[Ip-health] KEI Request Re: Failure to Disclose Federal Funding in UPenn Bennett et al Patents for Gene Therapy to Treat Blindness

James Love james.love at keionline.org
Thu Sep 19 06:50:13 PDT 2019


This is a separate letter, by Kathryn Ardizzone, to the NIH, regarding 2
patents assigned to the UPenn that list 3 inventors: Jean Bennett, Therese
Cronin, and Luk Vandenberghe.

Among the evidence regarding federal funding of the inventions was an
article titled “Efficient transduction and optogenetic stimulation of
retinal bipolar cells by a synthetic adeno-associated virus capsid and
promoter,” first published in August of 2014, that lists Therese Cronin,
Luk Vanderberghe, and Jean Bennett as three of nine authors, which
describes technology used in the patents, and includes in the article’s
“conflict of interest statement” discloses that Therese Cronin, Luk
Vanderberghe, and Jean Bennett “are co-authors on a US patent application
for ‘Enhanced AAV-mediated gene transfer for retinal therapies[,]’” which
is the exact title of the two patents.

https://www.keionline.org/31601

The inventions at issue in these patents expand on the technologies in
Luxturna, a gene therapy that treats a type of blindness. Luxturna is
currently sold by Spark Therapeutics at a price of $425,000 per eye.

For more on KEI’s work on non-disclosure of federal funding in medical
technology patents, please see:
https://www.keionline.org/bayh-dole/failure-to-disclose

A PDF version of the request is available here, and the full text of the
request follows below.

-----------------------------------------------

Knowledge Ecology International
1621 Connecticut Avenue NW
Suite 500
Washington, DC 20009
www.keionline.org

September 9, 2019

Michelle Bulls
Director
Office of Policy for Extramural
Research Administration (OPERA)
National Institutes of Health
Via Email: michelle.bulls at nih.gov

Re: Apparent Failure to Disclose Government Funding Associated with Two
Patents in “Enhanced AAV-Mediated Gene Transfer for Retinal Therapies,”
Invented by Jean Bennett and Others and Assigned to the University of
Pennsylvania

Dear Ms. Bulls:

Knowledge Ecology International (KEI) requests that the National Institutes
of Health (NIH) investigate the apparent failure to disclose federal
support of two patents in adeno-associated viral (AAV) gene therapies, in
violation of the Bayh-Dole Act, 35 U.S.C. §§ 200 et seq.

The patents, both titled “Enhanced AAV-mediated gene transfer for retinal
therapies,” are U.S. Patent Nos. 9,567,376 (the “‘376 patent”) and
10,266,845 (the “‘845 patent”). The inventors listed on the patents are
Jean Bennett, Therese Cronin, and Luk Vandenberghe. Both patents were
assigned to the Trustees of the University of Pennsylvania.

Evidence suggests that the inventions benefited from grants from the NIH.
Specifically, in the paper “Efficient transduction and optogenetic
stimulation of retinal bipolar cells by a synthetic adeno-associated virus
capsid and promoter,” there is strong evidence that NIH funding is related
to both the ‘367 and the ‘845 patents.

Among other similarities to the patents, the paper:

* was authored by Bennett, Cronin and Vandenberghe (the inventors on the
patents);

* describes an AAV vector to treat blindness involving the same amino acid
sequence as the inventions described in the patents; and

* lists, as a conflict of interest, that Bennett, Cronin and Vandenberghe
“are co-authors on a U.S. patent application for ‘Enhanced AAV mediated
gene transfer for retinal therapies,’” the exact same title as the ‘376 and
‘845 patents.

The paper discloses two NIH grants, “NEI/NIH 8DP1 EY023177,” and
“1R24EY019861-01A1,” including one grant, EY023177, for which Jean Bennett
was the principal investigator, at or around the time that the subject
inventions were likely discovered.

While the paper discloses two NIH grants, the patents contain no statement
of government support, which is required for any invention developed
pursuant to a federal funding agreement.

When federal grants support a new technology, the grant recipient must make
certain disclosures to the funding agency. These disclosures alert the
government to the rights that it retains in federally-sponsored inventions,
including a “nonexclusive, nontransferrable, irrevocable, paid-up license
to practice or have practiced for or on behalf of the United States any
subject invention throughout the world,” 35 U.S.C. § 202(c)(4), and the
right to “march-in” and compel additional licensing of an invention when,
among other reasons, the contractor, assignee or licensee has not taken
steps to achieve practical application, 35 U.S.C. § 203(a).

Failure to comply with the Bayh-Dole Act’s reporting requirements
undermines one of the stated policy objectives of the legislation: “to
ensure that the Government obtains sufficient rights in federally supported
inventions to meet the needs of the Government and protect the public
against nonuse or unreasonable use of inventions.” 35 U.S.C. § 200. If an
agency is not aware of inventions it has supported, it cannot ensure that
the objectives of the Act is being met.

We respectfully urge the NIH to investigate the apparent non-disclosures
and take appropriate remedial action, including asserting the government’s
rights in the patented inventions.

The Law

The Bayh-Dole Act and federal regulations and guidelines make clear several
obligations for contractors in the disclosure of government rights in
subject inventions, including: (1) a requirement to disclose that federal
funding contributed to an invention; (2) NIH contractual requirements for
disclosure; and (3) required language to be inserted in patent applications
and patents, stating the role of federal funding and the government’s
rights.

Under 35 U.S.C. § 202(c)(1), any contractor that receives funding from the
federal government is required to “disclose each subject invention to the
Federal agency within a reasonable time after it becomes known to
contractor personnel responsible for the administration of patent matters.”

Under 37 C.F.R. § 401.3(a), each federal funding agreement shall contain
the “standard patent rights clause” found at 37 C.F.R. § 401.14, barring
specific circumstances and exceptions. Subsection (c)(1) of the patent
rights clause outlines the disclosure requirements.

37 C.F.R. § 401.14(c)(1)

(c) Invention Disclosure, Election of Title and Filing of Patent
Application by Contractor

(1) The contractor will disclose each subject invention to the Federal
Agency within two months after the inventor discloses it in writing to
contractor personnel responsible for patent matters. The disclosure to the
agency shall be in the form of a written report and shall identify the
contract under which the invention was made and the inventor(s). It shall
be sufficiently complete in technical detail to convey a clear
understanding to the extent known at the time of the disclosure, of the
nature, purpose, operation, and the physical, chemical, biological or
electrical characteristics of the invention. The disclosure shall also
identify any publication, on sale or public use of the invention and
whether a manuscript describing the invention has been submitted for
publication and, if so, whether it has been accepted for publication at the
time of disclosure. In addition, after disclosure to the agency, the
Contractor will promptly notify the agency of the acceptance of any
manuscript describing the invention for publication or of any on sale or
public use planned by the contractor.

According to 37 C.F.R. § 401.14(f)(4) and NIH Guidelines for Grants and
Contracts, grant recipients must include the following language in their
patent applications and patents:

“This invention was made with Government support under (grant/contract
number) awarded by the (Federal agency). The Government has certain rights
in the invention.”

Finally, under 35 U.S.C. § 202(c)(6) and 37 C.F.R. § 1.77(b)(3),
contractors are required to state within the patent application or patent
that the federal government contributed funding to support the discovery of
the invention and that the government retains certain rights.

35 U.S.C. § 202(c)(6)

(c) Each funding agreement with a small business firm or nonprofit
organization shall contain appropriate provisions to effectuate the
following:

(6) An obligation on the part of the contractor, in the event a United
States patent application is filed by or on its behalf or by any assignee
of the contractor, to include within the specification of such application
and any patent issuing thereon, a statement specifying that the invention
was made with Government support and that the Government has certain rights
in the invention.

The Patents

The inventions described in the patents are “capsid proteins and
adeno-associated viruses capable of targeting various types of ocular cells
including bipolar and horizontal cells[,]” as well as their methods of
administration to treat ocular disorders. The patents claim “[a] method of
preventing, arresting progression of, or ameliorating vision loss
associated with an ocular disorder in a subject, [with] . . . a composition
comprising a recombinant adeno-associated virus (AAV) having a recombinant
AAV capsid comprising a mutation in aa 587-595 of the AAV8 capsid protein
sequence[.]”

Both patents list an earliest priority date of February 8, 2013.
Accordingly, KEI assumes that the inventions described in the February 8,
2013 application occurred in 2011 or 2012.

Bennett is listed as an inventor on nine patents featuring AAV vectors
assigned to Penn, with earliest priority dates ranging from 2001 to 2014,
including the ‘376 and ‘845 patents. Of the nine patents, five disclose
support from NIH grants. Bennett was listed as the Principal Investigator
for two of those grants: EY-010820 (1995 to 2007), and EY-023177 (2011 to
2015).

It thus appears that when the subject invention was “conceived or first
actually reduced to practice in the performance of work under a funding
agreement,” Bennett was receiving funding from the NIH to research gene
therapies to treat ocular disorders.

The Article

As noted previously, KEI discovered strong links between the ‘376 and ‘845
patents and a PubMed article that discloses two NIH grants.

The article titled “Efficient transduction and optogenetic stimulation of
retinal bipolar cells by a synthetic adeno-associated virus capsid and
promoter,” first published in August of 2014, lists Therese Cronin, Luk
Vanderberghe, and Jean Bennett as three of nine authors. As previously
noted, Cronin, Vanderberghe, and Bennett are the co-inventors on the
patents.

The technology described in the article is almost identical to that of the
patents. The article describes how the researchers “adapted the capsid
library approach to enhance AAV-mediated retinal bipolar cell expression”
and how “[a] favorable variant, derived through . . . AAV8 capsid mutants,
was identified.” It lists almost the exact same gene location (between
amino acids 585 and 593/594) as do the patents (585 to 595). Likewise, the
two patents both claim “[a]n adeno-associated virus (AAV) having a
recombinant AAV capsid comprising a mutation, in aa 587-595 of the AAV8
capsid protein sequence[.]”

Most compellingly, the article’s “conflict of interest statement” discloses
that Therese Cronin, Luk Vanderberghe, and Jean Bennett “are co-authors on
a US patent application for ‘Enhanced AAV-mediated gene transfer for
retinal therapies[,]’” which is the exact title of the two patents.

PubMed’s conflict-of-interest policy requires authors to disclose any
financial relationship with “any for-profit product discussed or implied in
the text of the article[.]” The conflict-of-interest statement in the
PubMed article, disclosing Cronin, Vanderberghe, and Bennett’s rights in a
patent application having the same title as the patents, is compelling
evidence that the technology discussed in the article and the patented
inventions are one in the same, especially considering the overlap in the
timing, substance, and authorship of the patents and article.

Other Evidence Linking the Inventions

The article discloses the support of NIH Grant Nos. EY-023177 and
EY-019861. Jean Bennett is the principal investigator listed on EY-023177,
which funded her research from 2011 to 2015. KEI also notes that Therese
Cronin worked in Bennett’s lab, and Luk Vandenberghe also worked at the
University of Pennsylvania and was also funded by several Penn grants.

“Subject Inventions”

As noted previously, the Bayh-Dole Act and implementing federal regulations
impose a series of disclosure requirements on recipients of federal grants,
with respect to any “subject invention.”

The Bayh-Dole Act defines a “subject invention” as “any invention of the
contractor conceived or first actually reduced to practice in the
performance of work under a funding agreement,” and defines a contractor as
“any person, small business firm, or nonprofit organization that is party
to a funding agreement.” 35 U.S.C. § 201(e),(c).

The technology described in the PubMed Article was developed with the
support of NIH Grant Nos. EY-023177 and EY-019861. If, as KEI suspects, the
inventions covered by the ‘376 and ‘845 patents are the same as the
technology described in the article, then the inventions are “subject
inventions” under the Bayh-Dole Act, and disclosure was required.

Neither the ‘376 nor the ‘845 patent discloses any federal funding or
includes a government interest statement, in apparent violation of the
Bayh-Dole Act and associated federal regulations.

Patent 9,567,376
Title: “Enhanced AAV-mediated gene transfer for retinal therapies”
Inventors: Therese Cronin, Jean Bennett, and Luk Vandenberghe
Filing Date: August 14, 2014
Earliest Priority: U.S. Provisional Patent Application No. 61/762,775,
filed Feb. 8, 2013

Patent 10,266,845
Title: “Enhanced AAV-mediated gene transfer for retinal therapies”
Inventors: Therese Cronin, Jean Bennett, and Luk Vandenberghe
Filing Date: August 24, 2016
Earliest Priority: U.S. Provisional Patent Application No. 61/762,775,
filed Feb. 8, 2013

Grant EY-023177
Title: “Broad Spectrum Molecular Therapy for Blinding Retina Disorders”
PI/Project Leader: Jean Bennett
Organization: University of Pennsylvania
Grants in RePORTER from 2012 to 2015
Project Start: September 30, 2011
Project End: July 31, 2017

Grant: 1R24EY019861-01A1
Title: “Therapeutic Approaches for ABCA4-Associated Disorders”
PI/Project Leader: Rando L. Allikmets
Organization: Columbia University Health Sciences
Year of Award: 2011
Budget Start: August 1, 2011
Budget End: July 31, 2012

Remedies

KEI respectfully urges the NIH to promptly investigate the apparent
non-disclosure and take all appropriate remedial action, including taking
title to the patents. Failure to disclose subject inventions pursuant to 35
U.S.C. § 202(c)(1) permits the federal government to “receive title to any
subject invention not disclosed to it within such time[.]”

If the NIH never revokes a patent or imposes any meaningful sanctions,
universities and other contractors will continue to underreport federal
funding. A certificate of correction on the patent, as Penn and other
institutions have issued in the past, does not send a strong enough signal
regarding the public’s right to know its rights in patented inventions.

Here, the failure to disclose concerns a gene therapy that may promise a
great benefit to patients, but could come at a steep cost to patients,
third-party payors, and the U.S. healthcare system. The inventions expand
upon the technology behind voretigene neparvovec-rzyl (Luxturna™), an AAV
vector gene therapy that treats an inherited form of blindness. Luxturna
was discovered by Jean Bennett and others and is sold by Spark Therapeutics
for $850,000 ($425,000 per eye).

The disclosure requirements were designed to protect the government’s
rights in federally-sponsored technology such as biomedical inventions. We
are asking the NIH to ensure that when taxpayer investments are relevant to
an invention, the government is diligent in ensuring that the public’s
rights are acknowledged and secured. In order to protect the public’s
rights, we ask that the government take possession of patents when grant
recipients do not make timely disclosures, as is required by law, and as
appears to be the case here.

Sincerely,

Kathryn Ardizzone
Counsel
Knowledge Ecology International
1621 Connecticut Ave NW Suite 500
Washington, D.C. 20009
(202) 332-2670
kathryn.ardizzone[at]keionline.org


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