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Junwon Kim Doohyun Lee Changmin Park Wonyoung So Mina Jo Taedong Ok Jeongjin Kwon Sunju Kong Suyeon Jo Youngmi Kim Jihyun Choi HyoungCheul Kim Yoonae Ko Inhee Choi Youngsam Park Jaewan Yoon MoonKyeong Ju Junghwan Kim Sung-Jun Han Tae-Hee Kim Jonathan Cechetto Jiyoun Nam Peter Sommer Michel Liuzzi Jinhwa Lee Zaesung No 《ACS medicinal chemistry letters》2012,3(8):678-682
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John H. Cardellina II Virginia I. Roxas-Duncan Vicki Montgomery Vanessa Eccard Yvette Campbell Xin Hu Ilja Khavrutskii Gregory J. Tawa Anders Wallqvist James B. Gloer Nisarga L. Phatak Ulrich H?ller Ashish G. Soman Biren K. Joshi Sara M. Hein Donald T. Wicklow Leonard A. Smith 《ACS medicinal chemistry letters》2012,3(5):387-391
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Inventorship and Ownership
Considerations and Pitfalls
with Collaborative Research: Patent
Highlight
Collaborations can be very productive and beneficial
for research.
However, there are a number of considerations and pitfalls with regard
to issues of inventorship and ownership that should be considered
before entering into any research agreement to avoid the possible
loss of patent rights.Collaborative research between
companies presents some very unusual and complex patent considerations
concerning inventorship and ownership, which can have important consequences
on the value of a patent. The chances for obtaining strong patents
can be improved by entering into appropriate research and licensing
agreements before an invention is made based on the collaborative
effort. Failure to properly consider the inventorship and to enter
into appropriate agreements can have disastrous consequences.Inventorship and ownership are important and intertwined issues
in collaborative research. The concept of “inventorship”
can be very confusing for many researchers, since researchers are
accustomed to considerations of whether an individual should be listed
as an “author” on journal article, which is very different
from whether a person may be an inventor on a patent. A person may
have made some truly useful contributions to a research project, which
rightfully suggests that they should be included on any published
article that reports on the project. In addition, although a variety
of skills and contributions are needed to bring an invention to the
market place, not all of the participants
are considered inventors.The inventor is a person who conceived of the
invention.1 Conception is more than contemplating
a desirable result or goal.2 The inventor
must have a “definite and permanent” idea of the invention
such that it is susceptible to being reduced to practice without undue
experimentation.3 Once conception is complete,
participants who reduce the invention to practice using routine skill
and confirm its utility are not inventors.4An historic case in which inventorship was a key issue was Burroughs Wellcome Co. v. Barr Laboratories Inc.(5) This case involved the determination of the proper
inventors of seminal patents of Burroughs Wellcome relating to the
use of AZT to treat AIDS. Barr argued that the patent should include
NIH researchers Broder and Mitsuya as inventors because they did the
initial cell culture assays with AZT to show activity in vitro. Barr wished to have the NIH scientists named as inventors because
if they were inventors, Barr would have a license from NIH and not
be liable for infringement. Despite the fact that Broder and Mitsuya
participated in the “reduction to practice” of the invention,
it was determined by the court that they were not inventors on the patent because they did not participate in the conception of the invention.The courts very recently revisited this
issue in Falana
v. Kent State University.6 In Falana, KDI (a spin-off company from Kent State) hired Dr.
Seed to work on a project synthesizing and developing chiral additives
for liquid crystal displays. Dr. Seed, in turn, hired Dr. Falana to
work on the project. Dr. Falana independently synthesized various
compounds and developed a synthesis protocol for developing a new
class of chiral additives. One of the compounds synthesized by Dr.
Falana was “Compound 7”, which was an SS enantiomer. Dr. Falana left KDI, and Dr. Seed subsequently used
the synthesis protocol developed by Dr. Falana to synthesize “Compound
9”. Compound 9 was an RR enantiomer, which
fell within the generic class of compounds developed by Dr. Falana.
KDI and Kent State then filed a patent application, which claimed
a genus of compounds that did not include Compound
7, synthesized by Dr. Falana. However, the specification of the patent
application disclosed the synthesis method of Dr. Falana. Dr. Falana
was not included as an inventor, and he filed a law suit to have himself
named as a coinventor. The court posed the question at issue as being,
“whether a putative inventor who envisioned the structure of
a novel chemical compound and contributed to the method of making
the compound is a joint inventor of claim covering that compound.”7 In considering this question, the court noted
that “the conception of a chemical compound necessarily requires
the knowledge for making that compound”. If such knowledge
is “nothing more than the use of ordinary skill in the art”,
development of the method would not generally be a sufficient contribution
so as to amount to joint inventorship of the claimed compound.8 However, the court went on to state that, “where
the method requires more than the exercise of ordinary skill, however,
the discovery of that method is as much a contribution to the compound
as the discovery of the compound itself...a putative inventor who
envisioned the structure of a novel genus of chemical compounds and
contributes to the method of making that genus contributes to the
conception of that genus”. The court also noted that once that
method has been become part of the public knowledge, the person who
developed the method would not necessarily be an inventor of later
developed species.9 The court thus concluded
that Dr. Falana, by providing the method of making the claimed compounds,
contributed to the conception of the claimed genus of compounds and
that Dr. Falana should be named as a coinventor.The older decision Burroughs Wellcome Co. and
the recent decision of Falana show that the contribution
of each person working on a project must be considered in determining
inventorship. It is important to review not only what each person
did but also what was already known or “routine” practice
at the time. If a person performed routine experiments on compounds
that were synthesized by someone else or if the person synthesized
compounds using routine protocols, where the structure of the compounds
was developed by someone else, that person is likely not an inventor.
On the other hand, if the person contributed something that was essential
for developing the invention, e.g. a new synthesis method that allows
the compounds to be made, then that person may be an inventor. The
potential ramifications in making errors in the inventorship are discussed
below with regard to “ownership” of patent rights.Unless there is an agreement to the contrary, the inventors are
considered to be the owners of a patent. If there are coinventors,
then the coinventors are co-owners, as well. Under U.S. laws,10 one co-owner/inventor can sell the patented
invention without having permission from or having to pay royalties
to the other coinventors. Thus, it becomes important for a company
or university to make sure that proper ownership of an invention is
in place.The potential damage resulting from errors in the
areas of inventorship
and ownership can be seen from Ethicon, Inc. v. United States
Surgical Corp.(11) Dr. In-Bae Yoon
conceived of a safety feature to prevent accidental injury during
use of a surgical device. Dr. Yoon met Young Jae Choi and asked him
to help on several projects, for which Mr. Choi was not paid. Mr.
Choi suggested several modifications to the device. After 18 months,
Mr. Choi stopped cooperating with Dr. Yoon and Dr. Yoon subsequently
filed a patent application on the invention (including the modifications
of Mr. Choi) in which he named himself the sole inventor. Dr. Yoon
exclusively licensed the patent to Ethicon.Ethicon sued United
States Surgical Corp. for infringement and,
during discovery, U.S. Surgical Corp. learned of Mr. Choi’s
involvement in the development of the invention. U.S. Surgical Corp.
signed an agreement with Mr. Choi, whereby Mr. Choi gave U.S. Surgical
Corp. a license under the patent. After signing the license, U.S.
Surgical Corp. asked the court to correct the inventorship of the
patent to add Mr. Choi as an inventor and to dismiss the suit because
U.S. Surgical was now an authorized licensee under the patent. The
court held that Mr. Choi was coinventor on the patent and dismissed
the suit against U.S. Surgical Corp. in its entirety.The error
in the inventorship resulted in Ethicon’s complete
loss of any possible damages from U.S. Surgical Corp. However, one
way in which Ethicon could have been further protected from the ramifications
of such an error would be if Mr. Choi had been under an obligation
to assign any rights to any developments he made to Dr. Yoon/Ethicon.
If such an obligation to assign ownership had been in place, even
if Mr. Choi had later been named an inventor, he would not have been
able to license the technology to U.S. Surgical Corp.However, Bd. of Trustees of Leland Stanford Jr. University
v. Roche Molecular Systems(12) illustrates
it is also important to consider the type of assignment document used
to transfer the ownership of the invention. In Stanford there were two competing potential assignment contracts at issue.
Upon joining a laboratory at Stanford as a research fellow, inventor
Holodniy signed an agreement stating, “I agree to assign or confirm in writing to Stanford...right, title and interest in...such
inventions as required by Contracts or Grants”. Holodniy later
went to Cetus and continued working on the same technology. Holodniy
signed a second agreement with Cetus stating that he “will
assign and do[es] hereby assign to Cetus, [his] right,
title, and interest in each of the ideas, inventions and improvements”
that he might devise “as a consequence of” his work
at Cetus. As a result, there were seemingly two competing assignments
of rights to the invention.However, the Court held that the
agreement signed with Stanford
was not an assignment of Holodniy’s rights to the invention.
The language of the contract was found to be an agreement to assign
the rights in the future, but with the agreement in question, no rights
had actually been transferred yet. The agreement with Cetus, on the
other hand, was found to be a legal affirmative assignment of rights
in the invention.Thus, as well as considering inventorship,
it is further important
that the language used in employment contracts be reviewed and properly
worded so as to clearly transfer the ownership of any inventions developed.
Similarly, when a research agreement is entered into, before any research
commences, it is extremely important for the parties involved to determine
where the ownership of any inventions that are developed will reside
and to have a written agreement to that effect. The failure to have
a proper agreement may result in the complete loss of ownership of
the invention or of the value of the invention.This material
is public information and has been prepared solely
for educational purposes to contribute to the understanding of U.S.
intellectual property law. This article reflects only the personal
views of the authors and is not individualized legal advice. It is
understood that each case is fact-specific and that the appropriate
solution in any case may vary. 相似文献
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In some drug discovery approaches, it is advantageous
to restrict
the access of compounds to the CNS to minimize the risk of side effects.
By choosing appropriate physicochemical properties and building in
the ability to act as substrates for active efflux transporters, it
is possible to achieve CNS restriction and still retain sufficient
absorption through the intestinal epithelium to retain good oral bioavailability.
Potential risks in employing this approach are considered.For drugs that are required
to act at targets outside of the central nervous system (CNS), it
may be advantageous to minimize drug exposure in the CNS. Many instances
exist where side effects have been attributed to on- or off-target
actions of a drug in the CNS that lead to issues of safety and tolerability.
Furthermore, in the research phase, the ability to test a novel pharmacological
mechanism could be limited by such side effects.The first generation
of histamine H1 antagonists used for the treatment
of allergic reactions serves as an example, whereby diphenhydramine,
while effective as an antiallergic agent, also caused somnolence and
other CNS side effects as a result of engagement with H1 receptors
in the brain. The second generation agents, for example, cetirizine,
had reduced side effects with reduced somnolence at therapeutic doses,
while the third generation, including fexofenadine, were free of sedation
at doses higher than those used for treatment of allergic reactions.
This progression resulted from increasing CNS restriction of these
agents, thereby increasing their peripheral H1 selectivity.1 Other examples include antimuscarinic agents
used for the treatment of overactive bladder, which act by binding
to muscarinic receptors in the bladder detrusor muscle. Effects such
as cognitive impairment, particularly in elderly patients, have been
reported for agents such as oxybutynin, which penetrate the CNS readily
and are thus able to interact with centrally located muscarinic receptors.
Other agents such as darifenacin and 5-hydroxymethyltolterodine (active
metabolite of fesoterodine) are not associated with CNS side effects
and are largely excluded from the CNS.2Therefore, a general approach that may be advantageous when
considering
peripherally located drug targets is to restrict the access of compounds
to the CNS while maintaining appropriate exposure in peripheral tissues.
This may apply particularly when the peripheral therapeutic target
is known to be present in the CNS but whose engagement there is not
required for desired pharmacological activity. However, it also represents
a general means of minimizing risk of unexpected off-target effects
in the CNS, thereby increasing therapeutic index.The properties
of the brain capillary vascular endothelium that
supply blood to the CNS provide a barrier to the free exchange of
blood-borne solutes. Efficient tight junctions between adjacent brain
vascular endothelial cells (BVECs) restrict passage of solutes between
adjacent cells (paracellular movement) so that to traverse the endothelium,
compounds have to cross the BVEC plasma membrane (transcellular movement).
Hence, the physicochemical properties of a brain penetrant compound
need to be compatible with the ability to diffuse passively across
the plasma membrane and/or participate in active uptake. In addition,
ATP-dependent transporter proteins such as P-glycoprotein (P-gp) and
Breast Cancer Resistance Protein (BCRP), expressed in the BVEC apical
membrane, are capable of ejecting substrate compounds from the cell.
These features of the BVECs constituting the blood–brain barrier
(BBB) offer opportunities to design compounds with properties that
exploit the requirement for transcellular movement and presence of
transporter proteins, to achieve the goal of restricted CNS penetration.However, the properties of orally administered compounds should
also be compatible with those required for absorption across the intestinal
epithelium that acts as a permeability barrier in the gastrointestinal
tract. Molecular weight (MW) < 500, polar surface area (PSA) <
140, and <10 rotatable bonds have been associated with good oral
absorption, while MW < 450 and PSA < 70 have been indicated
as requirements for good CNS penetration.3,4 Hence, to favor
restriction from the CNS while allowing good absorption in the gastrointestinal
tract may point to an area of compatibility of MW of 450–500
and PSA of 70–140. Like the BVECs, the intestinal epithelium
contains several efflux transporter proteins, including P-gp and BCRP,
expressed on the apical membrane of intestinal epithelial cells (enterocytes)
(Figure (Figure11).Open in a separate windowFigure 1Schematic diagram of the distribution
of transporter proteins in
the intestinal epithelium and brain vascular endothelium.P-gp and BCRP are expressed at comparable levels
in human brain
capillaries, and in mouse gene knockout studies, it has been shown
that they may both contribute to exclusion of substrates from the
brain.5 This suggests that design of compounds
that act as substrates for both P-gp and BCRP may maximize their CNS
restriction. Indeed, P-gp and BCRP display considerable overlap in
their substrates (e.g., imatinib is a substrate of both), although
some compounds are exclusively substrates of one or the other (e.g.,
cetirizine is P-gp only). Increasing MW and PSA increases the likelihood
of compounds to act as substrates of P-gp. Additional features include
possession of hydrogen bond acceptors and modest ionization potential
(acid pKa > 4; basic pKa < 8). These features broadly align with those identified
for balancing CNS restriction and intestinal absorption.Targeting
efflux transporters as part of a drug discovery strategy
may suggest a conundrum if efflux transporter expression in enterocytes
renders CNS restriction and good oral absorption incompatible. However,
this could be a misconception as there are several instances of drugs
that are substrates of P-gp and BCRP, CNS restricted, and possess
good oral bioavailability. Considering drug doses commonly prescribed
for clinical use (10–500 mg) and the resulting range of drug
concentrations likely to exist in the gastrointestinal lumen following
an oral dose (assuming dissolution in ∼250 mL), P-gp is often
likely to be saturated by drug substrates in the gut, given that the Km for P-gp is usually in the range 1–100
μM.6 In contrast, systemic unbound
drug concentrations are likely to be in the submicromolar range and
hence unlikely to be at concentrations sufficient to saturate transporters
in the BVECs. For example, the antitumor agent imatinib is a P-gp
and BCRP substrate, with limited brain exposure and high oral bioavailability.7 The unbound plasma Cmax of imatinib following a dose of 400 mg is approximately 250 nM and
is unlikely to saturate P-gp or BCRP at the BBB. The antiviral protease
inhibitors ritonavir and indinavir serve as other examples of CNS
restricted P-gp substrates having high (60–78%) oral bioavailability.5Steady state brain concentrations of a
compound result from the
net effect of passive and active movements across the BBB, so strategies
designed to exclude compounds from the brain could focus on active
and passive processes. Maintaining very low passive permeability such
that equilibrium between blood and brain tissue is not allowed to
occur may have the drawback of impairing intestinal absorption. While,
in this case, a nonoral dose route could be explored, oral administration
is usually the preferred dose route. In our opinion, the strategy
most likely to deliver CNS restriction with good oral absorption is
to maintain an efflux rate at the BBB that greatly exceeds influx
rate, whereby efflux is mediated by P-gp and BCRP against a background
of low-moderate passive permeability. We have utilized this approach
successfully at Pfizer to design CNS restricted orally bioavailable
ligands.5 A series of CNS restricted histamine
H3 antagonists was designed to minimize clinical adverse events such
as insomnia that would otherwise be observed. Optimizing PSA, reducing
passive permeability, and introduction of activity as P-gp and BCRP
substrates led to demonstration of CNS restriction in in vivo tissue partition experiments in rat. Good oral bioavailability (>50%)
was maintained in rat while brain receptor occupancy data confirmed
that CNS restriction was maintained over 7 days of dosing, and electroencephalography
data demonstrated the desired TI for efficacy over insomnia.While the H3 antagonist approach dealt with an extracellular target,
the design of CNS-restricted drug candidates for intracellular drug
targets must incorporate sufficient cellular permeability to reach
the site of action, yet maintain low BBB penetration. Therefore, the
use of cell-based primary screens together with timely in
vivo efficacy and CNS restriction experiments is vital to
ensure that candidate compounds combine efficacy and CNS restriction.
By application of this approach, we have developed CNS restricted
ligands (rat unbound brain:plasma ratio 0.015) for an intracellular
target having high cellular potencies (IC50 ≤ 20
nM) combined with good oral absorption, as demonstrated by linear
pharmacokinetics over a wide dose range (0.25–1000 mg/kg) in
preclinical rodent safety studies.There are identifiable risks
associated with building in P-gp and
BCRP active efflux to a drug approach, some of which can be addressed
by evaluation of clinical data. A drug–drug interaction (DDI),
potentially leading to unwanted CNS penetration, could arise if a
P-gp substrate is concomitantly administered with a P-gp inhibitor.
However, considering the free drug exposures expected at the BBB,
only a very potent P-gp inhibitor could be expected to elicit a significant
effect. DDI associated with absorption could be expected, given P-gp
expression along the intestinal epithelium. Nevertheless, clinical
data obtained with the P-gp substrate digoxin suggest that in the
majority of cases when a P-gp inhibitor and substrate are coadministered,
the digoxin AUC change was less than 2-fold.8 It is also possible that P-gp substrates will display nonlinear
dose versus exposure relationships, depending on their Km for P-gp.
However, as metabolism by CYP3A4, and hence first-pass extraction,
often accompany P-gp affinity,6 it may
be difficult to assess the contribution of each enzyme to any nonlinearity
observed. Presently, our ability to accurately predict absorption
of P-gp and BCRP substrates is limited until more quantitative information
on intestinal transporter expression become available. A number of
polymorphisms of P-gp and BCRP are present in the human population
that could lead to interpatient variability. For instance, the MDR1
gene single nucleotide polymorphism C3435T is linked to decreased
duodenal P-gp expression and modest increases in digoxin exposure.
Similarly, changes in BBB permeability and P-gp expression may occur
with aging and in certain disease states that may alter the degree
of CNS restriction. Finally, a significant concern in compound selection
for clinical studies may be whether CNS restriction measured preclinically
accurately predicts that which occurs in human. Many preclinical evaluations
are conducted in rodents whose transporter expression profile at the
BBB differs from human. Furthermore, a number of recent studies indicate
that the degree of CNS restriction can exhibit species differences
whereby higher primate species, including human, may display significantly
higher CNS exposure than in rodents.5In conclusion, designing in CNS restriction can be used to improve
drug safety. Targeting the efflux transporters P-gp and BCRP alongside
modest passive permeability can confer significant CNS restriction
while retaining good oral bioavailability, cell penetration, and pharmacological
activity. However, there are identifiable risks with this strategy
that may be clarified as further clinical data emerge. 相似文献
11.
Fumito Takada Takahito Kasahara Kentaro Otake Takamitsu Maru Masanori Miwa Kei Muto Minoru Sasaki Yoshihiko Hirozane Masato Yoshikawa Junichiro Yamaguchi 《ACS medicinal chemistry letters》2022,13(9):1421
We report the discovery of two compounds, TKD150 and TKD152, that promote the aggregation of α-synuclein (aSN) using a real-time quaking-induced conversion (RT-QuIC) assay to detect abnormal aSN. By utilizing a Pd-catalyzed C–H arylation of benzoxazole with iodoarenes and implementing a planar conformation to the design, we successfully identified TKD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PA86, the two identified compounds were able to promote aggregation of aSN at twice the rate. Application of TKD150 and TKD152 to the RT-QuIC assay will shorten the inherent lag time and may allow wider use of this assay in clinical settings for the diagnosis of α-synucleinopathy-related diseases. 相似文献
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