part one.pdf - office for research ethics and integrity

© 2013 Winston & Strawn LLP

Global Biosimilar Developments

Brought to you by Winston & Strawn’s

Intellectual Property Practice Group

© 2013 Winston & Strawn LLP 2

Today’s eLunch Presenters

Gareth MorganIntellectual Property

London

[email protected]

Gail StandishIntellectual Property

Los Angeles

[email protected]


The Goal

Encourage competition, leading to increased access to biological products for patients.


EU Biosimilars – Basics

Well-trod biosimilar approvals system

Implemented into law 2005

Part of the “abridged” Article 10 procedures

But... biosimilars are not treated as generics


The Impetus

EU procedure was formed from litigation

Sandoz sued the Commission over Omnitrope

Positive opinion from EMA – Commission rejected

First biosimilar approval (prior to implementation)


Focus on Article 10.4

Article 10.4

“Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided.”

Recital 15

Biosimilar products do not usually meet all requirements for a generic.

First biosimilar approval (prior to implementation)


Generics of biologics?

Not quite, EMA is cautious with biosimilars

“differences relating to raw materials”

“differences relating to manufacturing techniques”

Risk creating heterogeneity in the end product


Clinical requirements push up costs

Clinical trial requirement is usually two-way comparison against the reference product

Aim is to demonstrate similarity, benefit:risk not an issue

Clinical trials usually involved

Results in increased cost


How does the EU specify requirements?

Product/process specific data requirements (clinical and non-clinical)

Overarching guideline

Non-clinicalClinicalQuality

General guidelines – biotech-derived proteins

IFN-αEPOHGH G-CSFInsulin LMWHMabs


Current guidance seems strict

EMA overarching guideline:

“It should be recognised that, by definition, similar biological medicinal products are not generic medicinal products, “

But recent draft guidances show a softening in attitudes


US Biosimilars Pathway – The Genesis

The Patient Protection and Affordable Care Act Signed into law on March 23, 2010

Amended the Public Health Service Act (“PHS”) to create an accelerated pathway for approval of biosimilars

Added Section 351(k), the application process and Section 351(l), the “patent” process

The Patent Act Added Section 271(e)(2)(C) to create an act of artificial

infringement for filing an application under 351(k)


The Players

Reference Product Sponsor

(“RPS”)

Filed an original biologics license

application (“BLA”) pursuant to 351(a)

Demonstrated that the biological was “safe, pure, and

potent”

Biosimilar Applicant (“BA”)

Filed a biosimilar or interchangeable

license application pursuant to 351(k)

Demonstrate biosimilarity (and/or interchangeability) to

an approved BLA product


The Terms

BIOSIMILAR INTERCHANGEABLE

•Highly similar to Reference Product•Minor differences with clinically inactives

•No clinically meaningful differences with SAFETY/PURITY/POTENCY

Virus, Therapeutic Serum, Toxin, Antitoxin, Vaccine, Blood, Blood Product or

component, Allergenic Product, Protein or analogous product, or Arsphenamine (or

derivative) – Generally made from human or animal materials

•Biosimilar and•Expected to give same clinical result as Reference Product in any patient, and•If administered more than once, the risks of safety or efficacy of alternating between the biosimilar and the reference product is no greater than using reference only

Biological Product subject to an approved BLA and shown to be “safe, pure, and potent” that is

made in facility designed to assure the same

BIOLOGIC PRODUCT

REFERENCE PRODUCT


The Approval Process

Totality of the Evidence Standard Give-and-take between the FDA and the Biosimilar

Applicant The FDA has requested and suggested early, thorough

communications with the office during the preclinical studies, clinical trial design and performance, and application process

Prevent unnecessary and perhaps unethical clinical studies Ensure adequate studies

FDA has discretion to waive analytical, preclinical, and clinical studies for a biosimilar, if deemed appropriate


The Charge: Determine Biosimilarity

Hatch-Waxman

Determination

Biosimilars ActDetermination


The FDA: Guidances

The FDA has issued “Guidances for Industry” related to Biosimilar Applications

Take home Case-by-case basis; Totality of the Evidence review

Note – no Guidance yet on Interchangeables


The Exclusivity: The Reference Product

The first Biosimilar Application may not be filed until

4 years after approval.

Any Biosimilar Application may not be approved until12 years after RPS approval.


The Exclusivity: First Interchangeable

FIRST Approved Interchangeable shall enjoy exclusivity until the earlier of:

1 year after first commercial marketing of the interchangeable;

18 months after A final court decision on all patents-in-suit asserted against biosimilar applicant by

RPS, or

Dismissal (with or without prejudice) of patent litigation suit against biosimilar applicant;

42 months after Approval of Biosimilar Application if patent litigation is still ongoing; or

18 months after Approval of Biosimilar Application if not sued by RPS


The Confidential Information: What?

Submission of a Biosimilar Application requires providing the RPS access to: A copy of the application as submitted to the FDA;

Other information describing the process(es) used to manufacture the biosimilar;

Optionally, additional information requested by or on behalf of the RPS; and

“Any other information that the [biosimilar applicant] determines, in its sole discretion, to be appropriate.”


The Confidential Information: To Whom?

Recipients of this information: Outside counsel designated by the RPS; and

One in-house counsel All recipient counsel are barred from any patent prosecution

related to the reference product.

Patent Owner may be allowed access if Patent is exclusively licensed to RPS;

Owner has retained right to assert the patent or participate in litigation; and

Must agree to be bound by confidentiality provisions as set forth in the statute.

Is subject to same terms as provided above, regarding counsel –including the patent prosecution bar.


The Confidential Information: Limits on Disclosure

No recipient of confidential information shall provide that information to any other person or entity (including outside scientific consultants or other outside counsel) without prior written consent by Biosimilar Applicant RPS

FDA


The Confidential Information: Limits on Use

Use of Confidential Information Solely for determining, with respect to each patent owned,

assigned to, or exclusively licensed to/by the RPS, whether a claim of patent infringement could reasonably be asserted if the Biosimilar Applicant made or sold the product in the United States.

No confidential information can be included in any publicly available complaint or other pleading.


Confidential Information: Biosimilar Applicant Concerns

Confidential information could contain patentable inventions or trade-secret information. Potentially protect this information prior to disclosure by

filing patent applications or ensuring adequate protection procedures in place for trade secrets.

Act requires disclosure of all pertinent information, including entire 351(k) application.


Confidential Information: RPS Concerns

ParadigmShift

Those who filed prior to enactment of Biosimilars Act were working under assumption that NO ONE but FDA would have any access to their information.

Only protection is the FDA.

Comparisons for Determining Biosimilarity or Interchangeability seem to require disclosure of at least SOME confidential information to the Biosimilar.

THEN NOW


Hatch-Waxman v. Biosimilars Act


The Products Covered

Hatch-Waxman 2 Generic Pathways for

Small Molecules 505(b)(2) or “Paper ANDAs”

ANDAs Requires only bioequivalence

studies to be Therapeutically Equivalent & fully substitutableby pharmacies

Biosimilars Act 2 Categories of “Follow On”

Biologicals Biosimilars

Interchangeables Requires clinical data to be fully

substitutable by pharmacies


The Exclusivities

Pioneer Generic Pediatric

Hatch-Waxman

Biosimilars

5-year Marketing 6 months for First

PIV Filing

6 months to all exclusivities and

Orange Book Patents

12-year marketing1 year for First

Approved Interchangeable

6 months to 12-year marketing and

4-year filing


The Litigation

No Orange Book or publicly available listing of relevant patents for biological products

No FDA notification of invalidity positions required –notification of RPS optional

Notice to RPS -> Suit = 245-250 days

No automatic 30-month stay

Process patents available

Biosimilar applications may have novel aspects, patentable material.

RPS has early and full access to Application

Public listing of “Pioneer” patents in Orange Book

Provide FDA with certification of invalidity, unenforceability, and/or non-infringement

Notice Letter -> Suit = 45 Days

Automatic 30-month stay of FDA approval during patent litigation if suit filed within 45 days

No process patents; no patentably distinct work in ANDA

Brand has no access to ANDA until after litigation has been filed or by consent of parties after notice

Hatch-Waxman Biosimilars Act


The Timeline: Overview

351(k) Application Accepted for

Review

Provide Notice and Access to

RPSRPS to

provide Patent List

Biosimilar Applicant’s Patent

List & Claim-by-Claim Invalidity

Analysis

RPS Responsive

Statement re: Validity

Good faith Negotiations

re: Patent List

20 Days

60 Days

60 Days

60 Days

Not set


The Patents: Preliminary Exchanges

351(k) provides a detailed step-by-step process by which the RPSand Biosimilar Applicant exchange information and proposed patents.

RPS BIOSIMILAR APPLICANT

Patents allegedly infringed by Biosimilar

Additional patents allegedly infringed by Biosimilar

Patents available for licensing Willingness to license those patents

Litigation Position:•Infringement Contentions and Responses to Invalidity Positions

Litigation Position:•Invalidity, Unenforceability,NoninfringementContentions OR•Intent to wait for market until patent expiry


The Patents: Good-faith Negotiation

After exchange of all the preliminary information, 351(l) requires “good-faith negotiations” intended to determine which of the patents provided by either party will be subject to an action for patent infringement.

Agreement or Disagreement triggers the next steps of the process.


The Patents: Good-faith Negotiation

Biosimilar Applicant will provide number of patents it believes should be subject to litigation

Simultaneous exchange of Patent Lists either party believes should be litigated

NOTE: The number of RPS-listed patents cannot exceed the Biosimilar Applicant-listed patents

(If zero, RPS can list 1 patent)

30 Days after exchange of lists, RPS shall file patent infringement suit of each patent on list

DISAGREE

30 days after agreement, RPS shall file suit for patent infringement for each patent

agreed to

AGREE


The Patents: Newly Issued or Licensed Patents

If the RPS is issued a new patent or obtains an exclusive license to a different patent it believes would be infringed by the Biosimilar Applicant’s biological product, it has 30 days to supplement its list.

This patent is still subject to Good-faith Negotiations (and the patent limits if no agreement is reached).

Arguably, if only one patent is allowed for the RPS to assert (because of Biosimilar Applicant’s unwillingness to list any patents), a new patent would necessarily be excluded from assertion.

The Biosimilar Applicant has 30 days to respond with claim-by-claim analysis and licensing decision.

Note that these patents are subject to Preliminary Injunction.


The Question Everyone is Asking: As a Biosimilar Applicant - Why even list patents?

A logical question is why would a BiosimilarApplicant list any patents when the RPS would then be limited to only 1 patent? If the Biosimilar Applicant does not list any relevant patents,

then it is subsequently precluded from filing any type of Declaratory Judgment action against the RPS for a declaration of

Invalidity,

Enforceability, or

Non-infringement.

But still subject to declaratory judgment if on RPS’s list of relevant patents, but did not make the trial list.


The Patents: Notice & Preliminary Injunction

Biosimilar Applicant Must notify RPS at least 180 days prior to first commercial

marketing date.

RPS After receipt of marketing notice, may request Preliminary

Injunction against Biosimilar Applicant preventing manufacturing or commercial sale for any patent that is included in the patent lists (provided by either the RPS or the Biosimilar Applicant).


The Damages

MANDATORY permanent injunction if: RPS filed suit within 30 days;

Final judgment of infringement from which no appeal can be taken (excluding Supreme Court certiorari); AND

FDA has yet to approve biosimilar for marketing because of 12-year exclusivity.

Permissive permanent injunction if any of the above cannot be met but RPS can establish eBay factors.

ONLY Reasonable Royalty if: Suit was filed after 30-day deadline, or

Was filed timely but dismissed (with or without prejudice) or not prosecuted to judgment in good faith.


Outstanding Questions

How similar is similar?

How does one demonstrate sufficient “interchangeability”?

Are there sufficient protections for RPS’s confidential information? What about information submitted before the new statute?

Are there sufficient protections for BiosimilarApplicants’ newly patentable subject matter within their applications?


EU Biosimilars – Where are we heading?

Outward relaxation of requirements

New guidance notes stress role of comparability studies

EMA is likely to become more flexible

Global reference product will dramatically reduce costs


New guidance

Draft new guideline on beta-interferons

[in relation to the requirement to use a primary efficacy variable in the pivotal clinical biosimilar trial] “in a biosimilar framework, since the focus of the biosimilarity exercise is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been established by the reference product.”

Similar phrases repeated in biosimilar Mab guideline


Mab guidance

Guidance has been adopted

High level but suggests it is relatively permissive:

“the focus of the biosimilarity exercise is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been established by the reference product”

“extrapolation of clinical efficacy and safety data to other indications of the reference Mab not specifically studied.....is possible based on the overall evidence of comparability ....with adequate justification”


And a global reference product?

Strong EMA/FDA collaboration here – Commission is keen not to lag behind US

Should soon be possible to submit studies in both jurisdictions using same study data – after revision of overarching guideline

Waiting for guidance on the bridging studies required to satisfy RAs of identity of reference products


Questions?


Thank You.

part one.pdf - office for research ethics and integrity

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