Three current patent law developments affecting those seeking FDA approval and conducting clinical trials.

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Patents: Clinical Trials and Regulatory
Fall 2018Jeff B. Vockrodt
Arent Fox LLP

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1. Helsinn v. Teva – Supreme Court Update and State of
Patenting around Clinical Trials
2. Safe Harbor – Hospira $70 million damages for pre-
approval batches
3. Standing on Appeal for Inter-partes Review
Key Patent Issues involving Clinical Trials

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The Supreme Court granted cert to decide the question
Whether, under the Leahy-Smith America Invents Act, an inventor’s
sale of an invention to a third party that is obligated to keep the
invention confidential qualifies as prior art for purposes of
determining the patentability of the invention.
Helsinn v. Teva

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Pre-AIA 102: A person shall be entitled to a patent unless … (b) the
invention was … on sale in this country [before the critical date]
Post-AIA 102: A person shall be entitled to a patent unless . . . (1)
the claimed invention was … on sale, or otherwise available to the
public before the [critical date]
Helsinn argues that otherwise available to the public signals that
prior art must be publicly described and available, pre-AIA cases
allowed PO’s secret sales as prior art.
Helsinn v. Teva

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The pre-AIA statute interpretation does not distinguish between
non-informing and informing prior sales.
The type of agreement here was a supply and distribution
agreement, and its existence was publicly know but did not disclose
the critical dose of the patent claims.
This distinguishes The Medicines Co. v. Hospira, where a supply
contract to patent owner was not the type of sale that could invoke
the on-sale bar.
Helsinn v. Teva

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Prior use has same issue and that could be affected
by Supreme Court decision
How will this affect clinical trials?
Helsinn v. Teva

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Public Use or Sale - Details Known (Prior Art)
Public Sale - Details Unknown (Helsinn-Supply and Distribution Agreement?)
Public Use - Details Unknown (Dey v Sunnovian – other party clinical trials)
Secret Sale - (The Medicines Co v. Hospira – supply agreement didn’t count)
- Other secret sales count, do they under AIA?
Secret Use - (Metallizing PO's use invalidating but not 3d party use)
- Did AIA change this?
Where do we Stand?

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Not ready for patenting – negates on sale bar
• Cases have denied ongoing clinical trials help show invention
not ready for patenting
• Little or no incentive to wait unless there is real demonstrable
doubt that invention might work
Experimental use exception inapplicable once the invention has
been reduced to practice. In re Omeprazole Patent Litig., 536 F.3d
1361 (Fed. Cir. 2008)
To File or Not to File: Is that a question?

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Cases have been lenient in the absence of clinical data supplied
with the application:
Even though the written description does not disclose efficacy or hyperemia
data for the claimed formulation, such clinical profile information is
supported because the formulation itself is described and the profile
information is an inherent property of the formulation.
Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293 (Fed. Cir. 2015)
To File or Not to File: Is that a question?

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Consider practical risk that third party disclosure could emerge.
New use claims are particularly susceptible because prior art
assertion of use may be considered enabling prior art under
Rasmussen v. SKB, which held that the level of enablement for
purposes of prior art is less than what is required under 35 U.S.C. §
112.
To File or Not to File: Is that a question?

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Amgen v. Hospira – Safe Harbor
Sept 2015, Amgen sued Hospira for infringement of U.S. Pat. Nos. 5,756,349 to Lin and
5,856,298 to Strickland in the D. Delaware based on Hospira’s filing of its BLA for erythropoietin
(EPO).
The ‘349 patent claimed:
1. Vertebrate cells which can be propagated in vitro and which are capable upon growth in
culture of producing erythropoietin in the medium of their growth in excess of 100 U of
erythropoietin per 106 cells in 48 hours . . . .
The ‘298 patent claimed:
1. An isolated biologically active erythropoietin isoform having a single isoelectric point and
having a specific number of sialic acids per molecule, said number selected from the group
consisting of 1-14, and said isoform being the product of the expression of an exogenous DNA
sequence in a non-human eukaryotic host cell.

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Epogen® -- Amgen v. Hospira
During the course of seeking approval for EPO, Hospira produced
21 batches of EPO active pharmaceutical ingredient (API).
Each batch was used for one or more of biosimilarity testing,
updating product specification, process validation, stability testing or
continued process verification.
A jury found the ‘298 patent infringed and awarded Amgen $70
million reasonably royalty for 14 of Hospira’s 21 pre-approval
batches.

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Safe Harbor § 271(e)
35 U.S.C 271(e)(1), the safe harbor states:
It shall not be an act of infringement to make, use . . . a patented invention
… solely for uses reasonably related to the development and submission of
information under a Federal law which regulates the manufacture, use or
sale of drugs or veterinary biological products.
The safe harbor “permits the use of patented invention[s] to acquire
information for regulatory approval of drugs . . .” Abtox Inc. v. Exitron,
Corp., 122 F.3 1019 (Fed. Cir. 1997)

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Amgen argues Safe Harbor inapplicable
Amgen argued safe harbor only applied to seven of Hospira’s
twenty-one drug substance batches.
Hospira performed biosimilarity testing on drug product batches not
drug substance batches. In the past, Hospira made 26 DP batches
from 4 DS batches.
The FDA never required Hospira to produce more batches beyond
the first seven.

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Amgen argues Safe Harbor inapplicable
Hospira’s updated BLA does not list any of the 14 batches falling
outside the safe harbor defense.
FDA guidance only requires three batches to perform stability
testing.
Hospira’s regulatory lead “admitted that she did not know why
Hospira made as many batches as it did, and she assumed
Hospira’s supply team (not the regulatory team) made those
decisions.”

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Hospira’s pre-approval activity found to infringe
Hospira asked the judge to set aside the jury’s verdict as being
contrary to law.
The district judge upheld the jury’s verdict August 27, 2018,
awarding pre- and post- judgment interest.
The case is now ready for appeal to the Court of Appeals for the
Federal Circuit.

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Momenta v. Bristol Myers Squibb
Early in the phase I development of a biosimilar of Orencia®,
Momental filed an Inter Partes Review (IPR) attacking Bristol Myers
Squibb’s U.S. Pat. No. 8,476,239.
.

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The Board Institute’s IPR and found
CTLA4Ig had been on the market for years in an injectable form,
and it was known that a subcutaneous version was desirable as it
allowed for home use and would increase patient compliance.
The prior art reference Carpenter taught there were only a limited
number of excipients and sucrose was preferred.
Other prior art taught it was necessary to make subcutaneous
formulations isotonic.

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The Board sided with BMS and upholds
The parties disputed whether a trial-and-error optimization could be
performed to achieve the desired isotonicity.
“Given the statements in Carpenter cast doubt on whether the
guidance it provides will result in a successful formulation, we are
not persuaded that even highly skilled artisans would have
expected success.”
The Board, therefore, upheld the patentability of all claims and
Momenta appealed to the Federal Circuit.

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Standing to Appeal
On appeal, BMS moved to dismiss Momenta’s appeal and the
Federal Circuit ruled that parties should brief the question of
appellate standing.
The Federal Circuit oral argument was held in December 2017, and
standing is the only issue that was addressed in the oral argument.

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Standing to Appeal
Article III of the constitution limits courts (but not the USPTO) to
hearing “cases or controversies.”
This concept has limited court’s ability to hear declaratory judgment
actions, as in the case of Medimmune v. Genentech.
The Federal Circuit has recently held those same limits apply when
a petitioner appeals the PTAB’s decision to uphold a patent, and
there is no underlying litigation between the parties. Consumer
Watchdog v. WARF.

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Standing to Appeal
BMS has argued that Article III standing requires the biosimilar
applicant to have filed an aBLA.
Momenta argues that its commercial plan to eventually develop a
biosimilar in this space combined with the adverse judgment and
estoppel from the IPR make this case sufficient case or controversy
for appellate standing.

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Standing to Appeal
Congress clearly intended IPRs to allow third parties to challenge
patents without waiting to be sued for patent infringement.
However, Article III standing is a constitutional requirement.
If a biosimilar manufacturer cannot appeal an adverse ruling from
the PTAB it will severely limit the utility of IPR in the biologics
space.
Given the broader constitutional question and importance of
BPCIA, this case is a likely candidate for Supreme Court review.