Astellas Pharma Inc. v Aragon Pharmaceuticals, Inc

Case •

[2022] APO 36

•

23 May 2022

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Astellas Pharma Inc. v Aragon Pharmaceuticals, Inc. [2022] APO 36

Patent Application:             2018206695

Title:Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer

Patent Applicant:                Aragon Pharmaceuticals, Inc.

Opponent:Astellas Pharma Inc.

Delegate:Felix White

Decision Date:  23 May 2022

Hearing Date:  14 February 2022, by VC

Catchwords:  PATENTS – Method of treating non-metastatic castration resistant prostate cancer with second generation anti-androgens – novelty – information implicitly disclosed to the skilled reader – claims 1-16, 22-31 and 33-35 (apalutamide and enzalutamide claims) found not novel – clarity and support – all claims found clear and supported

Representation:                   Counsel for the applicant: Katrina Howard SC

Patent attorney for the applicant: Duncan Longstaff and Michael Christie, Spruson & Ferguson

Counsel for the Opponent: Christian Dimitriadis SC and Melanie Evetts

Solicitor for the Opponent: Jaimie Wolbers and Simone Mitchell, MinterEllison

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Application:             2018206695

Title:Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer

Patent Applicant:                Aragon Pharmaceuticals, Inc.

Date of Decision:                23 May 2022

DECISION

The opposition succeeds on the ground of lack of novelty for claims 1-16, 22-31 and 33-35 (the apalutamide and enzalutamide claims).  I give Aragon Pharmaceuticals, Inc. a period of one (1) month to file amendments pursuant to subsection 60(3B).  I award costs according to Schedule 8 against Aragon Pharmaceuticals, Inc.

REASONS FOR DECISION

Background

  1. Australian Patent Application 2018206695 (“The Application”) was filed on 16 July 2018 in the name of Aragon Pharmaceuticals, Inc (“The Applicant”) as a divisional application of application 2013323861 (“The Parent”) and claiming its earliest priority date of 26 September 2012.[1]

    [1] Although ultimately not determinative in this decision, it is worth flagging that the Parent had been granted the benefit of an extension of time under s223 to rely on the grace period provisions of s24(1)(a) with respect to the prior art document referred to in this proceeding as D2.  D2 had been raised in examination of this Application but was disregarded when the Applicant drew the Examiner’s attention to the grace period in the parent.

  2. The Application was advertised as accepted on 2 July 2020, with claims directed to methods of treating non-metastatic castration-resistant prostate cancer with three defined anti-androgens.  The Application was amended after acceptance with the effect of restructuring the claim set to split each of the three drugs into separate independent claims.

  3. A Notice of Opposition was filed on 2 October 2020 by Astellas Pharma Inc. (“The Opponent”).  The Statement of Grounds and Particulars (“SG&P”) was filed on 4 January 2021.

  4. Evidence in Support was filed on 6 April 2021, consisting of:

    ·A declaration by Dr. Francis Xavier Parnis (“Parnis #1”) dated 1 April 2021, and Exhibits FXP-1 to 31

    ·A declaration by Dr. Marc Dror Michaelson (“Michaelson #1) dated 31 April 2021, and exhibits MDM-1 to 25

    ·A declaration by Jaimie Maree Wolbers (“Wolbers #1”) dated 6 April 2021, and exhibits JMW-1 to 34.
    Ms. Wolbers is a solicitor for the Opponent, and this declaration primarily establishes publication dates for the documents mentioned in the SG&P.[2]

    [2] This declaration also contained a statement that the Opponent intended to contest the application of the grace period to D2.

  5. Evidence in Reply was filed on 7 July 2021, consisting of:

    ·A declaration by Dr. Paul Norman Mainwaring (“Mainwaring”) dated 6 July 2021 and exhibits PNM-1 to 27

  6. Evidence in Answer was filed on 9 September 2021, consisting of:

    ·A second declaration by Dr. Parnis (“Parnis #2) dated 8 September 2021 and exhibits FXP-31[sic] to 40

    ·A second declaration by Dr Michaelson (“Michaelson #2) dated 2 September 2021 and exhibits MDM-26 to 33

    ·A second declaration by Ms. Wolbers (“Wolbers #2”) dated 9 September 2021

  7. The numerous prior art documents mentioned in the evidence are cross-referenced in multiple declarations.  For brevity I have only included the citation details of documents relevant to the outcome herein.  Full citation details of all documents mentioned can be found in the SG&P.

  8. The Opposition proceeded to hearing, held by videoconference on 14 February 2022.

  9. The grounds pressed by the Opponent were lack of novelty, lack of inventive step, lack of clarity and lack of support.  The support ground was only pressed in the event that the ground of lack of novelty was not made out; essentially on the basis that the level of disclosure in the specification was equal to or less than the level of disclosure in the citations.

Applicable Law

  1. The present application is governed by the Patents Act 1990[3] as amended by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 as the application was filed after 15 April 2013.[4]  Thus, the standard of proof that applies in the present case is the balance of probabilities.  I must accept the application if I am satisfied, on the balance of probabilities, that the application complies with the Act.  If I am not so satisfied, then I can refuse the application, but not before giving the Applicant a reasonable opportunity to amend (subsection 60(3B)).

    [3] References to legislation in this decision are to this Act unless indicated otherwise.

    [4] For completeness, the application of the grace period would be determined under the Act effective as of 17 September 2012, which is pre-Raising the Bar.  The applicability of Raising the Bar to s24 is based on the date of publication of the information in question.

Field of the Application

  1. The application is entitled “Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer”.  The field of the invention is prostate cancer therapy, in particular therapy of non-metastatic castrate-resistant prostate cancer (“nmCRPC”) with drugs that target the androgen receptor.  The meaning and significance of these terms will become evident as this decision progresses.

The person skilled in the art

  1. It is well established that many of the issues in an opposition are answered by reference to the person skilled in the art:

    “He is the person to whom the patent is addressed and who must construe it. He is the person whose knowledge will determine whether a patent is novel. He is the person who will judge whether a patent is obvious.”[5]

    [5]Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at 70.

  2. The hypothetical skilled person works in the field with which the invention is connected and is a non-inventive person or team likely to have a practical interest in the subject matter of the invention.[6]  However it must be borne in mind that the person skilled in the art is not a real person but an artificial construct, a “pale shadow”[7] that is nonetheless useful as a tool of analysis.

    [6]Op cit at 70-72.

    [7] AstraZeneca AB v Apotex Pty Ltd [2015] HCA 30 at [23]

  3. The field of the invention is prostate cancer therapy.  The Applicant did not make any particular submissions about the identity of the skilled worker or team.  The Opponent submitted that the person skilled in the art would be a medical oncologist or urologist working in the field of prostate cancer.[8]  However, as the skilled team includes those with a practical interest in the field, I am minded to consider the skilled team as being a clinical trials unit of a pharmaceutical company with all of the knowledge and skills attendant thereto, rather than an individual physician.

    [8] Opponent’s written submissions (“OS”) at 28

  4. Nevertheless, I can use the evidence of the witnesses to inform my conclusions as to what the notional skilled team would have known or done.  I will weigh this evidence as appropriate throughout my consideration.

Disclosure of the specification

  1. I will provide an overview of the disclosure of the specification at this point but will turn to specifics as necessary throughout the decision.

  2. After a formal “summary of the invention” statement that mimics the claims, the specification provides an overview of the role of the androgen receptor in prostate cancer (p. 4-7), provides a definition of castration resistant prostate cancer (p. 8), and provides the structures and functional description of three second-generation anti-androgens (ARN-509, enzalutamide and RD162)[9] which are said to exhibit true antagonist activity against the androgen receptor (p. 9-11). 

    [9] The specification also refers to these by chemical name, which is unwieldy: I will refer to them either by codename or drug name in this decision.

  3. The structures of the three anti-androgens are shown at p. 10-11.  The specification also identifies these compounds by CAS registry numbers. The parties referred to these drugs by their current common names throughout their submissions which I will follow for clarity.

Apalutamide (ARN-509)

Enzalutamide (MDV3100)

RD162

  1. At paragraph [0043] on p. 12, the specification reports the results of a phase II clinical trial of 240 mg/day ARN-509 in men with non-metastatic castration resistant prostate cancer.  This study recorded declines in PSA levels of 50% (PSA50) and 90% (PSA90) in 91% and 55% of patients respectively after 6 months of treatment.  This paragraph is notable as it is the only disclosure of clinical (or preclinical) results in the specification.

  2. The next part of the specification contains a glossary of terms (p. 12-15), routes of administration and treatment regimens (p. 16-17) and a set of illustrative embodiments that also mimic the claims (p. 18-20).  The description part of the specification concludes with a “prophetic example” of a protocol for a phase III clinical trial of ARN-509 in men with non-metastatic castration resistant prostate cancer (p. 20-25).

Principles of construction

  1. The task of construing the specification and claims is one that should be approached through the eyes of the skilled worker, with reference to the specification as a whole, and above all with a generous measure of common sense.[10]  

    [10] Cf Eli Lilly and Company Limited v Apotex Pty Ltd [2013] FCA 214 at 139

  2. In this case I have the benefit of evidence from three expert witnesses who are intimately familiar with, and highly skilled in, the field of prostate cancer treatment.  I am satisfied that they each are in a position to inform me what the skilled worker would know and do.  However the job of construing the claims and applying the law is one for the delegate.  So when there is disagreement between the experts I will come to my decision by assessing the strength of the evidence in the usual way.

  3. The claims define the scope of the monopoly sought, so it is appropriate to first understand the scope of what is being opposed.

Structure of claims:  apalutamide claims, enzalutamide claims, RD162 claims, and shared claims

  1. The specification concludes with 35 claims.  As a result of the amendment after acceptance, there are effectively three separate streams of claims, each directed to methods of treatment of nmCRPC with a specified androgen receptor agonist.  The agonists are defined in the claims by systematic chemical names, which makes the claims a little cumbersome.  The full claim set is provided in an annex to this decision.

Independent claims 1, 29 and dependent claims 2-10 and 30 (“The apalutamide claims”)

  1. Claim 1 reads as follows:

    1.            A method of treating a male human with non-metastatic castration-resistant prostate cancer, the method comprising administering an anti-androgen at a dose of about 30 mg per day to about 480 mg per day to a male human in need of such treatment, wherein the anti androgen is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, and wherein the anti-androgen is administered in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy.

  2. It was not disputed by the parties that this claim refers to the compound also known as apalutamide or ARN-509.

  3. This claim is therefore directed to

    ·     a method of treating nmCRPC in a male human in need thereof,

    ·     by administering a dose of 30-480 mg of apalutamide per day,

    ·     in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy (collectively referred to as androgen deprivation therapy or ADT). 

  4. Dependent claim 2 specifies that the nmCRPC is “high risk”.

  5. Dependent claims 3-8 specify particular preferred aspects of the dosing scheme, including oral administration, continuous daily administration and various daily dosages including 240 mg per day.

  6. Dependent claims 9-10 separate the embodiments where the ADT is a GnRH agonist and orchiectomy, respectively.

  7. Claim 29 is a distinct independent claim of a method “for” treating nmCRPC in a male human in need thereof, the method “consisting essentially of” administering apalutamide at an unspecified dose in combination with ADT.[11] 

    29.          A method for treating a male human with non-metastatic castration-resistant prostate cancer, the method consisting essentially of administering an anti-androgen in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy to a male human in need of such treatment, wherein the anti-androgen is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2 fluoro-N-methylbenzamide.

    [11]“Consisting essentially of” is commonly used in patent documents as a “partially closed term”.  I understand it to mean that other aspects of the treatment are not limited as long as they do not materially affect or interfere with the effect of apalutamide on the disease, consistent with the definition at [0019] of the description.  Nothing turns on this phrase in the decision.

  8. Dependent claim 30 specifies a number of daily dosages of apalutamide.

Independent claims 11, 31 and dependent claims 12-16 (“The enzalutamide claims”)

  1. These essentially parallel the apalutamide claims except that the drug is enzalutamide and the preferred dose is 160 mg per day.

    11.          A method of treating a male human with non-metastatic castration-resistant prostate cancer, the method comprising administering an anti-androgen at a dose of about 30 mg per day to about 480 mg per day to a male human in need of such treatment, wherein the anti-androgen is 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, and wherein the anti-androgen is administered in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy.

    31.          A method for treating a male human with non-metastatic castration-resistant prostate cancer, the method consisting essentially of administering an anti-androgen in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy to a male human in need of such treatment, wherein the anti-androgen is 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide.

  2. It was not disputed by the parties that these claims refer to a compound also known as enzalutamide or MDV3100.

Independent claims 17, 32 and dependent claims 18-21 (“The RD162 claims”)

  1. These essentially parallel the above except that the drug is RD162 and there is no preferred dose.  These claims have not been opposed.[12]

    [12] OS at 4.

Shared claims

  1. Claims 22-28 and 33 are dependent claims that append to all the three streams.  These have therefore been opposed to the extent that they relate to apalutamide and enzalutamide.  These claims specify that where the androgen deprivation therapy is a GnRH agonist, the agonist is one of leuprolide, buserelin, naferelin, histrelin, goserelin or deslorelin.

  2. Claims 34-35 are independent claims that nevertheless refer to all three drugs.  These are likewise opposed to the extent that they relate to apalutamide and enzalutamide.  These claims are so-called “Swiss type” claims[13] that are directed to a method of using the three drugs for manufacturing a medicament for treatment of nmCRPC in combination with ADT.  The only difference between these claims is that in claim 34 the daily dose is specified at 30-480 mg/day whereas in claim 35 the dose is unspecified.

    [13] As will be covered later in this decision, Swiss type claims have been described as “purpose limited manufacture claims”.  Novelty can arise from the specification of a new clinical purpose of an otherwise known drug.  Although the enforceable scope of treatment method and Swiss type claims are directed at different points of the pharmaceutical supply chain, the level of disclosure for satisfaction of the reverse infringement test is the same if the therapeutic purpose is the same.

    34.         Use of an anti-androgen for the manufacture of a medicament for treating non metastatic castration-resistant prostate cancer, wherein the anti-androgen is:

    4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2 fluoro-N-methylbenzamide,

    4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, or

    4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide;

    wherein the medicament is administered to provide a dose of said anti-androgen of about 30 mg per day to about 480 mg per day and wherein said medicament is administered in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy.

    35.          Use of an anti-androgen for the manufacture of a medicament for treating non metastatic castration-resistant prostate cancer, wherein the anti-androgen is:

    4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide,

    4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, or

    4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide;

    wherein the medicament is administered in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy.

Citations pressed for novelty and inventive step

  1. In response to the parallel streams of apalutamide and enzalutamide claims, the Opponent has provided two distinct sets of prior art.  Although many issues relating to claim construction and common general knowledge apply equally to both drugs, the disclosure of the two sets of prior art is necessarily different. At this point I will set out my understanding of the two sets of disclosures.  In my consideration of novelty I will refer to common principles where possible and discuss the apalutamide and enzalutamide prior art separately where necessary.

Apalutamide (ARN-509) 

  1. The Opponent raised prior art documents D1, D2-D3,[14] D4-D7 and D18-D19. These were said mainly to relate to the same clinical trial.  The Opponent’s submissions were primarily directed to D2 (which as per footnote 14 I will not investigate further) and D7.  I will focus my consideration on D7.

    ·     D7: Rathkopf, D.E. et al “43 - Phase I/II safety and pharmacokinetic (PK) study of ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase I results of a Prostate Cancer Clinical Trials Consortium study.” (2012) 30 (5 Supplement) Journal of Clinical Oncology, Abstract 43 (Exhibit JMW-12)

    [14] At this point it is worth noting that the Applicant’s position is that that D2 and D3 ought to be removed from consideration under the grace period provisions of s24(1).  Although they were published more than 12 months before the effective filing date of this application (as governed by Reg 2.3(4) as in force in September 2012, cf footnote 4) an extension of time for satisfying the grace period provisions was granted under s223 in the parent application.  The Applicant submits this applies equally to the divisional application.  The Opponent disputed this but indicated during the hearing they would not press the matter if it were not crucial to their success in this proceeding.  I have therefore not investigated this matter further.

  1. D7 is short enough to enclose here in full (emphases are mine):

    Background: In CRPC, androgen receptor (AR) overexpression is associated with resistance to first-generation anti-androgen therapy such as bicalutamide. ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data shows that ARN-509 binds AR with 5-fold greater affinity than bicalutamide, and induces tumor regression in hormone-sensitive and CRPC xenograft models.

Methods: In this open-label, Phase 1/2 study, mCRPC patients received ARN-509 orally on a continuous daily dosing schedule. In Phase 1 , 7 doses (30, 60, 90, 120, 180, 240, 300 mg) were tested using standard 3x3 dose escalation criteria to assess safety, PK, and determine the recommended Phase 2 dose (RP2D). Preliminary anti-tumor activity was assessed by PSA kinetics, radiographic responses, circulating tumor cells (CTCs), and FDHT-PET imaging.

Results: Twenty-four patients (median age 68 yrs, Gleason Score 8; prior docetaxel 13%) were enrolled. The most common Grade 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 treatment related Grade 3 adverse event (abdominal pain) at 300 mg, possibly related to a higher pill burden, which led to an additional 3 patients being enrolled at the highest dose with no further dose limiting toxicities. PK was shown to be linear and dose-dependent. Twelve patients (55%) had ≥ 50% PSA declines. To date, 7 patients have discontinued the study due to progression, with the longest patient still on study for more than 1 year. FDHT-PET imaging demonstrated AR blockade at 4 weeks across multiple dose levels. Based on preclinical assessment of maximum efficacious dose, PK, and promising activity across all doses, 240 mg was selected as the RP2D

Conclusions: In this Phase 1 study, ARN-509 was shown to be safe and well tolerated, with promising preliminary activity based on PSA and pharmacodynamic evidence of AR antagonism. The Phase 2 portion of the study will enroll up to 90 patients with treatment-naïve non-metastatic and mCRPC.   

  1. It is clear that D7 provides a direction to administer 240 mg of ARN-509 daily to, inter alia, non-metastatic CRPC patients.

Enzalutamide (MDV100) 

  1. The Opponent raised D8-D10, D13-D17, D20-D24 as being relevant to enzalutamide. 

  2. D17 is the FDA approved label for enzalutamide.[15]  Each of D9, D10, D14, D15, and D24 relate to the first phase I/II clinical trial of enzalutamide, a clinical trial numbered NCT00510718.  D16 and D21-D23 relate to the first phase III trial of enzalutamide known as the AFFIRM study.  D8 refers to the phase II STRIVE clinical trial.  D13 is a review article and D20 is published commentary.[16]  The Opponent’s submissions were primarily directed to D9, D8, D13, D16 “for illustrative purposes”.  I will focus my consideration on one document per clinical trial: D8 (STRIVE), D9 (NCT00510718) and D16 (AFFIRM).

    ·     D8: (STRIVE) ClincalTrials.gov listing for NCT01664923 (version 1, submitted 13 August 2012) (Exhibit JMW-13)

    [15] Exhibit JMW-22

    [16] OS at 62

  3. D8 is the clinical protocol for the STRIVE trial.  It discloses administration of 160 mg/day enzalutamide[17] to prostate cancer patients.  The eligibility criteria include ongoing androgen deprivation therapy, castrate levels of testosterone, and progressive disease defined by PSA progression and/or radiographic progression while on primary androgen deprivation therapy.[18]

    ·     D9: (NCT00510718) Scher, H. et al "Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study" (2010) 375 The Lancet, 1437-1446. (Exhibit JMW-14)

    [17] “Arms”, p.5 of D8

    [18] “Eligibility”, p.6 of D8

  4. D9 is a clinical paper in the Lancet discussing the results of the NCT00510718 Phase I/II trial of MDV3100.  It discloses daily doses of between 30-600 mg and established a maximum tolerated dose of 240 mg.[19]  Although the abstract of D9 refers to patients with metastatic CRPC, the “Study Design” at p. 1438 rh column specifies that eligible patients had progressive castration-resistant disease, defined as rising PSA at castrate levels of testosterone, with or without detectable metastases.  Seven patients had no detectable metastases, with rising PSA being the only evidence of disease.[20]

    ·     D16: (AFFIRM) Sher, H.I. et al “Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy” (2012) 367 (13) The New England Journal of Medicine, 1187-1197 (Exhibit JMW-21)

    [19] Abstract: “Methods and Findings” of D9

    [20] Table 1 and “Results” at p. 1440 rh column of D9

  5. D16 is a clinical paper in the New England Journal of Medicine entitled “Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy”.  It discloses the results of a trial in men with castration-resistant prostate cancer of either 160 mg/day enzalutamide or placebo.[21]  The inclusion criteria were apparently in the supplemental material which was not provided in evidence, however D16 discloses that 490 patients entered the study with PSA progression only and enzalutamide improved their survival compared to placebo with a hazard ratio of 0.62.[22]

    [21] Abstract: “Methods” of D16

    [22] Fig 2 “Type of progression at study entry” of D16

  6. I note that the Opponent no longer presses D16 for the purposes of novelty,[23] apparently because the Opponent concedes that D16 is only directed to metastatic CRPC (presumably because of the prior chemotherapy despite the apparent evidence of “PSA progression only” set out above above).  Certainly Dr Michaelson only considered D16 to relate to metastatic disease.[24]

    [23] OS at 101

    [24] Michaelson #1 at 179

  7. In view of my findings on novelty it is not necessary to refer to D16 further.

Novelty

  1. The novelty requirement is set out in subsection 7(1) of the Act.[25]

    (1)  For the purposes of this Act, an invention is to be taken to be novel when compared with the prior art base unless it is not novel in the light of any one of the following kinds of information, each of which must be considered separately:
      (a)  prior art information (other than that mentioned in paragraph (c)) made publicly available in a single document or through doing a single act;

    [25] Paragraph 7(1)(c) is not relevant for this decision

      (b)  prior art information (other than that mentioned in paragraph (c)) made publicly available in 2 or more related documents, or through doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art would treat them as a single source of that information;

  1. As the Applicant pointed out[26] the High Court has stated that the basic test for novelty is the “reverse infringement” test, that is, “whether the alleged anticipation would, if the patent were valid, constitute an infringement”.[27]  However the “reverse infringement test” cannot be simplified to “had the claim been infringed?”.  Subsection 7(1) explicitly states that it is the information content of the prior art that leads to lack of novelty. 

    [26] Applicant’s written submission (“AS”) at 165

    [27] Meyers Taylor Pty Ltd v Vicarr Industries (1977) CLR 228 at 235

  2. Therefore, in terms of the information content of the prior art, the General Tire[28] test of whether there are “clear and unmistakable directions” to what the patentee has claimed is more instructive.

    [28] General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (1972) RPC 457 at 485-486

  3. The Applicant also pointed to the long-established legal principle of Hill v Evans[29] that in order to be anticipatory a prior documentary disclosure must provide information that is equal in specificity and completeness to the invention claimed.  I understand this principle to mean that a broader (less specific) or non-enabling (less complete) disclosure cannot anticipate a claim because as such it does not provide a clear and unmistakable direction for the skilled worker to do something that would fall within the scope.   This is consistent with all the familiar metaphors of “planting the flag” and “accuracy of a sniper”, bearing in mind of course that a prior document can provide more than one clear and unmistakable direction, and that the documents must be read through the eyes of a person skilled in the art.  Features do not need to be made explicit in the prior art where the skilled addressee would have perceived the existence of those features from their reading of that citation.[30]

    [29] Hill v Evans (1862) 6 LT 90

    [30] OS at 98, citing Novozymes Australia Pty Ltd v Danisco A/S (2013) 99 IPR 417 at [108], and C Van der Lely NV v Bamfords Ltd [1963] RPC 61

  4. At the end of the day, the question for assessment of novelty simply is: does the prior art information provide clear and unmistakable directions to perform the claimed methods – does it direct the reader to treat nmCRPC with apalutamide (or, respectively, enzalutamide) in combination with ADT?

The Applicant’s four pronged argument

  1. At the hearing, the Applicant proposed four lines of argument as to why the present claims were not anticipated by the citations raised by the Opponent.  These strands are woven through their written submissions,[31] but can be summarised as follows:

    ·     The structures of apalutamide and enzalutamide were not disclosed in the purportedly novelty destroying documents;

    ·     The citations do not disclose administration to nmCRPC patients;

    ·     The citations do not disclose administration to patients in combination with androgen deprivation; and

    ·     The claims to methods of treatment require achievement of the desired therapeutic effect and the prior art must disclose that a therapeutic effect would be achieved.

[31] Many of these points are made in parallel through the Applicant’s written submissions.  I will endeavour to footnote specific points made by the Applicant when practical to do so.

  1. In order for the Applicant’s case for novelty to succeed, it would suffice for any one of these lines to be made out.  I will therefore deal with each in turn.

Do the citations provide an enabling disclosure of the drugs?

Apalutamide – D7

  1. D7 refers to apalutamide as ARN-509.  The structure of ARN-509 is disclosed in D19[32] and that document is clearly identifiable by its title “ARN-509: A Novel Antiandrogen for Prostate Cancer Treatment”.  I therefore conclude the skilled worker would have had no doubt about the identity of the molecule used in D7 as of the priority date.

    [32] Clegg, N.J. et al “ARN-509: a novel anti-androgen for prostate cancer treatment” (2012) 72(6) Cancer Research, 1494-1503, Exhibit JMW-26

Enzalutamide – D8/D9

  1. D8 refers to enzalutamide by name.  D9 refers to MDV3100.  D16 refers to enzalutamide “formerly known as MDV3100”.  The structure of MDV3100 is disclosed in D11.[33]  Although the name MDV3100 is not found in the title of D11, it is found in the abstract and as such could readily be identified.  D17 which is the USFDA approved label for enzalutamide also contains its structure and was published online on 31 August 2012.[34]  I therefore conclude that the skilled worker would have had no doubt about the identity of enzalutamide/MDV3100 as of the priority date.

    [33] Tran, C. et al “Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer” (2009) 324 Science, 787-790

    [34] Wolbers #1 at 54

What is non-metastatic castration resistant prostate cancer?

  1. Prostate cancer is a disease caused by neoplastic transformation of cells of the prostate.  It is usually detected by the presence of elevated levels of prostate specific antigen (PSA) in blood.[35]

    [35] See e.g. Mainwaring at 53

  2. Initial treatment usually involves removal of the tumour by surgery or radiation – however this does not always remove all of the cancer.  Rising levels of PSA is an indication of  “recurrent prostate cancer”.[36]  The speed at which PSA rises is often represented by an estimated "PSA doubling time” (PSADT).

    [36] See e.g. Michaelson #1 at 52-57, Description at [0030]

  3. The specification explains at [0024] that prostate cells, like many other male reproductive organs, require stimulation via the androgen receptor (AR) for their development and maintenance, and this dependence continues even after the cells become cancerous. 

  4. For this reason, a common treatment approach for recurrent or aggressive prostate cancer is androgen deprivation therapy (ADT) to prevent the production of androgen hormones by the body.[37]  The major androgen produced by the body is testosterone, which is produced by the testes in response to stimulation by gonadotropin (aka luteinising hormone (LH)) which is itself produced by the pituitary gland in response to gonadotropin releasing hormone (GnRH aka LHRH).[38]  The two most common forms of androgen depletion are orchiectomy (removal of the testes), and GnRH agonists (“medical castration”) which overstimulate the pituitary gland[39] but then deplete gonadotropin production.  GnRH agonists need to be administered continuously – this can be on a frequency of several months.[40]

    [37] See e.g. Michaelson #1 at 58-64

    [38] Mainwaring at 50-52

    [39] Causing an initial burst of gonadotropin which in turn can be managed by GnRH antagonists as discussed by Dr. Mainwaring at 93 – nothing turns on this.

    [40] Mainwaring at 89

  5. Castration Resistant prostate cancer (CRPC) is thus understood by the experts to mean disease progression, including rising serum PSA levels, while maintaining castrate levels of testosterone (being < 50 ng/dL or < 1.7 nmol/L).[41]

    [41] Michaelson #1 at 65, Mainwaring at 95, Parnis #1 at 65

  6. The experts differ on the long-term treatment prospects of medical castration.  Dr Michaelson stated[42] that patients on medical castration remain so for the rest of their lives “to prevent rising androgen levels from fuelling prostate cancer”.  However, Dr. Mainwaring pointed to “intermittent androgen blockade” as being an option that is available based on the discretion of the physician and patient – this technique involves discontinuing GnRH agonists when PSA has fallen to a nadir and recommencing once it reaches a specific level.[43]  Dr Parnis agrees with Dr. Mainwaring but with the caveat that once a cancer became castration resistant he would never consider withdrawing ADT.[44]

    [42] Michaelson #1 at 64

    [43] Mainwaring at 92

    [44] Parnis #1 at 58

  7. I should note at this point that neither surgical nor medical castration do not remove all production of testosterone from the body - some is produced by the adrenal gland[45] – nor would they preclude tumour escape by constitutive activation of the AR.  It is therefore unsurprising that further research in prostate cancer therapy has focused on the AR.

    [45] Mainwaring at 91

  8. Non-metastatic CRPC (nmCRPC) is also understood by the experts to mean different things.  To Dr Michaelson, it is CRPC without detectable metastases on bone, CT, or MRI scans[46] who may be asymptomatic but in his opinion are likely to develop metastases within two years.[47]  Dr Michaelson also understood that patients without detectable metastases were nonetheless likely to have undetectable metastases and therefore in his opinion there is not a clear distinction between metastatic and non-metastatic (or in his words “pre-metastatic”) CRPC.[48]  Dr Parnis provides a definition of nmCRPC[49] that is broadly consistent with the definition at paragraph [0033] of the Application.  In their replies to Dr Mainwaring, both the Opponent’s experts opined that CRPC was a continuum and that the distinction between mCRPC and nmCRPC was a “semantic” or “definitional” one based on whether metastases were large enough to detect with the detection methods available at any given time.[50]

    [46] Michaelson #1 at 46-50 and 67-68

    [47] Michaelson #1 at 68-70

    [48] Michaelson #1 at 74

    [49] Parnis #1 at 372

    [50] Michaelson #2 at 16, Parnis #2 at 32

  9. Dr Mainwaring also generally agrees with the definition in the Application,[51] but at that point his opinion differs.  His understanding is that nmCRPC was considered to be a biologically and clinically distinct disease state.[52]  So on that point there is significant disagreement with Dr. Michaelson, and indeed the Applicant advances a theory that “nmCRPC is a biologically and clinically distinct disease state from mCRPC”[53] which they then use to support their position that “mCRPC treatments do not simply translate to nmCRPC treatments”.[54]

    [51] Mainwering at 96

    [52] Mainwaring at 98

    [53] AS at 74 et seq

    [54] AS at 97 et seq

  10. However, Dr Mainwaring seems happy to state[55] that the terminology “non-metastatic castration resistant prostate cancer” simply refers to prostate cancer without detectable metastases and with rising PSA at castrate levels of testosterone.

    [55] Mainwaring at 162(f)

  11. This disagreement potentially calls into question whether nmCRPC even exists as a disease state.  However, for practical purposes the definition at [0033] of the Application appears to provide clear diagnostic criteria:  the patient must have

    ·     received ADT;

    ·     have increasing PSA in the presence of castrate levels of testosterone; and

    ·     have no detectable metastases.

  12. I cannot envisage any other way a clinician could distinguish between the disease states: even if nmCRPC were to be “biologically and clinically distinct” from mCRPC, there is no other way to distinguish it, as the presence of the cancer cannot be directly observed and can only be inferred from rising PSA levels.

  13. This raises the possibility that the scope (and indeed duration) of the state of nmCRPC will in all likelihood shrink over time – as the sensitivity of scanning improves then metastases will be able to be detected at an earlier stage.  An alternative definition, that nmCRPC for the purposes of the claims should be only assessed in terms of scanning sensitivity as of the priority date, seems unworkable in practice.  Although this could be said to support the position that nmCRPC is not a disease, in practical terms it would simply mean that any monopoly would shrink over time which does not seem to offend the public interest.

Do the citations disclose patients with nmCRPC?

Apalutamide - D7

  1. The Applicant’s position is that D7 does not disclose a study in nmCRPC, but only discloses that a phase II study will enrol patients with nmCRPC.  I nevertheless fail to see how this is not a clear and unmistakable direction in the sense of General Tire to treat patients with nmCRPC.

Enzalutamide - D8

  1. The Applicant’s position is that D8 does not disclose treatment of nmCRPC patients.  Dr Mainwaring’s view is that D8 does not state that any nmCRPC patients had been enrolled.[56]

    [56] Mainwaring at 365

  2. As indicated earlier, D8 discloses that the inclusion criteria of the study were PSA progression and/or radiologic progression, and the patients needed to be asymptomatic or mildly symptomatic for prostate cancer.  Dr Michaelson understands this to mean that the trial included men who had nmCRPC.[57]  Dr Parnis understands this to mean that the study was designed to enrol nmCRPC patients.[58]

    [57] Michaelson #1 at 329 (a)

    [58] Parnis #1 at 265

  3. While Dr Mainwaring is correct that there is no evidence that nmCRPC patients were actually enrolled, I consider the inclusion criteria to encompass three separate clear and unmistakable directions:  enrol patients with PSA progression only (i.e. nmCRPC patients); enrol patients with radiological (metastatic) progression only; and enrol patients with both PSA and radiological progression. 

  4. This is not a situation where a single direction could be carried out in multiple ways – there are three clear and separate directions.  The first direction is to enrol nmCRPC patients.  Neither of the Opponent’s experts had any difficulty observing this.

Enzalutamide - D9

  1. As discussed above, the study design of D9 included CRPC patients “with and without detectable metastases” and seven patients were disclosed as not having evidence of detectable metastases.

  1. The Applicants position on D9 is “It does not follow from the fact that some patients enrolled in the study did not have observable metastases that they had nmCRPC”.[59]  This is based on Dr Mainwaring’s view that  “this does not indicate to me that those 4 patients had nmCRPC” and that in his view D9 provides no evidence that nmCRPC patients were treated.[60]  There is no further rationale provided for Dr. Mainwaring’s hesitation to recognise patients with no observable metastases as non-metastatic.[61] 

    [59] AS at 339

    [60] Mainwaring at 315 and 320

    [61] Dr Parnis speculates in his Evidence in Reply that this may have been due to the discussion of previous lines of hormonal therapy in D9, but disagrees that the presence of prior therapy would be a necessary indicator of metastatic disease (Parnis #2 at 86-88)

  2. Dr Michaelson’s reading of D9 is that it discloses administration of enzalutamide to men with no detectable metastases i.e. nmCRPC patients.[62]  Dr Parnis also recognised that the patients treated in D9 included non-metastatic patients.[63]

    [62] Michaelson #1 at 101and 337 (a) 

    [63] Parnis #1 at 136, Parnis #2 at 91(a)

  3. I concede there is some ambiguity over whether the number of non-metatstatic patients reported as being treated in D9 was seven or four, but that is beside the point.  For the purposes of General Tire there is a clear and unmistakable direction to enrol nmCRPC patients (from the study design, for the same reason as D8).  Indeed there is a clear and unmistakable disclosure that the drug was given to nmCRPC patients.

Would the skilled addressee have recognised the presence of ADT in the citations?

  1. None of the citations explicitly disclose that the patients in the clinical trials were given ADT in combination with enzalutamide or apalutamide.  For the purposes of assessing novelty the General Tire test is quite strict: if a citation could be read in a way that does not infringe the patent then it is not anticipatory.  For the Applicant’s case to succeed it is merely necessary to establish that the skilled addressee could read each disclosure such that the patients in the trials are not receiving ADT.

What do the experts say about the presence of ADT?

  1. Dr Michaelson’s understanding is that “once patients commence medical castration, they remain on it for the rest of their life to prevent rising androgen levels from fuelling the prostate cancer”.[64]  He further specifies that ADT was maintained as standard practice even when additional agents were introduced into a patients treatment protocol and that ADT was mandatory for clinical trials in CRPC.[65] 

    [64] Michaelson #1 at 64

    [65] Michaelson #1 at 66

  2. In his evidence in reply he concedes that ADT may be withdrawn but this was “very rare” in his experience.[66]  He further specifies that withdrawing ADT would fail to maintain castrate levels of testosterone that are “typically required for clinical studies”.[67]  Dr Parnis’s evidence[68] is consistent with this.

    [66] Michaelson #2 at 19

    [67] Michaelson #2 at 20

    [68] Parnis #1 at 58, 86, Parnis #2 at 24-25, 33-36  

  3. Dr. Mainwaring states that it was “not uncommon” for nmCRPC patients to forego ADT or at least request intermittent ADT “while the prostate cancer disease was not causing physical symptoms”.[69]  At paragraph 100 he provides more detail, to the effect that patients with PSA doubling times of more than 12 months were often not subjected to ADT, although this decision was one made with reference to factors including patient preference, age, psychological health and comorbidities.

    [69] Mainwaring at 98 and 570

  4. Dr. Mainwaring further says it would be “unwise to speculate” about the potential interactions of GnRH agonists and an anti-androgen, in the absence of specific description of continued ADT.[70]

    [70] Mainwaring at 486

  5. Nevertheless, Dr. Mainwaring is happy to conclude that the example described at [0043] of the specification would have involved ADT due to references to GnRH agonists and orchiectomy elsewhere, even though it is not specifically described at that point.[71]

    [71] Mainwaring at 563

  6. The following issues with Dr. Mainwaring’s evidence led me to lower the weight I can give to it:

  • Inconsistency[72] regarding whether a specific description of continued ADT is required.

  • The very definition of CRPC: even Dr. Mainwaring admits that CRPC is defined as PSA progression at castrate levels of testosterone.  Although I find it plausible that patients may request to go off ADT at least intermittently, there is very a strong implication that CRPC patients are receiving ADT – which is how they have castrate levels of testosterone.  This is even more so for the clinical trials (which all the citations represent) which all have strict inclusion criteria of castrate levels of testosterone.

    [72] Between paragraphs 486 and 583 of his declaration

  1. On the latter point, I find the following flow chart[73] to be particularly useful as an illustration of the recommended approach in the field. 

[73] Taken from p. 171 of Exhibit MDM-29 entitled Clinical Guidelines in Oncology - Prostate Cancer, discussed in Michaelson #2 at 23-26

  1. This chart illustrates three possible lines of ADT (orchiectomy, and LHRH agonist with or without additional antiandrogen).  Notably, all three lines have the same denouement i.e. relapse which can be metastatic or non-metastatic.  Regardless of the therapy or the outcome, the footnote “m” at relapse indicates “assure castrate levels of testosterone”.  I take this to be strong evidence that relapsing i.e. castration-resistant prostate cancer is always to be treated with ADT.

  2. I therefore find that the skilled reader would have implicitly understood that patients with relapsing (i.e. castration resistant) prostate cancer should be receiving ADT, particularly those participating in clinicial trials.

  3. I would add in passing that if this point had fallen in the Applicant’s favour then the Opponent’s alternative ground for lack of support would have been made out.  This is because the only clinical example in the specification does not disclose the presence of ADT, so if the skilled reader would not have recognised the presence of ADT in the citations then they could hardly be said to have read it in to the example in the specification – and consequently the claims would not correspond to the technical contribution as required by CSR.[74]

    [74] CSR Building Products Ltd v United States Gypsum Co [2015] APO 72.

Do the “method of treatment” claims require clinical efficacy?

  1. In order to address this question it is necessary to understand what the term “method of treatment” as used in the claims[75] means.  I have three sources of information available on this:  the disclosure of the specification itself; the evidence of the experts and the way Australian courts have considered the term in past cases.

    [75] I note that claims 29, 31, 32 and 34-35 use the word “for” instead of “of” – in view of my findings nothing turns on this distinction.

The specification

  1. The term “treatment” is rather broadly defined in the specification at [0053] as:

    The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease disease [sic] or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, delaying progression of [sic] condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either [sic] prophylactically and/or therapeutically.

  2. It seems safe to say that “treating” nmCRPC within the meaning this definition extends to administering a drug to nmCRPC patients with some hope of improving their condition or prospects.

The experts

  1. Dr Mainwaring refers to “treatment” in a number of different contexts:

    ·     “a management or treatment regime best suited to each patient’s natural history.”[76]

    ·     “approved” treatments in Australia, particularly those with subsidies under the Pharmaceutical Benefits Scheme.[77]

    ·     heterogenous journeys with varying responses to treatment.[78]

    ·     treatment decisions are taken by the patient.[79]

    ·     a clinical trial is a “new treatment” but “patients in a phase III trial should not be expected to be treated.”[80]

    ·     distinguishing between investigational treatment and effective treatment.[81]

    ·     achieving observable and measurable outcomes.[82]

    [76] Mainwaring at 20

    [77] Mainwaring at 43

    [78] Mainwaring at 59

    [79] Mainwaring at 98

    [80] Mainwaring at 171

    [81] Mainwaring at 172

    [82] Mainwaring at 230, with reference to the specification at [0053-0054], [0043], [0092-0093]

  2. Dr Parnis makes abundant use of the word “treatment” throughout his evidence but apart from an acknowledgement of the above definition in the patent[83] he does not explicitly define what he understands it to mean.  In context he seems to use it synonymously with “administration” and he does not appear associate it with any absolute requirement for clinical benefit.

    [83] Parnis #1 at 366

  3. In his response to Dr. Mainwaring, Dr Parnis considered treatment efficacy to be a broad range of criteria including non-increasing PSA while noting that the claims did not state any requirement for treatment effectiveness.[84]

    [84] Parnis #2 at 68-69

  4. Dr Michaelson’s usage of the word “treatment” (and his response to Dr Mainwaring)[85] is similar to that of Dr Parnis.

    [85] Michaelson #2 at 50

  5. The net evidence of the experts on the meaning of “method of treating” is therefore ambiguous at best.  What is clear is that they recognise that “treatment” as defined in a patent application is somewhat different from the everyday interactions of a physician acting in the best interests of an individual patient.

The courts

  1. At this point I think it is useful to turn to the decision of the High Court in Sanofi[86] which definitively established the patentability of method of treatment claims under Australian law, in contradiction to a long-running history of such claims begin considered unpatentable.

    [86] Apotex Pty Ltd v Sanofi-Aventis Australia Pty Ltd & Ors [2013] HCA 50

  2. The claim at issue in Sanofi was

    A method of preventing or treating a skin disorder, wherein the skin disorder is psoriasis, which comprises administering to a recipient an effective amount of a pharmaceutical composition containing as an active ingredient a compound of the formula I or II [leflunomide] (emphasis added)

  1. The High Court majority recognised (apparently using the words purpose, therapeutic use, and method of treating interchangeably) that novelty of such a claim comes from its hitherto unknown therapeutic purpose:

    Claim 1 is recognisably a claim limited to the specific purpose of preventing and treating psoriasis.  Given the prior art, any novelty and inventive step reposes in, and is confined to, that hitherto unknown therapeutic use of leflunomide.[87]

Novelty of purpose can confer novelty even if a substance is known, a principle determined in the NRDC Case, which can be seen in the relevant passages extracted above. Provided a hitherto unknown therapeutic use of a pharmaceutical substance or compound can satisfy the requirements of novelty and inventive step and is not obvious, such a use can be an invention within the meaning of s 18(1)(a) of the 1990 Act, irrespective of whether it is a first or subsequent novel use.[88]

[87] Sanofi at 289

[88] Sanofi at 291

  1. The High Court majority also drew a distinction between a “method of treatment” and the “activities of doctors”.  Without putting an explicit definition on either, the High Court majority understood the former to be fundamentally economic in nature but the latter to be essentially non-economic and unlikely to be patentable:[89]

    There is, however, a distinction which can be acknowledged between a method of medical treatment which involves a hitherto unknown therapeutic use of a pharmaceutical (having prior therapeutic uses) and the activities or procedures of doctors (and other medical staff) when physically treating patients.  Although it is unnecessary to decide the point, or to seek to characterise such activities or procedures exhaustively, speaking generally they are, in the language of the NRDC Case, "essentially non‑economic" and, in the language of the EPC and the Patents Act 1977 (UK), they are not "susceptible" or "capable" of industrial application.  To the extent that such activities or procedures involve "a method or a process", they are unlikely to be able to satisfy the NRDC Case test for the patentability of processes because they are not capable of being practically applied in commerce or industry, a necessary prerequisite of a "manner of manufacture".[90]

    [89] See also the last setence of para 285 in Sanofi

    [90] Sanofi at 287

  2. To me, this indicates that a “method of treatment” is to be understood in the patent sense as a clinical program as carried out by drug manufacturers, marketers and study designers[91] as opposed to atomised interactions of physicians and patients, even if the latter is closer to the strict wording of the claim.

    [91] Noting that in Faulding a clinical trial disclosure was found to be capable of being anticipatory

  3. I also note that Justice Hayne’s dissenting opinion construed treatment as a process carried out on an individual rather than at a population level and considered that such a personal process could not be patentable.[92]

    [92] Sanofi at 159-165

  4. I therefore come to the understanding that method of treatment claims, as they have been interpreted to be valid under Australian law, should be construed as a therapeutic program applied to a population, rather than one or more individual acts of treatment.

Of v For

  1. The Applicant submitted[93] that the finding in Mylan,[94] that the requirement for therapeutic effect in UK authorities could be distinguished from the claims considered in that case, provided an implication that a “method of” claim could be construed differently in Australia.  The applicant submits in such a case “in order to be novelty-defeating, the prior art must disclose that the therapeutic effect would be achieved.”

    [93] AS at 191

    [94] Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd (2020) 279 FCR 354

  2. The ‘711 patent under discussion in Mylan involved

    7. A method for the prevention and/or treatment of retinopathy, the method comprising administration of fenofibrate or a derivative thereof to a patient in need thereof. (emphasis added)

  1. The Full Court’s finding in Mylan was  “It is apparent, therefore, that the principles on which [UK Authorities] proceeded in each case are not the principles developed under Australian case law as applied in BMS v Faulding and Merck v Arrow.”[95]

    [95] Mylan at 111

  2. The Full Court in Mylan makes it clear that it considers that its construction and application of principle is consistent with those two cases.  But the claims in suit in those cases do not support the Applicant’s proposition that different constructions reside in the terms “of’ and “for”.

  3. The claims in suit in BMS v Faulding[96] were:

    1. A method for administration of taxol to a patient suffering from cancer comprising infusing from 135 to 175 mg/m2 of taxol over a duration not exceeding 6 hours.


    1. A method for treating cancer in a patient suffering therefrom including infusing from 135 to 175 mg/m2 of taxol over a duration less than 6 hours wherein said method results in a reduction of hematological toxicity and neurotoxicity compared with infusing greater than 170 mg/m2 of taxol over a duration of 24 hours. (emphases added)

    [96] Bristol-Myers Squibb Company v FH Faulding & Company Ltd (2000) 97 FCR 524 (“Faulding”)

  4. The claims in suit in Merck v Arrow[97] were:

    [97] Merck & Company Inc v Arrow Pharmaceuticals Ltd (2006) 154 FCR 31

    1. A method of preventing osteoporosis in a human, comprising orally administering to said human a pharmaceutically effective amount comprising about 35 mg of alendronate monosodium trihydrate on an alendronic acid active basis as a unit dosage according to a continuous schedule having a dosage interval which is once weekly.


    2. A method of treating osteoporosis in a human, comprising orally administering to said human a pharmaceutically effective amount comprising about 70 mg of alendronate monosodium trihydrate on an alendronic acid active basis as a unit dosage according to a continuous schedule having a dosage interval which is once weekly.


    3. A method for treating or preventing osteoporosis in a human, said method comprising orally administering to said human a pharmaceutically effective amount of a pharmaceutically acceptable salt of alendronate, said pharmaceutically acceptable salt being selected from the group consisting of sodium, potassium, calcium, magnesium and ammonium salts, as a unit dosage according to a continuous schedule having a dosage interval which is once weekly. (emphases added)

  5. Therefore the Full Federal Court does not appear to consistently place any premium on the words “of” and “for” in this context.  Neither did the High Court in Sanofi when it concluded that a method of treatment gained its novelty by therapeutic purpose rather than therapeutic effect.[98]

    [98] Although the Sanofi decision didn’t explicitly reject the construction of the claims by therapeutic effect, it implicitly did so in rejecting the primary judge’s construction: cf Sanofi at 208 and 290

  6. In conclusion, I can find no basis in the authorities for the Applicant’s proposition that a class of claims to “methods of treatment” exists which requires a demonstrated therapeutic effect in order to be anticipated.  The authorities do not appear to draw any distinction between methods of or for treatment, and indeed the High Court preferred to give weight to therapeutic purpose rather than therapeutic effect when construing such claims.

  7. I note that at the hearing the Applicant referred to my decision in Gliknik[99] in which I gave regard to UK authority when applying sufficiency requirements of s40(2)(a) to treatment method claims.  I do not see there is any inconsistency in this approach given that novelty and sufficiency are different legal requirements.  Furthermore, even when considering the UK principles in Gliknik I acknowledged that the Australian claims needed to be construed under Australian law with regard to their therapeutic purpose.

    [99] Gliknik, Inc. v CSL Behring Lengnau AG (2020) APO 46

  8. Turning briefly to the Swiss-type claims, these have been construed in Australian law as being purpose-limited manufacture claims.[100]  It follows that a disclosure of purpose that is anticipatory for treatment methods would also be anticipatory for Swiss-type manufacture claims.

    [100] Mylan at 195-198

  9. The Applicant spent a considerable amount of submissions seeking to distinguish the present case from Mylan, dissecting the findings on each piece of prior art in Faulding (which was cited at length in Mylan), presumably because the Applicant was concerned that the fact patterns of Mylan and Faulding was uncomfortably close to the instant case.  As the Applicant submitted, each case is different, but I rather see a closer similarity to the situation in Mylan in the present case.

  10. In Faulding the claims were distinguished not by treatment of disease (the same disease, cancer, that Taxol was previously known to treat) but by optimisation of the dosage regimen.  The Federal Court concluded that anticipation of the claimed dosage regimen did not occur until trials had shown it to be “feasible”.[101]

    [101] Faulding at 71-72

  11. On the other hand the citations in the present case are much more analogous to the ACCORD protocol that was found to be anticipatory in Mylan “a disclosure that [the drug] was to be deliberately administered with [a second drug] with the aim of preventing or treating [a disease] in patients in need of such treatment.”[102]

    [102] Mylan at 105

  12. Even on the point of dosing, the dosages in the prior art are the same as the most preferred dosages in the claim:  daily dosing of 240 mg apalutamide (D7) and 160 mg enzalutamide (D8).  (On the other hand it is not evident that D9 discloses that nmCRPC patients should particularly receive 160 mg enzalutamide:  240 mg daily was found to be the maximum tolerated dose.)

Evaluation of Novelty

  1. Returning to the judgment of Lord Westbury in Hill v Evans:

    "The question then is, what must be the nature of the antecedent statement? I apprehend that the principle is correctly thus expressed: - the antecedent statement must be such that a person of ordinary knowledge of the subject would at once perceive, understand, and be able practically 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."

  1. I am satisfied that D7 gives the skilled worker enough information to practically apply 240 mg of apalutamide a day to nmCRPC patients in combination with ADT.

  2. I am satisfied that D8 gives the skilled worker enough information to practically apply 160 mg of enzalutamide a day to nmCRPC patients in combination with ADT.

  3. I am satisfied that D9 gives the skilled worker enough information to practically apply 60-300 mg (preferably 240 mg) of enzalutamide a day to nmCRPC patients in combination with ADT.

  4. I cannot see that anything else must be ascertained by the skilled worker to apply this information.

  5. Therefore D7 anticipates independent claims 1, 29, 34 and 35.

  6. D8 anticipates independent claims  11, 31, 34 and 35.  D9 also anticipates claims 11, 31, 34 and 35.

Dependent claims

  1. The dependent claims can be classed into three groups:  those relating to high risk nmCRPC, those relating to dosing and those relating to type of ADT.

  2. I will deal with the latter two first as they require less consideration.

Dosing claims (3-8, 13-14, 30)

  1. In terms of dosing, D7 discloses continuous daily dosing of 240 mg apalutamide.  This anticipates claims 3-8 and 30.

  2. D8 discloses continuous daily dosing of 160 mg enzalutamide.  This anticipates claims 13-14.  D9 anticipates claim 13 but not 14.

ADT claims (9-10, 15-16, 22-28 and 33)

  1. In terms of type of ADT, the claims split out orchiectomy from GnRH agonists, and then split out separate known GnRH agonists in separate claims. 

  2. I have found that the skilled worker would have considered it implicit that the nmCRPC patients should be administered ADT.  The expert evidence is that the nature of the ADT is not particularly important as long as it results in castrate levels of testosterone. Although the experts did not address this directly (and the Opponent did not include any detailed discussion of claims 22-28 in their submissions) I am comfortable finding that the skilled worker would have recognised that nmCRPC patients should be administered any or all available ADT.  In fact the most likely scenario is that the person skilled in the art would understand that different patients would have different ADT. 

  3. I can therefore distinguish this scenario from one where “an instruction could be carried out in multiple ways” which is not anticipatory according to General Tire.  Rather it is a scenario where the implicit instruction for ADT would be carried out in multiple ways, i.e. it constitutes a clear and unmistakable (albeit implicit) direction to treat patients who have been given each and every kind of ADT.

  4. Put another way, I cannot see how splitting the therapeutic purpose of treating nmCRPC into arbitrary treatment subsets could confer novelty when the skilled worker would have been aware of each of the subsets.

  5. Claims 9-10, 15-16, 22-28 and 33 are therefore also anticipated.

High Risk Claims (2, 12)

  1. These claims are directed to a treatment of a subset of nmCRPC patients:  those who are said to be “high risk”.

  2. The specification defines high risk nmCRPC as referring to the probability of developing metastases.[103] This is then defined with respect to PSA doubling time (PSADT) and sets out a range of possible definitions of high risk: PSADT from 1 month up to 20 months. A PSADT of 10 months is set out as a particularly preferred definition and this appears again in the inclusion criteria of the prophetic clinical trial example at [0094]. It seems, in the absence of further definition in the claims, that it can encompass patients with a PSADT of 20 months or less.

    [103] Description at [0048]

  3. Dr Mainwaring’s evidence is that there was no accepted definition of “high risk” nmCRPC as of the priority date.[104]  He identifies “high risk” as being defined in the description at the passages mentioned above[105] but says he would not have used that term himself.

    [104] Mainwaring at 211, suggesting that the concept had not even been recognised.

    [105] Mainwaring at 224-225

  4. Dr Michaelson’s evidence is that a PSADT of <10 months is associated with risk of developing metastases[106] and would be a trigger for a clinician to consider whether further intervention is necessary, but that PSADT by itself is insufficient to establish a patient’s risk, without consideration of other factors such as PSA level.[107]  In his evidence in reply, he pointed to a clinical trial of denusomab in castration-resistant prostate cancer patients that used PSADT of <10 months as an inclusion criterion.[108]  Dr Parnis made a similar observation.[109]

    [106] Michaelson #1 at 69

    [107] Michaelson #1 at 293

    [108] Michaelson #2 at 14 and MDM-28

    [109] Parnis #1 at 379

  5. Dr Michaelson nevertheless considers that treatment of nmCRPC with apalutamide and enzalutamide would include high risk patients.[110]  Dr Parnis has the same view.[111]

    [110] Michaelson #1 at 334-5

    [111] Parnis #1 at 423

  6. Taking all the evidence together, and bearing in mind that I am construing methods of treatment at the population level rather than the individual, I consider on the balance of probabilities that the citations, as read by the person skilled in the art, provide a direction to administer apalutamide or enzalutamide to both high risk and low risk nmCRPC patients.

  7. Similarly to the ADT claims, I do not consider that splitting the claims into arbitrary subgroups can confer novelty in this instance.

  8. Claims 2 and 12 therefore also lack novelty.

Conclusion on Novelty

  1. In sum, claims 1-16, 22-31 and 22-25 lack novelty.

Inventive Step

  1. As I have found all opposed claims lack novelty, consideration of the ground of inventive step is redundant.  However, given that I have found that the prior art provided clear and unmistakable directions to carry out the inventions claimed, it would follow that the skilled worker would also have been led to do this with a reasonable expectation of success.

  2. For completeness, I note that the Opponent pressed a case for lack of inventive step in view of common general knowledge alone.[112]  Although it is hardly determinative for this case, I am broadly convinced by the Opponent’s proposition (and broadly unconvinced by the Applicant’s rebuttals[113]) in view of my findings on common general knowledge above, as well as the following two principles:

    ·     Applying known second-generation anti-androgens to a disease known to have an androgen receptor component would seem to be an obvious thing to do.

    ·     If the Applicant’s contention, that there is no requisite expectation of success for safety and/or efficacy before human clinical trial data is reported, was to be accepted then patent protection for methods of treatment would have to be equated with the first reporting of human clinical trial data.  And this would strike me as having problematic implications e.g. for the ethics of trial design.

    [112] OS at 151-175

    [113] AS at 221-227

Clarity

  1. The Opponent advanced two attacks on the clarity of the claims.  The first, that potentially affects all claims, is that it is not clear where the boundaries of “non-metastatic” CRPC end.  The Opponent asserts this would be the case if the evidence of Dr Mainwaring, that patients with no evidence of metastases nevertheless were not nmCRPC patients, was accepted.[114]

    [114] OS at 205, referring to Mainwaring at 320

  2. However I have found earlier that the only workable definition for “non-metastatic” CRPC is patients with no detectable metastases.  Although this is one that has the potential to change over time as detection technology improves, the metes and bounds of the claim at any given time are nonetheless clear.

  3. The second attack is on the definition of “high risk” nmCRPC.  However as can be seen by my discussion of claim 2 it is possible to put a construction on this term.

  4. The ground of lack of clarity therefore fails.

Support

  1. The Opponent advanced the ground of lack of support narrowly, in that only if the citations were found not to be an enabling disclosure of the claims, then the specification, in their submission, could not be an enabling disclosure either.

  2. I would note that this is not an automatic “squeeze” for the Opponent, as the specification does provide some data that is different to that of the citations: it does disclose the results of a phase II trial of apalutamide in nmCRPC patients specifically.  Admittedly this trial does not specify whether the patients had ADT or not, but I have found earlier that the skilled reader would understand that the nmCRPC patients would be expected to be on ADT.

  3. In light of my findings above as to what the skilled worker would understand, it follows that the ground of lack support (even if still pressed) would fail.

Conclusion

  1. I have found claims 1-16, 22-31 and 33-35 lack novelty.  There is clearly a set of amendments that would allow the application to proceed to grant.  Pursuant to s60(3B) I allow the applicant a period of one (1) month to make appropriate amendments.

Costs

  1. It is conventional that costs follow the event and I see no reason to deviate in this case.  I therefore award costs according to Schedule 8 against Aragon Pharmaceuticals, Inc.

Felix White

Delegate of the Commissioner of Patents

Annex – Opposed Claims

  1. A method of treating a male human with non-metastatic castration-resistant prostate cancer, the method comprising administering an anti-androgen at a dose of about 30 mg per day to about 480 mg per day to a male human in need of such treatment, wherein the anti androgen is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2 fluoro-N-methylbenzamide,

    and wherein the anti-androgen is administered in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy.

  2. The method of claim 1, wherein the non-metastatic castration-resistant prostate cancer is a high risk non-metastatic castration-resistant prostate cancer.

  1. The method of claim 1 or claim 2, wherein the 4-[7-(6-cyano-5 trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2 fluoro-N methylbenzamide is administered orally to the male human.

  1. The method of claim 3, wherein the 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8 oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered daily to the male human.

  1. The method of claim 3, wherein the 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8 oxo-6-thioxo-5, 7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to the male human at a dose of about 180 mg per day to about 480 mg per day.

  1. The method of claim 3, wherein the 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8 oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to the male human at a dose of:

    (a) about 30 mg per day;

    (b) about 60 mg per day;

    (c) about 90 mg per day;

    (d) about 120 mg per day;

    (e) about 240 mg per day;

    (f) about 300 mg per day;

    (g) about 390 mg per day; or

    (h) about 480 mg per day.

  2. The method of claim 3, wherein the 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8 oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to the male human at a dose of about 240 mg per day.

  1. The method of claim 3, wherein the 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8 oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to the male human on a continuous daily dosage schedule.

  1. The method of claim 3, wherein the 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8 oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered in combination with orchiectomy.

  1. The method of claim 3, wherein the 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8 oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is administered in combination with a GnRH agonist.

  1. A method of treating a male human with non-metastatic castration-resistant prostate cancer, the method comprising administering an anti-androgen at a dose of about 30 mg per day to about 480 mg per day to a male human in need of such treatment, wherein the anti-androgen is 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, and wherein the anti-androgen is administered in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy.

  1. The method of claim 11, wherein the non-metastatic castration-resistant prostate cancer is a high risk non-metastatic castration-resistant prostate cancer.

  1. The method of claim 11 or claim 12, wherein the 4-(3-(4-cyano-3 (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide is administered orally to the male human.

  1. The method of claim 11, wherein the 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide is administered orally to the male human at a dose of about 160 mg per day.

  1. The method of claim 11, wherein the 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide is administered in combination with orchiectomy.

  1. The method of claim 11, wherein the 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide is administered in combination with a GnRH agonist.

  1. A method of treating a male human with non-metastatic castration-resistant prostate cancer, the method comprising administering an anti-androgen at a dose of about 30 mg per day to about 480 mg per day to a male human in need of such treatment, wherein the anti androgen is 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, and wherein the anti-androgen is administered in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy.

  1. The method of claim 17, wherein the non-metastatic castration-resistant prostate cancer is a high risk non-metastatic castration-resistant prostate cancer.

  1. The method of claim 17 or claim 18, wherein the 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4 ]oct-5-yl]-2-fluoro-N-methylbenzamide is administered orally to the male human.

  1. The method of claim 17, wherein in the 4-[7-[ 4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4 ]oct-5-yl]-2-fluoro-N-methylbenzamide is administered in combination with orchiectomy.

  1. The method of claim 17, wherein the 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4 ]oct-5-yl]-2-fluoro-N-methylbenzamide is administered in combination with a GnRH agonist.

  1. The method of any one of claims 10, 16 or 21, wherein the GnRH agonist is leuprolide, buserelin, naferelin, histrelin, goserelin or deslorelin.

  1. The method of claim 22, wherein the GnRH agonist is leuprolide.

  1. The method of claim 22, wherein the GnRH agonist is buserelin.

  1. The method of claim 22, wherein the GnRH agonist is naferelin.

  1. The method of claim 22, wherein the GnRH agonist is histrelin.

  1. The method of claim 22, wherein the GnRH agonist is goserelin.

  1. The method of claim 22, wherein the GnRH agonist is deslorelin.

  1. A method for treating a male human with non-metastatic castration-resistant prostate cancer, the method consisting essentially of administering an anti-androgen in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy to a male human in need of such treatment, wherein the anti-androgen is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide.

  1. The method of claim 29, wherein the anti-androgen is administered orally to the male human at a dose of:

    (a) about 30 mg per day;

    (b) about 60 mg per day;

    (c) about 90 mg per day;

    (d) about 120 mg per day;

    (e) about 240 mg per day;

    (f) about 300 mg per day;

    (g) about 390 mg per day; or

    (h) about 480 mg per day.

  2. A method for treating a male human with non-metastatic castration-resistant prostate cancer, the method consisting essentially of administering an anti-androgen in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy to a male human in need of such treatment, wherein the anti-androgen is 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide.

  1. A method for treating a male human with non-metastatic castration-resistant prostate cancer, the method consisting essentially of administering an anti-androgen in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy to a male human in need of such treatment, wherein the anti-androgen is 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide.

  1. The method of any one of claims 29 to 32, wherein the GnRH agonist is leuprolide, buserelin, naferelin, histrelin, goserelin or deslorelin.

  1. Use of an anti-androgen for the manufacture of a medicament for treating non metastatic castration-resistant prostate cancer, wherein the anti-androgen is:

    4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2 fluoro-N-methylbenzamide,

    4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, or

    4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide;

    wherein the medicament is administered to provide a dose of said anti-androgen of about 30 mg per day to about 480 mg per day and wherein said medicament is administered in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy.

  1. Use of an anti-androgen for the manufacture of a medicament for treating non metastatic castration-resistant prostate cancer, wherein the anti-androgen is:

    4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide,

    4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, or

    4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide;

    wherein the medicament is administered in combination with a gonadotropin releasing hormone (GnRH) agonist or orchiectomy.


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Cases Cited

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Statutory Material Cited

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