An Update on Biosimilars and Biosimilar Litigation in the US · PDF fileAn Update on Biosimilars and Biosimilar Litigation in the ... • Amgen Inc. et al ... •Janssen’s motion

S K G F. C O M © 2015 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved.

An Update on Biosimilars and Biosimilar

Litigation in the US

Paul A. Calvo, Ph.D.

1 February 2016

2nd Biologics and Biosimilars

Congress - Berlin

S K G F. C O M © 2015 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved.2

Years of Nothing and Now…


Biosimilar approvals in Europe*Product name Active substance Authorization date Manufacturer/

Company name

Abasaglar (previously Abasria) insulin

glargine

9 Sep 2014 Eli Lilly/Boehringer

Ingelheim

Abseamed epoetin alfa 28 Aug 2007 Medice Arzneimittel Pütter

Accofil filgrastim 18 Sep 2014 Accord Healthcare

Bemfola follitropin alfa 24 March 2014 Finox Biotech

Binocrit epoetin alfa 28 Aug 2007 Sandoz

Biograstim filgrastim 15 Sep 2008 CT Arzneimittel

Epoetin alfa Hexal epoetin alfa 28 Aug 2007 Hexal

Filgrastim Hexal filgrastim 6 Feb 2009 Hexal

Filgrastim ratiopharm filgrastim 15 Sep 2008

Withdrawn on 20 Apr

2011

Ratiopharm

Grastofil filgrastim 18 Oct 2013 Apotex

Inflectra infliximab 10 Sep 2013 Hospira

Nivestim filgrastim 8 Jun 2010 Hospira

Omnitrope somatropin 12 Apr 2006 Sandoz

Ovaleap follitropin alfa 27 Sep 2013 Teva Pharma

Ratiograstim filgrastim 15 Sep 2008 Ratiopharm

Remsima infliximab 10 Sep 2013 Celltrion

Retacrit epoetin zeta 18 Dec 2007 Hospira

Silapo epoetin zeta 18 Dec 2007 STADA R & D

Tevagrastim filgrastim 15 Sep 2008 Teva Generics

Valtropin somatropin 24 Apr 2006

Withdrawn on 10 May

2012

BioPartners

Zarzio filgrastim 6 Feb 2009 Sandoz


Biosimilar approvals in USProduct name Active substance Authorization date Manufacturer/

Company name

Zarxio Filgrastim 6 March 2015 Sandoz

• 4 applications currently pending:

• Celltrion: infliximab

• Apotex: filgrastim

• Apotex: pegfilgrastim

• Hospira: epoetin alfa

• Amgen: adalimumab


FDA Issues Final Biosimilars

Guidelines• On April 28, 2015 FDA issued 3 final guidance documents on biosimilarity

• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

• Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein

• Questions and Answers Regarding Implementation of the Biologics Price Competition

and Innovation Act of 2009

• Documents reiterate use of a totality of the evidence approach for review of

applications for biosimilar products

• Encourages a stepwise approach to demonstrating biosimilarity – including

comparison of proposed product with reference in terms of structure,

function, animal toxicity, human PK/PD, clinical immunogenicity, and

clinical safety/effectiveness – with only rare exceptions.


• Changes from draft version of guidances

• Most of discussion of interchangeability was removed - separate

guidance document that is forthcoming.

• Sponsor will need to provide information to demonstrate biosimilarity

based on data directly comparing the proposed biosimilar product to

reference product.

• Elaborate on the type of bridging data needed when a biosimilar

applicant seeks to use a non-US licensed comparator product to

support a demonstration of biosimilarity.


Guidelines


• Changes from draft version of guidances cont’d:

• Specific comments have been provided for biosimilar developers

considering manufacturing/process changes after completing the

initial analytical similarity assessment including a requirement to

demonstrate comparability between the pre- and post-change

proposed product.

• More detailed comments regarding animal toxicity studies were

added.

• Previous Q and As relating to what constitutes the “publicly-available

information” that should be included in a 351(k) application and

whether an applicant can include a request for reference product

exclusivity in its 351(a) application were deleted – an indication that

the FDA is still considering its position on these points.


Guidelines


What is coming in 2016?

• Considerations in Demonstrating Interchangeability With a Reference

Product

• Labeling for Biosimilar Products

• Statistical Approaches to Evaluation of Analytical Similarity Data to

Support a Demonstration of Biosimilarity


Purple Book

• Lists of Licensed Biological Products with Reference Product Exclusivity

• Includes Biosimilarity or Interchangeability Evaluation

• Include date a biological product was licensed under 351(a)

• Whether FDA evaluated the biological product for reference product

exclusivity under section 351(k)(7)

• Biosimilar and interchangeable biological products licensed under

section 351(k) will be listed under the reference product to which

biosimilarity or interchangeability was demonstrated.

• Contains NO PATENT INFORMATION – no plan to include patent

information in the future.


State Anti-Substitution Bills

• 8 states—Delaware, Florida, Indiana, Massachusetts, North Dakota,

Oregon, Utah and Virginia—have enacted laws that limit biosimilar

substitution to those drugs that the FDA has deemed interchangeable.

• California, Illinois, Colorado, Maryland, New Jersey and North Carolina

advancing legislation that would allow substitution of interchangeable

biologics if the prescribing physician does not prohibit it, the pharmacist

provides notification and details of the switch, the cost of the biosimilar is

less, the patient is informed and written records are maintained.


Patent Exchange Timeline

Biosimilar

application

accepted

for FDA

review

20 Days

Applicant must notify

RPS and provide copy

of application

60 Days

RPS provides

list of patents

60 Days

BA must

provide RPS

with detailed

statement

60 Days

RPS provides

own detailed

statement

Negotiations

Negotiations

fail

15 Days 5 Days

BA notifies

RPS of

number of

patents to

be litigated

Parties exchange

lists of patents

to be litigated

30 Days

RPS must

bring suit


• Amgen Inc. et al. v. Sandoz Inc. et al., case number 15-1499, in the U.S.

Court of Appeals for the Federal Circuit – Neupogen

• Patent exchange process is optional

• 180 Days’ Notice Prior to First Commercial Marketing Must Await

Licensure

• Sandoz requested an extension to file a petition for a writ of certiorari

to US Supreme Court. Deadline is now February 16, 2016.

Litigation involving Patent Provisions


• Janssen Biotech, Inc. et. al. v. Celltrion Healthcare Co., Ltd. et. al., Civil

Action No. 1:15-cv-10698, U.S. District Court for the District of

Massachusetts – Remicade

• Janssen’s motion to stay the proceedings with respect to U.S. patent

6,284,471

• The cross motions for summary judgment in light of the Federal

Circuit’s Amgen v. Sandoz decision

• Janssen’s motion to modify the protective order and Celltrion’s

alternative cross motion to stay Janssen’s motion.




• Amgen v. Apotex, case number 15-cv-62081, in the U.S. District Court

for the Southern District of Florida

• December 30, 2015 - Apotex filed its opening appellate brief. Because

the parties completed the patent dance under 42 U.S.C. § 262(l)(2)–

(l)(5) prior to initiation of suit, notice of commercial marketing is not

required

• Further, Apotex argues that making the 180-day notice period

mandatory in all cases—as opposed to just cases where the biosimilar

applicant chooses not to participate in the patent dance—would amount

to a de facto extension of the 12-year exclusivity period granted under

the BPCIA


Cancellation Proceedings at the

USPTO

• AIA introduced new cancellation proceedings that are instituted

at the USPTO

• Inter Partes Review

• Post Grant Review

• Increased interest due to filings of Kyle Bass

• Ampyra – Acorda Therapeutics

• Imbruvica – J & J and Pharmacyclics

• Lialda and Gattex – Shire

• Thalomid – Celgene

• Tecfidera - Biogen


Inter partes review at a glance

• Post-issuance nullity proceeding against any patent - ~120

bio/pharma;

• Based on novelty/obviousness of prior art patents and printed

publications (not double patenting or ODP)

• Brought within 1 year of service of complaint against petitioner –

or counterclaim of infringement; exception in case of joinder

• ~80% of IPRs have parallel litigation


IPRs filed for biosimilars• Hospira – (IPR 2013-00365) filed June 19, 2013 on US Pat. No. 6,747,002 –

Janssen Pharmaceuticals

• Challenged claims covering dosing regimen for EPO

• Janssen disclaimed the challenged claims – petition is moot

• Boehringer Ingelheim – (IPR2015-00415, 417, and 418) – filed December 15, 2014

on US Pat. Nos. 7,820,161, 7,976,838, and 8,329,172 – Genentech Inc. and

Biogen Inc.

• Institution of 2 of 3 petitions

• BI requested adverse judgment


• IPR2016-00383 (Genzyme Corp.) (U.S. Patent No. 6,331,415)

• Petitioner: Genzyme Corp.

• Patent Title: Methods of Producing Immunoglobulins, Vectors and Transformed Host

Cells for Use Therein

• Patent Owner: Genentech, Inc. and City of Hope

• IPR2016-00408, 00409 (Boehringer Ingelheim) (U.S. Patent No.

8,889,135)

• Petitioner: Boehringer Ingelheim Corp., Boehringer Ingelheim International GmbH,

Boehringer Ingelheim Pharma GmbH & Co. KG, Boehringer Ingelheim

Pharmaceuticals, Inc., Boehringer Ingelheim USA Corp.

• Patent Title: Methods of Administering Anti-TNFα Antibodies

• Patent Owner: AbbVie Biotechnology Ltd.

IPRs filed for biosimilars


First IPR FWD for biologic - Myozyme

• BioMarin Pharmaceutical Inc. v. Genzyme Therapeutic Products Ltd.

Partnership, case numbers IPR2013-00534 and IPR2013-00537, and

BioMarin Pharmaceutical Inc. v. Duke University, case number IPR2013-

00535 – Myozyme

• 1. A method of treating a human patient with Pompe's disease,

comprising intravenously administering biweekly to the patient a

therapeutically effective amount of human acid alpha glucosidase,

whereby the concentration of accumulated glycogen in the patient is

reduced and/or further accumulation of glycogen is arrested.

• Obvious over two separate obviousness grounds


Myozyme - continued• PTAB agreed that it could not have been predicted with "absolute certainty"

that Pompe disease could be treated safely and effectively using GAA.

• However, there was sufficient motivation to pursue the clinical development

of treatment as disclosed in prior art.

• Only missing element was the biweekly dosing schedule. But,

experimentation needed to achieve this treatment regime was "nothing

more than" routine.

• No nexus between the evidence related to long-felt but unmet need,

skepticism, praise, and commercial success because PTAB characterized

the invention as limited to biweekly administration feature.

• Because the secondary considerations related to the merits of the

therapeutic compositions of GAA, they were inapplicable to the present

invention.


• PTAB Denies IPR Institution on AbbVie’s Humira

• The PTAB denied institution on two of Amgen’s IPR petitions (IPR2015-

01517, IPR2015-01514) against AbbVie’s Humira. The patents,

8,916,157 and 8,916,158, are directed to formulations of Humira, that

Amgen argued were obvious because they combined adalimumab, a

known antibody, with known excipients for antibody formulations.

• PTAB held: “Amgen has not persuaded us that ‘[t]he skilled person

would have had a reasonable expectation of success in applying the

formulations commercially available and taught in the literature [to

adalimumab].”

IPRs filed for biosimilars


Lower Burden of Proof

• No “presumption of validity”

• Preponderance of the evidence standard to prove unpatentabiliity

− Compare with “clear and convincing” standard in district court to prove

invalidity

• In re Baxter Intern., Inc., (Fed. Cir. 2012)

− “a prior court decision in which a party has failed to prove a patent

invalid does not bar the [PTO] from subsequently…[finding] that the

patent is, indeed, invalid.” (O’Malley J. concurring in denial of en banc)

− “If the PTO later considers the validity of that same patent, it does so

based on the evidence before it and under the lesser burden of

proof that applies in reexamination proceedings.” Id.


Expeditious Resolution and Patent

Certainty

• IPR will most times be faster than district court

• Fast pace favors generic/biosimilar—could nullify any “delays”

• Allows generic/biosimilar to be aggressor

• Force settlement


Bioproduction patents – New

IPR battleground?

• Any form of delay favors reference product sponsor – be it a first

biosimilar applicant or any subsequent filer

• Preemptive IPR filings (prior to 351(k) submission) could induce stay in

DC pending resolution

• Timing could end up being quicker than exchange process

• PTAB technical expertise and broader claim construction heavily favors

attack at USPTO rather than DC

• IPR challenges could limit reference product sponsor ability to go out

and find additional IP to exclusively license to use in later attacks


Thank you

Paul A. Calvo, Ph.D. – Director

Sterne, Kessler, Goldstein & Fox

1100 New York Avenue, NW

Washington, DC 20005

Tel. no. 202.772.8846

Email. [email protected]