Merck & Cie - [2020] APO 45

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Merck & Cie [2020] APO 45

Patent Number: 2012200512

Title:Crystalline forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride

Patentee: Merck & Cie

Delegate: Dr Leslie F. McCaffery, Deputy Commissioner of Patents

Decision Date: 7 October 2020

Hearing Date: 30 April 2020 by teleconference.

Catchwords: PATENTS – Re-examination – Inventive step – Insufficient evidence to establish obviousness – Re-examination completed.

Representation: Patent attorney for the applicant: Davies Collison Cave, Sydney

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Number: 2012200512

Title:Crystalline forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride

Patentee: Merck & Cie

Date of Decision: 7 October 2020

DECISION

I am not practically certain that the granted patent is invalid in view of the evidence provided with the re-examination request.

The present re-examination process is therefore completed.

REASONS FOR DECISION

Onus

The request for examination for the present application was filed on 12 April 2013. Substantive amendments of the Patents Act 1990 (the Act) brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (RTB) therefore do not apply to the present application. This includes the amendment to subsection 60(3A) that allows the Commissioner to refuse a patent if satisfied on the balance of probabilities that a ground of opposition exists. Prior to 15 April 2013, the Commissioner had the power to revoke a patent but only where the Commissioner was practically certain that the granted patent was invalid.[1]
[1] F. Hoffmann-La Roche AG v New England Biolabs Inc. (2000) 50 IPR 305 at [67]; Commissioner of Patents v Sherman (2008) 79 IPR at [18].

Unless otherwise indicated, any subsequent reference in this decision to sections of the Act relate to the Act prior to amendment by the RTB.

Background

Polymorphs are different crystal forms of an organic or inorganic compound. One definition is the ability of a material to crystallise as two or more distinct crystal species, while other authors use the term more broadly to include not only the distinct crystal states but also the amorphous (disordered) state and solvates (where solvent molecules are incorporated in the crystal lattice).[2] I note the references to polymorphs of the present patent include solvates, which is consistent with the latter approach. I will follow this approach in the present decision.
[2] Exhibit JSR-9 at 1.1.

Polymorphism is apparently commonly encountered in pharmaceuticals, with literature indicating between 32-51% of small chemicals exist as polymorphs, and if solvates are included this ratio increases to 56-87%. This feature is an important consideration in pharmaceutical formulations since most drug products are administered orally, and the most popular dosage forms are tablets and capsules.[3]
[3] Supra.
Australian Patent 2012200512 (the patent), in the name of Merck & Cie (the Patentee) was granted on 11 February 2016. The patent claims an earliest priority date of 17 November 2003. The patent claims formulations of a specific polymorph of the compound (6R)-L-erythro-tetrahydrobiopterin dihydro-chloride (referred to as Form B). The formulations comprise one, or both, of the pharmaceutical excipients polyvinylpyrrolidone (PVP) and/or dicalcium phosphate (DCP).
On 23 October 2017, FB Rice Patent and Trade Mark Attorneys, Melbourne (the Requestor) filed a request for re-examination. Following consideration of the material provided by the Requestor a re-examination report issued on 21 December 2017. Objections were raised by the Examiner under the ground of inventive step. The Patentee requested an extension to respond and the first report was re-issued on 2 March 2018.
The Patentee subsequently filed a response on 2 May 2018. The Examiner was not satisfied that the response addressed the issues raised in the first re-examination report and a further re-examination report was issued on 21 August 2018. An extension of time was requested, and the second report was re-issued on 17 October 2018.
A response was filed on 17 December 2018. However, the Examiner did not consider that this overcame the objections and issued a further re-examination report on 11 April 2019.
The Patentee filed another response together with amendments on 7 June 2019. The Examiner was not satisfied that the response overcame the outstanding issues. The Patentee was advised that the case would be assigned to a hearings officer to consider revocation, and they could request a hearing.
The Patentee sought a stay on the re-examination process pending allowance of the amendments, but on 22 November 2019 the Supervising Examiner, Oppositions and Hearings advised the Patentee that there was no basis for a stay of proceedings. The amendments were subsequently advertised for opposition on 3 December 2019.
The Patentee requested a hearing on 12 December 2019. The matter was initially to be heard from written submissions but on 30 January 2020, the Patentee requested an oral hearing. The hearing was held on 30 April 2020 by teleconference.

The Re-examination request

The Requestor raised the following grounds for re-examination:
a)the invention so far as claimed in any claim is not novel;
b)the invention so far as claimed in any claim does not involve an inventive step; and
c)the claims of the application are not fairly based.

Nine prior art documents were provided with the request. The numbering below is consistent with the documents as raised by the Examiner in the subsequent re-examination report.

D1 MATSUURA, S. et al., Journal of Biochemistry, 1985, vol. 98, pp. 1341-1348.

D3 MATSUURA, S. et al., Chemistry Letters, 1984, pp. 735-738.

D4US 4,713,454 (Shiratori Pharmaceutical Co. Ltd.) published 14 August 1991.

D5 US 4,920,122 (Suntory Ltd.) published 11 March 1992.
D6 US 4,778,794 (Suntory Ltd.) published 11 March 1992.
D7 US 4,701,455 (Burroughs Wellcome Co.) published 20 October 1987.
D8 US 4,665,182 (Burroughs Wellcome Co.) published 12 May 1987.
D9 US 4,587,340 (Burroughs Wellcome Co.) published 6 May 1986.

The gist of the Requestor’s submissions are as follows:

The claims lack novelty in view of the disclosure in D5 and D6 of a tablet formulation including tetrahydrobiopterin dihydrochloride and PVP (Examples 1 and 2 of each document).

The claims lack inventive step in view of each of the documents given above and the common general knowledge (as supported by Dr Marshall’s evidence). D1, D3 and D4 disclose Form B (-)-tetrahydrobiopterin dihydrochloride and D5 to D9 disclose biopterin compounds including (-)-tetrahydrobiopterin dihydrochloride in tablet formulations comprising PVP.
The claims lack fair basis. The claims were amended during prosecution (and more than 11 years after the original filing) to define Form B in combination with PVP and/or DCP. This is not a specific selection that is fairly based on the provisional or complete application. In particular the selection of PVP (and other derivatives of PVP as defined in the claims) from a list that was not part of the inventive concept represents a departure from the invention described in the earlier documents and is therefore not fairly based on those documents.

The only ground raised in the re-examination reports was inventive step. 11 documents were raised in the first re-examination report. In addition to the documents referred to in the re-examination request above, the Examiner also raised:

D2 EP 0079574 (Kanegafuchi Kagaku Kogyo Kabushiki Kaisha), published 4 March 1987.

D10 Handbook of Pharmaceutical Excipients, 4th ed., pp 74-77, 184-185 and 508-513, (2003).

D11Lieberman et al, Pharmaceutical Dosage Forms, Tablets, 2nd Ed, Vol 1, 1989: pages 107, 152, 153, 164 and 165.

The Examiner noted that the specification acknowledged that Form B was known from D1 to D4, and that its outstanding properties make it “especially feasible” for pharmaceutical application. They considered that the “specification does not appear to suggest any particular problem when formulating compositions of the polymorphic Form B, nor does it indicate that there is any particular difficulty in formulating Form B” and that as a consequence “there are no proposed solutions which have a need for invention when preparing a pharmaceutical composition”. The Examiner also noted the absence of any formulation examples in the specification and that PVP and DCP are mentioned only “in passing as examples of typical excipients amongst many others”.
The Examiner went on to note in the re-examination report that an inventive step objection had been raised in examination reports prior to acceptance on the basis that the claims differed from the prior art only in the inclusion of PVP and/or DCP. The use of these had been considered as being routine, but the applicant had drawn analogies to the circumstances of Bristol Myers Squibb v Apotex,[4] and argued that these excipients (either alone or in combination) provided improved hygroscopicity that could not have been predicted. The application was accepted in view of this argument. However, the Examiner considered that the material provided by the Requestor established that the use of these ingredients was obvious.
[4] Bristol Myers Squibb v Apotex Pty Ltd [2015] FCAFC 2
The first re-examination report raised an inventive step objection based on any one of D1 to D9. D5 was identified as the closest prior art and was said to disclose pharmaceutical compositions comprising L-erythro-tetrahydrobiopterin and that common pharmaceutically acceptable components such as PVP could be included in the formulations. The Examiner acknowledged that D5 does not disclose or discuss the specific crystalline form of the L-erythro-tetrahydrobiopterin dihydrochloride but noted that it was known from citations D1 to D4. They argued that:
“D5 alone supports the previous assertion that the claimed invention lacks an inventive step, and that the use of excipients is merely routine. Certainly in light of D5 a person of ordinary skill would be expected to simply substitute the amorphous tetrahydrobiopterin with the improved polymorphic Form B. Furthermore the additional citations D6-D9 all appear to also show exemplary tablet formulation comprising biopterin compound formulated together with the known excipient polyvinylpyrrolidone.

In addition evidence has been supplied that suggests polyvinylpyrrolidone was also well known in the art as a general excipient suitable as a slightly hygroscopic excipient suitable for use where moisture sensitivity is a problem (see D10 and D11). Similarly dicalcium phosphate is a well-known pharmaceutical excipient. Furthermore as previously raised during examination, and highlighted by the 3rd party, from the specification the choice of these particular excipients is not discussed, or presented as overcoming any particular problem, there are no examples or suggestion that they provide any particular benefit over the many alternatives which are also listed. While the applicant has previously argued that PVP was not known or suggested for its use in a formulation where hygroscopicity was a concern, evidence to the contrary has been presented and found to be persuasive.

In light of the discussion, evidence and additional citations it is considered that the invention defined by claims 1-20 does not involve an inventive step in light of any one of the citations D1-D9. The features of the tablet formulation and processes for preparing them relate only to non-inventive steps that a person skilled in the art would directly and without difficulty, by routine steps alone, arrive at a solution which is the same as the claimed solution.”

The first re-examination report also raised an inventive step objection in view of the disclosure of any one of D1-D4 when combined with the disclosure of any one of D5-D9. The Examiner noted that D1-D4 differ from the claimed invention only in the choice of the excipients PVP and DCP, and D5-D9 each differ only in the use of the specific crystalline Form B. They argued that a person skilled in the art would, in seeking a solution to the problem being addressed, be motivated to combine the disclosures of any one of the documents D1-D4 with any one of D5-D9 and arrive at a solution which is the same as the claimed invention.

Construction

The principles of construction are well established. As Middleton J stated:
“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.”[5]
[5] Eli Lilly and Co Ltd v Apotex Pty Ltd [2013] FCA 214; 100 IPR 451 at 482 [139].
Middleton J went on to provide a useful summary of relevant principles:[6]
[6] Ibid at [143].

a patent is a public instrument which must, if it is to be statutorily valid, define a monopoly which is not reasonably capable of being misunderstood;
the Court, when reading the entire patent specification, must place itself in the position of a person who is skilled in the relevant art, given their general knowledge, and the common general knowledge and the state of the art that existed before the priority date of the patent;
the words used in a specification, including the claims, are to be construed from this standpoint in a “common sense” and not abstract manner;
what is disclosed in the body of the specification will also assist the skilled person in the art to understand the claims, bearing in mind that a patent is a unilateral document and the Patentee has chosen particular words to describe the invention;
the claims define the monopoly claimed by the patent;
terms which are unclear in the claims may be defined or clarified by reference to the body of the specification;
language which has no positive meaning in the claims may become clear when the specification is used as a “dictionary” for the jargon in the claims; and
that said, given the special function of the claims, it is impermissible to read into a claim an additional integer, or otherwise vary the scope of the claim by reference to the body of the specification.

Middleton J also cautioned that:
“It is clear from the above propositions (particularly the latter three points) that the use the Court can make of the body of a specification will vary from case to case. As Apotex submitted, there is a fine line between using the specification to construe the claim, and using the specification in such a way that adds an impermissible gloss to the claims.”[7]
[7] Ibid at [144].

The person skilled in the art

The person skilled in the art is the hypothetical person to whom the specification is addressed.[8] This determination plays a central role in determining the validity of the patent:
“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...”[9]
[8] General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (1971) 1A IPR 121 at 134.
[9] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980; 49 IPR 225 at [70]-[71].
The person skilled in the art is assumed to be a skilled but unimaginative and non-inventive worker in the field of the invention.[10] One formulation describes them as “those likely to have a practical interest in the subject matter of [the] invention.”[11] Notably:
“The identification of the relevant field will, in its turn, determine the characteristics of the notional worker skilled in the art who must provide the answer to the question of whether the invention was obvious. Such characteristics will include the qualifications of the notional worker, the setting in which he or she operates and the practices and techniques that he or she will regard as commonplace and known.”[12]
[10] Minnesota Mining and Manufacturing Co & 3M Australia Pty Ltd v Beiersdorf (Aust) Ltd [1980] HCA 9; (1980) 144 CLR 253 at 293.
[11] Catnic Components v Hill & Smith Ltd [1982] RPC 183.
[12] Aktiebolaget Hässle v Alphapharm Pty Ltd supra at 465.
The Requestor provided evidence from several declarants with their request:

Dr Bernard Schircks dated 5 July 2017 and Annexes A-D (Schircks). Dr Schircks is a Technical Director of Schircks Laboratories, Switzerland.

Professor Norboerto Masciocchi dated 24 July 2017 and Annexes A-B (Masciocchi).
Professor Masciocchi is a Professor of Chemistry at the Department of Science and High Technology of the University of Insubria-Como (Italy).

Dr Philip Andrew Marshall dated 18 October 2017 and Exhibits PAM-1 to PAM-17 (Marshall). Dr Marshall is currently a consultant specialising in the pharmaceutical and life science industry.

The applicant provided evidence from several declarants in their responses to re-examination reports:

Dr James S Rowe dated 31 October 2018 and Annexes JSR-1 to JSR-3 (Rowe 1). Dr Rowe is currently an independent consultant in matters relating to pharmaceutical and veterinary dosage forms.

Dr James S Rowe dated 30 November 2018 and Annexes JSR-4 to JSR-6 (Rowe 2).

Dr James S Rowe dated 14 December 2018 and Annexes JSR-7 to JSR-12 (Rowe 3).

Professor Jorg Breitkreutz dated 14 December 2018 and Annexes JB-1 to JB-9 (Breitkreutz). Professor Breitkreutz is Head of the Institute of Pharmaceuticals and Biopharmaceutics at Heinrich-Heine-University, Düsseldorf.

Dr Andreas Furger dated 2 April 2020 and Annex AF-1 (Furger). Dr Furger is a patent attorney at Merck & Cie.

A declaration by Dr Mark Henderson was also provided in the Patentee’s response dated 1 May 2018. This declaration was originally filed in proceedings related to Indian Patent 252305. This patent is a family equivalent of the present patent but relates to the process of making polymorphic Form B rather than a pharmaceutical composition comprising polymorphic Form B. The Patentee submitted that the declaration is still relevant to this matter as it relates to the issue of common general knowledge.
The Patentee submitted that:

“The person skilled in the art is identified by examining the nature of the invention and the industry concerned. Here the invention generally concerns new formulations of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride… and processes for preparing same.”

The Patentee did not identify a specific person skilled in the art, but this submission suggests that they consider that the skilled person is a formulation scientist. Similarly, neither the Requestor nor the Examiner identified a specific skilled person, but the arguments and submissions in both cases are consistent with the skilled person being a formulation scientist. I am satisfied that this is a reasonable representation of the person skilled in the art in the present case.
The Patentee stated that both Dr Rowe and Professor Breitkreutz have “comprehensive” knowledge and experience of drug formulation. In comparison, they acknowledged that Dr Marshall has “experience in the development of various pharmaceutical formulations and medicaments” but noted that he provided no evidence of experience in performing polymorphic screening and did not identify any literature about polymorphism. They also noted that Dr Schircks is the proprietor of a company that produces a competing product to the Patentee and that Professor Masciocchi provides no evidence of experience in small drug formulation.
I do not consider that the matters identified by the Patentee preclude me from taking the evidence from Dr Marshall, Dr Schircks and Professor Masciocchi into account. In the case of Dr Schircks and Professor Masciocchi, the evidence provided was in relation to specific technical issues, and in the case of Dr Marshall there is nothing in the Patentee’s submissions that would lead me to disregard his evidence. I will consider the evidence of all declarants to the extent appropriate on any point.

The specification and claims

The specification states that the biosynthesis of neurotransmitting catecholamines from phenylalanine requires the cofactor (6R)-L-erythro-tetrahydrobiopterin at the monooxygenation step of phenylalanine and tyrosine. A decrease in this factor is thought to cause several neurological disorders including Parkinsonism and atypical phenylketonuria. (6R)-L-Erythro-tetrahydrobiopterin is therefore an effective therapeutic agent for treatment of such disorders.[13]
[13] Specification at page 1, line 7.
The specification states that (6R)-L-erythro-tetrahydrobiopterin is difficult to handle and is therefore produced and supplied as its dihydrochloride salt, in some cases in ampoules under nitrogen because of its hygroscopicity and sensitivity to oxidation.[14]
[14] Specification at page 1, line 15.
The specification goes on to say that:

“The present invention relates to crystal forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride and hydrates and solvates thereof. This invention also relates to processes for preparing the crystal forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride and hydrates and solvates thereof. This invention also relates to compositions comprising selected and stable crystal forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride or a hydrate thereof and a pharmaceutically acceptable carrier”.[15]

[15] Specification at page 1, line 1.

Several prior art disclosures are referred to in the specification:

“S. Matsuura et al. describes in Chemistry Letters 1984, pages 735-738 and Heterocycles, Vol. 23, No. 12 1985 pages 3115-3120 (6R)-tetrahydrobiopterin dihydrochloride as a crystalline solid in form of colourless needles, which are characterised by X-ray analysis disclosed in J. Biochem. 98, 1341-1348 (1985). An optical rotation of 6.81° was found the crystalline product, which is quite similar to the optical rotation of 6.51° reported for a crystalline solid in form of white crystals in example 6 of EP-A2-0191335”.[16]

[16] Specification at page 2, line 1.

The specification states that results obtained during the development of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride revealed that the known crystalline solids disclosed in the above prior art can be designated as Form B (or polymorph B).[17] This polymorph is apparently a slightly hygroscopic anhydrate with the highest thermodynamic stability and has other favourable properties that make it “especially feasible” for pharmaceutical processing.[18] The specification goes on to state that:

“However, there is a need for other stable forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride with satisfactory chemical and physical stability for a safe handling during manufacture and formulation as well as providing a high storage stability in its pure form or in formulations. In addition, there is a strong need for processes to produce polymorph B and other crystalline forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride on a large scale in a controlled manner.”

[17] Specification at page 2, line 8.

[18] Specification at page 2, line 19.

To this end the specification states that the compound may exist in different crystal forms, including polymorphic forms and solvates, and that:

“The continued interest in this area requires an efficient and reliable method for the preparation of the individual crystal forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride and controlled crystallization conditions to provide crystal forms, that are preferably stable and easy to handle and process in the manufacture and preparation of formulations, and that provide a high storage stability in substance form or as formulated product, or which provide less stable forms suitable as intermediates for controlled crystallisation for the manufacture of stable forms.”[19]

[19] Specification at page 3, line 3.

Pharmaceutically acceptable ingredients are said to be “well known” for the various types of formulation, and may be binders, excipients, lubricants, surfactants, sweetening and flavouring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, antioxidants and carriers.[20] All examples given in the specification relate to the preparation, characterisation and interconversion of the various polymorphs. No formulation examples are provided.
[20] Specification at page 25, line 7.
The claims consist of 31 claims. Only tablet formulations comprising Form B are claimed – no formulations are claimed that comprise any of the other polymorphs described in the specification, even though some are said to be suitable for formulation. The claims are defined as comprising a purified crystalline polymorph of Form B. I understand this to mean that the tablets comprise the active agent in the particular crystalline form, rather than for example, the crystal form being formulated in a manner that would result in a product in which the crystalline form is no longer present.
Claims 1, 4, 5, 9, 10, 11, 12 and 19 are independent claims defining various tablet formations comprising Form B together with PVP and/or DCP. The scope of the claims therefore include formulations in which only one of PVP or DCP is present, as well as formulations in which both are present. Claims 23 to 28 define processes for the preparation of these formulations. Form B is also characterised in different independent claims by various specific peaks in the X-ray powder diffraction pattern or by reference to the spectrum shown in Table 2.
The reference to PVP in the claims includes linear, branched and crosslinked forms of PVP. I understand this to include known materials Povidone (a linear form of PVP) and Crospovidone (a cross-linked form of PVP).[21] Povidone and Crospovidone are known binders and disintegrants.[22] The claims do not define any specific amount of PVP. In Claims 1, 4 and 19, PVP is defined as a “pharmaceutically acceptable ingredient”, whereas in Claims 5, 9, 10, 11 and 12 it is defined as a “biologically degradable polymeric binder”. The difference in the terminology used (ingredient as opposed to binder) suggests that there is a different meaning afforded to each term. The specification provides a general description of the ingredients as follows:

“Pharmaceutically acceptable ingredients are well known for the various types of formulation and may be for example binders such as natural or synthetic polymers, excipients, lubricants, surfactants, sweetening and flavouring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, antioxidants and carriers for the various formulation types.”

[21] Merck Index, 13^th Edition, 2001, Entry 7783. This reference was provided by the applicant on 15 September 2015 during the examination of the application before acceptance.

[22] Merck Index, ibid. See also Marshall at [30].

I understand this to mean that the definition of Claim 1 is not limited only to the use of PVP as a binder, but that it may be added for another purpose.
DCP is referred to throughout the claims as “an excipient”. The specification gives DCP as a specific example of “phosphates”, which are given in the specification as the only illustrative example of an excipient. Dr Marshall stated that DCP is a known diluent or filler, and that diluents are typically present in the range of 10-80% w/w.[23] The specification also refers to solid carriers, including “talc, clay, microcrystalline cellulose, silica, alumina and the like”.[24] These also appear to be typical fillers or diluents. No evidence was provided as to the specific meanings of, and differences between, the terms carriers and excipients. The term “excipient” as used in the specification appears narrower to that used by Dr Marshall, who stated that:

“non-active ingredients, commonly termed excipients used in tablet compositions may include one or more diluents (e.g. fillers or bulking agents), binders (e.g. granulating agents), disintegrants or swelling agents, glidants (e.g. flow aids), pigments, and sweeteners/flavours”[25] [emphasis added].

[23] Marshall at [30].

[24] Specification at page 26, line 21.

[25] Marshall at [28].

Dr Rowe’s use of the term excipient in his evidence is also consistent with this meaning. I therefore understand this to mean that DCP is used as a non-active ingredient, and while it is typically used as a filler or diluent, it is not limited to such in the present claims.
The claims are given in full in the attachment.

Inventive step

Section 7 of the Act sets out that an invention is taken to involve an inventive step unless it would have been obvious to the person skilled in the art in the light of the common general knowledge, either considered alone or together with the prior art. The prior art is information that the skilled person could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant.

The test for whether an invention is obvious is whether it would have been a matter of routine to proceed to the claimed invention[26] In Alphapharm,[27] the High Court accepted the approach taken by Graham J in Olin Mathieson,[28]where he posed the reformulated Cripps question:
“Would the notional research group at the relevant date, in all the circumstances, ... directly be led as a matter of course to try [the claimed combination] in the expectation that it might well produce a [useful or better result]?”
[26] Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; 148 CLR 262 at 286.
[27] Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59 at [53]; (2002) 212 CLR 411 at [53].
[28] Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at [187].

The problem to be solved

The Patentee submitted that the problem lies in the preparation of a formulation of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride that has high storage stability. They referred to the evidence of Dr Rowe and Professor Breitkreutz in support of this submission. In particular, Dr Rowe stated that:

“The paragraph abridging pages 2 and 3 of the specification states that that there is a need for stable forms, and that these forms should have "satisfactory chemical and physical stability for a safe handling during manufacture and formulation". The specification also states that the stable forms of the active should also provide "high storage stability in its pure form or in formulations". I consider that these are problems that the invention described in the specification is trying to solve. From my reading of this paragraph, I consider that the patent specification will address problems such as stable forms having the requisite stability for manufacture and formulation and also provide high storage stability, either as the stable form itself or as part of a formulation of the stable form.”[29]

[29] Rowe 3 at [10].

Dr Breitkreutz stated that

“I observe that the patent application refers to various crystalline forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride and also processes for the manufacture of the various crystalline forms and solid formulations containing said forms. The specification teaches me that there are difficulties in formulating and handling said compound due to poor stability.”[30]

[30] Breitkreutz at [8].

He concluded that:

“…I am taught that there was a need at the time for more stable forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, which includes more stable formulations to address the high storage stability issue as discussed in the specification.”[31]
[31] Breitkreutz at [9].

The Requestor did not articulate a specific problem, but they noted that during the prosecution of the application hygroscopicity had been identified by the Patentee as a problem that the claimed invention addressed. The Requestor stated that there was no hygroscopicity problem identified in the specification, and particularly not by any reformulation development around Form B with any advantageous excipients.[32] They argued that:

“In other words, it is submitted that there was no hygroscopic instability problem as such for polymorph Form B that required addressing by identifying advantageous excipients. There is no evidentiary basis at all for establishing any such problem. The Patentee appears to have originally identified polymorph Form B per se in its priority specification, acknowledged that polymorph Form B was known in its originating complete specification and tried to pursue identifying other more stable crystalline forms without success, and then switched its problem/solution approach during prosecution (and more than 11 years after its original filing) without support and contrary to its own admissions in an attempt to unjustifiably obtain protection around the later registered pharmaceutical formulation.”

[32] Re-examination request cover letter at pages 14 to 15.

The examiner similarly did not identify a specific problem in the re-examination report, noting that the specific choice of excipients was not discussed or presented as overcoming any particular problem.
I acknowledge that there appears to have been a shift in the nature of the claimed invention during prosecution of the case. But despite this apparent shift I am satisfied that the problem to be solved, as provided by the Patentee, is the provision of a formulation of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride that has high storage stability.

The common general knowledge

The inventive step determination requires a consideration of the common general knowledge:

“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.”[33]
[33] Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9; 144 CLR 253 at 292.

It is not sufficient that a document is publicly available for it to be considered part of the common general knowledge in the art. There must be evidence of its general acceptance and assimilation by the person skilled in the art.[34]
[34] Aktiebolaget Hassle v Alphapharm Pty Ltd supra at [31].
The person skilled in the art in this case is a formulation scientist.
There was no dispute as to the literature routinely consulted by formulation scientists. Dr Marshall stated that these included published scientific papers, conference proceedings, textbooks, formularies and indexes of pharmaceutical products, regulatory databases including freedom of information summaries, patent specifications, product information from pharmaceutical companies and articles in trade literature.[35] He also provided details of a number of specific texts and databases.[36] Dr Marshall and Dr Rowe also agreed on the common general knowledge in relation to formulation excipients.[37] Dr Marshall stated that:

“… classes of common excipients included filler/diluents, binders, disintegrants, lubricants, surfactants, glidants, colours, flavours, and buffers. Fillers/diluants were used to bulk out the tablet since the active typically comprised a small amount, which could be soluble or insoluble, and some particularly common excipients were lactose, microcrystalline cellulose, saccharides, and dicalcium phosphate. Binders were used to bind together constituents and included gelatin, povidone, hydroxylpropyl cellulose, hydroxylpropylmethyl cellulose (HMPC), and starches.

Disintegrants assisted the tablet disintegrating smaller protions following administration to facilitate dissolution, some of which also had a dual property of being a binder, and some particularly common disintegrants included cross-linked povidones, cross-linked polymers, povidone, and gums/clays…”[38]

[35] Marshall at [14].

[36] Marshall at [15]-[20].

[37] Marshall at [27]-[35], Rowe 1 at [13]-[14].

[38] Marshall at [33].

Dr Marshall went on to state that:

“The excipient selection can also depend on the method being used, which may also depend on the properties of the API. For example, a hygroscopic drug may lend itself to direct compression technique. This may also lend itself to narrowing the selection of certain excipients. For example, some excipients could be used depending on the degree of hygroscopicity, such as microcrystalline cellulose, polyethylene glycols, povidone, or starches, since they are also slightly hygroscopic and can sacrificially compete with the moisture preferentially to that of the hygroscopic active. However, the impact of other hygroscopic excipients(s) on disintegration would need to be checked.”[39]

[39] Marshall at [34].

Dr Rowe did not dispute this statement, adding that he considered the choice of excipient “would most definitely” depend on the properties of the active, as well as other requirements of the tablet.[40]
[40] Rowe 1 at [14].

At hearing the Patentee conceded that (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, PVP and DCP each individually forms part of the common general knowledge in the art.[41] However they submitted that the following does not form part of the common general knowledge:

The existence of polymorphic forms (including polymorphic Form B) of the compound (which I understand to mean (6R)-L-erythro-tetrahydrobiopterin dihydrochloride) and any chemical or physical properties of such forms;
The hygroscopic nature of the compound; and
The combination of the compound (and hence any of its polymorphs) with either PVP or DCP.[42]
[41] Patentee written submissions for hearing at [73].
[42] Patentee written submissions for hearing at [74].

I consider these statements to be an accurate reflection of the common general knowledge in this case. The evidence before me indicates that while (6R)-L-erythro-tetrahydrobiopterin dihydrochloride was known to exist as in a white crystalline solid, this was the only crystal form described in the prior art. Polymorphism requires at least two different crystal forms and it was only once the Patentee discovered different crystal forms then the white crystal of the prior art could be considered a polymorph. The Patentee designated the known crystal form as Form B. The existence of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride as polymorph forms was therefore not common general knowledge before the priority date.
Notwithstanding that conclusion, I note that the Merck Index lists (6R)-L-erythro-tetrahydrobiopterin dihydrochloride as crystals from HCl with a melting point of 245-246 degrees.[43] This appears to correspond to the physical properties of the crystals described in D1 and D3, which the Patentee acknowledges is Form B. Given that the Merck Index was accepted by the declarants as being part of the documentation routinely consulted by those in the art, the listing of the particular crystal form in Merck could be indicative of that being the “reference standard” for (6R)-L-erythro-tetrahydrobiopterin dihydrochloride.
[43] Exhibit PAM-3.
The evidence also suggests to me that stereochemically-pure (6R)-L-erythro-tetrahydrobiopterin dihydrochloride has only been obtained in one form. There is no clear evidence of any other physical form of purified (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, such as an amorphate, before the priority date. If it were the case that the compound was only known in one form or that the Merck Index entry were the generally accepted standard, then any reference to (6R)-L-erythro-tetrahydrobiopterin dihydrochloride before the priority date might implicitly be directed to that particular crystal form.
However, no evidence was provided on these points and I therefore cannot conclude that the crystal form given in the Merck Index entry is part of the common general knowledge in relation to (6R)-L-erythro-tetrahydrobiopterin dihydrochloride. It follows that any properties of that crystal form would similarly not constitute common general knowledge. Specifically, no evidence was provided concerning the storage stability of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride. The only apparent evidence on this point came from Dr Rowe, who stated in response to statements by Dr Marshall that there was no apparent moisture sensitivity problem with Form B disclosed in the specification that:

“…the Schircks product identified on page 1 of the specification provides the compound tetrahydrobiopterin as a dihydrochloride salt (but not as a specific polymorph), which is known to be hygroscopic and oxygen sensitive. This is clearly stated on the packaging label for tetrahydrobiopterin tablets as manufactured by Schircks Laboratories. A copy of this label is reproduced as Exhibit JSR-11.”[44]

[44] Rowe 3 at [29].

Dr Rowe gives no indication as to the date of this label, or indeed the physical form of tetrahydrobiopterin used in the formulation, but I understand the assertion to be that tetrahydrobiopterin was known to be hygroscopic and oxygen-sensitive prior to the priority date. However, even if this label was published prior to the priority date there is no evidence that the Schircks product had risen to the level where the product and the properties given on the label could be considered common general knowledge.

There was also no evidence that tablets comprising (6R)-L-erythro-tetrahydrobiopterin dihydrochloride together with PVP and/or DCP were known or even common general knowledge, even though as conceded by the Patentee, the individual excipients may be.

Matters of routine

Dr Rowe and Dr Marshall each provided evidence of the steps they would take if tasked with preparing a tablet formulation.

Dr Marshall stated that when given a formulation task, he would routinely perform a literature search to refresh his background knowledge and identify any relevant information for the formulation task.[45] In determining the constituents of a formulation, preliminary and primary consideration is given to the properties of the active pharmaceutical ingredient (API) before considering suitable excipients. To that end he required information about the target site and physicochemical properties, in order to select appropriate ingredients.[46] Factors that may influence the dissolution or release rate of the active from a tablet included properties of the active (water solubility, water sensitivity, hygroscopicity, pH sensitivity, pK, particle morphology, salt type, polymorphic forms), non-active excipients (binders, disintegrants, lubricants, anti-adherants, fillers, binders etc), and tablet compression parameters and physical properties of the oral dosage form as a result of the non-active excipients used.[47] Dr Marshall stated that

“Typically desired properties of a tablet are prescribed, although stability of the API is a key consideration. In most cases, various properties of the active are provided (e.g. by the API supplier or manufacturer) or readily available (e.g. Merck Index, MIMs, Australian Prescription Products Guide), although routine experiments are conducted to determine the properties if not readily available or to check on properties provided. For example, it was routine to check solubilities, pK, pH stability, moisture sensitivity and hygroscopicity of APIs (e.g. humid environment test).[48]

[45] Marshall at [15].

[46] Marshall at [21]-[22].

[47] Marshall at [23].

[48] Marshall at [24].

Dr Rowe noted that Dr Marshall’s statements on this point were made without a full knowledge of the pharmaceutical ingredient or whether it was intended to achieve a particular aim or solve a particular problem.[49] Nevertheless he stated that:

“There are many different features that need to be taken into consideration when developing a new tablet formulation of an active pharmaceutical agent. Knowledge of a variety of physicochemical properties would be necessary in the development of a new formulation. However it is critically important that the specific requirements of new formulations are detailed to the formulator. That is, one cannot simply commence a task as stated above without the knowledge of what one is trying to achieve in a new formulation and the knowledge of physicochemical properties of the active pharmaceutical ingredient. These requirements would typically include the nature of the active pharmaceutical ingredient, the dosage form, half life of the drug, etc. In instances where I have been asked to prepare a new purpose-specific formulation, I am often provided with a product briefing document. In instances where I consult to a third party, this document is usually prepared by a client's product development committee, which can comprise people from the marketing department, regulatory affairs and the production department. In instances where I was part of the organisation, I would be involved in the product development committee as part of the research and development department (i.e. as a formulator). In a case where I am asked to prepare a new formulation I would also need to know the physicochemical properties of the active ingredient of the formulation. This would include solubility (e.g. in water, lipids, other solvents), pH v stability profile, existence of polymorphs, melting point, known interactions with excipients, intrinsic dissolution rate and partition coefficients. This knowledge, in addition to the information in relation to what is to be achieved by the formulation, would influence the type of formulation and the choice of excipients used in the formulation.”[50]

[49] Rowe 1 at [16].

[50] Rowe 1 at [8].

One of the key issues in the present case related to polymorphic screening during the development of new formulations. Both Dr Rowe and Dr Marshall identified the existence of polymorphs as one of the factors they would consider during the formulation process.[51] My understanding is that this is not a mandatory step in the art, though it is advised in order to avoid issues that might arise later in product development, particularly in order to obtain a storage-stable formulation.[52]
[51] Marshall at [23], Rowe at [8].
[52] Exhibit JSR-9.

The prior art

Eleven documents were referred to during the re-examination. For convenience these are repeated below:

D1 MATSUURA, S. et al., Journal of Biochemistry, 1985, vol. 98, pp. 1341-1348.

D2 EP 0079574 (Kanegafuchi Kagaku Kogyo Kabushiki Kaisha), published 4 March 1987.

D3 MATSUURA, S. et al., Chemistry Letters, 1984, pp. 735-738.

D4US 4,713,454 (Shiratori Pharmaceutical Co. Ltd.) published 14 August 1991.

D10 Handbook of Pharmaceutical Excipients, 4th ed., pp 74-77, 184-185 and 508-513, (2003).

D11Lieberman et al, Pharmaceutical Dosage Forms, Tablets, 2nd Ed, Vol 1, 1989: pages 107, 152, 153, 164 and 165.

The re-examination report indicated that the claims lacked inventive step in view of each of D1 to D9, or a combination of any one of D1 to D4 with any one of D5 to D9. Despite additional submissions and further information, this same objection was maintained throughout the re-examination. I will deal with each of these in turn, as well as inventive step in view of the common general knowledge alone.

Inventive step in view of the common general knowledge alone

Both the requestor and the examiner noted that Form B is known. In particular, the Requestor submitted in their covering letter that:
“…while other forms of saproterin may have been less stable in certain environments, polymorph form B was already known to be very stable and not problematically moisture sensitive. In fact AU’512 clearly acknowledges that polymorph form B was known and had exceptional stability even in the presence of water/moisture, which is also supported in its own specification by extensive stability experiments and data. For example, on page 17 of the specification for AU’512 reference is made to
“Polymorph B is a very stable crystalline form, that can be easily filtered off, dried and ground to particle sizes desired for pharmaceutical formulations. These outstanding properties renders polymorph form B especially feasible for pharmaceutical application.”
The Patentee noted that no obviousness objection had been raised during the re-examination on the basis of common general knowledge alone, and that none of the documents raised in the reports had been asserted as forming part of the common general knowledge. They also noted that Dr Marshall had been unable to identify any polymorphism or crystal morphology, and that it was only after being provided with D1 that he acknowledged crystal forms.[53]
[53] Patentee’s written submissions at hearing at [87] referencing Marshall at [69] and [71].
The basis of the Requestor’s submissions on this point appears to be the material provided in the present specification. There does not appear to be any other evidence in relation to the stability of Form B and what was known prior to the relevant date. As noted by the Full Bench of the Federal Court in AstraZeneca v Apotex:[54]

“…whether a claim of a patent is invalid for lack of inventive step is to be determined by comparing the invention, so far as claimed, against the common general knowledge and any 7(3) information. The question is then whether the invention would have been obvious to the hypothetical person skilled in the art in light of that knowledge considered separately from, or together with, the s 7(3) information. So understood, it is apparent that the relevant provisions of the Act do not expressly or impliedly contemplate that the body of knowledge against which the question whether or not an invention, so far as claimed, involves an inventive step is to be determined may be enlarged by reference to the inventor’s (or patent applicant’s) description in the complete specification of the invention including, in particular, any problem that the invention is explicitly or implicitly directed at solving.
If the problem addressed by a patent specification is itself common general knowledge, or if knowledge of the problem is s 7(3) information, then such knowledge or information will be attributed to the hypothetical person skilled in the art for the purpose of assessing obviousness. But if the problem cannot be attributed to the hypothetical person skilled in the art in either of these ways then it is not permissible to attribute a knowledge of the problem on the basis of the inventor’s ‘starting point’ such as might be gleaned from a reading of the complete specification as a whole.”
[54] AstraZeneca AB v Apotex Pty Ltd (2014) 107 IPR 177; [2014] FCAFC 99 at [202]-[203].

No evidence has been adduced to establish that the known crystal form now referred to as Form B and its chemical or physical properties, was common general knowledge at the relevant time. It follows that the claims are inventive in view of the common general knowledge alone.

Inventive step in view of the cited documents and common general knowledge
Documents D1, D3 and D4.

D1, D3 and D4 each disclose the synthesis of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride as crystalline solids. The present patent acknowledges that these products correspond to Form B. None of these documents specifically disclose formulations comprising the compound, but each highlights the biological significance of the 6R-stereoisomer and notes the need for sufficient quantities to be prepared for clinical studies.
D4 arguably represents the closest of the similar prior art documents D1, D3 and D4, and from a practical point of view, if the claims are inventive in view of D4 then they would also be inventive in view of the remaining documents. I will therefore limit my discussion of these citations to D4. The Patentee also submitted that documents D1 and D3 would not have been ascertained, understood, and regarded as relevant, but conceded that D4 would have been. This is largely a moot point in view of the approach I am taking.

D4 discloses a large-scale preparation of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride. The Patentee submitted that:

“[T]here is no teaching in D4 in relation to crystalline attributes or polymorphic forms of the Compound, let alone a specific polymorphic form and any related advantages. A person skilled in the art would not be motivated to screen polymorphs of the Compound or expect that the polymorph now designated Form B in the specification would have the advantages now described. Furthermore, there is no motivation in D4 for a person skilled in the art to make the presently claimed tablet formulations comprising a polymorph of the Compound with polyvinylpyrrolidone and/or dicalcium phosphate as excipients to provide high storage stability formulations.”

I acknowledge the Patentee’s submissions on the polymorphic screening being used to identify a number of polymorphic forms of the substance. I also acknowledge that such screening processes can be unpredictable as to whether a substance will show any polymorphism, and if it does, how many polymorphic forms it will exist in. However, while there may be a high level of unpredictability in a polymorphic screen, simply performing a screen will not be sufficient in and of itself to establish inventiveness. Reductio ad absurdum if a polymorphic screen was carried out on a known material and no other polymorphic forms were identified, the mere unpredictability of that screening could not be used as a basis to claim an otherwise obvious formulation of the known material.

The situation is of course more complex here. The Patentee has identified that the compound can exist in 15 different forms. There may indeed be others that have not been found in the polymorph screening process. That is the nature of polymorphism. But in my opinion the number of polymorphic forms that the compound can exist is not determinative of inventive step. The question, as is the case with any invention, is whether the skilled person would have been directly led as a matter of course to try the invention as claimed in the expectation that it might well work.[55] There are no special rules for polymorphs – inventive step is determined on the facts of the case and what would have been obvious to the person skilled in that art.
[55] Aktiebolaget Hassle v Alphapharm Pty Ltd supra at [54].

The problem in the present case is the provision of a formulation of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride that has high storage stability. The invention does not lie in providing the crystal form now referred to as Form B – Form B was already known. I agree that D4 does not disclose the crystalline attributes or polymorphic forms of the compound. But I do not agree with the Patentee’s submission that there is no disclosure of the specific polymorph. The crystal form of the compound now referred to as Form B is disclosed in the document. The Patentee has discovered a number of other crystal forms and therefore the existing crystal form is now referred to as a polymorph. That does not change the nature of the disclosure provided by D4 and what a person skilled in the art would have done as a matter of routine if they were seeking to prepare a formulation with high storage stability.

82. The examiner argued during re-examination that any properties would be intrinsic to the known crystal form. I agree but consider that if those properties were hitherto unknown and exploited in a manner that would not have been obvious at the time, then there may be invention. To that end, it is the inventiveness of the claimed combination as a whole that must be considered (noting in this case that there are three different combinations).

The aim of D4 is to provide a purified form of the (6R)-stereoisomer. While the document discusses the potential use of the compound in the treatment of hyperphenylalaninemia, there is no disclosure or discussion of any formulations, or of the properties of the crystalline product other than the stereochemical purity, the optical rotation and some spectroscopic data. My understanding from the evidence is that a de novo approach would be required for the preparation of any pharmaceutical formulation, let alone a formulation comprising the particular crystal form having improved storage stability.
In this regard, oral formulations, including tablets, are particularly desirable and Dr Marshall stated that a number of factors can influence a formulator’s selection of excipients. Prior to reading the specification, he provided some preliminary considerations based on his literature search of sapropterin (the free base of the present compound), including:[56]
[56] Marshall at [61] to [64].

Sapropterin is orally administered as the dihydrochloride salt.
Formulation can be relatively simple solid-dose tablet for immediate release containing around 50-100 mg.
Sapropterin bioavailability and pharmacokinetic profile are expected to be within usual limits of a rapid release tablet with high bioavailability of the active.
The dihydrochloride will be water-soluble to provide a suitable dissolution profile for immediate release, although the high melting point may indicate a lesser degree of solubility.
Sapropterin contains an amino group, so excipients containing reducing sugars may be less preferred due to the known Maillard reaction of such excipients with primary and secondary amines. Preferred excipients would be water-insoluble phosphates, anhydrous lactose, some starches, calcium sulfate, carbomer, carboxymethylcellulose, gums, chitosan, polymethacrylates, PVP, polyethylene glycols, and polyoxyethylene glycols.
He did not identify any polymorphism or crystal morphology. This would form part of a routine testing in development of a tablet medicament.
Hygroscopicity is unknown, although it would be tested for when developing the tablet formulation. Any hygroscopicity issues could be addressed by selecting known suitable excipients such as MCC, anhydrous lactose, polyethylene glycol, polyoxyethylene glycols, povidone (PVP), or starches, together with appropriate manufacturing controls and methods.
Stability in presence of light, oxygen, water, pH variations are unknown, although likely to be stable at low pH. Stability testing is routine and a regulatory requirement of product registration.
Other factors to be considered when selecting an excipient include physical properties (fluidity compactability, compressability, particle size, pressure hardness profile), physiologically inertness, chemical properties (hygroscopicity or slightly hygroscopic if used with a slightly hygroscopic drug), compatibility with other ingredients, chemical stability on aging), colourless, tasteless, mouth-feel, and inexpensive.

Upon reading the specification Dr Marshall provided further evidence in relation to polymorphism and hygroscopicity. He considered that an attempt to uncover polymorphism is typically only undertaken when there is a reason to believe that absorption is likely to be dissolution rate limited. For relatively water-soluble compounds this approach may not be warranted, but a knowledge of potential polymorphic behaviour is important.[57] Dr Marshall went on to say that PVP and/or DCP were well-known, routine and obvious choices.[58]
[57] Marshall at [82]
[58] Marshall at [107]-[108].

Dr Rowe stated that if faced with providing a solution to the problem of formulations of tetrahydrobiopterin having a high storage stability, he would have considered a number of alternatives, including but not limited to:^[59]
[59] Rowe 3 at [33].

Different options for packaging (for example, inclusion of a desiccant in the container).
Addition of excipients to provide or enhance storage stability.
Use of coatings.
Consideration of different salt forms.
Investigation and comparison of polymorphic forms of the compound.

He acknowledged in relation to the second option that PVP and DCP were known excipients at the time, but stated that other excipients such as talc, microcrystalline cellulose, various forms of silica, and starch would also be suitable. He noted that Dr Marshall had been unable to identify polymorphism, hygroscopicity and stability of the compound, and without such information he would be unable to offer an opinion in relation to the excipients to be used in the formulation.[60]
[60] Rowe 2 at [26].

In short, the evidence from the experts indicates that there were a number of alternative strategies that could be employed to formulate (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, and even if seeking an excipient to improve the stability of the formulation, there were a number of alternatives that could be employed. In view of these alternatives, Dr Marshall considers it would be obvious to select the present excipients, while Dr Rowe considers it would not be.
I share the concerns raised in the re-examination report that the choice of DCP and/or PVP as ingredients in the formulation is prima facie an obvious one. These are well-known and widely used excipients. But the question is not whether the excipients are well-known and widely used in formulations but whether, based on the evidence before me, it would have been obvious to use those specific excipients in order to improve the storage stability of formulations comprising (6R)-L-erythro-tetrahydrobiopterin dihydrochloride.

Much of the discussion concerning storage stability focussed on hygroscopicity, particularly in relation to PVP. In this regard, Dr Marshall considered that if hygroscopicity was an issue then PVP was well known for use with slightly hygroscopic drugs,^[61] but also stated that he did not identify any indication of a moisture sensitivity problem from the specification.[62]I understand these submissions to be based on the disclosure in the present application which suggests that Form B is relatively stable. Storage stability testing showed little decrease in crystal purity after 8 months.[63] Suspension of the crystal in various solvents under nitrogen showed little loss of the crystal form, while some yellowing occurred when the crystal was suspended in ethanol under air.[64]
[61] Marshall at [113].
[62] Marshall at [107].
[63] Specification at Example A24, Table 3.
[64] Specification at pages 35 to 36.
Given Dr Marshall’s evidence on this point, it is difficult to see how the claimed combination would be obvious if seeking to provide an improved storage stable formulation of tetrahydrobiopterin. PVP and DCP are indeed well-known, and in the case of PVP it is also one of a group of excipients that is known to act sacrificially with hygroscopic actives. However, Dr Marshall did not perceive a moisture issue with Form B, even in view of additional information provided by the stability testing described in the specification, which suggests that it would be unlikely that the skilled person would be directly led to use an excipient with such properties. Obviousness might also be established if the skilled person were directly led to the use of the excipients for another purpose, but there is no other evidence that would teach towards the use of PVP or DCP over any other known excipients.
Dr Marshall appears to suggest that it is the intrinsic stability of Form B itself that solves the problem of providing a storage stable formulation and that the further addition of PVP and/or DCP has no stabilising effect. This being the case, these excipients would represent mere choices from the available equivalent alternatives and would likely be considered obvious on that basis. This was also at the heart of the inventive step objections raised in the re-examination reports. However, the only evidence I have before me on that point was provided by the Patentee, who referred to a commercial product, Kuvan, which falls within the scope of the claims.[65] The Patentee provided the prescribed storage conditions for a competing Schircks product,[66] and noted that it has a shelf life at room temperature of about 2 months, required freezing for longer shelf life and showed poor stability overall. In contrast the Kuvan product has a shelf life of two years at room temperature and much higher stability than the Schirck’s product.
[65] Patentee’s submissions at hearing at [148].
[66] Patentee’s response dated 1 May 2018, Attachments C and D.
I recognise that there are shortcomings with this evidence. The Schircks label provided by the Patentee does not specify the ingredients in the formulation other than the active agent, and I have no evidence that would enable me to unequivocally determine whether the product referred to by the Patentee contains Form B. Nevertheless, Dr Schircks stated that his company sold formulations comprising Form B prior to 17 November 2003,[67] and the inference I draw from his statements is that the product referred to by the Patentee is such a formulation.
[67] Schircks at [4].
Furthermore, as noted by the examiner during the re-examination process, Kuvan contains both DCP and PVP. No material has been provided, either in the specification or in any response, to show that PVP and DCP each possess improved stability over any other excipient. Indeed, there is no suggestion in the specification that these excipients are in any way advantageous, but arguably that relates to whether the claims to such formulations are fairly based (as discussed below) rather than obviousness. Comparative data on that point may have facilitated a resolution of the present matter, but the onus in this regard does not lie with the Patentee and there is no requirement that they provide such data. The Requestor, while providing experimental evidence to show that some Schircks products sold before to the priority contained Form B, did not provide any comparative data in support of their assertions that the present invention did not solve any stability problem and that the choice of PVP and/or DCP provided no advantages over the intrinsic properties of Form B, or any other commonly used excipients. I otherwise have no evidence to refute the Patentee’s assertions that these excipients, alone or in combination, provide for improved storage stability over and above the intrinsic stability of Form B.

The absence of comparative data for the individual components notwithstanding, the evidence does not support the proposal that PVP (or DCP for that matter) would be a mere selection from a number of obvious and equivalent alternatives. My understanding of Dr Schircks’ evidence is that the Schircks product contains tetrahydrobiopterin, ascorbic acid, acetylcysteine, Ac-Di-Sol (a carboxymethyl cellulose), sodium stearylfumarate, Emcocel 50 and Emcocel 90 (microcrystalline celluloses of different particle size).[68] Notably it contains microcrystalline celluloses, which both Dr Marshall and Dr Rowe stated were also one of a group of excipients used sacrificially with hygroscopic ingredients. However, the Schircks product is significantly less stable than Kuvan, and indeed appears less stable than Form B per se as tested in the present application. If the Schirck’s product does indeed contain Form B then this suggests that the various possible choices of excipient are not merely equivalent, and that there may a degree of unpredictability in their use.
[68] Schircks, Annexes B and C.
I note that Dr Marshall was set the task of providing a tablet formulation of sapropterin (the free base of the active ingredient), so the evidence he provided appears to relate more to early stage formulation development rather than later development stages where storage stability is a key consideration and studies such as polymorph screening may be performed. Dr Rowe highlighted in this in his statements that:[69]
“Throughout paragraphs 1 to 46 of Dr Marshall’s declaration, he has listed various excipients, techniques and general principles that could potentially be helpful if asked to prepare a tablet formulation. However the excipients and techniques that would be used for a specific tablet formulation are critically dependent on the nature of the active and also guidance provided at the outset in the form of an aim to be achieved or a problem to be solved by the formulation. I note that Dr Marshall has not provided any opinion in relation to particular excipients or techniques to be used in a specific tablet formulation, which is understandable since he has not been instructed in relation to what the active pharmaceutical ingredient to be formulated is, and additionally, whether the formulation is to achieve a certain aim or solve a particular problem.”
[69] Rowe 1 at [16].
Dr Rowe further noted that even once Dr Marshall had been advised that the active ingredient was sapropterin, he had still not been advised whether the formulation was intended to solve a particular problem.[70] It was only after seeing the patent that Dr Marshall specifically identified PVP and DCP as being obvious choices rather than any of the other alternatives he outlined in his preliminary statements. There is a risk in such situations of evidence being tainted by hindsight, and I consider this lessens the weight that can be given to Dr Marshall’s evidence. The present determination has also not been helped by the evidentiary constraints of re-examination where the requestor is not a party to the process and there is no opportunity for further iterations of evidence or, in the case of post-grant court proceedings, cross examination to further explore the issues in contention.
[70] Rowe 2 at [4].

On balance there is insufficient evidence for me to determine that the claims are invalid on the ground of lack of inventive step in view of D4 and the common general knowledge.

Document D2

D2 discloses the chemical synthesis of various acyl derivatives of (6R,S)-L-erythro-tetrahydrobiopterin dihydrochloride. The document also discloses the preparation of (6R,S)-L-erythro-tetrahydrobiopterin dihydrochloride from L-rhamnose. The product of this process is a racemic mixture rather than the pure 6R-stereoisomer. The citation does not disclose any formulations. I consider this is of little relevance to the present determination.

Documents D5 and D6

100.D5 and D6 are similar disclosures which describe the use of tetrahydrobiopterin derivatives in the treatment of infantile autism. As an initial observation, the specific stereochemistry at the 6-position of the active ingredient is not provided in the biochemical studies and formulation examples. A tablet formulation containing “tetrahydrobiopterin” is described in each. The stereochemistry of the active is not specified in the tablet formulation example, but the citations state that:
“Among the compounds shown above, 5,6,7,8-tetrahydrobiopterin and salts thereof are preferable. In consideration of several factors such as toxicity, L-erythro-5,6,7,8-tetrahydrobiopterin and salts thereof are most preferable”.[71]
[71] D5 and D6 at column 3, lines 16 to 21.

101.D5 and D6 further state that, “optically active L-erythro-5,6,7,8-tetrahydrobiopterin and salts thereof”, referred to as the form that exists in vivo, is the most preferred for use in the treatment of autism, but the L-erythro and non-optically active forms have relatively low toxicity, and can be used in the treatments.[72] My understanding of D5 and D6 is therefore that there is no specific disclosure of the 6R-stereoisomer or the crystalline form thereof.
[72] D5 and D6 at column 5, lines 9 to 30.
102.The Patentee submitted that:

“…a person skilled in the art seeking to make a tablet formulation would more likely follow the teaching provided in Example 2 of D5 or D6, which lists lactose and microcrystalline cellulose as excipients for tablets, rather than the teaching in either Example 1 or 8 (for granules) (see for instance, subsection ii) of paragraph 33 of Rowe #3 and the table of paragraph 32 of Marshall)… In any event, there is no motivation or suggestion in this document to seek out a particular polymorph of the Compound. In light of these reasons, we respectfully submit that a person skilled in the art reading D5 or D6 would not be motivated to produce the presently claimed tablet formulations comprising a specific polymorph of the Compound with polyvinylpyrrolidone and/or dicalcium phosphate as excipients to provide high storage stability formulations.”

103.Dr Marshall stated that these documents disclose “tetrahydrobiopterin dihydrochloride, Kollidon (PVP), ascorbic acid and 5 parts L-cysteine hydrochloride, DOPA, excipient (mannitol or lactose) and disintegrator corn starch or hydroxypropyl cellulose, which is granulated and mixed with microcrystalline cellulose and magnesium stearate to form tablets”.[73] On the other hand, the Patentee acknowledged that D5 and D6 disclose various formulations (granules, tablet, capsule, injection and suppository), but submitted that PVP is listed as an excipient for the granule form only and no tablet form is disclosed that contains PVP.[74]
[73] Marshall at [72] and [73].
[74] Patentee’s submissions at hearing at [110].
104.I do not consider that either of these statements is an entirely accurate representation of the disclosure in D5 and D6. Example 1 of the citations discloses the preparation of granules which includes the step of dissolving PVP in water and mixing this solution with ascorbic acid and L-cysteine. Tetrahydrobiopterin dihydrochloride is added to obtain a uniform solution. This solution is then added to an excipient (mannitol or lactose) and disintegrant (corn starch or hydroxypropyl cellulose), kneaded, granulated, dried and sieved to give the final granules.[75]
[75] D5 and D6, Example 1.
105.Example 2 states that “a uniform solution of tetrahydrobiopterin was prepared as in Example 1 and mixed with 58 parts of lactose and 15 parts of microcrystalline cellulose” [emphasis added]. Magnesium stearate was then added, and the resulting mixture was pelletised to form tablets.[76] Contrary to the statement of Dr Marshall, I do not consider that this process involves preparation of a granule followed by addition of microcrystalline cellulose and magnesium stearate to form tablets. Rather, I understand the process to use the solution of PVP, ascorbic acid, L-cysteine and tetrahydrobiopterin as prepared in the first step of Example 1. This solution is then mixed with lactose and microcrystalline cellulose and pelletised to form the tablet. And the final tablet, contrary to the submissions of the Patentee at hearing, contains PVP.
[76] D5 and D6, Example 2.
106.No evidence was given on this point, but the tableting example provided in D5 and D6 appears to be a wet granulation process.[77] None of the formulations involves the use of a crystalline form of the active (which would be used in solution in any case), and I am unable to determine based on the evidence as to whether such a process would necessarily result in a product comprising the active in a crystalline form as required by the present claims. The evidence suggests to me that a direct compression or dry granulation process would generally be used where an active or the ingredients are sensitive to moisture and heat.[78] There is no indication in D5 and D6 of any stability problems that would teach or suggest the use of entirely different tableting conditions and the specific crystal form of the active ingredient to arrive at the present invention.
[77] Marshall at [42] to [45].
[78] Marshall at [46].
107.I therefore consider that in view of the evidence provided that the claims are inventive in view of D5 and D6 and the common general knowledge in this field.
Documents D7 to D9
108.D7, D8 and D9 are related patents describing the use of substituted pterins in the treatment of various diseases of the brain and peripheral nervous system. Tetrahydrobiopterin is used as a control in biological studies, but it is not specified whether this is the racemic mixture, an optically pure material, or whether it is being used as the dihydrochloride salt. One example common to the three patents provides a generic example wherein the pterins of the invention are formulated with ascorbic acid, corn starch, PVP, stearic acid and magnesium stearate. There is no disclosure or suggestion of any compositions containing (6R)-L-erythro-tetrahydrobiopterin dihydrochloride.
109.I therefore consider that in view of the evidence provided that the claims are inventive in view of D7 to D9.

Inventive step in view of a combination of documents

110.The consideration of inventive step under the Act allows for the combination of prior art information, provided the skilled person could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood, regarded as relevant, and combined the separate pieces of prior art information.
111.The examiner considered the claims were obvious in view of a combination of any of D1 to D4 with any one of D5 to D9 on the basis that D1 to D4 differ in the choice of PVP and/or DCP and D5 to D9 differ in the use of Form B, and the skilled person would, in seeking a solution to the problem being addressed, be motivated to combine the disclosures to arrive at the claimed invention. No specific reasoning was provided as to why the person skilled in the art would be motivated to combine these documents, or the specific problem that was being addressed.
112.As noted above, documents D5 and D6 appear to involve wet granulation techniques that even in combination with D4 would not appear to provide the formulations defined by the present claims. I consider these of little relevance in the present determination.
113.In the case of D7 to D9, these documents relate to the preparation and use of substituted biopterins. The first consideration is whether the prior art information would have ascertained, understood and regarded as relevant by the skilled persons. In this regard, D5 to D8 were retrieved by Dr Marshall and identified as relevant in his initial search (with the disclosure provided by D9 being similar to D7 and D8). Tablet formulations comprising the substituted biopterins together with PVP are disclosed. Dr Marshall stated that:[79]
[79] Marshall at [57].
“I found patent documents useful in obtaining a commercial understanding of the technology in the field, which provided ideas for various formulations one might take. Approaches taken for structurally similar compounds can inform since they may have similar functionality, chemical and physiochemical properties. In particular, I look to the working examples in a relevant patent document to inform of an approach that I would expect to work with at least some degree of success, even though commercially I may decide on a different strategy (e.g. stability considerations compatibility of ingredients, cost of goods or available machinery/equipment at my disposal).”
114.In addition to D5 to D9, Dr Marshall identified several other documents that he considered relevant, including US 6544994 which discloses formulations of tetrahydrobiopterin with tetrahydrofolic acid derivatives and various excipients (in several different tablet formulations): starch, lactose, talc, maize starch, acetylcellulose, diethylphthalate, silicone HK-15, polyethylene glycol 6000, polymethacrylate, polysorbitol 80, dimethylpolysiloxane, sodium hydroxide and magnesium stearate.
115.On further consideration of D5 to D9 and US 6544994, he stated that:[80]
[80] Marshall at [58].
“However, on my review of these documents, the pharmaceutical preparations described therein covered tablet formulations and preparations that were not the inventive focus of those documents and simply served to enable testing to be undertaken, and in any case they described very routine and common formulation approaches by using standard and well-known preferred excipients and preparation methods.”
116.These statements essentially confirm that the excipients described in these documents are well known, and do not really add anything over the common general knowledge already discussed above. Moreover, as indicated by Dr Marshall, the formulations described in these documents were intended to enable testing to be undertaken rather than providing improved storage stability. There is nothing in these documents that would lead the skilled person to consider these relevant to the problem here.

117.In summary, there is insufficient evidence for me to conclude that the claims lack inventive step.
Fair basis
118.As mentioned previously, the Requestor submitted that the claims lacked fair basis, and in particular that:
“the Patentee appears to have originally identified polymorph Form B per se in its priority specification, acknowledged that polymorph Form B was known in its complete specification and then tried to pursue identifying other more stable crystalline forms without success, and then switched its problem/solution approach during prosecution (and more than 11 years after its original filing) without support and contrary to its own admissions in an attempt to unjustifiably obtain protection around the later registered pharmaceutical formulation.”
119.They also noted that there was only the single reference to PVP in the specification, and no specific disclosure of the features of PVP being “linear, branched or crosslinked” (as defined by Claim2), “a biologically degradable polyvinylpyrrolidone” (as defined by Claim 3), “a biologically degradable polymer which may be linear, branched or crosslinked” (as defined by Claim 4), “a biologically degradable polymeric binder” (as defined by Claim 5) or “a biologically degradable crosslinked polymer” as defined by Claim 16. They argued that:
“In view of the Mond Nickle rules applicable to the ground of fair basis (Mond Nickel Co. Ltd.'s Application 65 RPC 123), the specific selection of “polyvinylpyrrolidone” from a list that was not part of the inventive concept provides a “wholly silent” selection. Also in accordance with Delnorth Pty Ltd v Dura-Post (Aust) Pty Ltd at [2008] FCA 1225 [20]-[21] by Gyles and Coopers Animal Health Australia Ltd v Western Stock Distributors Pty Ltd (1987) 15 FCR, citing Buckley LJ in Re Stauffer Chemical Company’s Application [1977] RPC 33 at 54, provided that if an additional feature involves bringing something new into the combination which represents a departure from the idea of the invention described in the earlier document, then it could not be fairly based upon the earlier document.”
120.At hearing the Patentee submitted that fair basis and novelty had been acknowledged by the Commissioner during the re-examination process, and that the hearing should only consider the contended ground of inventive step. If there were additional issues identified during the hearing, then these should be the subject of a subsequent re-examination process. I agree that this is the most appropriate approach. The following is therefore an observation on the issue raised by the Requestor.
121.The Requestor’s submissions are directed to the amendment of the claims during prosecution to limit the scope to matter that they did not consider was fairly based on the specification as filed. The Requestor did not raise the issue, but a consequence of an amendment being allowed which would result in a specification claiming matter that was not in substance disclosed in the specification as filed is that the new matter may be determined to have a later priority according to Section 114 which provides that:
(1)Where a claim of a complete specification claims matter that was in substance disclosed as a result of amending the specification, the priority date of the claim must be determined under the regulations.
122.Regulation 3.14 provides that the priority date is taken to be the date of filing of the statement of proposed amendments that resulted in the disclosure referred to in subsection 114(1).
123.Beach J in CSIRO v BASF recently considered the allowability of an amendment under S102(1) of the Act.[81]This consideration was under the current requirements, but Beach J provided a useful analysis of the authorities on fair basis under the Act prior to the amendments made under the RTB:
[81] Commonwealth Scientific and Industrial Research Organisation v BASF Plant Science GmbH [2020] FCA 328.
·     The High Court in Lockwood v Doric noted that fair basis is concerned “purely with the relationship between the body and claims of the one specification”.[82] The High Court accepted that there were two subsidiary tests (sub-tests) for fair basis which were relevant to the consideration of fair basis: whether there is there “a real and reasonably clear disclosure” of the invention in the specification,[83] and whether the claims travel beyond the subject matter of the invention described in the specification.[84]
[82] Lockwood Security Products v Doric Products [2004] HCA 58 at [27]; (2004) 217 CLR 274.
[83] Société Des Usines Chimiques Rhône-Poulenc v Commissioner of Patents [1958] HCA 27; (1958) 100 CLR 5
[84] Olin v Super Cartridge [1977] HCA 23; (1977) 180 CLR 236.
·     Merely matching a consistory clause with a claim does not affirmatively establish fair basis. Other parts of the specification may demonstrate the invention to be narrower than the consistory clause.[85]
[85] Ibid at [173].
·     It is not sufficient in and of itself that the effect of the amendment is to narrow the scope that was claimed to be a subset of what was disclosed in the application as filed. As stated in Astrazeneca v Apotex:
“A very general description of an invention in a specification before amendment might not contain a real and reasonably clear disclosure of more specific embodiments of the invention subsequently disclosed and claimed after amendment. …Whether or not there is a real and reasonably clear disclosure in the specification before amendment of what is claimed in such circumstances is the question that arises in this case.”[86]
[86] AstraZeneca AB v Apotex Pty Ltd (2014) 226 FCR 324 at [244].

·     The task of determining allowability of an amendment requires the amendment to be precisely identified and then compared with the application as filed. The first step involves identifying the difference between the specification prior to amendment and the specification as it reads if it was to be amended. The specification as proposed to be amended is read as a whole to determine whether it would claim matter not in substance disclosed in the specification as filed. The words “as a result of the amendment” are not to be confused with the expression “after the amendment”.[87]
[87] RGC Mineral Sands Pty Ltd v Wimmera Industrial Minerals Pty Ltd (1998) 89 FCR 458 at 466.
·     The relevant disclosure in the application as filed does not need to be as part of the invention as originally claimed.
·     Even though the concept of intermediate generalisation has developed under UK patent law and have become relevant to Australian law following the RTB Act, they were a prohibited amendment under subsection 102(1) prior to the RTB Act.[88] (Intermediate generalisation occurs where a feature is only disclosed in a particular context but an amendment seeks to introduce it into a claim deprived of that context).
[88] Les Laboratoires Servier v Apotex Pty Ltd (2010) 273 ALR 630 at [25].
124.In the present case, fifteen different crystalline forms are described. Forms A, B, F, J and K are anhydrates. Forms C, D, E, H and O are hydrates. Forms G, I, L, M and N are solvates. Forms A and C to O are said to be useful intermediates and starting materials for the preparation of stable polymorph forms.[89] A further object of the invention is said to be a pharmaceutical compositions of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in crystal form A, B, D, E, F, J, K, L and O or combinations thereof. Crystal forms A, D, E, F, J, K, L and O are apparently, in principle, also suitable for pharmaceutical compositions under certain conditions.[90]
[89] Specification at pages 3 to 14.
[90] Specification at page 23, line 22.
125.Forms B and D are said to be especially suitable for formulation, and the invention is said to be “particularly directed to a pharmaceutical composition comprising polymorph Form B or hydrate form D of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride and a pharmaceutically acceptable carrier or diluent.”[91] Form B is apparently the most stable of the crystal forms and can be used in a broad range of formulations, even in the presence of humid components without the formation of hydrates.[92] Example A24 describes various storage stability tests on Form B.[93] However while the specification indicates that Forms B and D are of particular interest in the invention, the specification goes on to state that the discussion of formulations of the crystal forms are intended to include Forms A, B, D, E, F, J, K, L and O.
[91] Specification at page 24, lines 1 to 8.
[92] Specification at page 23, line 16.
[93] Specification at pages 35 to 36.
126.The specification places no particular limitations on the type of formulation that can be used and includes a range of solid and liquid oral formulations including capsules, tablets, pills, troches, aqueous suspensions, elixirs and syrups.[94] Dosage forms are said to depend on the type of formulation and the administration time periods, and may be from 0.1 to 50 mg.[95] There are no examples, illustrative or otherwise, of formulations comprising any of the polymorphic forms.
[94] Specification at page 24, line 23.
[95] Specification at page 24, line 10.

127.Claims defining Form B in combination with PVP and/or DCP were first incorporated by an amendment dated 25 February 2014. Consistory statements corresponding to the claims were only incorporated with the amendments filed on 15 September 2015. I consider it clear from the specification prior to those amendments that it relates to the identification and characterisation of polymorphs of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride. While there is a broad discussion of formulations, the specification does not specify, or even suggest, which of the ingredients or formulation(s) would be useful for each of the nine different forms. This is consistent with the evidence of Dr Rowe, who stated that:
“The patent specification relates to specific crystal forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride and processes for their preparation, as stated in the abstract and also in the first paragraph on page 1 of the specification. The specification also provides that the crystal forms are either intermediates for preparation of a stable polymorphic form, which I understand to be denoted as Form B, or are themselves suitable for solid formulations.”[96]
[96] Rowe 3 at [7].
128.Dr Marshall commented that the specification appeared to be focussed on identifying other crystalline forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride,[97] and in his analysis of the specification observed that:
[97] Marshall at [113].
“In looking at excipients on pages 25 and 26… the listed excipients simply provide a broad list of the most common and routine excipients, so the invention does not appear to be directed at addressing any formulation problem by identifying any excipients with any particular unforeseen advantages.”[98]
[98] Marshall at [104], table entry referring to page 23, paragraph 3.
129.A similar concern was alluded to in the first re-examination report,[99] wherein the Examiner stated in relation to the consideration of inventive step that:
[99] Re-examination report dated 21 December 2017.
“Examples of excipients are provided, with an abundance of alternatives, as wells as suitable forms of the crystalline forms themselves being powders, granules, suspensions or solutions. Pharmaceutical acceptable ingredients are stated as being ‘well known for the various types of formulation’ and include binders, excipients, lubricants, surfactants, sweeteners, flavours, coating materials, preservatives dyes and so on…examples of each are provided in the form of extensive lists (see pages 24-27) these lists do not indicate any particular preferences and can be understood as illustrating suitable and equivalent components, any of which might be chosen.”
130.The Examiner went on to note that:
“The specification does not provide any actual examples of a pharmaceutical composition or demonstrate that any have been made. Polyvinyl pyrrolidine and / or dicalcium phosphate, are mentioned in passing as examples of typical excipients amongst many others (see page 25). It is noted that, in the amended specification as accepted, there is additional consistory statements provided on substitute pages 3 - 3b that relate to the nature of the excipients namely, polyvinylpyrrolidone (PVP) and dicalcium phosphate.”
131.Despite these concerns, the Examiner considered the claims fairly based in view of the consistory statements which were added to the description prior to acceptance.
132.Fair basis does not require that there be specific examples of the claimed invention, nor even that a feature of the claims be highlighted in the specification as inventive. But as noted above from AstraZeneca v Apotex, a very general description of an invention in a specification before amendment might not contain a real and reasonably clear disclosure of more specific embodiments of the invention subsequently disclosed and claimed after amendment.
133.In the present case there is a broad disclosure of the use of PVP and DCP in pharmaceutical formulations. However, this disclosure is in the context of the active ingredient being selected from one of nine different forms of (6R)-L-erythro-tetrahydrobiopterin and the formulations including various solid and liquid forms. Moreover during prosecution of the application the Patentee submitted that the use of PVP and DCP, alone or in combination, overcame a problem of hygroscopicity with Form B. Similar submissions were made during the re-examination process and at hearing. Prima facie there was nothing in the application as filed that informed of the selection of the particular formulation being a tablet, or the specific ingredients PVP and/or DCP, nor the specific benefits provided by such ingredients individually or in combination. As a consequence, I have concerns as to whether the specification as filed provided a real and reasonably clear disclosure of the claimed invention.
134.The Patentee has not had the opportunity to provide submissions on this point. I will direct that an Examiner consider this information with a view to deciding whether to commence re-examination of the present patent on the ground of fair basis, and any other considerations that may arise from that determination.

Conclusion
The re-examination is concluded.

Dr Leslie F. McCaffery
Deputy Commissioner of Patents

Attachment

1. A pharmaceutical tablet formulation comprising a purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern comprising characteristic peaks expressed in d-values (Å): 8.7±0.1-0.2° (vs), 5.63±0.1-0.2° (m), 4.76±0.1-0.2° (m), 4.40±0.1-0.2° (m), 4.00±0.1-0.2° (s), 3.23±0.1-0.2° (s) and 3.11±0.1-0.2° (vs); or which exhibits a characteristic X-ray powder diffraction pattern substantially as exhibited in FIG. 2; and polyvinylpyrrolidone as a pharmaceutically acceptable ingredient and/or dicalcium phosphate as an excipient.

2. A pharmaceutical tablet formulation according to claim 1, wherein the polyvinylpyrrolidone is linear, branched or crosslinked.

3. A pharmaceutical tablet formulation according to claim 1 or 2, wherein the polyvinylpyrrolidone is a biologically degradable polyvinylpyrrolidone.

4. A pharmaceutical tablet formulation comprising a purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern comprising characteristic peaks expressed in d-values (Å): 8.7±0.1-0.2° (vs), 6.9±0.1-0.2° (w), 5.90±0.1-0.2° (vw), 5.63±0.1-0.2° (m), 5.07±0.1-0.2° (m), 4.76±0.1-0.2° (m), 4.40±0.1-0.2° (m), 4.15±0.1- 0.2° (w), 4.00±0.1-0.2° (s), 3.95±0.1-0.2° (m), 3.52±0.1-0.2° (m), 3.44±0.1-0.2° (w), 3.32±0.1-0.2° (m), 3.23±0.1-0.2° (s), 3.17±0.1-0.2° (w), 3.11±0.1-0.2° (vs), 3.06±0.1-0.2° (w), 2.99±0.1-0.2° (w), 2.96±0.1-0.2° (w), 2.94±0.1-0.2° (m), 2.87±0.1-0.2° (w), 2.84±0.1-0.2° (s), 2.82±0.1-0.2° (m), 2.69±0.1-0.2° (w), 2.59±0.1-0.2° (w) and
2.44±0.1-0.2° (w); and polyvinylpyrrolidone as a pharmaceutically acceptable ingredient and/or dicalcium phosphate as an excipient, wherein the polyvinylpyrrolidone is a biologically degradable polymer which may be linear, branched or crosslinked.

5. A pharmaceutical tablet formulation comprising a purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern substantially as exhibited in FIG. 2; and polyvinylpyrrolidone as a biologically degradable polymeric binder and/or dicalcium phosphate as an excipient.

6. A pharmaceutical tablet formulation according to any one of claims 1 to 5, wherein form B exhibits a characteristic X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 5.63 (m), 4.76 (m), 4.40 (m), 4.00 (s), 3.23 (s) and 3.11 (vs).

7. A pharmaceutical tablet formulation according to any one of claims 1 to 6, wherein form B exhibits a characteristic X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 6.9 (w), 5.90 (vw), 5.63 (m), 5.07 (m), 4.76 (m), 4.40 (m), 4.15 (w), 4.00 (s), 3.95 (m), 3.52 (m), 3.44 (w), 3.32 (m), 3.23 (s), 3.17 (w), 3.11 (vs), 3.06 (w), 2.99 (w), 2.96 (w), 2.94 (m), 2.87 (w), 2.84 (s), 2.82 (m), 2.69 (w), 2.59 (w) and 2.44 (w).

8. A pharmaceutical tablet formulation according to any one of claims 1 to 7, wherein the formulation comprises polyvinylpyrrolidone and dicalcium phosphate.

9. A pharmaceutical tablet comprising a purified crystalline polymorph of (6R)-L-erythro-
tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 5.63 (m), 4.76 (m), 4.40 (m), 4.00 (s), 3.23 (s), 3.11 (vs); or which exhibits a characteristic X-ray powder diffraction pattern as exhibited in FIG. 2; and polyvinylpyrrolidone as a biologically degradable polymeric binder and dicalcium phosphate as an excipient.

10. A pharmaceutical tablet comprising a purified crystalline polymorph of (6R)-L-erythro-
tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 6.9 (w), 5.90 (vw), 5.63 (m), 5.07 (m), 4.76 (m), 4.40 (m), 4.15 (w), 4.00 (s), 3.95 (m), 3.52 (m), 3.44 (w), 3.32 (m), 3.23 (s), 3.17 (w), 3.11 (vs), 3.06 (w), 2.99 (w), 2.96 (w), 2.94 (m), 2.87 (w), 2.84 (s), 2.82 (m), 2.69 (w), 2.59 (w), and 2.44 (w); and polyvinylpyrrolidone as a biologically degradable polymeric binder and dicalcium phosphate as an excipient.

11. A pharmaceutical tablet comprising a purified crystalline polymorph of (6R)-L-erythro-
tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern as exhibited in FIG. 2; and polyvinylpyrrolidone as a biologically degradable polymeric binder and dicalcium phosphate as an excipient.

12. A pharmaceutical tablet comprising only one active ingredient, wherein said active ingredient consists essentially of purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 5.63 (m), 4.76 (m), 4.40 (m), 4.00 (s), 3.23 (s), 3.11 (vs); or which exhibits a characteristic X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å): 8.7 (vs), 6.9 (w), 5.90 (vw), 5.63 (m), 5.07 (m), 4.76 (m), 4.40 (m), 4.15 (w), 4.00 (s), 3.95 (m), 3.52 (m), 3.44 (w), 3.32 (m), 3.23 (s), 3.17 (w), 3.11 (vs), 3.06 (w), 2.99 (w), 2.96 (w), 2.94 (m), 2.87 (w), 2.84 (s), 2.82 (m), 2.69 (w), 2.59 (w), and 2.44 (w); or which exhibits a characteristic X-ray powder diffraction pattern as exhibited in FIG. 2; and polyvinylpyrrolidone as a biologically degradable polymeric binder and dicalcium phosphate as an excipient.

13. A pharmaceutical tablet or tablet formulation according to any one of claims 1 to 12, wherein the purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride is of at least about 98% purity by high performance liquid chromatography.

14. A pharmaceutical tablet or tablet formulation according to any one of claims 1 to 13, further comprising folate alone or together with arginine.

15. A pharmaceutical tablet or tablet formulation according to any one of claims 1 to 14, further comprising a lubricant.

16. A pharmaceutical tablet or tablet formulation according to claim 15, wherein the lubricant is a fatty acid salt.

17. A pharmaceutical tablet or tablet formulation according to any one of claims 1 to 16, further comprising a vitamin.

18. A pharmaceutical tablet or tablet formulation according to any one of claims 1 to 17, wherein the vitamin is Vitamin C.

19. A pharmaceutical tablet or tablet formulation comprising a purified crystalline polymorph of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, form B, which exhibits a characteristic X-ray powder diffraction pattern comprising characteristic peaks expressed in d-values (Å): 8.7±0.1-0.2˚ (vs), 5.63±0.1-0.2˚ (m), 4.76±0.1-0.2˚ (m), 4.40±0.1-0.2˚ (m), 4.00±0.1-0.2˚ (s), 3.23±0.1-0.2˚ (s) and 3.11±0.1-0.2˚ (vs); or which exhibits a characteristic X-ray powder diffraction pattern substantially as exhibited in Figure 2; and polyvinylpyrrolidone as a pharmaceutically acceptable ingredient and/or dicalcium phosphate as an excipient, and further comprising a fatty acid salt, Vitamin C and isotonic agent.

20. A pharmaceutical tablet or tablet formulation according to claim 19, wherein the isotonic agent is a sugar.

21. A pharmaceutical tablet or tablet formulation according to any one of claims 1 to 14, further comprising a lubricant, a vitamin and a sugar.

22. A pharmaceutical tablet or tablet formulation according to any one of claims 1 to 14 or 21, wherein the polyvinylpyrrolidone is a biologically degradable crosslinked polymer.

23. A process for preparing a pharmaceutical tablet formulation according to any one of claims 1 to 8, the process comprising

(a) providing a purified crystalline polymorph of form B of (6R)-L-erythro-tetrahydrobiopterin
dihydrochloride of at least about 98% purity by high performance liquid chromatography, and

(b) mixing the purified crystalline polymorph with polyvinylpyrrolidone and/or dicalcium phosphate.

24. A process according to claim 23, wherein the mixing step (b) involves mixing the purified crystalline polymorph with polyvinylpyrrolidone and dicalcium phosphate.

25. A process for preparing a pharmaceutical tablet according to any one of claims 9 to 12, the process comprising

(a) providing a purified crystalline polymorph of form B of (6R)-L-erythro-tetrahydrobiopterin
dihydrochloride of at least about 98% purity by high performance liquid chromatography, and

(b) mixing the purified crystalline polymorph with polyvinylpyrrolidone and dicalcium phosphate.

26. A process according to claim 25, wherein the mixing step (b) involves mixing the purified crystalline polymorph with polyvinylpyrrolidone and dicalcium phosphate.

27. A process for preparing a pharmaceutical tablet or tablet formulation according to any one of claims 13 to 22, the process comprising

(a) providing a purified crystalline polymorph of form B of (6R)-L-erythro-tetrahydrobiopterin
dihydrochloride of at least about 98% purity by high performance liquid chromatography, and

(b) mixing the purified crystalline polymorph with polyvinylpyrrolidone and dicalcium phosphate.

28. A process according to claim 27, wherein the mixing step (b) involves mixing the purified crystalline polymorph with polyvinylpyrrolidone and dicalcium phosphate.
29. A pharmaceutical tablet or tablet formulation prepared by the process of any one of claims 23 to 28.

30. A pharmaceutical tablet or tablet formulation according to any one of claims 1 to 12 and processes for preparing same, substantially as herein described with reference to the examples and/or Figure 2.

31. A pharmaceutical tablet or tablet formulation according to any one of claims 1 to 22, 29 or 30, wherein the purified crystalline polymorph, form B, is provided as a fine powder with a particle size range from about 0.2 μm to 500 μm.