Alkermes, Inc v Nektar Therapeutics

[2007] APO 39

ABSTRACTS OF DECISIONS

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Application  :          No. 760537 in the name of Nektar Therapeutics

Title:          Perforated Microparticles and Methods of Use

Action:          Opposition under section 59 by Alkermes, Inc.

Decision:          Issued  18 December 2007

Abstract

None of the claims are entitled to claim priority from the priority document PD1 and hence documents D4-D6 are all part of the prior art base for the purposes of novelty. Neither D5 nor D6 deprive any of the claims of their novelty.  However, D4 deprives claims 1- 19, 23-39, 42-46, 49, 50, 51 of their novelty as these claims include vaccination.  In contrast, claims 20-22, 40, and 41, 47 and 48, 52 are novel in light of the D4 because this citation does not disclose the claimed microparticles to be suspended in a non-aqueous suspension medium, particles with a mean geometric diameter of 1-30µm and less than 5 µm respectively or an immune response which is enhanced by at least 25%.  

Claims 10-29, 31-34 define microparticles which enhance the effect of immunoactive agents or immunomodulators other than antigens for vaccines. Such claims (as they relate to immunomodulators other than vaccines) are novel in light of D4 which primarily focused on vaccination and did not provide sufficient disclosure to deprive other types of immunomodulation of their novelty.

Only D5 was found to be part of the prior art base for inventive step but the opponent failed to show that the importance of surfactants in improving flowability of the microparticles would have been recognised at the relevant date by the skilled worker.  Hence none of the citations deprived any of the claims of their inventive step. 

PATENTS ACT 1990

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Re:Patent Application No. 760537 in the name of Nektar Therapeutics and an opposition under section 59 by Alkermes, Inc.

BACKGROUND

1.Patent application 760537 (35469/99) now in the name of Nektar Therapeutics was filed on 31 March 1999 under the provisions of the PCT.  It claimed priority from a number of earlier US basic applications:

09/106,932 filed 29 June 1998 (PD-2)
09/133,848 filed on 14 August 1998 (PD-3),
PCT/US98/20603 filed 29 September 1998 (PD-4)
PCT/US98/20602 filed 29 September 1998 (PD-5)
PCT/US98/20615 filed on 29 September 1998 (PD-6)
PCT/US98/20613 filed on 29 September 1998 (PD-7)
09/218,213 filed on 22 December 1998 (PD-8)
09/219,736 filed on 22 December 1998 (PD-9)
09/218,209 filed on 22 December 1998 (PD-10) and
09/218,212 filed on 22 December 1998 (PD-11). 

2.Four of the priority documents were PCT applications (PD4-7) which had equivalent Australian applications (summarised in annex 1).   One of these Australian applications [10644/99 (757337) related to PD-4] claimed priority from an earlier US basic application [60/060337 (PD1)] filed on 29 September 1997.  As this priority did not flow through to the opposed application, the Australian equivalent of PD4 (757337) had an earlier priority date than the current application and was part of the prior art base for novelty for the current application.  The Australian equivalent of PD4 was therefore raised as a whole of contents citation during examination.  To overcome the objection, the applicant amended the patent request form of the current application to claim divisional status from PD4 allowing it to claim priority back to the filing date of PD1.  

3.The parent Australian application (757337) was advertised accepted on 20 February 2003 and a notice of opposition was filed on 20 May 2003 by Advanced Inhalation Research, Inc.  A decision on that  opposition was issued on the parent case on 6 June 2006 [Nektar Therapeutics v Advanced Inhalation Research Inc [2006] APO 26]. The current (divisional) Australian application was advertised accepted on 15 March 2003 and a notice of opposition was filed on 15 August 2003 by Alkermes, Inc. All evidence stages were completed by 6 September 2006 and the matter was set for hearing in Canberra on 14 December 2006.

4.The applicant was represented by Mr Brendan Nugent and Mr Andrew Davey, patent attorneys from Griffith Hack, Brisbane and the opponent was represented by Dr Thomas M. Boyce, Dr Nick Finnie and Dr Vaughan Barlow, patent attorneys from Pizzeys Patent and Trade Mark Attorneys, Canberra. 

SPECIFICATION

5.The specification relates to perforated microparticles which are used for the targeted delivery of an immunoactive agent (such as a vaccine).  The specification notes that mucosal administration of some molecules is particularly attractive because it could elicit a local immune response at the point of entry of the pathogen providing a first line of defence against the pathogen.  It also allows the molecules to bypass the digestive tract of the GI tract.

6.The admitted prior art had disclosed previous attempts to use the mucosal route using liposome formulations for intranasal vaccines but while these compositions were found to elicit an immune response, they were extremely labile and susceptible to degradation over time.

7.Other prior art attempts used dry powder inhalers (DPIs) which rely on the patient's inspiratory effect to introduce a dry powder medicament into the lungs.  However, conventional powdered preparations for use in DPIs often fail to provide accurate reproducible dosing over extended periods because they tend to aggregate due to hydrophobic or electrostatic interactions between the fine particles.  Fine particle aggregation disrupts the aerodynamic properties of the powder thereby preventing large amounts of the aerosolised medicament from reaching the deeper airways of the lung where it is most effective.

8.The specification then refers to the disclosures of 2 of its priority documents (US applications 09/218209 and 09/219736 - PD-10 and PD-9 respectively) which describe dry powders which were hollow and porous to use in the targeted delivery of bioactive agents in inhalation devices such as dry powder inhalators.  Such preparations were more stable and had improved flowability compared with prior art preparations.  They also had good aerodynamic characteristics which were particularly compatible with inhalation therapies.  Such advantages were discussed at length in the related opposition and were the subject of the parent claims.

9.In addition to the invention claimed in the parent application, the applicants also “surprisingly” found that the hollow particles also had an “adjuvant” effect which enhanced the immune response of an incorporated agent by an order of magnitude greater than that provoked by comparable prior art vaccine formulations (see page 4, lines 2-6).  The specification suggests that the immunoenhancing effect of the microparticles also applies to other “immunoactive agents” or “immunomodulators”. 

10.The terms “immunomodulator” and “immunoactive agent” are used interchangeably in the specification and include any agent which can produce a desired immune response (see page 9, lines 16-22).  Such agents would include not only the foreign antigens used in vaccination (defined in claim 1) but also entities which suppress an autoimmune or allergenic response or which modify (eg stimulate or augment) an existing immune response.  In this context, agents such cytokines, immunoglobulins, DNA, RNA and anti-sense constructs as well as smaller molecules that might function as potentiators, co-factors or penetration enhancers would fall within the scope of the terms  (see page 20, line 10 - page 21, line 4).

11.In both the vaccine and immumomodulator/immunoactive agent delivery systems, the specification noted (at page 23, lines 18) that (unlike prior art formulations), it has surprisingly been found that the incorporation of relatively high levels of surfactants or biocompatible wall forming material (eg phospholipids) may be used to improve powder dispersibility, increase suspensions stability and decrease powder aggregation in the microparticles.  In this regard, the specification noted that the particulates will preferably comprise greater than 1% up to 20% w/w surfactant and more preferably up to 50%.  The specification also described embodiments with even higher levels up to 100% surfactant where the surfactant was a phospholipid.

12.The specification ends with 52 claims of which claims 1, 7, 10, 14, and 35 are independent.  The most relevant claims for this decision are claims 1, 10 and 14 which read as follows:

1.A method for providing an enhanced active immunization comprising administering to a patient a therapeutically or prophylactically effective amount of a medicament that comprises a plurality of microstructures that comprise a structural matrix associated with one or more vaccines, wherein said structural matrix comprises at least 5% w/w of a biocompatible surfactant and exhibits a structural morphology selected from the group consisting of voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations, holes and combinations thereof, and said biocompatible surfactant is selected from the group consisting of saturated and unsaturated lipids, non-ionic detergents, non-ionic block copolymers, ionic surfactants, cationic surfactants, biocompatible fluorinated surfactants, and combinations thereof; and
allowing said administered medicament to provide an enhanced active immunisation, wherein said enhanced active immunisation is enhanced relative to the immune response elicited by comparable vaccines delivered via an aqueous carrier in the substantial absence of said microstructures.

10.A method for providing an enhanced treatment of an autoimmune disease or disorder comprising administering to a patient a therapeutically or prophylactically effective amount of a medicament that comprises a plurality of microstructures that comprise a structural matrix associated with one or more immunomodulators, wherein said structural matrix comprises at least 5% w/w of a biocompatible surfactant and exhibits a structural morphology selected from the group consisting of voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations, holes and combinations thereof, and said biocompatible surfactant is selected from the group consisting of saturated and unsaturated lipids, non-ionic detergents, non-ionic block copolymers, ionic surfactants, cationic surfactants, biocompatible fluorinated surfactants, and combinations thereof; and
allowing said administered medicament to provide an enhanced treatment of an autoimmune disease or disorder, wherein said enhanced treatment of an autoimmune disease or disorder is enhanced relative to the treatment elicited by comparable immunomodulators delivered via an aqueous carrier in the substantial absence of said microstructures.

14.Use of an immunoactive agent in the manufacture of a medicament for the enhanced modulation of the immune system of a subject wherein the medicament comprises a plurality of microstructures that comprise a structural matrix associated with one or more immunoactive agents, wherein said structural matrix comprises at least 5% w/w of a biocompatible surfactant and exhibits a structural morphology selected from the group consisting of voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations, holes and combinations thereof, and said biocompatible surfactant is selected from the group consisting of saturated and unsaturated lipids, non-ionic detergents, non-ionic block copolymers, ionic surfactants, cationic surfactants, biocompatible fluorinated surfactants, and combinations thereof; and
wherein said modulation of the immune system of a subject comprises an immune response which is enhanced relative to the immune response elicited by comparable immunoactive agent delivered via an aqueous carrier in the substantial absence of said microstructures.

13.A summary of the structure of the other claims is presented in annex 2 attached to this decision.

DECISION

Priority date

Priority claim to  PD4-7

14.The opponent argued that the current (divisional) application was not fairly based of any of its priority documents and was therefore only entitled to claim priority from its own filing date (31 March 1999).  As a consequence, according to the opponent, the Australian equivalents of the four PCT priority documents are part of the prior art base for whole of contents novelty and deprive the claims of their novelty:

WC1:AU 10644/99 published after 31 March 1999 but having a priority date of 29 September 1997, June 1998 or 29 September 1998 [this is the related opposition case; it is also equivalent to the priority document PD4 (PCT/US98/20603)];

WC2:AU 11857/99 published after 31 March 1999 but having a priority date of 29 September 1997, June 1998 or 29 September 1998 [Equivalent to PD5 (PCT/US98/20602)];

WC3:AU 96770/98 published after 31 March 1999 but having a priority date of 29 September 1997, June 1998 or 29 September 1998 [Equivalent to PD6 (PCT/US98/20615)];

WC4:AU 96772/98 published after 31 March 1999 but having a priority date of 29 September 1997, June 1998 or 29 September 1998 [Equivalent to PD7 (PCT/US98/20613)].

15.I note that the Commissioner has rejected arguments in previous oppositions that a document which failed the test for fair basis could pass the more stringent test of novelty.  Thus, in The Regents of the University of California The Dow Chemical Company [2001] APO 34 (26 July 2001), the delegate noted

"Although the tests for novelty and fair basis are not the same I cannot agree with [the] argument.  The disclosure in the specification which is sought to be used for the purpose of novelty, also serves to support of the claims in so far as fair basis is concerned.  Thus, whatever is fairly based cannot be held not novel and whatever is not fairly based cannot be used as an anticipation." 

16.In Orenco Systems, Inc v Everhard Industries Pty Ltd [1999] APO 68 (26 October 1999), the delegate noted:

"The opponent's argument in effect is that the amended claims are disclosed in the originally filed specification for the purposes of assessing novelty, but are not disclosed for the purposes of fair basis as they have been broadened beyond what was described.  Although the tests for fair basis and novelty are not the same, I have difficulty with the logic of this argument.

A similar argument was put to me in Firebelt Pty Limited v MacDonald Johnston Engineering P/L [1994] APO 67 (25 November 1994) in considering the fair basis of a petty patent on a provisional application. In that case, I said that either the claims were fairly based on the earlier application, in which case the claims were entitled to the earlier priority date, or if there was such a discernible shift away from the provisional application such that the claims were defining a different invention, there would be no lack of novelty."

17.In Evans Deakin Engineering Pty Ltd v the ANI Corporation Ltd [2001] APO 66, the delegate agreed with both of these decisions and came to the same conclusion as did the delegates in ICU Medical Inc v Becton, Dickinson and Company in [2006] APO 1 and Anthony William Kennedy and John Charles Hitchen V Termi-Mesh Australia Pty Ltd [2003] APO 50, DuBois Ltd v Brackley Industries Pty Ltd [2003] APO 44.

18.Despite these decisions, the opponent argued that such an outcome was technically possible because the tests for fair basis and novelty were different and they insisted that I consider the issue in detail in this decision.  In the opponent’s view, none of the current priority documents had a “real and reasonably clear disclosure” of the claimed invention because they failed to foreshadow the enhanced immune response of the claimed microparticles.  However, they also argued that these documents gave the skilled worker a “clear and unmistakeable direction” to use such microparticles in immunisation.  According to the opponent, this was sufficient for novelty because the teaching would “inevitably result” in a particle with an enhanced immunogenic effect (as per General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd [1972] RPC 45 at page 486).

19.In my view, the opponent’s argument is fundamentally flawed.  If the priority document contained “clear and unmistakeable directions” to the claimed microparticle as they have argued, then the microparticle would inherently have the property of “enhanced immunogenicity”.  This feature would be an inevitable result of the disclosure and therefore implicitly disclosed in the priority document.  It is therefore both “real” and “reasonably clear”.  There is no requirement for the priority documents to have recognised the enhanced immunogenicity as the opponent has argued.  For fair basis, it is not necessary to provide every detail of the invention just enough to disclose the claimed invention.  As noted in Anaesthetic Supplies v Rescare Ltd 28 IPR 383 (at 401):

“All that the provisional specification needs to do is describe generally and fairly the nature of the invention, and not to enter into all the minute details as to the manner in which the invention is to be carried out.  It is a mode of protecting the inventor until the time of filing the final specification.  It is not intended to be a complete description of the invention, but simply to disclose the invention fairly, though in a rough state.  The interval of time between the provisional and the final is intended to provide an opportunity of development and precise expression of the invention foreshadowed in the provisional.”

20.Of course, if the priority document does not clearly teach the skilled person to produce a microstructure with enhanced immunogenicity, the claimed microspheres would not be “plainly foreshadowed” by the priority documents and would lose their priority date.  However in such cases, the disclosure in WC1-4 would also fail to contain “clear and unmistakable directions” to the claimed invention and would also not deprive the claims of their novelty (as per General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd [1972] RPC 45).

21.Either way, it is not possible for the priority documents WC1-4 to fail the fair basis test and still deprive the current claims of their novelty.  Hence WC1-4 are not relevant for the purposes of novelty.  

Priority claim to PD1

22.While the opponent primarily focussed on the priority dates of PDs 4-7 (WC1-4), the key priority issue concerns PD1.  At least one of the novelty citations raised by the opponent (D5) was published after PD1 was filed and will only be relevant for novelty if the claims are found not to be fairly based on the disclosure in PD1. As a consequence, it is important to determine whether the current claims are fairly based on PD1.

23.In the opposition on the parent application, the parent application was found not to be fairly based on PD1.  Claim 1 of the parent reads as follows:

1.A powder composition comprising a plurality of perforated microstructures, said microstructures comprising a bioactive agent selected from the group consisting of anti-allergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, anti-infectives, leukotriene inhibitors or antagonists, antihistamines, anti-inflammatories, anti-neoplastics, anti-cholinergics, anaesthetics, anti-tuberculars, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, anti-sense agents, proteins, peptides and combinations thereof, a mean aerodynamic diameter of less than 5µm, and a bulk density of less than about 0.5g/cm³, wherein, when suspended in a fluid medium, the volume of the medium displaced by the perforated microstructures comprises less than 70% of the average volume defined by the microstructure boundary if the microstructure were solid.

24.The earlier decision on the parent application found that there was not a "real and reasonably clear" disclosure of either powder compositions or particles with particular MAD and bulk density values in PD1.  As a consequence, none of the parent claims as they encompass either feature are entitled to the priority date of PD1.

25.The independent claims of the divisional application are not limited to microparticles with  particular MAD or bulk density values and so may not have the same priority problems as the parent application had.  Under sub-regulations 3.12(2C) and (2D), a claim in a divisional application has the same priority date as if the claim had been in the parent.  This means that if there were substantially different claims in the divisional compared with the parent application, it is possible for the two to have different priorities and even for the later divisional application to have an earlier priority date than its parent.

26.The invention disclosed in PD1 was a stabilised respiratory dispersion for the pulmonary delivery of one or more bioactive agents comprising a suspension medium having dispersed therein a plurality of perforated microstructures comprising at lease one bioactive agent wherein said suspension  medium substantially permeates said perforated microstructures.   On page 22, lines 27 et seq, the priority document notes that surfactants can be optionally associated with the microstructures and that while not necessary to practice the invention have some advantages including increased dispersion stability or increased bioavailability on administration.  The priority document notes on page 25, lines 2 et seq that the % surfactant could include upwards of 5%.     

27.In contrast to the current claims, the priority document did not contemplate that the microstructures should be used outside this dispersion environment.  As noted in the related decision on the parent application, the expansion of the claims to include microparticles outside this specific stabilised environment was a “significant departure” from the original invention disclosed in the priority document and “places a very different complexion on the character of the invention” (as per Coopers Animal HealthAustralia Ltd v Western Stock Distributors Pty Ltd (1987) 11 IPR 20).

28.The fair basis test of Lockwood v Doric (supra) requires a comparison between what the earlier specification says is the invention and what the later claims define as the invention.  PD1 clearly discloses and defines the invention as a suspension system where the suspension medium substantially permeates the perforated microparticles.  The formulations envisaged by the opposed claims are not limited to such a stabilised dispersion and therefore are not fairly based on PD1.

29.PD1 also does not explicitly disclose the use of the stabilised dispersions in vaccination.  The applicant argued that the description in the priority document on page 8, lines 17 et seq envisages that “any therapeutic or diagnostic agent” could be incorporated into the stabilised dispersions.  PD1 also provided a list of bioactive agents including “proteins and peptides”.  The applicant argued that this was a sufficient disclosure of an antigen for vaccine administration.

30.However, the entire focus of PD1 (see page 1, line 17-page 2, line 6, for example) was to targeted drug delivery not vaccination.  It is not clear from PD1 that a therapeutic agent would encompass prophylactic agents such as vaccines.  Proteins and peptides have a number of different therapeutic activities other than being antigenic and there is no suggestion in PD1 that the proteins and peptides are to be used in a vaccine.  In any event, even if the disclosure of PD1 could be broadly read to include vaccination, PD1 did not recognise the adjuvant effect of the microparticles which made them particularly useful in vaccination or immunomodulation. 

31.The opposed specification noted that there was an unexpected “adjuvant effect” with vaccination (page 9, lines 4-5) and expressed “surprise” that the microparticles could be so useful in vaccination (page 4, lines 2-5).  Neither observation was made in PD1.  Given these concessions, there appears to have been a selective advantage in using the microparticles in vaccination compared with the general drug delivery systems disclosed in PD1 which had not been recognised in that document.  My view is that this selection is another significant departure from the disclosure in PD1 and there has not been a real and reasonably clear disclosure of this feature in the earliest priority document.  As a result, none of the current claims are entitled to the priority date of PD1 and all the documents cited by the opponent are relevant for novelty.

Novelty

Law relating to Novelty

32.The test for novelty has been discussed recently in the Full Federal Court decisions of Pfizer Overseas Pharmaceuticals  v Eli Lilly and Company [2005] FCAFC 224 (see paragraphs 311 et seq) and Bristol-Myers Squibb Company v FH Faulding & Co Limited (2000) 97 FCR 524. As noted in both decisions, the basic test for novelty is the "reverse infringement test" as set out in Meyers Taylor Pty Ltd v Vicarr Industries (1977) 137 CLR 228 at page 235 where Aickin J stated:

"The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged invention would if the patent were valid, constitute an infringement."

33.Infringement is said to occur where "each and every one of the essential features of that claim have been taken"  (Rodi and Wienenberger AG v. Henry Showell Ltd (1969) RPC 367).

34.However, as Pfizer noted it is not sufficient for a citation to contain all the essential features of the claim, there must be “clear and unmistakable” directions to the claimed invention.  In that regard, the Full Court referred to three key decisions:

Canadian General Electric Co v Fada Radio Limited [1930] AC 97:

“…it is not enough to prove that an apparatus described in an earlier specification could have been used to produce this or that result.  It must also be shown that the specification contain clear and unmistakeable directions to use it.”

General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd [1972] RPC 45:

“a signpost, however, clear, upon the road to the patentee’s invention will not suffice.  The prior  inventor must be clearly shown to have planted his flag at the precise destination before the patentee”

ICI Chemicals v Lubrizol Corp (2000) 106 FCR 214

‘... skilled addressees are not required to rummage through the prior patentee’s "flag locker" to find a "flag which the [prior patentee] possessed and could have planted".’

35.Novelty can however be found where a feature is not explicitly mentioned but nonetheless present as an inherent feature as an inevitable result of the disclosure. As noted in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (supra)  at page 486:

"if in carrying out the directions contained in a prior inventor's publication will inevitably result in something being made or done which, if the claim of the opposed specification were a claim of a valid patent, would constitute an infringement of that claim, then that claim would have been anticipated".

36.However as also observed by the same court:

"If ... the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way that would not do so, the patentee's claim will not be anticipated."

37.In addition, as noted in the Pfizer decision, a citation to deprive a claim of its novelty must be the same as the claimed invention for the purposes of “practical utility”.  In other words, the citation has to “enable” the skilled worker to produce the invention from the written disclosure.   The basic principle is explained in Hill v Evans (1862) 4 De G F & J 288; 45 ER 1195be where the court noted

“…the antecedent statement must be such that a person of ordinary knowledge in the subject would at once perceive, understand, and be practically able to apply the discovery without the necessity of making further experiments and gaining further information before the invention can be made useful.  If something remains to be ascertained which is necessary for the useful application of the discovery that affords sufficient room for another valid patent”.

Novelty determination in the current case

38.While claim 1 is quite lengthy, it can be distilled into the following list of essential features:

a)   a method for enhancing active immunization using microspheres associated with one or more vaccines;

b)   whose structural matrix contains at least 5% w/w of a biocompatible surfactant (selected from a broad group of surfactants); and

c)   which exhibits a structural morphology containing voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations, holes and combinations thereof.

39.The claimed microspheres are also defined by their ability to enhance the immune response relative to that elicited by comparable vaccines delivered via an aqueous carrier in the substantial absence of said microstructures.

40.Independent claims 10 and 14 can be similarly deconstructed to a small number of essential features.  For claim 10, the essential features are:

a)   A method for enhanced treatment of an autoimmune disease or disorder comprising administering to a patient a therapeutic or prophylactic effective amount of a medicament that comprises a plurality of microstructures comprising a structural matrix associated with one or more immunomodulators,

b)   Wherein said matrix contains at least 5% w/w of a biocompatible surfactant (selected from a broad group of surfactants); and

c)   exhibits a structural morphology containing voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations, holes and combinations thereof.

41.For claim 14, the essential features are:

a)Use of an immunoactive agent in the manufacture of a medicament for the enhanced modulation of the immune system of a subject where the medicament comprises a plurality of microstructures whose structural matrix is associated with one or more immunoactive agents

b)and which matrix also contains at least 5% w/w of a biocompatible surfactant (selected from a broad group of surfactants); and

c)exhibits a structural morphology containing voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations, holes and combinations thereof.

42.As with claim 1, the medicament of methods of claim 10 and claim 14 are also defined in terms of a desired result.  In the method of claim 10, the treatment of the autoimmune disease is enhanced relative to the treatment elicited by comparable immunomodulators delivered via an aqueous carrier in the substantial absence of said microstructures.  In the method of claim 14, the modulation of the immune system is enhanced relative to the immune response elicited by a comparable immunoactive agent delivered via an aqueous carrier in the substantial absence of said microstructures.

43.As noted above, the terms “immunomodulator” (in claim 10) and “immunoactive agent” (in claims 14) both encompass vaccination but also include any agent which provides a desired immune response in a subject (see page 9, lines 16-28). 

Documents relied on at the hearing

44.In their statement of grounds and particulars, the opponent referred to 3 prior art documents which were published before the earliest priority date of the opposed specification.  They referred to these documents as D4, D5 and D6 based on the numbering system of the parent application:

D4:Published Ph.D. thesis by Justin Hanes at the Massachusetts Institute of Technology (MIT) entitled "Polymer Microspheres for Vaccine Delivery" dated September 1996, archived by the MIT library on 31 July 1997 (at which time the thesis could have been viewed at the Institute Archives) and catalogued there on 5 December 1997 (at which time the cataloguing record was made public).  It is not clear which of these dates would be considered the correct publication date.  However as both dates are before the filing date of PD2 (which is the earliest possible priority date), D4 is clearly part of the prior art base for novelty. 

D5:International Patent Application WO 97/44013 by Massachusetts Institute of Technology and The Penn State Research Foundation published on 27 November 1997 (after the filing of PD1 but before the date of filing of PD2);

D6:US patent number 5, 611,344 by Bernstein et al published 18 March 1997 (prior to the filing of PD1).

45.I’ll consider each of these documents separately below.

Prior Art document D4

46.The closest art relied on by the opponent is D4 which discloses a method of vaccine delivery using antigens incorporated into polymeric porous microspheres (containing voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations, holes and combinations thereof as defined in claim1 above). 

47.To enhance the effectiveness of the vaccine delivery system, D4 investigates ways of improving both the adjuvant (immunoenhancing) effect of the particles and their mode of delivery.  The citation discusses the “depot theory of adjuvant action” (see pages 24 and 27 for example) whereby the slow and sustained release of an antigen (from a “depot”) allows more efficient processing by immunocompetent cells increasing the immune response and causing the adjuvant effect observed in the opposed specification.   

48.In chapter 7, D4 specifically discusses PLGA microspheres for pulmonary vaccine delivery.  It notes that dry powder formulations (DPF’s) are gaining increasing attention as ideal aerosol formulations for pulmonary delivery.  According to D4, the primary disadvantage of DPFs is that they have poor flowability and aerosol properties (see page 128, line 1) and it concludes that the optimization of aerosol properties of the DPF is essential to its eventual success.  In this regard, D4 notes that both the presence of surfactant and the porosity (or lightness) of the particle both improve aerosolization efficiency (see page 128, lines 18-20).

49.Given this broad disclosure, this citation clearly teaches a method for enhancing active immunization using microspheres which exhibits a structural morphology containing voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations, holes and combinations thereof and which broadly include a surfactant to improve aerosolization properties. 

50.In their written submissions, the applicant argued that D4 did not disclose at least 5% w/w of a biocompatible surfactant as required by the opposed claims. According to the applicant, the only particles in D4 which contain a surfactant contain 45 ± 6 µg/mg of DPPC (see table 7-1 at page 129).  This is a w/w measurement and equates to 4.5% w/w.  A tolerance of 0.6 µg/mg (±0.6%) is noted and said to be the standard deviation in a footnote to table 7-1.  The opponent argued that this discloses a range of particles some of which would clearly fall within the claimed surfactant range (at least 5% surfactant) and deprive at least claim 1 of its novelty. 

51.The applicant argued that absent any description of the data used to obtain these numbers, how it was distributed or how it was statistically analysed, it is not correct to suggest this discloses any specific figure above or below 4.5%.  I disagree.  The concept of standard deviation is a well known statistical measure of diversity in a system.  The skilled worker would understand that man-made particles are not necessary uniform in composition and would use standard deviation as a means of measuring the expected diversity.  This is so well known that I would not expect a citation to provide a description which outlined details of how the data was generated.  The net result is that, given a standard deviation of ±0.6%,  some of the exemplified microparticles in table 7-1 would have a surfactant concentration which falls within the range defined in the opposed claim 1.

52.In addition, the citation as a whole teaches that surfactants improve the porosity of a microparticle (see for example page 132, line 25 and page 128) which is important to improve aerosol flowability and aerosolization (see page 134, lines 3-13).  This provides a clear teaching to use surfactants in microparticles.  The skilled reader would not read this teaching as being limited to a particular surfactant concentration but understand it to mean a sufficient concentration of surfactant to achieve a particular result.  The skilled worker would consider the range of surfactant concentrations defined in the current claim 1 (above 5% w/w) as being contemplated by the disclosure particularly as example in table 7-1 of D4 clearly places the surfactant concentrations of the citation in the same general range as the current specification.  There is no suggestion that above 5% w/w surfactant has some selective advantage or that the skilled worker would be taught against using such a range.  In my view, this teaching is sufficient to disclose the feature of at least 5% w/w surfactant.

53.In evidence in answer, Dr Tarara did not attempt to distinguish the claims based on the presence or concentration of surfactant.  Instead he argued (see paragraphs 8- 10 of his declaration dated 7 September 2005) that D4 did not demonstrate the immunisation effect of microparticles containing DPPC and that therefore there was no evidence that D4 had produced particles which enhanced an immune response as required by all the claims. 

54.However, D4 discloses that microparticles act as a depot or adjuvant in enhancing the immune response.  While an enhanced immunisation effect may not have been actually demonstrated in the citation, this was recognised by the citation to be an expected and inherent result of the depot effect. In my view, this is sufficient to deprive claims 1, 7, 14 and 35 of their novelty at least in relation to vaccination.  As noted in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (supra)  at page 486:

"if in carrying out the directions contained in a prior inventor's publication will inevitably result in something being made or done which, if the claim of the opposed specification were a claim of a valid patent, would constitute and infringement of that claim, then that claim would have been anticipated".

55.D4 also discloses the use of microstructures, perforated microstructures or hollow perforated microstructures (claims 26-28, 43-45) with a mean aerodynamic diameter of between about 0.5 µm and about 5 µm (claims 23, 46) containing a surfactant as a penetration enhancing excipient (claim 15) in a dry powder inhaler (claim 39) for the targeted delivery of a vaccine via the pulmonary tract (claims 4, 9, 34).  This type of pulmonary delivered vaccine would stimulate an immune response particularly in the mucosa (claims 32-33, 49).  As a consequence, claims 4, 9, 15, 23, 26-28, 34, 39, 43-46, and 49 also lack novelty in light of D4 at least in relation to vaccination.

56.Claims 2, 8, 16-19, 36, 37 define particular surfactants or concentrations of surfactants.  The general disclosure in D4 clearly teaches using surfactants to improve the porosity of microstructures and thereby enhance their immunogenicity.  The skilled worker from their common general knowledge would be aware of the range of surfactants available including those specifically defined in the claims.  There is no suggestion that the specifically claimed surfactants (or the claimed concentration) have any surprising or selective advantage over any other surfactant (or concentration of surfactant).  As a consequence, the broad disclosure of D4 of “surfactant” would encompass the particular surfactants (and their concentration) defined in claims 2, 8, 16-19, 36, 37. As a result, these claims also lack novelty at least in relation to vaccination.

57.Claims 3, 29-32, 38 define particular antigens, vaccines or immunoreactive agents.  D4 provides a general method for vaccination not limited to any particular agent.  Without evidence of a surprising or selective advantage or an issue of enablement for any of particular entities defined, the citation is sufficient to deprive claims 3, 29-32 and 38 of their novelty at least in relation to vaccination.

58.Claims 5 and 6 and 50 and 51 further define the addition of an immunogenicity modifying excipient including mannans, cell-binding polysaccharides, co-factors, cytokines and combinations thereof.  D4 suggest that the microparticles could themselves be made to be adjuvant-active (see paragraph 2.3 on page 32) and discloses number of ways which this immunogenic enhancing effect could be achieved (see paragraphs 2.3.2-2.3.3.3 and chapter 8).  This broad disclosure deprives claims 5, 6, 50 and 51 of their novelty.

59.In contrast, claims 20-22, 40-42 require the claimed microparticles to be suspended in a non-aqueous suspension medium.  As noted in the opposition decision on the parent application [Nektar Therapeutics v Advanced Inhalation Research Inc [2006] APO 26 (6 June 2006)], the disclosure of D4 is limited to dry powder PLGA microsphere formulations. Given this, the claims to a non-aqueous suspension medium are novel in light of the disclosure in D4.

60.Further, claims 24 and 47 and claims 25 and 48 define particles with a mean geometric diameter of 1-30µm and less than 5 µm respectively.  D4 discloses particles of mass-mean diameters of around 43.4 µm and the removal of spheres less than 20 µm by filtration (see page 74 and figure 4.1b on page 76). D4 also teaches that large particle size (i.e. greater than 5 µm) translates into good flowability characteristics (see page 128, lines 9-16).  This appears to teach away from the smaller microparticle size defined in the opposed claims which means these claims are novel in light of D4.

61.Finally, claim 52 defines a use as claimed in claim 35 wherein such an immune response is enhanced by at least 25%.  There is no evidence of this level of improvement in D4 and hence this claim is novel in light of that citation.

62.I note that claims 10-29, 31-34 also define microparticles which enhance the effect of immunoactive agents or immunomodulators other than vaccines.  As noted above, these agents could include cytokines, immunoglobulins, DNA, RNA and anti-sense constructs as well as smaller molecules that might function as potentiators, co-factors or penetration enhancers.  The one remaining question for novelty against D4 is whether D4 discloses these other aspects of the claimed invention outside vaccination. 

63.There were sections in D4 which acknowledged that the microparticles would have a broader role in drug delivery and particularly identified cytokines as potentially useful drugs (see Chapters 4 and 7).  However the primary focus of D4 was on vaccination and in that context the references to cytokines were only passing comments in the background discussions.  D4 did not disclose that the cytokines were necessarily immunoactive agents and did not teach that the immunomodulating effect of such agents (in contrast to their immunogenicity) would be enhanced with the disclosed microparticles. 

64.In my view, the passing references to cytokines are insufficient to establish “clear and unmistakable directions” to the claimed invention. These are more in the nature of rummaging through the prior patentee’s "flag locker" to find a “flag which the [prior patentee] possessed and could have planted” (as per ICI Chemicals v Lubrizol Corp (2000) 106 FCR 214). As such, I find that claims 10-29, 31-34 are novel as they relate to immunoenhancing methods (other than vaccination).

Prior Art document D5

65.D5 is a patent application which discloses the use of aerodynamically light microparticles as carriers in the pulmonary delivery of therapeutic, prophylactic or diagnostic agents.  Different properties of the particle can contribute to the aerodynamic lightness including the composition forming the particle, and the presence of irregular surface structure or pores or cavities within the particle (see page 11, lines 10-12). 

66.The citation noted that a variety of bio-active agents could be incorporated within the particles including antibodies and antigens which otherwise would have to be administered by injection to elicit an appropriate response (see page 15, lines 23-24).  The citation also specifically referred to the use of biodegradable particles in “single shot” immunisation by vaccine delivery (page 1, lines 14-17).

67.The applicant argued that the key difference between D5 and the current claims is it did not disclose at least 5% surfactant.   In evidence in answer, Dr Tarara noted at paragraph 11 that D5 does not describe addition of a surfactant to reduce density of the particles.  The only description of a surfactant is listed as an example as a therapeutic agent of interest.  According to Dr Tarara, for the most part, the particles in D5 are prepared using a solvent extraction process as described on pages 17 and 18 and there is no suggestion or examples demonstrating the addition of any surfactant in the opposed application.

68.There was some dispute at the hearing whether both examples 2 and 3 of D5 disclosed the use of surfactants in the manufacture of the microparticle.  In example 2 (page 22, line 15 to page 23, line 21), polymeric particles were generated using a blend of PLAL- Lys and PLGA-PEG.  The example noted (at page 23, line 6-9) that variables such as surfactant type (eg PVA and PEG) and concentration can be manipulated to alter the size distribution of the particles.  As the opponent suggested, this appeared to imply that the PEG present in the particles acted as a surfactant.

69.The applicant argued that although PEG itself is a surfactant, there was no evidence that the PLGA-PEG copolymer also acts as a surfactant.  The applicant noted that this co-polymer was not listed as a suitable non-ionic surfactant in the opposed specification (see page 22, line 30 et seq) nor is it disclosed in “McCutcheons Emulsifiers and Detergents” which is referred to in that passage.  The opponent did not dispute the applicant’s argument and therefore I accept that example 2 does not disclose the use of 5% surfactant in the microparticles as required by the claims. 

70.In contrast, example 3 (page 25, line 27- page 26, line 10) of D5 disclosed particles made from 100% of the surfactant PEG prepared by spray drying PEG from a solution in dichloromethane.  This applicant noted that this example did not disclose the use of these particles in delivering a vaccine (or any other therapeutic agent) and they argued that this was also not contemplated from the example.  However as the opponent noted, page 11, line 29, PEG was listed as a preferred polymer which could form the light, aerodynamic particles of the invention.  Although example 3 does not contain a therapeutic agent, the specification as a whole clearly contemplates this use. 

71.However, example 3 was just one preferred embodiment of the invention.  The citation as a whole contains no general teaching of the importance of surfactants in the general method.  This is in contrast to both the opposed specification and D4 which both describe the importance of surfactants (see page 23, line 18-20 of the opposed specification and page 132, line 25 and page 128 of D4).

72.Because D5 does not explain the importance of surfactant in the microparticle, there is no motivation for the skilled worker to include surfactant and the citation therefore does not provide clear and unmistakeable directions to the claimed invention.  Based on example 3, the skilled worker could incorporate 5% surfactant but there was no particular incentive for him to do so from the citation as a whole.  As a consequence, the skilled worker would be at least as likely to make a microparticle without surfactant as one with surfactant.  Such a disclosure is insufficient to establish a lack of novelty [as per General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (supra)].   Hence D5 does not deprive any of the claims of their novelty.

Prior Art document D6

73.D6 discloses a microencapsulated fluorinated gas for use as an ultrasound imaging contrast agent.  Because the microcapsules are merely used to enhance the image in an ultrasound, there is no suggestion that they induce an immunisation effect as required by the opposed claims.  Hence, D6 does not deprive any of the claims of their novelty.

Inventive Step

74.The opponent argued at the hearing that the documents D4-D6 all deprived the claims of their inventive step. Sections 7(2) and (3) of the Patents Act [1990] (outlined below) state the requirements for inventive step:

(2)For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with the information mentioned in subsection (3).

(3)The information for the purposes of subsection (2) is:

(a)any single piece of prior art information; or

(b)a combination of any 2 or more pieces of prior art information;

being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood, regarded as relevant and, in the case of information mentioned in paragraph (b), combined as mentioned in that paragraph.

75.The opponent failed to provide any evidence that D4-D6 were documents which a person skilled in the art would have been reasonably expected to have ascertained. Without such evidence, it is difficult to believe that either D4 or D6 would have been reasonably ascertained by a skilled worker [as per Commissioner of Patents v Emperor Sports Pty Ltd [2006] FCFCA 26 (10 March 2006)].

76.D4 is a PhD thesis which is only available from a particular library and it is not clear that a person skilled in the art would be reasonably able to locate it in their search. D6 discloses a microencapsulated fluorinated gas for use as an ultrasound imaging contrast agent which is  unrelated to the field of vaccination, the subject of the current claims.  My view is that the opponent has failed to establish that either of these documents are part of the prior art base for inventive step and hence has failed to establish that any of the claims lack an inventive step in light of D4 or D6.

77.With regard to D5, my view is that the skilled worker would have been reasonably expected to have ascertained this document despite the opponent’s failure to explicitly demonstrate this in their evidence.  D5 is a published patent and is therefore searchable using standard data base searching tools.  The skilled worker is a formulation chemist interested in solutions to the problem and would have been particularly interested in new developments in vaccine delivery systems which would be foreshadowed in the patent literature.  In routinely searching the patent literature, it is reasonable to expect that the skilled worker would have ascertained D5.  Having ascertained the document, the skilled worker would have understood it and regarded it as relevant to the problem of improving drug and vaccine delivery.  I therefore accept that D5 is part of the prior art base for inventive step.

78.The key difference between D5 and the opposed claim 1 is the presence of at least 5% surfactant. As noted above, D5 disclosed the use of surfactant in one of their examples but does not contain a clear and unmistakeable direction to include it into a microparticle.  The opponent argued that the skilled worker would know the role of surfactants from their common general knowledge and would be directly led to use surfactants in a microparticle based on this knowledge. 

79.While I accept this is a potential argument, the onus is still on the opponent to establish their case and they failed to do this.  There was no real evidence that the role of surfactants in improving a particle’s flowability was part of the common general knowledge nor any evidence that a skilled worker armed with this knowledge would be directly led to add surfactant to their perforated microparticles.  The opposed specification noted (at page 23, lines 18) that (unlike prior art formulations), it has surprisingly been found that the incorporation of relatively high levels of surfactants or biocompatible wall forming material (eg phospholipids) may be used to improve powder dispersibility, increase suspensions stability and decrease powder aggregation in the microparticles.  This suggests that the role of surfactants was not well known as the opponent has argued.  As a consequence, the opponent’s inventive step case fails and the evidence before me does not establish that any of the claims are obvious in light of D5.

Manner of Manufacture

80.The opponent argued that the microstructures and their use failed the threshold test for patentability because they were known in the prior art and therefore not a manner of manufacture. This reasoning simply restates the opponent’s novelty and inventive step arguments which have already been fully considered under those grounds.  My decision has been outlined there and I do not propose to revisit the same issues under a different ground.

Section 40

81.While the opponent raised a number of section 40 objections against the parent application, they did not provide any written submissions against the divisional under this ground and did not pursue the issue at the hearing.  I agree that there are no obvious problems with section 40 which would warrant any of the claims being clearly invalid [as per Hoffman-la Roche AG v New England Biolabs Inc [2000] FCA 283 (28 April 2000)]. Hence my view is that the claims meet the section 40 requirements of the Patents Act [1990].

CONCLUSION

82.None of the priority documents WC1-4 deprive any of the claims of their novelty.  If the document did not contain enough information to establish fair basis for a claim, it would not then be sufficient to deprive the same claim of its novelty.

83.None of the claims are entitled to claim priority from the priority document PD1 and hence documents D4-D6 are all part of the prior art base for the purposes of novelty. Neither D5 nor D6 deprive any of the claims of their novelty.  However, D4 deprives claims 1- 19, 23-39, 42-46, 49, 50, 51 of their novelty as these claims include vaccination.  In contrast, claims 20-22, 40, and 41, 47 and 48, 52 are novel in light of the D4 because this citation does not disclose the claimed microparticles to be suspended in a non-aqueous suspension medium, particles with a mean geometric diameter of 1-30µm and less than 5 µm respectively or an immune response which is enhanced by at least 25%.  

84.Claims 10-29, 31-34 also encompass microparticles which enhance the effect of immunoactive agents or immunomodulators other than antigens for vaccination.  Such claims (as they relate to immunomodulators other than vaccines) are novel in light of D4 which primarily focused on vaccination and did not provide sufficient disclosure to deprive other types of immunomodulation of their novelty.

85.Only D5 was found to be part of the prior art base for inventive step but the opponent failed to show that the importance of surfactants in improving flowability of the microparticles would have been recognised at the relevant date by the skilled worker.  Hence none of the citations deprived any of the claims of their inventive step. 

86.Otherwise, there are no glaring section 40 problems with the opposed application.As the specification clearly contains patentable subject matter, I allow the applicant 60 days in which to propose amendments to overcome the deficiencies noted in this decision.

COSTS

87.In matters before the Commissioner, costs generally follow the event.  In this case, the opponent was partly successful.  I therefore award costs against the applicant.

Karen Ayers
Delegate of the Commissioner of Patents

18 December 2007

Patent attorneys for the applicant  :  Griffith Hack, Brisbane

Patent attorneys for the opponent   :  Pizzeys Patent and Trade Mark Attorneys, Canberra

Annex 1

Summary of Internal Nomenclature as well as the relationship between the priority documents and the Whole of Contents citations

Nomenclature	Reference	Earliest priority	Publ. date	comments
PD-1	US 60/060337	29/9/97	Not relevant	Priority not originally claimed (outside the 12 month Paris convention period) but added when opposed application claimed divisional status from AU 10644/99 (757337)
PD-2	US 09/106,932	29/6/98	Not relevant	Also a priority document for AU 10644/99 (757337)
PD-3	US 09/133,848	14/8/98	Not relevant	Also a priority document for AU 10644/99 (757337)
PD-4	PCT/US98/20603	29/9/97	8/4/99	Equivalent to AU 10644/99 (757337) – WC1
PD-5	PCT/US98/20602	29/9/97	8/4/99	Equivalent to AU 11857/99 – WC2
PD-6	PCT/US98/20615	29/9/97	8/4/99	Equivalent to AU 96770/98 – WC3
PD-7	PCT/US98/20613	29/9/97	8/4/99	Equivalent to AU 96772/98- WC4
PD-8	US 09/218,213	22/12/98
PD-9	US 09/219,736	22/12/98
PD-10	US 09/218,209	22/12/98
PD-11	US 09/218,212	22/12/98
WC1	AU 10644/99 (757337)	29/9/97	8/4/99	Related opposed case – parent application; equiv to PD4 (PCT/US98/20603)
WC2	AU 11857/99	29/9/97	8/4/99	Equivalent to PD5 (PCT/US98/20602)
WC3	AU 96770/98	29/9/97	8/4/99	Equivalent to PD6 (PCT/US98/20615)
WC4	AU 96772/98	29/9/97	8/4/99	Equivalent to PD7 (PCT/US98/20613)
D4	Ph.D. thesis by Justin Haynes entitled "Polymer Microspheres for Vaccine Delivery"	N/A	31/7/97
D5	WO 97/44013	24/6/96	27/11/97
D6	US 5, 611,344	5/3/96	18/3/97

Annex 2 – Claim Structure of the opposed specification and Novelty comparison with D4

claim

dependent on?

additional features to independent claim/site of disclosure in D4

spec surf

spec Ags

target delvry

immuno mod. excip

spec immuno-active agents

penet enhance excip

non-aq susp med

spec. MAD

spec gd

matrix struct

spec immune response

DPI

% enhance result

Novel in light of D4?

1

nil

N

2

1

Y-broadly disclosed see page 128, lines 18-20

N

3

1

Y –see document as a whole

N

4

1

Y-see eg page 126, lines 3 et seq

N

5

1

Y – see paragraph 2.3

N

6

5

Y-see above

N

7

nil

N

8

7

Y-see above

N

9

7

Y-see above

N

10

nil

N

11

10

Y –see document as a whole

N

12

10

Y-see above

N

13

10

Y-see above

N

14

nil

N

15

14

Y-broadly disclosed see page 128, lines 18-20

N

claim

dependent on?

additional features to independent claim/site of disclosure in D4

spec surf

spec Ags

target delvry

immuno mod. excip

spec immuno-mods/ia agents

penet enhance excip

non-aq susp med

spec. MAD

spec gd

matrix struct

spec immune response

DPI

% enhance result

Novel in light of D4?

16

15

Y-broadly disclosed see page 128, lines 18-20

N

17

14

Y-see above

N

18

16

Y-see above

N

19

14

Y-see above

N

20

14

Y-not disclosed

Y

21

20

Y-not disclosed

Y

22

20

Y-not disclosed

Y

23

14

Y- see pages 134-5

N

24

14

Y taught away see page 74

Y

25

14

Y –see above

Y

26

14

Y –see document as a whole

N

27

14

Y –see above

N

28

27

Y –see above

N

29

14

Y –see above

N

30

14

Y –see above

N

31

30

Y –see above

N

claim		dependent on?		additional features to independent claim/site of disclosure in D4
spec surf	spec Ags	target delvry	immuno mod. excip	spec immuno-mods/ia agents	penet enhance excip	non-aq susp med	spec. MAD	spec gd		matrix struct	spec immune response		DPI	% enhance result		Novel in light of D4?
32	14			Y -see chapter 7	N
33	14			Y –see above	N
34	14			Y-see above	N
35	nil			N
36	35			Y-see above	N
37	36			Y-see above	N
38	35			Y-see above	N
39	35			Y -see chapter 7		N
40	35			Y-not disclosed	Y
41	40			Y-not disclosed	Y
42	40			Y-not disclosed	Y
43	35			Y		N
44	35			Y		N
45	44			Y		N
46	35			Y-see above		N
47			35	Y-see above		Y
48			35	Y	Y
49			35	Y –see above	N
50			35	Y-see above	N
51			50	Y-see above	N
52			35	Y not disclosed	Y