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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   

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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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