biosimilars: navigating current legal and regulatory...

Biosimilars: Navigating Current

Legal and Regulatory Challenges Exploring How the First Biosimilar Cases are Shaping the Industry and Biologics Patents

Today’s faculty features:

1pm Eastern | 12pm Central | 11am Mountain | 10am Pacific

The audio portion of the conference may be accessed via the telephone or by using your computer's

speakers. Please refer to the instructions emailed to registrants for additional information. If you

have any questions, please contact Customer Service at 1-800-926-7926 ext. 10.

THURSDAY, APRIL 23, 2015

Presenting a live 90-minute webinar with interactive Q&A

Nathaniel S. Edwards, Ph.D., IP Counsel, Biogen, Cambridge, Mass.

Mary Henninger, Ph.D., Partner, McNeill Baur, Johns Creek, Ga.

Sanya Sukduang, Partner, Finnegan Henderson Farabow Garrett & Dunner, Washington, D.C.

Tips for Optimal Quality

Sound Quality

If you are listening via your computer speakers, please note that the quality

of your sound will vary depending on the speed and quality of your internet

connection.

If the sound quality is not satisfactory, you may listen via the phone: dial

1-866-819-0113 and enter your PIN when prompted. Otherwise, please

send us a chat or e-mail [email protected] immediately so we can address

the problem.

If you dialed in and have any difficulties during the call, press *0 for assistance.

Viewing Quality

To maximize your screen, press the F11 key on your keyboard. To exit full screen,

press the F11 key again.

FOR LIVE EVENT ONLY

Continuing Education Credits

For CLE purposes, please let us know how many people are listening at your

location by completing each of the following steps:

• In the chat box, type (1) your company name and (2) the number of

attendees at your location

• Click the word balloon button to send

FOR LIVE EVENT ONLY

Biosimilars: Navigating Current Legal

and Regulatory Challenges

Nathaniel Edwards, IP Counsel, Biogen

Mary Henninger, Partner, McNeill Baur

Sanya Sukduang, Partner, Finnegan

April 23, 2015

BPCIA: The Sleeping Giant Awakes

The BPCIA was signed into law on March 23, 2010, amended

– § 351 of the PHSA (42 U.S.C. § 262)

– § 271(e) of the Patent Act

– Created a statutory framework for FDA approval of new

product as “biosimilar” to or “interchangeable” with

“reference” products

Significant activity begins in 2014-2015

– Several biosimilar applications filed

– 1st series of litigations

– FDA responds to Citizen Petitions

– FDA approves 1st biosimilar

5

Today’s Agenda

Update in recent biosimilar litigations

Regulatory developments

Patent prosecution considerations

Q&A

6

7

Update on BPCIA Litigations

BPCIA Litigation ≠ Hatch Waxman

No Orange Book listing

– Biosimilar applicant has burden of identifying relevant patents during development work

No limitation on types of patents to assert

– Hatch-Waxman limited to listing patents covering the active ingredient, formulations, and method of use patents

– BPCIA allows RPS to assert any patent that a claim of patent infringement “could reasonably be asserted”

No 30 month stay upon filing suit

No 180 day exclusivity for 1st filed biosimilar

180 day notice before 1st commercial marketing of biosimilar

8

Patent Litigation and FDA Approval

Patent litigation process cannot start until four

years after RP is first licensed

Patent litigation process does not stay FDA

approval of biosimilar application

– Even if biosimilar applicant indicates it will not

market until after patent expiry, FDA can still

approve application

Only way to stop biosimilar product from coming

onto the market is injunction from the court

– Timing will be critical

9

Biosimilar

files

Application

Biosimilar

Application

accepted by

FDA

Biosimilar

provides

confidential

info to RPS

RPS

provides

patent list to

Biosimilar

Biosimilar

provides RPS

with patent list

and detailed

statement

RPS provides

Biosimilar with

detailed statement

RPS & Biosimilar

negotiate final list of

patents to litigate

Agreement

reached

Biosimilar identifies

number of patents that

can be asserted

RPS files complaint Simultaneous exchange

of patent lists

RPS files complaint

180 days before Biosimilar

commercialization must notify RPS

? 20 days 60 days 60 days

60 days 15 days

no yes

30 days 5 days

30 days

10

Patent Exchange Process Under 42 U.S.C. § 262(l)

11

What happens if there is no biosimilar application on file?

12

Sandoz v. Amgen: Do You Need A Biosimilar Application?

Sandoz Inc. v. Amgen Inc., No. 13–2904 MMC, (ND Cal, 11.12.13)

– Sandoz filed a DJ action:

Two patents covering Enbrel are invalid/unenforceable and will not be infringed

No biosimilar application for Enbrel but conducting Phase III trials

– Amgen moved to dismiss on two related grounds:

No statutory authority to consider a patent dispute involving a biosimilar product until after such time as an application for FDA approval of the biosimilar product has been filed; and

No case or controversy

– No immediacy

– No reality

– No standing

– Sandoz argued controversy is real and immediate


Sandoz Inc. v. Amgen Inc., (ND Cal, 11.12.13)

– District Court GRANTED Amgen’s MTD for lack of SMJ

42 USC 262(l)(8): 180-Day notice of commercial marketing

does not grant Sandoz right to file DJ action when no

biosimilar application under 262(k) is on file;

Even if 262(k) application on file, applicant cannot file DJ until

complies with obligations under 262(l)(2)(A): copy of

application and manufacturing information;

No real and immediate injury to Sandoz

– Amgen never advised Sandoz it would sue and not in

position make such a determination because no

application on file;

– Amgen’s prior statements on patent ownership do not

constitute immediate threat to Sandoz

13



– Fed Circuit (773 F.3d 1274, Dec. 5, 2014) - AFFIRMED

No case or controversy – relying on traditional case or

controversy case law

– Particular facts presented did not “meet the requirements of

immediacy and reality”

– No immediacy because Sandoz was still conducting Phase III

trials

– Infringement suit has uncertainties because Sandoz’s product is

not final

– Consistent with Hatch-Waxman precedent finding no DJ

jurisdiction where ANDA application not yet on file

– No “immediate and significant” adverse impact on Sandoz at this

time

14



– Federal Circuit did not comment on BPCIA:

“Our resolution of this case makes it unnecessary for us

to address the district court's BPCIA rationale.”

“We do not address distinct questions that may arise as

Sandoz continues its efforts to develop and obtain

approval to market an etanercept product. In particular,

we do not address Sandoz's ability to seek a declaratory

judgment if and when it files an FDA application under

the BPCIA.”

15

Celltrion v. Kennedy: Do You Need A Biosimilar Application?

Celltrion Healthcare Co., Ltd. v. Kennedy, No. 14-2256-PAC

(SDNY 3.31.14)

– Celltrion filed DJ complaint alleging patents covering its Remsima

biosimilar (Remicade) are invalid

– Kennedy is a patent owner but not BLA holder

– Kennedy filed MTD for lack of SMJ

No case or controversy

– Celltrion was in discussions with the FDA regarding its Remsima

application but had not yet filed

– BPCIA prevents DJ action without an application

In opposition, Celltrion argued

– Substantial preparation and investment including completion of

clinical trial

– Kennedy has previously asserted patents in U.S. and foreign

jurisdictions

16

Celltrion v. Kennedy: Do You Need A Biosimilar Application?

Celltrion Healthcare Co., Ltd. v. Kennedy (SDNY 3.31.14)

District court GRANTED Kennedy’s MTD

– Celltrion still too far from obtaining FDA approval

No application on file

– Kennedy has not expressed clear intent to sue Celltrion

– BPCIA precludes DJ jurisdiction

“Even if the Court were to find that Celltrion had engaged in sufficient

meaningful preparation to market Remsima and that the threat of injury

was sufficiently demonstrable, the Court would still exercise its

discretion to decline to hear this case in light of the existence of

the BPCIA statutory framework for the resolution of patent disputes in

the licensing of biosimilars.”

“Skirting” BPCIA while “reaping its benefits” improper

Celltrion needs to use BPCIA against Janssen (BLA holder) before

litigating against Kennedy

17

18

Does a biosimilar applicant need to disclose its application and manufacturing information?

Patent Exchange Process Under 42 U.S.C. § 262(l)

Biosimilar

files

Application

Biosimilar

Application

accepted by

FDA

Biosimilar

provides

confidential

info to RPS

RPS

provides

patent list to

Biosimilar

Biosimilar

provides RPS

with patent list

and detailed

statement

RPS provides

Biosimilar with

detailed statement

RPS & Biosimilar

negotiate final list of

patents to litigate

Agreement

reached

Biosimilar identifies

number of patents that

can be asserted

RPS files complaint Simultaneous exchange

of patent lists

RPS files complaint

180 days before Biosimilar

commercialization must notify RPS

? 20 days 60 days 60 days

60 days 15 days

no yes

30 days 5 days

30 days

19

Confidential Disclosure of Biosimilar Application

Confidential information

– Within 20 days after Biosimilar applicant

receives notice that application has been

accepted for review, Biosimilar applicant “shall

provide”:

Copy of the application

Information that describes the process used to manufacture the

biological product and

“May provide” other information requested by the RPS

42 U.S.C. § 262(l)(2)

20


Access to confidential information 42 U.S.C. § 262(l)(1)(B)

– One in-house RPS lawyer who does not prosecute patents related

to RP

– Outside counsel who do not prosecute patents related to RP

– Owner of patent if not RPS and agrees to be bound by

confidentiality provisions

Limitation on disclosure 42 U.S.C. § 262(l)(1)(C),(D), (F)

– No disclosure to anyone else without prior written consent

Includes RPS employees, outside experts, or other outside counsel

– Information only used to determine identify relevant patents that “a

claim of patent infringement could reasonably be asserted”

– Confidentiality provisions govern until court enters protective order

21


42 U.S.C. § 262(l)(9)(C): Subsection (k)

application not provided:

If a subsection (k) applicant fails to provide the

application and information required under paragraph

(2)(A), the reference product sponsor, but not the

subsection (k) applicant, may bring an action under

section 2201 of title 28 for a declaration of infringement,

validity, or enforceability of any patent that claims the

biological product or a use of the biological

product”

Does this include patents covering methods of

manufacturing?

22

Preliminary Injunctions

Biosimilar applicant must give RPS 180-day notice before date of first commercial marketing of Biosimilar

“The subsection (k) applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k).” (42 U.S.C. § 262(l(8)(A))

After receiving 180-day notice, and before commercial marketing by Biosimilar, RPS may seek a preliminary injunction with respect to any patent:

– Identified during patent exchange but Biosimilar applicant excluded from the list of patents to litigate

RPS and Biosimilar applicant have a duty to cooperate in expediting discovery for purposes of preliminary injunction

23

Amgen v. Sandoz: Disclosure of Application

Amgen Inc. v. Sandoz Inc., No. 3:14-cv-04741-EDL (ND

Cal, 10.24.14)

– Sandoz offered to provide a copy of its biosimilar application for

Zarxio without confidentiality safeguards

– Amgen and Sandoz did not reach agreement on confidentiality

– Amgen files DJ complaint

Infringement, conversion and unfair competition under CA law

– Amgen filed a PI motion (2/5/2015)

Block commercial manufacture, use, offer to sell, sale within the

United States, or importation into the United States until

– BPCIA says “shall” disclose application (42 U.S.C. § 262(l)(2))

– Sandoz’s 180-day notice of commercial marketing premature because not

“before” being “licensed” by FDA (42 U.S.C. § 262(l)(8))

– Provide a copy of the application, complete patent exchange process,

provide notice of commercial marketing

24


Amgen Inc. v. Sandoz Inc., (ND Cal, 10.24.14)

– Sandoz’s opposition

BPCIA does not require disclosure of application

– provides remedies (DJ suit) if application not provided

– Amgen can assert all relevant patents (35 U.S.C. §271§(2)(C)(ii))

180 day notice of commercial manufacturing does not first

require FDA approval:

No irreparable harm

– Sandoz offered application with “industry standard” confidentiality

obligations by Amgen refused

– Amgen had right to sue immediately after expiration of 20 day

period to disclose application but waited 3 months

– Economic harm can be compensated with monetary damages

25


Mar. 19, 2015 (again on Apr. 15): D. Ct. denies Amgen’s PI

– Disclosure of biosimilar application is optional

“Shall” does not always mean mandatory particularly where the law

provides remedies for failure to comply

Biosimilar applicant confident with patent position can expedite

litigation by refusing to comply with BPCIA

– 180-day notice can be provided before FDA approval

“Licensed” does not require FDA approval prior to 180-day notice

“Before” modifies “first commercial marketing” not “licensed” thus must

give notice “before” marketing

Waiting until FDA approval will give RPS an additional 6 months

exclusivity not intended by BPCIA

– Denial of PI

Amgen only raised “speculative” notions of irreparable harm

Amgen did not provide any proofs of infringement

26


Amgen’s Citizen’s Petition

– Requests certification that applicant will comply with the disclosure

obligations of the BPCIA (application and manufacturing process)

– Requests that FDA won’t begin review until certification is received

Momenta Pharmaceutical’s comments

– FDA not part of information exchange

– Information exchange is optional

– BPCIA provides remedies if biosimilar applicant does not exchange

information

March 25, 2015: FDA denied Amgen’s Citizen’s Petition

– BPCIA does not require certification

– BPCIA does not describe FDA involvement in monitoring or enforcing

information exchange

– Competing interpretations of information exchange are subject of current

litigation

27

What Does This All Mean? No DJ jurisdiction until biosimilar application is filed

– Likely applies for both RPS, patent owners, and potential biosimilar

applicants

FDA will not get involved

– Intent on meeting 10 month approval goals

FY2014: Review 70% of biosimilar applications w/I 10 months

FY2015: Review 70% of biosimilar applications w/I 10 month

– Approval before litigation even starts?

Ability to expedite litigation unless reversed by Fed. Cir.

RPS must be ready to litigate immediately

– 35 USC §271(4)(D): cannot get injunction if biosimilar was approved prior to court

decision on infringement and validity

– Engage experts on infringement and validity

– Gather evidence for PI including irreparable harm

28 28

Regulatory Developments

29

How We Got Here

2009 2010 2011 2012 2013 2014 2015

EMA approves Zarzio

(Feb 2009)

US enacts BPCIA

(Mar 2010) FDA accepts Sandoz’s

351(k) application for

review (July 2014)

FDA public

hearing re: Zarxio

(Jan 2015)

FDA approves

Zarxio

(Mar 2015)

FDA draft guidance

(Feb 2012) FDA draft guidance

(May and August

2014)

FDA draft

guidance

(Mar 2013)

31

BPCIA & FDA Guidance

32

BPCIA Overview

Allows for “biosimilar” products

Allows for “interchangeable” products

Provides ~ 1 year exclusivity period for first

approved “interchangeable” product

Provides 12 year exclusivity period for RP

Allows biosimilar applicant to file application 4

years after RP is first licensed

Potential for FDA guidance

33

BPCIA Definition of “Biological Product”

A virus, therapeutic serum, toxin, antitoxin, vaccine, blood,

blood component or derivative, allergenic product, protein

(except any chemically synthesized polypeptide), or

analogous product, or arsphenamine or derivative of

arsphenamine (or any other trivalent organic arsenic

compound), applicable to the prevention, treatment, or cure

of a disease or condition of human beings

FDA definition of “protein” (FDA Q&A at 13):

– “[A]ny alpha amino acid polymer with a specific defined sequence

that is greater than 40 amino acids in size”

– “Compounds greater than 40 amino acids in size will be scrutinized

to determine whether they are related to a natural peptide of

shorter length and, if so, whether the additional amino acids raise

any concerns about the risk/benefit profile of the product.”

34

“Biosimilar” Products

“Biosimilar” means: – “(A) that the biological product is highly similar to the reference

product notwithstanding minor differences in clinically inactive

components; and

(B) there are no clinically meaningful differences between the

biological product and the reference product in terms of the safety,

purity, and potency of the product.”

42 U.S.C. § 262(i)(2)

– “Clinically meaningful differences could include a difference in

the expected range of safety, purity, and potency of the proposed

and reference products” (Scientific Considerations at 8.)

– Non-clinically meaningful differences could include “slight

differences in rates of occurrence of adverse events between the

two products.” (Scientific Considerations at 8.)

35

FDA Draft Guidance

Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (“Q & A”; Feb 2012)

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (“Scientific Considerations”; Feb 2012)

Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (“Quality Considerations”; Feb 2012)

Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants (“Formal Meetings”; March 2013)

Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (“Pharmacology”; May 2014)

Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (“RP Exclusivity”; Aug 2014)

36

FDA Promises Additional Draft Guidance in 2015

Biosimilars: Additional Questions and Answers

Regarding Implementation of the Biologics Price

Competition and Innovation Act of 2009

Considerations in Demonstrating

Interchangeability to a Reference Product

Labeling for Biosimilar Biological Products

Statistical Approaches to Evaluation of Analytical

Similarity Data to Support a Demonstration of

Biosimilarity

37

Factors FDA Will Consider to Determine

Whether Biosimilar Is “Highly Similar”

Expression System

Manufacturing Process

Assessment of Physiochemical Properties

Functional Activities

Receptor Binding and Immunochemical Properties

Impurities

Reference Product and Reference Standards

Finished Drug Product

Stability

38

FDA Guidance on Establishing Biosimilarity

Communication With FDA is Essential

– “FDA encourages sponsors to consult extensively with the

Agency after completion of comparative structural and

functional analysis (before finalizing the clinical program),

and throughout development as needed.” (Scientific

Considerations at 7-8.)

– “FDA also advises sponsors intending … to meet with FDA to

present their product development plans and establish a

schedule of milestones that will serve as landmarks for future

discussions with the Agency. FDA anticipates that early

discussions with FDA about product development plans and

about the appropriate scientific justifications will facilitate

biosimilar development.” (Scientific Considerations at 21.)

39


“FDA intends to use a risk-based, totality-of-the

evidence approach to evaluate all available data and

information submitted in support of the biosimilarity of the

proposed product.” (Scientific Considerations at 8.)

“The type and amount of analyses and testing that will be

sufficient to demonstrate biosimilarity will be determined

on a product-specific basis.” (Id.)

“[M]any product-specific factors can influence the

components of a product development program intended

to establish that a proposed product is biosimilar to a

reference product. Therefore, FDA will ordinarily provide

feedback on a case-by-case basis on the components of a

development program for a proposed product.” (Id. at 21.)

40


Structural and Functional Characterization

– “The more comprehensive and robust the comparative structural and functional characterization . . . the more useful such characterization will be in determining what additional studies may be needed.” (Scientific Considerations at 7.)

– Primary structures, such as amino acid sequence

– Higher order structures, including secondary, tertiary, and quaternary structure (including aggregation)

– Enzymatic post-translational modifications, such as glycosylation and phosphorylation

– Other potential variants, such as protein deamidation and oxidation

– Intentional chemical modifications, such as PEGylation sites and characteristics (Id. at 9.)

41


Animal data: “The sponsor should then consider the role of animal data in assessing toxicity and, in some cases, in providing additional support for demonstrating biosimilarity and in contributing to the immunogenicity assessment.” (Scientific Considerations at 7.)

– Animal Toxicity Studies: “As a scientific matter, animal toxicity data are considered useful when, based on the results of extensive structural and functional characterization . . . Animal toxicity studies are generally not useful if there is no animal species that can provide pharmacologically relevant data for the protein product.” (Scientific Considerations at 11.)

– Animal Immunogenicity Studies: “Animal immunogenicity assessments generally do not predict potential immunogenic responses to protein products in humans. However, when differences in manufacturing (e.g., impurities or excipients) between the proposed product and the reference product may result in differences in immunogenicity, measurement of anti-protein antibody responses in animals may provide useful information relevant to patient safety.” (Scientific Considerations at 12.)

– Animal PK and PD Measures: “Under certain circumstances, a single-dose study in animals comparing the proposed product and reference product using PK and PD measures may contribute to the totality of evidence that supports a demonstration of biosimilarity.” (Scientific Considerations at 12.)

42


Human Studies

– “In general, the clinical program for a 351(k) application

must include a clinical study or studies (including an

assessment of immunogenicity and PK or PD) sufficient to

demonstrate safety, purity, and potency in one or more

appropriate conditions of use for which the reference

product is licensed and intended to be used and for which

licensure is sought for the biological product, as set forth in

the PHS Act. The scope and magnitude of clinical

studies will depend on the extent of residual

uncertainty about the biosimilarity of the two products

after conducting structural and functional

characterization and possible animal studies.”

(Scientific Considerations at 12.)

43


Human Studies (cont.)

– PK / PD studies: “We have determined that both PK and PD studies . . . generally will be expected to establish biosimilarity, unless a sponsor can scientifically justify that an element is unnecessary.” (Scientific Considerations at 13.)

– Clinical immunogenicity studies: “[A]t least one clinical study that includes a comparison of the immunogenicity of the proposed product to that of the reference product will generally be expected.” (Scientific Considerations at 14.)

– Comparative clinical safety and effectiveness data

“If there are residual uncertainties about the biosimilarity of the two products after conducting structural and functional studies, animal toxicity studies, human PK and PD studies, and clinical immunogenicity assessment, the sponsor should then consider what comparative clinical safety and effectiveness data may be adequate.” (Scientific Considerations at 7.)

“Clinical studies should be designed such that they can demonstrate that the proposed product has neither decreased nor increased activity compared to the reference product.” (Scientific Considerations at 17.)

44

“Interchangeable” Products

“Interchangeable” means:

– Biosimilar to RP and

– Can be expected to produce the same clinical

result as the RP in any given patient, and

– For a biological product that is administered

more than once to an individual, the risk in

terms of safety or diminished efficacy of

alternating or switching between use of the

biological product and the RP is not greater

than the risk of using the RP without such

alteration or switch. 42 U.S.C. § 262(k)(4)

45


What’s the benefit for “interchangeability”?

– The interchangeable product “may be substituted for the reference

product without the intervention of the health care provider who

prescribed the reference product.”

– A biosimilar product cannot be switched for RP without doctor

intervention

42 U.S.C. § 262(i)(3)

FDA has not yet issued guidance on Interchangeability

– “At this time it would be difficult as a scientific matter for a

prospective biosimilar applicant to establish interchangeability in an

original 351(k) application. . . . FDA is continuing to consider the

type of information sufficient to enable FDA to determine that

a biological product is interchangeable with the reference

product.” Q & A at 11-12.

46


Exclusivity for first approved “interchangeable” product – No subsequent FOB can be found to be

interchangeable until earlier of

1 year after first commercial marketing of first interchangeable FOB

18 months after final court decision or dismissal with or without prejudice on patents involved in suit against first interchangeable FOB

42 months after approval of first interchangeable FOB if patent litigation is still ongoing within the 42 month period or 18 months after such approval if no patent suit was filed against first interchangeable FOB

42 U.S.C. § 262(k)(6)

47

FDA Guidance Misc. Issues

Reliance on Non-US Licensed Product Comparisons

– “In general, a sponsor needs to provide information to demonstrate

biosimilarity based on data directly comparing the proposed protein

product with the reference product. . . However, under certain

circumstances, a sponsor may seek to use data derived from

animal or clinical studies comparing a proposed protein product

with a non-U.S. licensed product . . . In such a case, the sponsor

should provide adequate data or information to scientifically

justify the relevance of this comparative data to an

assessment of biosimilarity and to establish an acceptable

bridge to the U.S.-licensed reference product.” (Quality

Considerations at 9.)

48

FDA Guidance Misc. Issues

Extrapolating to Other Indications

– “If the proposed product meets the statutory requirements for

licensure as a biosimilar product under section 351(k) . . . the

potential exists for the proposed product to be licensed for one or

more additional conditions of use for which the reference product is

licensed. However, the sponsor will need to provide sufficient

scientific justification for extrapolating clinical data to support

a determination of biosimilarity for each condition of use for

which licensure is sought.” (Scientific Considerations at 19; Q &

A at 9.)

49

FDA’s First Biosimilar Approval: Zarxio

50

First US Biosimilar Approved

On March 6, 2015, FDA approved the first US

biosimilar

Zarxio is a biosimilar of Amgen Inc.’s Neupogen

G-CSF analog – stimulates growth and

differentiation of certain types of white blood cells

Used to prevent infections during cancer therapy

Relatively small/simple biologic

51

First FDA Hearing

January 7, 2015, Oncologic Drug Advisory Committee

Meeting

First FDA hearing considering a biosimilar application

Considered Sandoz’s application for a filgrastim biosimilar

– Sandoz’s proposed product = Zarxio

– Reference product = Amgen Inc.’s Neupogen

Committee agreed that Zarxio was biosimilar to Neupogen

Committee agreed that Zarxio should be approved for the

same 5 indications as Neupogen

52

First FDA Hearing

FDA claims they are committed to an “abbreviated”

approval process

Still no mention of interchangeability

Minor differences are OK

– Different pH buffer system – patent considerations

Case by case totality of the evidence

– Structural / functional characterization + clinical studies

for a relatively simple product

FDA cares about European history

– Committee – without established European track

record, it would have been a much closer call

53

The FDA Allowed Extrapolation to Other

Indications

The FDA approved Zarxio for the same indications as

Neupogen:

– patients with cancer receiving myelosuppressive

chemotherapy;

– patients with acute myeloid leukemia receiving induction

or consolidation chemotherapy;

– patients with cancer undergoing bone marrow

transplantation;

– patients undergoing autologous peripheral blood

progenitor cell collection and therapy; and

– patients with severe chronic neutropenia.

54

Initial Implications

The door is open

FDA beats its goal of 10 month review

Case by case, totality of the evidence

Minor differences are OK

Phase III head-to-head trials as the norm?

European history matters

Extrapolation is possible

55

Open Questions

What about larger, more complex molecules?

– Data requirements

– Extrapolation

– Timelines

Naming

Interchangeability

Limits on extrapolation?

Structural differences?

Promotion

56

Prosecution Considerations for Biologics

57

Current Biosimilar Applications

Fusion proteins

– Amgen’s Neupogen® (Sandoz - approved)

– Amgen’s Neulasta® (Apotex)

– Amgen’s Epogen® and Janssen’s Procrit® (Hospira)

Antibodies

– Janssen’s Remicade® (Celltrion)

Likelihood of other classes of biosimilars?

58

Timing Considerations

12 year initial data exclusivity

6 months pediatric extension

No new indication extension

Biosimilar application may be filed 4 years after RP

licensed (4.5 years if pediatric extension granted)

USPTO is getting faster, resulting in less PTA

Initial patent term versus preclinical development

time

59

Definition: Biosimilarity

The biological product is highly similar to the RP

notwithstanding minor differences in clinically

inactive components; and

There are no clinically meaningful differences

between the biological product and the RP in

terms of the safety, purity, and potency of the

product.

60

42 USC § 262(i)(2)

Definition: Interchangeability

The biological product

– is biosimilar to the RP; and

– can be expected to produce the same clinical result as

the RP in any given patient; and

For a biological product that is administered more than

once to an individual, the risk in terms of safety or

diminished efficacy of alternating or switching between

use of the product and the RP is not greater than the risk

of using the RP without such alternation or switch.

May be substituted for the RP without the intervention of

the health care provider who prescribed the RP.

61

42 USC §§ 262 (i)(3); (k)(4)

FDA View on “Interchangeability”

J. Woodcock et al., Nature Reviews Drug Discovery 6: 437-442 (2007)

– To establish that two protein products would be substitutable,

the sponsor of a follow-on product would need to demonstrate

through additional clinical data that repeated switches

from the follow-on product to the referenced product (and vice

versa) would have no negative effect on the safety and/or

effectiveness of the products as a result of

immunogenicity. For many follow-on protein products—and

in particular, the more complex proteins—there is a significant

potential for repeated switches between products to have a

negative impact on the safety and/or effectiveness. Therefore,

the ability to make determinations of substitutability for follow-

on protein products may be limited.

62

Biosimilar Application Requirements

Information demonstrating that the biological product:

– Is biosimilar to a RP;

– Utilizes the same mechanism(s) of action for the proposed

condition(s) of use – but only to the extent the mechanism(s)

are known for the RP;

– Condition(s) of use proposed in labeling have been

previously approved for the RP;

– Has the same route of administration, dosage form, and

strength as the RP; and

– Is manufactured, processed, packed, or held in a facility that

meets standards designed to assure that the biological

product continues to be safe, pure, and potent.

63

42 USC §§ 262 (k)(2)(A)(i)

Data Considered in Showing Biosimilarity

Information demonstrating biosimilarity:

– Analytical studies demonstrating that the biological

product is “highly similar” to the RP notwithstanding

minor differences in clinically inactive components;

– Animal studies (including the assessment of toxicity);

and

– A clinical study or studies (including the assessment of

immunogenicity and pharmacokinetics or

pharmacodynamics) that are sufficient to demonstrate

safety, purity, and potency in 1 or more appropriate

conditions of use for which the RP is licensed and for

which licensure is sought for the biological product.

64

42 USC §§ 262 (k)(2)(A)(i)(I)

FDA Factors for Determining “Highly Similar”

Expression System

Amino acid sequence if protein

Manufacturing Process

Assessment of Physiochemical Properties

Functional Activities

Receptor Binding and Immunochemical Properties

Impurities

Reference Product and Reference Standards

Finished Drug Product

Stability

66

Biologics Portfolio of Multiple Inventions

Product (including

product by process)

Indications (including

subpopulations)

Route of administration

Dosage form

Dosage regime

Safety

Purity

Potency

Stability

Immunogenicity

Pharmacokinetics

Pharmacodynamics

Mechanism of action

Methods of

manufacture

67

Considerations for Product Inventions

Demonstrate differences from known products

– Nonobvious CDR sequences or fusion proteins

– Nonobvious glycosylation and phosphorylation patterns

– Product by process of using nonobvious cell lines

– Stable and potent formulations

Less may be more

– Consider initial prosecution of target species instead of genus

– Consider eliminating laundry lists of indications, routes of

administration, dosage forms, dosage regimes, etc.

Disclosure cuts both ways

– Consider maintaining as trade secret (e.g., proprietary cell lines)

68

Antibody Species Claims

1. An isolated monoclonal antibody that binds to protein X, wherein the

antibody amino acid sequence comprises a heavy chain variable

region sequence comprising a CDR1 comprising SEQ ID NO:1, a

CDR2 comprising SEQ ID NO:2, and a CDR3 comprising SEQ ID

NO:3, and comprises a light chain variable region comprising a CDR1

comprising SEQ ID NO:4, a CDR2 comprising SEQ ID NO:5, and a

CDR3 comprising SEQ ID NO:6.

2. The antibody of claim 1, wherein the heavy chain variable region

comprises an amino acid sequence at least 95% identical to SEQ ID

NO:7.

3. The antibody of claim 1, wherein light chain variable region comprises

an amino acid sequence at least 95% identical to SEQ ID NO:8.

69

Subpopulation Claims

No Orange Book or skinny labeling

Consider seeking claims to subpopulations

– A method of treating a lung cancer patient wherein the

level of protein X in the patient’s blood is at least 10

mg/kg, comprising administering to the patient an effective

amount of drug Y.

– A method of treating a lung cancer patient, comprising

ordering a test to determine the level of protein X in the

patient’s blood, and if the level is at least 10 mg/kg,

administering to the patient an effective amount of drug Y.

Linking Inventions to Reference Product Prescribing Information

70

71

Enbrel® Product

Enbrel (etanercept) is a dimeric fusion

protein consisting of the extracellular ligand-

binding portion of the human 75 kilodalton

(p75) tumor necrosis factor receptor (TNFR)

linked to the Fc portion of human IgG1. The

Fc component of etanercept contains the

CH2 domain, the CH3 domain and hinge

region, but not the CH1 domain of IgG1.

Etanercept is produced by recombinant

DNA technology in a Chinese hamster ovary

(CHO) mammalian cell expression system.

It consists of 934 amino acids and has an

apparent molecular weight of approximately

150 kilodaltons.

72

Enbrel® Dosage Form

The solution of Enbrel in the single-use prefilled syringe

and the single-use prefilled SureClick autoinjector is clear

and colorless, sterile, preservative-free, and is formulated

at pH 6.3 ± 0.2.

Enbrel is also supplied in a multiple-use vial as a sterile,

white, preservative free, lyophilized powder. Reconstitution

with 1 mL of the supplied Sterile Bacteriostatic Water for

Injection, USP (containing 0.9% benzyl alcohol) yields a

multiple-use, clear, and colorless solution with a pH of 7.4 ±

0.3.

73

Enbrel® Dosage Form

74

Enbrel® Dosage Forms and Strengths

50 mg single-use prefilled syringe with 0.98 mL of

a 50 mg/mL solution of etanercept

50 mg single-use prefilled SureClick® Autoinjector

with 0.98 mL of a 50 mg/mL solution of etanercept

25 mg single-use prefilled syringe with 0.51 mL of

a 50 mg/mL solution of etanercept

25 mg multiple-use vial with 25 mg of etanercept

75

Enbrel® Approved Uses and Dosing Regimes

Solution administered by subcutaneous injection

50 mg once weekly with or without MTX for Adult

RA and Psoriatic Arthritis

50 mg once weekly for Ankylosing Spondylitis

50 mg twice weekly for 3 months, followed by 50

mg once weekly for Adult Plaque Psoriasis

0.8 mg/kg weekly, with a maximum of 50 mg per

week for Polyarticular Juvenile Idiopathic Arthritis

in patients aged 2 years or older

76

Enbrel® Pharmacokinetics

In another study, serum concentration profiles at

steady state were comparable among patients with RA

treated with 50 mg Enbrel once weekly and those

treated with 25 mg Enbrel twice weekly. The mean (±

standard deviation) Cmax, Cmin, and partial AUC were

2.4 ± 1.5 mcg/mL, 1.2 ± 0.7 mcg/mL, and 297 ± 166

mcgh/mL, respectively, for patients treated with 50

mg Enbrel once weekly (N = 21); and 2.6 ± 1.2

mcg/mL, 1.4 ± 0.7 mcg/mL, and 316 ± 135 mcgh/mL

for patients treated with 25 mg Enbrel twice weekly (N

= 16).

77

Enbrel® Mechanism of Action

Etanercept is a dimeric soluble form of the p75

TNF receptor that can bind TNF molecules.

Etanercept inhibits binding of TNF-α and TNF-β

(lymphotoxin alpha [LT-α]) to cell surface TNFRs,

rendering TNF biologically inactive. In in vitro

studies, large complexes of etanercept with TNF-α

were not detected and cells expressing

transmembrane TNF (that binds Enbrel) are not

lysed in the presence or absence of complement.

78

Take Home Considerations

To date, biosimilar applications are directed to antibodies

and fusion proteins

Consider competing development and exclusivity timelines

when deciding when to file

Consider patent protection of multiple inventions originating

from RP information that will inevitably be disclosed to the

public in the label and that are required to demonstrate

biosimilarity

Consider early prosecution of species claims

BPCIA litigation is not equivalent to ANDA litigation; allows

assertion of any patent that “could reasonably be asserted”

Nathan Edwards is IP Counsel at Biogen and

establishes and executes IP strategies for a portfolio

of large molecules at all stages of development.

781.464.1989

[email protected]

79

Thank You!

Mary Henninger is a Partner in the Georgia

office of McNeill Baur and practices patent

prosecution and client counseling in the areas

of biotechnology and pharmaceuticals.

404.891.1400

[email protected]

Sanya Sukduang is a Partner in the Washington, DC

office of Finnegan and practices district court and

appellate patent litigation in a variety of technologies,

including pharmaceuticals and biotechnology.

[email protected]

202.408.4377

80

Thank You!

81

Disclaimer

These materials are public information and have been prepared solely

for educational and entertainment purposes to contribute to the

understanding of U.S. intellectual property law. These materials reflect

only the personal views of the authors and are not individualized legal

advice. It is understood that each case is fact-specific, and that the

appropriate solution in any case will vary. Therefore, these materials

may or may not be relevant to any particular situation. Thus, the

authors and Finnegan, Henderson, Farabow, Garrett & Dunner, LLP,

Biogen, and McNeill Baur, PLLC cannot be bound either philosophically

or as representatives of their various present and future clients to the

comments expressed in these materials. The presentation of these

materials does not establish any form of attorney-client relationship with

the authors or Finnegan, Henderson, Farabow, Garrett & Dunner, LLP,

Biogen, or McNeill Baur, PLLC. While every attempt was made to

ensure that these materials are accurate, errors or omissions may be

contained therein, for which any liability is disclaimed.

biosimilars: navigating current legal and regulatory...

Documents