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June 1, 2017 (Vol. 37, No. 11)

Industry Watch: Appellate Court Ruling on “On-Sale Bar” Will Affect Patent Cases beyond Helsinn

A recent decision by the U.S. Court of Appeals for the Federal Circuit (CAFC) will have a far-reaching effect on biopharma patent cases with its interpretation of the “on-sale bar” to patenting contained in the America Invents Act (AIA).

A three-judge CAFC panel invalidated four patents held by Helsinn Healthcare covering injection formulations of Aloxi® (palonosetron hydrochloride), a drug for reducing chemotherapy-induced nausea and vomiting.

The appellate court held May 1 that, under AIA’s U.S. Code Section 102(b), public disclosure of the sale of a patented item may be sufficient to invalidate a patent—even if details of the invention are not publicly disclosed—under the on-sale bar, which holds that an invention is unpatentable if it has been for sale for over one year prior to the patent filing.

Helsinn said the on-sale bar did not apply because the deal was subject to FDA approval, and because sale price and dosage strengths were not revealed when it disclosed license and supply agreements with distributor MGI Pharma. The CAFC disagreed, concluding that under AIA the offer, not the sale, acts as the bar since details are rarely disclosed: “If the existence of the sale is public, the details of the invention need not be publicly disclosed in the terms of sale.”

The CAFC’s decision sided with Teva Pharmaceutical Industries, which cited the on-sale bar in defending against a lawsuit filed by Helsinn in U.S. District Court for the District of New Jersey. Helsinn argued that Teva infringed on the patents in developing its generic palonosetron.

“While the decision is correct, it omits a discussion of the reasoning behind the on-sale bar,” said Matthew W. Siegal, partner in the Intellectual Property Group of law firm Stroock & Stroock & Lavan. “Patentees are precluded from extending the term of their patent. If they can begin soliciting offers for the patented goods more than a year before the filing date, they can artificially extend their 20-year term.”

Unsurprisingly, Helsinn and co-marketing partner Eisai said they “maintain their position that the patents protecting Aloxi are valid, and will pursue further legal options to protect and enforce such patents.”


Discovery & Development: A Breath of Fresh Biologics

The pulmonary route is the most direct path for a drug meant to treat a respiratory disorder. But this route can also be a dead end, at least for full-length mAbs and other biologics. These drugs tend to be larger than the small, synthetic molecule-based therapies that are commonly administered via inhalers.

Although full-length mAbs have been reported to have low bioavailability, smaller forms—such as antibody fragments and antibody mimetics—might overcome this problem. That is, the smaller forms might be able to better penetrate pulmonary tissues and reach target receptors. Ideally, the inhalation route could deliver high doses of antibodies directly to the lungs while limiting system exposure and reducing potential side effects.

The pulmonary route hasn’t worked so well for omalizumab, a mAb that is approved for subcutaneous administration in the treatment of asthma. In one recent study, disappointing results for the aerosolization of omalizumab were attributed to the pulmonary route’s failure to deliver enough of the drug to neutralize free systemic immunoglobulin E.

Nonetheless, other studies suggest that the delivery of mAb-derived biopharmaceuticals via the airways is feasible and efficient. For example, lower molecular weight and more potent forms of antibodies are being evaluated for topical delivery, including an anti-interleukin-13 Fab for the treatment of asthma and a highly potent nanobody to treat infection with the respiratory syncytial virus.

Another promising approach is being advanced by Pieris Pharmaceuticals. This company develops lipocalins, which are endogenous low-molecular-weight human proteins typically found in blood plasma and other body fluids. The company’s lipocalin development platform, Anticalin, recently figured in a partnership announced by Pieris and AstraZeneca.

Together, the partners intend to develop lipocalins that can mimic antibodies and bind to sites either on other proteins or on small molecules. AstraZeneca agreed to pay Pieris $45 million upfront and $12.5 million tied to initiating a Phase I trial of Pieris’ lead preclinical candidate, PRS-060, an interleukin-4 receptor alpha agonist designed to treat moderate to severe asthma. AstraZeneca also agreed to shell out up to $2.1 billion to Pieris in development-dependent milestone payments and eventual commercial payments. These milestones pertain not only to PRS-060, but also four additional lipocalin candidates that are targeting respiratory diseases.


Genomics & Proteomics: Transcriptomic Analysis Leads Syros to New Breast Cancer Drug Targets

Syros Pharmaceuticals recently announced that data generated through the use of its gene-control platform lead to the discovery of 14 new potential drug targets for triple negative breast cancer. The new discoveries are a validation of Syros’ approach to systematically analyzing regulatory regions of the genome in an attempt to identify novel targets for defined subsets of patients with diseases that have eluded other genomics-based approaches.

“Targeted drug discovery in cancer has focused on mutations in protein-coding regions of the genome, and while some cancers have been well served by this approach, many other cancers (including triple negative breast cancer) remain unaddressed,” explained Eric Olson, Ph.D., CSO of Syros.

“By analyzing the noncoding, regulatory region of the genome of tumor cells, we have uncovered new targets in subsets of triple negative breast cancer. Our focus on the regulatory genome, coupled with our expertise in drugging transcriptional targets to control the expression of genes, positions us to develop a new wave of genomic-based medicines for patients with diseases that have remained beyond the reach of other targeted approaches.”

Syros scientists were able to identify highly specialized regions of noncoding regulatory DNA, known as super-enhancers, using the company’s proprietary gene-control platform to analyze the regulatory genomes from 43 breast cancer patients’ tissue samples. The discovery also allowed the scientists to validate that super-enhancer analysis can be used to identify clinically relevant disease drivers in defined patient subsets. Moreover, enhancer-linked genes that were validated as essential for triple-negative tumor cell proliferation were identified using CRISPR-mediated gene disruption.

Syros’ drug discovery and development platform is the first to focus solely on the regulatory genome to systematically and efficiently identify disease-causing alterations in gene expression and create medicines to selectively target transcription to control the expression of genes with the aim of treating cancer, as well as autoimmune and rare genetic diseases.


Bioprocessing: Sartorius Stedim Biotech Launches Chemistry Testing Services

Sartorius Stedim Biotech (SSB) began offering chemistry testing services to be carried out by its subsidiary Sartorius Stedim BioOutsource. The company focuses on characterizing the physicochemical properties and structural attributes of therapeutic monoclonal antibodies (mAbs).

The company’s service platform methods have been developed to ensure rapid sample analysis and reporting for mAbs and biosimilars, according to a Sartorius official, who adds that this range of chemistry testing services complies with the well-established ICH Q6B scientific guidelines for pharmaceuticals for human use, and includes methods to characterize protein structure, carbohydrate profile, post-translational modifications, and impurities utilizing UHPLC and LC/MS instruments.

SSB has expanded laboratory space by 340 m2 at its facility in Glasgow, U.K., and has appointed new scientists with chemistry testing experience.

This chemistry testing offer complements the company’s existing range of off-the-shelf biological assays for biosimilar products, providing a complete solution from one contract partner, notes Daniel Galbraith, Ph.D., CSO at Sartorius Stedim BioOutsource. This allows structural and functional analyses to be conducted in parallel, to deliver a data package for regulatory submissions, he adds.

“Rapid data-driven decisions at critical stages are crucial for the successful development of biosimilars.

“Our chemistry testing services enable biosimilar manufacturers to benefit from side-by-side biological and physicochemical analyses to gain the in-depth characterization data required,” explains Dr. Galbraith, who points out that “expanding our portfolio with these new services was a logical step following the successful launch of our Released N-Glycan assay in 2016.”


Molecular Diagnostics: DNA Methylation Technologies Licensed by Cambridge Epigenetix

Cambridge Epigenetix said it has strengthened its position in epigenetic biomarker discovery by licensing technologies from Boston Children’s Hospital that the company said could improve the diagnosis and treatment of cancer and other diseases.

Through an exclusive license agreement whose value was not disclosed, Cambridge Epigenetix said it has licensed numerous epigenetic lab techniques that are related to profiling and altering DNA methylation. The methods include the specific and unbiased enrichment of 5mC and 5hmC via enzymatic glucosylation and the use of TETs for targeted epigenetic engineering.

By gaining access to the intellectual property, Cambridge Epigenetix said it can identify epigenetic biomarkers for noninvasive cancer diagnosis and other clinical applications, and build on offerings that include its TrueMethyl oxidative bisulfite sequencing kits for 5mC and 5hmC detection.

“5hmC is fundamentally linked to the expression of genes and to the identity of cells and tissue. This makes it a highly important epigenetic marker with the potential to improve patient outcomes through the early diagnosis and treatment of diseases such as cancer,” Cambridge Epigenetix CEO Jason Mellad, Ph.D., said in a statement. “This is a tremendous opportunity for Cambridge Epigenetix, enabling the company to utilize and offer our partners the most advanced epigenetic biomarker discovery technologies available in our key focus areas of oncology and liquid biopsy.”

The IP is based upon work by the research group of Anjana Rao, Ph.D., a researcher specializing in immunology and cancer epigenetics who was formerly with Boston Children’s Hospital and is now with the La Jolla Institute for Allergy and Immunology.

“The continued study of 5hmC and other oxidized methylcytosines is essential to enhance our understanding of human biology and health,” Dr. Rao stated. “I am delighted that Cambridge Epigenetix has chosen to license this technology and, through my role on the scientific advisory board, I will continue advising them on maximizing its application.”



























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