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Inhalers remain the cornerstone therapy for patients with asthma and chronic obstructive pulmonary disease (COPD). Over the past several decades, brand-name manufacturers have continued to sell most inhalers at high prices without the threat of direct generic competition. They have arranged for long periods of market exclusivity by obtaining patents not just on the active ingredients (primary patents) but also on peripheral aspects of these products, such as the propellants and delivery devices (secondary patents), and by shifting active ingredients to different devices (device hops), thereby adding new secondary patents.

The production of antibodies for therapeutic use in clinical medicine has become a focus of the biotechnology industry. In 2021, four of the top six selling prescription drugs were monoclonal antibodies, leading to a reported revenue of over US $ 67 billion dollars. Thus, it is no surprise that the otherwise arcane rules around antibody patents have become increasingly important to drug companies, health care providers, and consumers alike.

Product hops to albuterol inhalers containing hydrofluoroalkane rather than chlorofluorocarbons cost payers and patients billions of dollars. Without patent and regulatory reform, this pattern is likely to be repeated.

This Viewpoint discusses a current Supreme Court lawsuit, Amgen v Sanofi, involving Amgen’s broad patents on PCSK9 that could effectively prevent other manufacturers from producing similar or even clinically superior antibodies, with important negative consequences for patients.

This study evaluates sales revenue earned in the first 5 years for newly marketed brand-name drugs with and without an initial orphan drug designation.

This Viewpoint discusses 3 bills introduced recently in Congress that focus on patent eligibility, fraud, and quality and that have major implications for clinical medicine and pharmaceutical development.

This cohort study assesses the frequency of approval and marketing of skinny-label biosimilars and their savings to Medicare.

Pharmaceutical patents listed in the FDA’s “Orange Book” are some of the most valuable patents in the world. Accordingly, for this valuable subset of patents, it is paramount that the Patent & Trademark Office (PTO) correctly issue valid patents and preclude invalid patents from issuing. In this paper, we study what happens to those patents in litigation, reporting the results for every Orange Book patent case that resulted in a merits decision. We find that about 25% of active Orange Book patents were invalidated in court. Since these invalid patents could wrongly increase the costs of prescription drugs, we investigate what happens during prosecution of these patents at the PTO. Our study is the first to link the prosecution of Orange Book patents directly to litigation outcomes. Our goal is to determine if there are ways to identify and prevent the issuance of these later invalidated Orange Book patents. We find that litigated Orange Book patents have unique characteristics that distinguish them from other pharmaceutical patents. They are issued by a relatively small number of examiners. Most litigated patents (90%) are “secondary” patents – patents on smaller tweaks to an existing drug rather than a patent on a new chemical. The owners of these later-litigated patent applications treat them very differently than they do other patents in the same field. They are part of large patent families, suggesting that the applicants are trying to build a patent fence around a known product. They frequently employ a procedural device known as “Track One” to obtain quicker patent prosecution. They are more likely to be subject to rejections based on double-patenting. When initially rejected by the patent examiner, owners of these applications are more likely to fight back rather than amend their claims. All of this suggests that applicants enter prosecution with these patents knowing that they are important and likely destined for litigation, and that they are deliberately creating patent “thickets” to make it harder for generics to enter the market. Remarkably, we find that while patent examiners already have more time to spend on Orange Book patents than on other patents, the prosecution history of many of these invalidated patents are identical. That is, many of these invalidated patents have the same assignee, the same examiner and the same prosecuting attorney cut and paste rejections as well as responses, thus creating identical or very similar prosecution histories. We also find that while the patents that end up being litigated are clearly distinguishable from other pharmaceutical patents during patent prosecution, there is little difference in the PTO between the patents that end up surviving a court challenge and the ones that are invalidated. Our data offer important guidance for reforming the process of prosecuting Orange Book patents. We can and should take advantage of advance knowledge about the importance of these patents to give them a more thorough examination early on. At the same time, the experience with cut-and-paste rejections suggests that we cannot simply give examiners more time and hope that they will do a more thorough job. That not only helps inform the policy suggestions we offer, but it sheds light on a long-standing academic debate about how much time and money we should spend examining patents. Further, our data highlight the importance of secondary patents and patent thickets in Orange Book litigation. We offer a number of suggestions to simplify and streamline patent prosecution and litigation to make it harder to exclude generic entry with a thicket of bad patents.

Pharmaceutical patents represent some of the most valuable intellectual property assets for drug companies. These patents can be worth billions of dollars if found valid and infringed. Correspondingly, if invalidated, generic drug manufacturers can get to market earlier, generating billions of dollars of added revenue. Accordingly, drug patents are associated with high-value, high-cost, bet-the-company type prosecution and litigation. Women, however, are noticeably absent from pharmaceutical patent practice. Women represent only 30% of pharmaceutical patent litigators, and only 33% of pharmaceutical patent prosecutors. Some commentators argue that this lack of representation is due to a “pipeline” problem: we don’t see. women in STEM-focused legal careers because women are underrepresented in STEM undergraduate and graduate programs. Proponents of the pipeline argument contend that the solution to gender and racial homogeneity in patent practice is to simply graduate more women from STEM programs or to adopt more flexible requirements for entering patent practice. This study focuses on pharmaceutical patent litigation from 2009-2021. Specifically, this study reviews: (1) the patent prosecutors who obtained these valuable drug patents; (2) the USPTO patent examiners who reviewed these patents; and (3) both the generic and brand pharmaceutical patent litigators. We find significant gender disparities in the private sector lawyers at both the prosecution and litigation levels. The empirical study presented in this article refutes the pipeline argument when it comes to women in pharmaceutical patent prosecution and litigation. It shows that, for over a decade, women have consistently obtained undergraduate, masters, and doctorate degrees in the biological sciences at higher rates than men for over a decade.6 Furthermore, the study finds that women make up over two-thirds of law students with a health professions degree and over half with a natural sciences degree. Yet, despite having more education in the sciences, women are still underrepresented in private sector pharmaceutical patent prosecution and pharmaceutical litigation. Interestingly, however, this gender disparity does not carry over to public sector work in patent law. The study finds the U.S. Patent and Trademark Office (USPTO) is the one place where we see near parity between men and women in the pharmaceutical patent field: 45% women versus 55% men. Women at the USPTO Solicitor’s Office argue about the same number of cases at the Federal Circuit. Further, women make up nearly half of the Court of Appeals for the Federal Circuit. Finally, unlike the private sector, women at the USPTO are paid at the same rate and stay for the same amount of time as their male counterparts at the USPTO. Drug companies and law firms all state that diversity is an important aspect of their business models. But, as this study shows, there is a disconnect between rhetoric and action. The problem does not seem to stem from a lack of education or a lack of participation in the legal system. The problem may be a lack of opportunity given to women to participate in this type of valuable litigation. The solution may have to come from within the industry, specifically those who have control over hiring outside counsel. Law firm clients may have to use the power of the purse to help encourage greater diversity.

The underlying basis for patent law is a quid pro quo: the inventor discloses how to make and use the invention and in exchange for that disclosure, the public gives the inventor an exclusive right to practice that invention, for a limited time. Pervasive use of Artificial Intelligence (AI) technologies such as Generative Pre-trained Transformer 3 (GPT-3) and other similar AI tools may shift the balance of power envisioned in the patent system away from the public and towards the inventor. Specifically, GPT-3 and other AI products may allow inventors to claim significantly more in their patent than they originally invented, thus inequitably enlarging their exclusive rights without benefiting the public. Patent law has built in tools such as the enablement, utility and definiteness requirements to help limit the possible unjustified expansion of patent rights caused by pervasive use of AI. Additionally, if AI wholly disrupts the quid pro quo established by Congress, then patent law may have to adjust by moving from a peripheral claiming approach back to central claiming approach.

The balance between free speech and access to courts in defamation tort actions is fraught with public policy concerns. On one hand, plaintiffs should have unencumbered access to the justice system to remedy real harms brought upon them by defamatory statements. However, defamation suits should not be wielded to suppress the constitutionally protected free speech rights of news organizations and of concerned citizens that are vital for well-functioning democracies. This Article argues for a new type of remedy, namely enhanced Rule 11 attorney sanctions, such as suspension or debarment, that should be available to defendants of defamation suits brought by repeat players that use “cookie cutter” complaints. This Article specifically proposes a novel four-part test implicating use of attorney sanctions as a remedy for filing niche types of frivolous lawsuits. Per this test, a court should weigh the following factors to determine if such sanctions are warranted: (1) if the plaintiff habitually files and loses defamation-type suits to prevent protected free speech; (2) the nature of the defendant, especially if the defendant is a news organization; (3) the proportionality of the damages requested, and; (4) if a countersuit is at issue. In this Article, we examine a case study in the form of a decades’ long frivolous litigation pattern exhibited by Murray Energy and Robert-Murray-as-CEO. Murray Energy has been characterized as the single largest privately owned coal corporation in the United States, and thus constitutes a prominent actor well-suited for assessing the potential strengths and weaknesses of developing this new remedy. We ultimately conclude that enhanced Rule 11 attorney sanctions, as weighed and levied vis-a-vis the proffered test, could constitute a potentially potent deterrent to frivolous lawsuits designed to inhibit the free speech of the press and of concerned citizens—which indeed occupy a crucial watchdog role in healthy democracies.

Treatment of cells with epidermal growth factor (EGF) promotes the activation of the small GTP-binding protein Cdc42, as well as its phosphorylation in cells. The EGF-dependent phosphorylation of Cdc42 occurs at tyrosine 64 in the Switch II domain and appears to be mediated through the Src tyrosine kinase, because both the expression of a dominant-negative Src mutant (mouse Src(K297R)) and treatment of cells with the Src kinase inhibitor PP2 blocks the EGF-stimulated phosphorylation of Cdc42, whereas expression of an activated Src mutant (Src(Y529F)) promotes phosphorylation in the absence of EGF treatment. The EGF-stimulated phosphorylation of Cdc42 is not required for its activation, nor does it directly affect the interactions of activated Cdc42 with target/effector proteins including PAK, ACK, WASP, or IQGAP. However, the EGF-stimulated phosphorylation of Cdc42 is accompanied by an enhancement in the interaction of Cdc42 with the Rho-GDP dissociation inhibitor (RhoGDI). The EGF-stimulated activation of Cdc42 does require activated Src, as well as the Vav2 protein, a member of the Dbl family of guanine nucleotide exchange factors. Src catalyzes the tyrosine phosphorylation of Vav2, and overexpression of Vav2 together with activated Src (Src(Y529F)) can completely bypass the need for EGF to promote the activation of Cdc42. Thus, EGF signaling through Src appears to have dual regulatory effects on Cdc42: 1). it leads to the activation of Cdc42 as mediated by the Vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of Cdc42, which stimulates the binding of RhoGDI, perhaps to direct the movement of Cdc42 to a specific cellular site to trigger a signaling response, because Cdc42-RhoGDI interactions are essential for Cdc42-induced cellular transformation.

Cdc42 is a Ras-related protein that has been implicated in the control of normal cell growth, and when improperly regulated, in cellular transformation and invasiveness. A variety of extracellular stimuli, including epidermal growth factor (EGF), activate Cdc42. Here, we show that activation of Cdc42 protects the EGF receptor from the negative regulatory activity of the c-Cbl ubiquitin ligase. Activated Cdc42 binds to p85Cool-1 (for cloned-out-of-library)/β-Pix (for Pak-interactive exchange factor), a protein that directly associates with c-Cbl. This inhibits the binding of Cbl by the EGF receptor and thus prevents Cbl from catalyzing receptor ubiquitination. The role played by Cdc42 in regulating the timing of EGF receptor-Cbl interactions is underscored by the fact that constitutively active Cdc42(F28L), by persistently blocking the binding of Cbl to these receptors, leads to their aberrant accumulation and sustained EGF-stimulated ERK activation, thus resulting in cellular transformation.

Cdc42 is a small GTP-binding protein which has been implicated in a number of cellular activities, including cell morphology, motility, cell-cycle progression, and malignant transformation. While GTPase-defective forms of Cdc42 inhibit cell growth, a mutation [Cdc42(F28L)] that allows the constitutive exchange of GDP for GTP and is GTPase-competent induces cellular transformation. These results suggest that Cdc42 must cycle between its GTP- and GDP-bound states to stimulate cell growth. In attempting to design Cdc42 molecules with more potent transforming activity, we set out to generate other types of Cdc42 mutants capable of constitutive GDP-GTP exchange. Here, we describe one such mutant, generated by changing a conserved aspartic acid residue at position 118 to an asparagine. The Cdc42(D118N) protein exchanges GDP for GTP more rapidly than wild-type Cdc42, but significantly more slowly than the Cdc42(F28L) mutant. Despite its slower rate of activation, the Cdc42(D118N) mutant is more potent at inducing cellular transformation than the Cdc42(F28L) protein, and causes a significant loss in actin stress fibers, reminiscent of what is observed with fibroblasts transformed by oncogenic Ras mutants. Effector-loop mutations made within the D118N background inhibit Cdc42-induced transformation and Cdc42-mediated antiapoptotic (survival) activity to similar extents. In addition, mutating aspartic acid 121 (to asparagine), which forms part of a caspase cleavage site (DLRD, residues 118-121 of Cdc42), in combination with the F28L mutation generates a Cdc42 molecule [Cdc42(F28L/D121N)] with transforming activity significantly stronger than that of Cdc42(F28L). Thus, mutations that combine some capacity for cycling between the GTP- and GDP-bound states with increased survival against apoptotic signals yield Cdc42 molecules with the maximum capability for inducing cellular transformation.

Fas-mediated apoptosis results in the activation of caspases, which subsequently cleave cellular substrates that are essential for normal cell viability. In the present study, we show that the Ras-related GTP-binding protein Cdc42 is susceptible to caspase-catalyzed proteolysis in a number of cell lines, including NIH3T3 fibroblasts, human breast cancer cells (e.g. T47D), and COS-7 cells. Both caspase-3 and caspase-7 were able to catalyze the cleavage of Cdc42, whereas caspase-6 and caspase-8 were without effect. The susceptibility to the caspase-stimulated degradation is specific; although Rac can also serve as a caspase substrate, neither Rho nor Ras is degraded. Caspase sensitivity is conferred by a consensus sequence (DXXD) that lies immediately upstream of the Rho insert regions (residues 122-134) of Cdc42 and Rac. The removal of a stretch of residues (120) that includes the insert region or site-directed mutagenesis of either aspartic acid 118 or 121 within a constitutively active background (i.e. Cdc42(F28L)) as well as a wild-type Cdc42 background yields Cdc42 molecules that provide a marked protection against Fas ligand-induced apoptosis. Overall, these results are consistent with a model in which Cdc42 acts downstream of Fas, perhaps to influence the rate of apoptosis, with the ultimate caspase-mediated degradation of Cdc42 then allowing for a maximal apoptotic response.

Chemotherapeutic drugs that damage DNA kill tumor cells, in part, by inducing the expression of a death receptor such as Fas or its ligand, FasL. Here, we demonstrate that epidermal growth factor (EGF) stimulation of T47D breast adenocarcinoma and embryonic kidney epithelial (HEK293) cells protects these cells from Fas-induced apoptosis. EGF stimulation of epithelial cells also inhibited Fas-induced caspase activation and the proteolysis of signaling proteins downstream of the EGF receptor, Cbl and Akt/protein kinase B (Akt). EGF stimulation of Akt kinase activity blocked Fas-induced apoptosis. Expression of activated Akt in MCF-7 breast adenocarcinoma cells was sufficient to block Fas-mediated apoptosis. Inhibition of EGF-stimulated extracellular signal-regulated kinase (ERK) activity did not affect EGF protection from Fas-mediated apoptosis. The findings indicate that EGF receptor stimulation of epithelial cells has a significant survival function against death receptor-induced apoptosis mediated by Akt.

During apoptosis, engagement of the mitochondrial pathway involves a decisive event characterized by the release of mitochondrial intermembrane space proteins, such as cytochrome c . This permeabilization of the mitochondrial outer membrane depends on activation and oligomerization of multidomain Bcl-2-family proteins Bax or Bak. Although specific members of the Bcl-2 family can activate these proapoptotic proteins, we found that heat directly activated Bax or Bak to induce cytochrome c release. A preparation of mitochondria heated at 43°C released cytochrome c in association with Bak oligomerization, and Bcl-xL prevented these events. Similarly, heat induced the oligomerization of recombinant Bax, conferring an ability to permeabilize mitochondria. Compared with wild-type cells, bax –/– bak –/– mouse embryonic fibroblasts and mitochondria isolated from these cells were resistant to heat-induced cytochrome c release. Cytosol from untreated cells inhibited heat-activated Bax or Bak; however, depletion of cytosolic Bcl-xL ablated this protection. Although mitochondria heated in the presence of cytosol did not release cytochrome c , they displayed a dramatic increase in sensitivity to permeabilization by the BH3-only protein Bid. Additionally, a peptide corresponding to the BH3 domain of Puma counteracted the inhibitory effect of cytosol and permitted heat-activated Bak to permeabilize the mitochondria. Therefore, heat represents a condition under which multidomain proapoptotic proteins are activated, and this activation is regulated by both antiapoptotic and BH3-only members of the Bcl-2 family. Our results support an emerging paradigm, wherein the activation of Bax or Bak and the blockade of antiapoptotic Bcl-2 proteins are pivotal steps in the mitochondrial pathway of apoptosis.

Activation of 'initiator' (or 'apical') caspases-2, -8 or -9 (refs 1-3) is crucial for induction of apoptosis. These caspases function to activate executioner caspapses that, in turn, orchestrate apoptotic cell death. Here, we show that a cell-permeable, biotinylated pan-caspase inhibitor (bVAD-fmk) both inhibited and 'trapped' the apical caspase activated when apoptosis was triggered. As expected, only caspase-8 was trapped in response to ligation of death receptors, whereas only caspase-9 was trapped in response to a variety of other apoptosis-inducing agents. Caspase-2 was exclusively activated in heat shock-induced apoptosis. This activation of caspase-2 was also observed in cells protected from heat-shock-induced apoptosis by Bcl-2 or Bcl-xL. Reduced sensitivity to heat-shock-induced death was observed in caspase-2(-/-) cells. Furthermore, cells lacking the adapter molecule RAIDD failed to activate caspase-2 after heat shock treatment and showed resistance to apoptosis in this setting. This approach unambiguously identifies the apical caspase activated in response to apoptotic stimuli, and establishes caspase-2 as a proximal mediator of heat shock-induced apoptosis.

A response to Pervasive sequence patents cover the entire human genome by J Rosenfeld and C Mason. Genome Med 2013, 5:27. See related Correspondence by Rosenfeld and Mason, http://genomemedicine.com/content/5/3/27 and related letter by Rosenfeld and Mason, http://genomemedicine.com/content/6/2/15.

It is no secret that some Patent and Trademark Office (PTO) examiners operate more quickly than others. Previous studies have shown that an applicant’s ability to obtain a patent is inexorably linked to the random assignment of a patent examiner. However, not all patent examiners are created equal. Some patent examiners allow patent applications quickly within just one or two Office Actions resulting in only a few months of substantive patent prosecution. In contrast, other patent examiners constantly reject patents applications, which can result in unnecessarily delaying prosecution and years of substantive patent prosecution. This study focuses on how different examiners use prior art rejections to prolong or compact prosecution. This study demonstrates how two different populations of patent examiners (slow vs. fast) can achieve and even exceed their production goals by either an allowance or rejection strategy. The allowance strategy relies on granting a large number of applications with only a few rejections and usually within one or two office actions. The rejection strategy relies on rejecting a large number of applications using a wide variety of different rejection types. Unlike many studies, this is the first paper that evaluates patent quality based on individual examiner characteristics at the patent prosecution level focused on non-prior art rejections. In particular, high volume biotechnology examiners reject applications based mainly on obviousness type double patenting and indefiniteness rejections, while issuing fewer obviousness or anticipation type rejections. In contrast, low volume examiners reject applications based mainly on obviousness rejections. Furthermore, number of pages in the low volume examiners’ office actions are more than three times more than high volume examiners. Thus, low volume examiners are writing longer office actions and rejecting based on a wide variety of statutory authorities, while high volume examiners are writing shorter office actions based mainly on obviousness type double patenting issues. We find that different types of examiners use different strategies to maximize their “counts” in order to keep their production numbers high. Specifically, low volume examiners will generally reject applications creating lengthy prosecution histories while forcing the applicant to narrow claims. In contrast, high volume examiners will usually only make one rejection then allow the case, thus creating a small prosecution history with only small amendments to the claims. This results in a dramatic range of patent prosecution times as well as a large difference in claim scope. Slow examiners take approximately 5.85 years to issue a patent while fast examiner only take approximately 1.64 years. The added four years of prosecution greatly increases direct costs to the inventor (both in PTO and attorney fees) as well as indirect costs such as reduced growth in employment, sales and follow on innovation. Finally, there may be harms to not only the inventor, but to rivals in the form of diminished access to external capital and slower growth of follow on innovation.

Examiner interviews are one of the most powerful tools to help both inventors and examiners understand and overcome specific issues during prosecution. Direct discussions between an applicant and an examiner can help bridge the gap between misunderstandings of prior art, the invention or statements in the specification. When used correctly, examiner interviews can dramatically decrease the time in prosecution and help applicants quickly reach a final disposition. This study reviews approximately 1.1 million patent applications corresponding to every patent application with an examiner interview between 2007 to June 2020 to determine the effectiveness of examiner interviews. This study establishes that examiner interviews dramatically decrease the number of Office Actions needed to reach a final disposition (allowance or abandonment).

The United States Patent and Trademark Office is tasked with reading and reviewing patent applications to determine those applications which qualify for patent protection. Each application is reviewed by a specific patent examiner who should apply the standards of patentability in an even, fair, unbiased and consistent manner. This task requires the examiner not only to be internally consistent with the applications she reviews, but consistent with the behavior of other examiners within the same art unit. I find this may not be the case. I show two specific populations of examiners that may be harming the patent system. The first population may be acting as a “rubber stamp” by allowing patents with little to no review and/or amendments to the claims. In contrast, the second population may be acting to reject too many “good” patents. In this article, I argue that the incentive system may play a role in creating these two distinct populations of examiners. Additionally, I propose a holistic pre-grant prosecution history review of both low and high allowance rate examiners to ensure a more consistent application of patentability rules.