30. The use of any one of claims 27-29, wherein the medicament is administered in multiple daily doses.
31. The use of any one of claims 27-29, wherein the medicament is administered in a single daily dose.
phenoxyphosphinyl] methoxy]propyl]adenine.
0
13
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