duncan curley's presentation to the cipa life sciences conference 20th november 2014

© 2014 Innovate Legal Services Limited

SPCs: Targets for attack from generic pharma

A structured discussion.

CIPA Life Sciences Conference

Sutton Coldfield, 20th November 2014


Agenda

Recent developments in SPC law and practice that may affect the timing ofgeneric product launches

1. Combination products

2. SPC duration – UK IPO change of practice / Seattle Genetics reference

3. Neurim – do we care?

4. ‘Active ingredient’ – patent law intersects with regulatory law?

5. SPC extensions and deadlines for submission of applications


Key provisions of Regulation (EC) No 469/2009

Definitions – Article 1

• a medicinal product means any substance or combination of substancespresented for treating or preventing disease in human beings...and any substanceor combination of substances which may be administered to human beings...with aview to making a medical diagnosis or to restoring, correcting or modifyingphysiological functions in humans or in animals – Article 1(a)

• a product means an active ingredient or a combination of active ingredients of amedicinal product – that is protected by a basic patent – Article 1(b)

• a basic patent means a patent which protects a product ‘as such’, a process toobtain a product or an application of a product – Article 1(c)


Key provisions of Regulation (EC) No 469/2009

What is required to get a SPC? – Article 3

• a product that is protected by a basic patent - Article 3(a)

• a valid marketing authorisation to place the product on the market as amedicinal product - Article 3(b)

• the product must not already be the subject of a SPC - Article 3(c)

• the marketing authorisation must be the first authorisation to place the product onthe market - Article 3(d)


Topic no. 1: Combination products

The Actavis v Sanofi decision (C-443/12) of the Court of Justice of theEuropean Union issued on 12 December 2013 was an important decision forboth sides of the industry.

Why?

Previously, the practice of patent offices throughout Europe had sometimesbeen to grant multiple SPCs with the same underlying basic patent.


Combination products

This was of considerable assistance to patentee companies engaged in lifecycle management.

For example…

Basic patent granted that protects molecule A.

Subsidiary claims in the basic patent refer to the combination of A with a range of other compounds.

Several years later, a medicinal product is authorised in which A is the active ingredient.

A few years later still, a medicinal product is authorised in which active ingredients A and B arepresent (a combination drug product).

Under the old practice (i.e. before Actavis v Sanofi), 2 SPCs could be applied for and granted usingthe same basic patent, 1 SPC protecting active ingredient A and 1 SPC protecting the combinationA+B.



In Actavis v Sanofi, the Court of Justice said “no” to this type of practice, incertain circumstances (the quotes are from paragraph 41 of the decision):

“It should be recalled that the basic objective of Regulation No 469/2009 is tocompensate for the delay to marketing of what constitutes the core inventiveadvance that is the subject of the basic patent….”



“In the light of the need, referred to in recital 10 [of the SPC Regulation] to takeinto account all the interests at stake, including those of public health, if itwere accepted that all subsequent marketing of that active ingredient inconjunction with an unlimited number of other active ingredients, not protectedas such by the basic patent but simply referred to in the wording of the claimsof the patent in general terms, such as…”beta-blocking compound”, “calciumantagonist”, “diuretic”, “non-steroidal anti-inflammatory” or “tranquilizer”,conferred entitlement to multiple SPCs, that would be contrary to therequirement to balance the interests of the pharmaceutical industry andthose of public health as regards the encouragement of research within theEuropean Union by the use of SPCs”.



What happens to all of the SPCs for combination products that have alreadybeen granted on the basis of the practice before Actavis v Sanofi?

Answer

In practical terms, the patent offices will not be revisiting the validity of theseSPCs. They will therefore sit there until someone (generic pharma?) doessomething…

What?



Tactical considerations – generic pharma perspective

Ignore the SPC and just launch a generic alternative (risk of a lawsuit?)

Initiate a court procedure to have the invalid SPC revoked (brings the invalidityto the attention of other generic competitors)


Topic no. 2: SPC duration

UK IPO change of practice / Seattle Genetics

This relates to the calculation of the duration of an SPC.

Article 13(1) of the SPC Regulation states that:

“The certificate shall take effect at the end of the lawful term of the basic patentfor a period equal to the period which elapsed between the date on which theapplication for the basic patent was lodged and the date of the firstauthorisation to place the product on the Community, reduced by a periodof five years”.


SPC duration

What is the controversy?

There is likely to be a difference between:

the date of the decision to grant a marketing authorisation for a centrally-authorised medicinal product (made by the European Commission)

and

the date of notification of the grant of the marketing authorisation to the holder.


SPC duration

There could be several days difference between these dates.

Can therefore be very important – for generic pharma, every day counts!

So which date applies?


SPC duration

Decision by the UK IPO of 22 October 2013: Genzyme Corporation

(BL O/418/13)

The SPC (no. SPC/GB04/031) for the active ingredient colesevelam hydrochloride(marketed as the medicinal product Cholestagel) was set to expire on 9 March 2019.

Genzyme sought a 6-month paediatric extension to this SPC and at the same timerequested that the term of the SPC be corrected, because the relevant date forcomputation of the SPC should have been 12 March 2004 (the date of notification toGenzyme of the relevant marketing authorisation) – i.e. 2 days later than the date ofgrant of the marketing authorisation for Cholestagel, which was the date that the UK IPOhad used when it originally calculated the duration of the SPC.


SPC duration

Decision by the UK IPO of 22 October 2013: Genzyme Corporation

(BL O/418/13)

The UK IPO agreed with Genzyme and allowed the original date of expiry ofthe SPC to be rectified to 11 March 2019 (and so with the 6 month paediatricextension the SPC will now last until 11 September 2019).

Following this decision, the UK IPO issued a Practice Notice which said that itwas changing its practice to reflect the Genzyme decision.


SPC duration

Unfortunately, there are divergent practices on this issue in the various patentoffices throughout the EU.

Recent reference to the CJEU for clarification:

Case C-471/14 – Seattle Genetics.


SPC duration

What happens while the reference is pending?

Presumably, the UK IPO will continue to accept applications for rectification ofthe duration of an SPC.

Reaction by generic pharma?


Topic no. 3: the Neurim decision

Recap

Relates to Article 3(d) of Regulation No 469/2009.

Facts

Neurim obtained a patent (European patent no. 0518468) claimingformulations of melatonin, a natural hormone. Melatonin was known by thepriority date of Neurim’s patent; Neurim’s claims were to a novel method of useof melatonin. Neurim obtained a marketing authorisation for prolonged releasetablets of melatonin. The product is marketed under the brand name Circadin.


Neurim

Recap

Neurim applied to the UK IPO for a SPC. An objection was raised, based on aprevious veterinary marketing authorisation, for the use of melatonin in sheep(the product was called Regulin).

A previous decision of the Court of Justice (Pharmacia – Case C-31/03) was tothe effect that it makes no difference for the purpose of Article 3(d) whether thefirst marketing authorisation is for human or veterinary use, i.e. if there is aprevious authorisation for veterinary use, this “counts” for the purpose of Article3(d) and would prevent the grant of an SPC for the same product for medicinaluse in humans.


Neurim

Recap

At first instance, the decision by the UK IPO to reject Neurim’s SPC applicationwas upheld by Arnold, J. However, the Court of Appeal decided to refer thequestion of Neurim’s eligibility for a SPC to the CJEU:

“If Neurim are wrong, then the [SPC] Regulation will not have achieved its keypurpose for large areas of pharmaceutical research: it will not be fit forpurpose. Whether that is so or not is clearly a matter for the EU’s highestcourt”

- judgment of Jacob, L.J. in Neurim v Comptroller-General of Patents [2011] EWCA Civ 228.


Neurim

Recap

The main question referred:

In interpreting Article 3, when a marketing authorisation (A) has been granted for amedicinal product comprising an active ingredient, is Article 3(d) to be construed asprecluding the grant of an SPC based on a later marketing authorisation (B) which is fora different medicinal product comprising the same active ingredient where the limits ofprotection conferred by the basic patent do not extend to placing the product the subjectof the earlier [marketing authorisation] on the market within the meaning of Article 4?

In essence, does the existence of an earlier marketing authorisation for a veterinarymedicinal product preclude the grant of a SPC for a different use of the same product?


Neurim

Decision of the CJEU, 19 July 2012.

The decision states that the “fundamental objective” of Regulation No469/2009 is to ensure sufficient protection to encourage pharmaceuticalresearch, which plays a decisive role in the continuing improvement of publichealth (paragraph 22).

The decision also cites the Explanatory Memorandum in support of itsreasoning that a patent protecting a new application of a new or known productmay enable an SPC to be granted (paragraph 24).


Neurim

Decision of the CJEU, 19 July 2012.

The conclusion

The mere existence of an earlier marketing authorisation obtained for aveterinary medicinal product does not preclude the grant of an SPC for adifferent application (use) of the same product for which an MA has beengranted, provided that the application (use) is within the limits of protectionconferred by the basic patent relied upon for the purposes of the application forthe SPC (paragraph 27).


Neurim

Note the subsequent reluctance of Arnold, J. to endorse the Neurim decision ofthe CJEU.

The Judge said (in AstraZeneca v UK IPO [2012] EWHC 2840 (Pat) - 19 October 2012):

“I prefer the reasoning in [2 previous CJEU decisions] Synthon and Generics to that inNeurim. The reasoning in Synthon and Generics has the advantage that it is consistentwith Pharmacia, MIT and Yissum. Neurim is not only inconsistent with all those earlierdecisions, but also appears to me to place undue emphasis on the SPC Regulation’s firstobjective and to give insufficient weight to its second and third objectives and the actualwording of the Regulation”.


Neurim

Discussion

The rumour doing the rounds during 2012-2013

Some speculated that the Neurim decision signalled a more liberalinterpretation of Regulation No 469/2009 by the CJEU which would potentiallyallow more SPCs to be granted.

The reality

Neurim was probably a “one off” case and unlikely to be of much practicalrelevance – see the next case (Glaxo/vaccine adjuvants).


Topic no. 4: ‘active ingredient’

Vaccine adjuvants – the GSK case

Facts

GSK filed an application for a SPC for “an oil in water emulsion comprisingsqualene, DL-α-tocopherol and polysorbate 80”, an adjuvant called AS03which is protected by European patent no. 0,868,918.

Later, GSK filed a separate application for a SPC for a vaccine comprising aninfluenza virus antigen and the adjuvant AS03, which is protected by Europeanpatent no. 1,618,889.


‘Active ingredient’

Vaccine adjuvants – the GSK case

Facts

In both applications, GSK relied upon a marketing authorisation for a pre-pandemic influenza vaccine called Prepandrix.

Both applications were rejected by the UK Intellectual Property Office, on thebasis that AS03 was not an “active ingredient” of Prepandrix within themeaning of Article 1(b) of Regulation No 469/2009, whether in its own right orin combination with the antigen contained in Prepandrix, because AS03 did nothave a therapeutic effect on its own.



GSK appealed to the Patents Court.

Arnold, J. held in a judgment handed down on 21 March 2013 [2013] EWHC 619

(Pat) that the presence of AS03 in Prepandrix has three benefits:

1. increased immunogenicity, including a high antibody response;

2. antigen-sparing; and

3. cross-reactivity.

Furthermore, studies had demonstrated that the presence of AS03 is animportant factor in ensuring that the vaccine satisfies the criteria for licensingby the FDA and the EMA.



GSK argued (in summary):

That the fundamental objective of Regulation No 469/2009 was to ensuresufficient protection to encourage pharmaceutical research.

This had been a key plank of the CJEU’s reasoning in the Neurim decision.

That the case of the adjuvant AS03 was distinguishable on the facts from theprevious case (MIT, Case C-431/04) concerning the eligibility for a certificate ofan excipient / active ingredient combination, since in that case the excipient inquestion had no separate physiological effect on the body.



It was agreed that the following questions should be referred to the CJEU(Case C-210/13):

1. Is an adjuvant which has no therapeutic effect on its own, but whichenhances the therapeutic effect of an antigen when combined with thatantigen in a vaccine, an 'active ingredient' within the meaning of Article 1(b)of Regulation No 469/2009?

2. If the answer to question 1 is no, can the combination of such an adjuvantwith an antigen nevertheless be regarded as a 'combination of activeingredients' within the meaning of Article 1(b) of Regulation No 469/2009?



The Court of Justice issued a reasoned order on 14 November 2013.

“The meaning and scope [of terms such as ‘active ingredient’ in the SPCRegulation] must be determined by considering the general context in whichthey are used and their usual meaning in everyday language” (decision,paragraph 27).

“It is important to note that it is generally accepted in pharmacology that theterm ‘active ingredient’ does not include substances forming part of a medicinalproduct which do not have an effect on their own on the human or animalbody” (decision, paragraph 28).



CJEU reasoned order of 14 November 2013 (ctd.)

“…[I]n Directive 2001/83…the concepts of ‘active substance’ and ‘adjuvant’ areclearly distinct and that also holds, in the context of [the SPC Regulation], forthe concept of ‘active ingredient’, which cannot, as such, include an adjuvant”(decision, paragraph 38.

“…where a patent protects an adjuvant as such…an SPC cannot be granted inrespect of that adjuvant, since it cannot be regarded as a ‘product’ within themeaning of Article 1(b)…” (decision, paragraph 39).



CJEU reasoned order of 14 November 2013 (ctd.)

“…the Court did not [in Neurim] cast doubt on the principle that Article 1(b) ofRegulation No 469/2009 is to be interpreted narrowly…to the effect that theterm ‘product’ cannot cover a substance which does not correspond to thedefinition of ‘active ingredient’…” (decision, paragraph 44).



Discussion - wider implications of this decision?

Suggests that ‘active ingredient’ in the SPC Regulation should be understoodas a concept borrowed from pharmaceutical regulatory law.

What about products that are racemates (mixtures of enantiomers in which oneof them is inactive)?

Is it possible to get an SPC for a product consisting of a racemic mixture andthen get another SPC for a separately patented, purified active enantiomer?

Same ‘active ingredient’?



What is generic pharma’s appetite to bring SPC revocation cases that push theboundaries of SPC law?

Thoughts

Requires a lot of litigation ‘staying power’ – national revocation case, probablyrequiring a reference to the Court of Justice: 3-4 years duration (lots of £££)?

Outcome uncertain – CJEU decisions hard to predict (the Neurim pendulum –back and forth…)



Postscript - Case C-631/13: Forsgren – Protein D

Questions referred:

Question 1

Under Article 1(b) and Article 3(a) and (b) of Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6

May 2009 concerning the supplementary protection certificate for medicinal products, provided that the other conditions are met,

may a SPC be granted for an active ingredient protected by a basic patent (in this case, Protein D) where that active ingredient is

contained in the medicinal product (in this case, Synflorix) as part of a covalent (molecular) bond with other active ingredients but

nonetheless retains its own effect?

If Question 1 is answered in the affirmative:

Question 2.

2.1. Under Article 3(a) and (b) of Regulation (EC) No 469/2009, may a SPC be granted for the substance protected by the basic

patent (in this case, Protein D) where that substance has a therapeutic effect of its own (in this case, as a vaccine against

Haemophilus influenzae bacteria) but the authorisation of the medicinal product does not relate to that effect?

2.2. Under Article 3(a) and (b) of Regulation (EC) No 469/2009, may a SPC be granted for the substance protected by the basic

patent (in this case, Protein D) where the authorisation describes that substance as a 'carrier' for the actual active ingredients (in

this case, Pneumococcal polysaccharides) and the carrier, as an adjuvant, enhances the effect of those substances, but that

effect is not expressly mentioned in the authorisation of the medicinal product?


Topic no. 5: SPC extensions and deadlines for submission

Background

Regulation (EC) Nos. 1901/2006 and 1902/2006 on medicinal products for paediatric use

(in force from 26 January 2007).

Key requirement:

From 26 July 2008, companies have been obliged to submit the results of clinical trials

performed in children with an application for a new marketing authorisation (or obtain a

decision beforehand from the Paediatric Committee sitting within the EMA granting a

waiver or deferral of paediatric clinical trials).


SPC extensions

The reward

A six month extension to the SPC term on submission of the results ofpaediatric studies, whether or not the drug is shown to be efficacious inchildren. For blockbuster products, the 6 month extension to a SPC is likely tobe an extremely valuable reward, far exceeding the cost of undertaking thepaediatric studies.

Overall, the new paediatric extensions will translate to a cost to the NHS drugs bill of between £30million and £120 million a year – in England alone

- UK Government Partial Regulatory Impact Assessment


SPC extensions

Getting the 6 month SPC extension is not a trivial matter:

• all of the measures contained in a Paediatric Investigation Plan (PIP)must have been complied with;

• the product must be authorised in all EU Member States;

• relevant information on the results of the paediatric studies must beincluded in the SmPC.


SPC extensions

Paediatric Regulation [(EC) No. 1901/2006]

Conditions for the grant of a six month extension - Article 36(1):

Where an application under [the marketing authorisation procedures in]

Articles 7 or 8 includes the results of all studies conducted in compliance with

an agreed paediatric investigation plan, the holder of the patent or the SPC

shall be entitled to a six month extension of the period referred to in Articles

13(1) and 13(2) of the [SPC Regulation].


SPC extensions


Conditions for the grant of a six month extension

Article 36(2):

The inclusion in a marketing authorisation of the statement referred to in Article

28(3) shall be used for the purposes of applying paragraph 1 of [Article 36].

Article 36(3):

Where the procedures laid down in Directive 2001/83/EC have been used, the

six month extension of the period referred to in paragraph [36(1)] shall be

granted only if the product is authorised in all Member States.


SPC extensions


Article 28(3) – Statement of Compliance

If the application complies with all the measures contained in the agreed

completed paediatric investigation plan and if the summary of product

characteristics (SmPC) reflects the results of studies conducted in compliance

with that agreed paediatric investigation plan, the competent authority shall

include within the marketing authorisation a statement indicating compliance of

the application with the agreed completed paediatric investigation plan...


SPC extensions

Timing issue

SPC Regulation, Article 7(4)

The application for an extension of the duration of a SPC already granted shallbe lodged not later than two years before the expiry of the SPC.

In practice, this deadline is proving very demanding, with the EMA frequentlyrequiring lengthy paediatric studies and making it difficult for everything to befinished in time in order to get the SPC extension application filed by thedeadline.


SPC extensions

Timing issue

…but this deadline is not a ‘hard’ deadline, according to the UK Court ofAppeal in the case of E.I. du Pont Nemours & Co. v UK IPO [2009] EWCA Civ966.

As a result of this case, the UK IPO accepts that everything need not becomplete by the date of the application. An applicant for an SPC extensioncan supplement its application later than the 2 year deadline with missingmaterial that was not to hand at the date of the application.


SPC extensions

Timing issue

How late is “late”?

“…the Comptroller can and should take into account all relevant factors.These will include the reasons for the failure to include all the…materials in theapplication, the extent to which the applicant is guilty [sic] of unreasonableconduct or delay, or how close to the date of expiry of the SPC full compliance[with the requirements of the Paediatric Regulation] is expected” (paragraph58, per Jacob, L.J.).


SPC extensions

Implications for generic pharma companies’ launch plans

What if my long-planned launch date is delayed at the last minute by 6 months,by a late decision by the UK IPO to grant a SPC extension?


Questions?

duncan curley's presentation to the cipa life sciences conference 20th november 2014

Law