Thursday, May 31, 2018

Patents on drugs are not the only issue in the release of generic formulations

In a post titled The Myth of ‘Trivial’ Drug Patents , David Forman writes on IPWatchdog:

Follow-on patents are improvements on the original drug. Well-known examples of an improved formulation
are modified release formulations that may allow a patient to take a single pill rather than several pills a day.
Sometimes these are made by applying what may have become well-known methods for making modified release pills,
and as such may not be patentable. But if a new modified-release formulation would not have been obvious
and predictable from the prior art methods of making modified-release formulations, then it can be separately patentable.
Once the original patent expires the patent law does not prevent a generic competitor from making a generic version
of the original drug. Some critics complain that they should have the right to make not merely
the previously patented FDA-approved drug, but also the still-patented improvements.
This argument ignores that the public can choose between the generic version of the older
but effective drug and the convenient but more expensive patented version.
There is nothing unfair about this market choice. If the generic manufacturer is dissatisfied
it can challenge the validity of the modified-release patent in an ANDA case in district court
or file an IPR in the USPTO. Challenging the patent in these forums is expensive
but the costs are small compared to the amount that the generic manufacturer has saved
in the costs of discovering, developing, and gaining FDA approval of a pharmaceutical.

Back in September 2015, Gene Quinn at IPWatchdog wrote of an IPR petition by Kyle Bass challenging
US Patent 8,399,514 on the multiple sclerosis [MS] drug Tecfidera in the post With dubious logic and inaccurate statements of law,
PTAB denies another Kyle Bass IPR petition
, which petition relied on prior art by one Dr. Ludwig Kappos, an
expert in the field of multiple sclerosis:

Kappos was summarily dismissed by the Board. Under the first rationale it was dismissed
because the entirety of the study wasn’t provided, and in the second rationale it was dismissed
because the written description constituted nothing more than prior use. Put aside for a moment
that neither of those conclusions make any sense under any reading of U.S. patent law, which is
indeed problematic in its own right. What is really bizarre is that under the third rationale
Kappos is now characterized as constituting “a description.” Frankly, it seems the Board
wanted to have their cake and eat it too. Kappos cannot merely be about prior use if the Board
itself is relying on the description, which they have to realize is in writing as they are reading it.
Clearly the description of the Phase II pilot study is and should have been considered to be prior art.

this IPR institution denial decision has numerous logical and legal flaws. Clearly,
the description of the Phase II clinical trial was a publication that can be used
as prior art in an IPR proceeding. The petitioner submitted journals going back years
all teaching DMF as a means to treat multiple sclerosis. Thus, I have to wonder whether
this decision has more to do with Kyle Bass than with the law.

Given that IPR institution decisions are not appealable there will never
be a check on the egregious mistakes made by the Board in this situation.

IPBiz also discussed the problematic nature of this decision by PTAB in the
PTAB declines to institute IPR against Biogen's US 8,399,514 related to the MS drug Tecfidera

Kyle Bass later had a different petition on the Tecfidera patent granted, but failed in his attempt
to invalidate the claims of the '514 patent.
Kyle Bass loses challenge to MS drug Tecfidera on US Patent 8,399,514 in IPR2015-01993

An article by R. P. Spencer [ Pharm Pat Anal. 2014 Mar;3(2):183-98 ] discloses part of the history of Tecfidera and shows that issues
other than patent protection delay entrance of competitors:

As a case study of patent coverage for a repurposed drug, Biogen Idec's approach for Tecfidera(®),
an oral formulation of dimethyl fumarate, was analyzed. While mixtures of fumarates have been used
for over 50 years to treat psoriasis, Tecifidera is approved for the treatment of
relapsing-remitting multiple sclerosis. Biogen pursued claims to pharmaceutical formulations
and useful doses for treating multiple sclerosis, an approach that is relevant to pharmaceutical
lifecycle management in general. A survey of recent US, EP, and PCT patent applications indicate
other companies are developing competing fumarate formulations. While it is possible to pursue secondary patents
for compounds without composition of matter coverage, regulatory data exclusivity provides additional protection to delay competitors.

Of re-purposing, one notes that the costs of trials can far exceed the cost of drug discovery [related to Forman's text:
gaining FDA approval]

As to FDA regulations, one notes that Tecfidera was one of two MS related drugs to appear on the FDA's
list of Reference Listed Drug (RLD) Access Inquiries.
See The Trump FDA publishes list of Reference Listed Drug (RLD) Access Inquiries

As to a choice "between the generic version of the older
but effective drug and the convenient but more expensive patented version," see some of
the discussion surrounding the drug -- tenofovir alafenamide fumarate ("TAF")-- compared with the drug --tenofovir disoproxil fumarate ("TDF"), a component of Truvada. Truvada made the recent FDA list of Reference Listed Drug (RLD) Access Inquiries (with no REMS issue). The FDA approved generic Truvada in 2017, with Teva and Gilead making a deal. Some of the lawsuits involving Gilead and TAF are over issues other than patents,
including asserted ethics issues of delaying market entry of a drug with superior safety profiles.

***Separately from the May 2018 white paper of HHS as to costs to drug consumers, American Patients First :

Consumers who have not met
their deductible or are subject to
coinsurance, pay based on the
pharmacy list price, which is not
reduced by the substantial drug
manufacturer rebates paid to PBMs
and health plans. As a result, the
growth in list prices, and the widening
gap between list and net
prices, markedly increases consumer
out-of-pocket spending,
particularly for high-cost drugs
not subject to negotiation.
This is not only a fnancial challenge,
but a health issue as well: One
study found that consumers asked
to pay $50 or more at the pharmacy
counter are four times more likely
to abandon the prescription than a
consumer charged $10.

What had been a hidden negotiation
and wealth transfer between drug
manufacturers and PBMs is now a
direct increase on consumer out-ofpocket
spending that likely decreases
drug adherence and health outcomes.
The Growth of High-Cost Drugs
New challenges are emerging onto
this landscape. A growing number of
complex drugs account for a growing
percentage of health care spending.
The pharmaceutical industry
has shifted its attention to high-cost
drugs that face little to no competition,
because they ofer the freedom
to set high launch prices and increase
them over time.
Though these drugs ofer hope
to the 1 percent of insured benefciaries
who use them, they account
for 35-40% of health plan spending,
and will increase to over half of drug
spending over the next 5 years.12
Absent reform, the growth of high
cost drugs will further compound
the issues already described.


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