In our previous article, we covered FDA new drug approvals for 2018. In the present article, we look at patent filings, litigation, regulatory and clinical data, related to these drug approvals, as a case study of fusing complementary data sources to provide comprehensive pharma competitive intelligence.
Orange Book (or Approved Drug Products with Therapeutic Equivalence Evaluations) provides information on patents that are purported to protect an FDA approved drug. Multiple patents are often listed against an application in the Orange book. 204 unique patents were listed in the Orange Book for the 59 new drugs approved from the year 2018. Vertex Pharmaceutical’s Symdeko has the highest number of listed patents followed by Rigel Pharmaceutical’s Tavalisse and Array Biopharma’s Braftovi/Mektovi. Patents assigned to institutions such as MIT, University of California, Emory University, and the University of Massachusetts also featured in the list indicating prior licensing deals with the brand holder (Fig. 1.1). Most of these patents originate from the US (Fig. 1.2). A fair share of the patents originated in other advanced jurisdictions such as Europe (~10%) and Japan (~ 5%).
The listed patents may fall under 3 categories: i) active ingredients/compounds, ii) formulations, and iii) methods of use. Our analysis reveals 32.8% of the 2018 listed patents relate to the active ingredients/compounds, 26% were directed to formulations, and 41.2% were directed to methods of use (Fig. 1.3).The brand holders may advantageously list patents against more than one Orange book entry. For instance, patents listed under Gilead’s antiretroviral combination therapeutic Biktarvy (bictegravir, emtricitabine and tenofovir alafenamide) are also covered in its earlier FDA applications related to Descovy (emtricitabine and tenofovir alafenamide) and Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide). A quick look at Gilead’s product line reveals 21 active and unique listings in the Orange Book database.
Source: FDA Fig. 1) Orange book listed patents. 1.1) Assignees. 1.2) Priority Countries 1.3) Claim Type 1.4) Patent Details - Earliest Priority Year
Orange Book listed patents are often subject of litigation before courts and the Patent Trial and Appeal Board (PTAB). Our analysis of the 2018 listed patents revealed 8 of the 204 listed patents were cited in 24 litigation events. The majority of these cases were US District Court proceedings initiated by the patent holders. Gilead featured predominantly with cases filed against generic manufacturers such as Mylan, Teva Pharmaceutical Industries, Lupin, Cipla, and Aurobindo Pharma (Fig. 2.1). Interestingly, Gilead recently filed for an infringement suit (case number: 3:19-cv-00529) against Zydus Cadila’s generic version of Truvada (emtricitabine/tenofovir). The patents asserted here include Emory University’s patents US 6,642,245 and US 6,703,396 listed under Biktarvy. Significantly, these patents were also asserted in 18 other cases filed by Gilead. Patent holders may be targeted via Inter Partes Review (IPR) and other related PTAB proceedings. Two PTAB cases (IPR2018-00739 and IPR2019-00554) challenge the validity of Arbutus patents US 9,364,435 and US 8,058,069. The Arbutus patents were listed under Alynylam’s recently approved drug patisiran (ONPATTRO). Both of the PTAB cases relate to Moderna’s on-going challenge of Arbutus’ patents on lipid nanoparticle technology (Fig. 2.2).
Source: Litigation Databank Fig. 2) Litigation of Orangebook Listed Patents. 2.1) Main Plaintiffs vs. Defendants. 2.2) Case Timeline. 2.3) Litigation details
On the clinical trial front related to 2018 approved drugs, we found about 2,294 clinical trials related to the active ingredient of the approved drugs enrolling over 246,937 participants. The most number of trials were attributed to cannabidiol – 150 in count - enrolling 151,46 participants (Fig. 3.1) recruited from a wide variety of age groups and conditions such as anxiety, epilepsy, schizophrenia, heart failure, Crohn’s disease and opioid addiction. Rifamycin has 25,507 enrollments for 118 different trials related to diverse conditions such as traveller’s diarrhea, tuberculosis, sickle cell disease and irritable bowel syndrome. The high enrollment indicates the broad applicability of these therapeutics as opposed to drugs targeting rare diseases. Of the trials, 357 are related to cancer, tumors and neoplasm, 68 for liver related conditions, 42 for HIV infection, and 40 are related to opioid and alcohol use. There are a total of 31 trials related to epilepsy. Phenylketonuria and bacterial infections are the subject of 11 trials each.
Source:Clinical Trials database Fig. 3) Approved drugs in 2018. 3.1) Active pharmaceutical Ingredient. 3.2) Clinical Trials by Phase. 3.3) Trials Funding distribution
Among the trials related to the approved active ingredients, about 539 trials are in Phase 1, 677 are in phase 2 and 582 in Phase 3, and 112 in Phase 4 (Fig. 3.2). Many of these advanced trials may result in FDA approvals for additional disease conditions. About 68% of all clinical trials are industry funded (Fig. 3.3). Among the listed industrial sponsors of the trials, Pfizer is attributed to a total of 68 different trials for five anti-cancer small molecules –binimetinib,dacomitinib,glasdegib,lorlatinib, and talazoparib. Moxidectin, another drug under study by Pfizer, is an anthelmintic. Eli Lilly is listed against 54 studies for two different drugs –baricitinib, for interventions related to autoimmune disorders such as juvenile idiopathic arthritis, atopic dermatitis, SLE, and alopecia among others, and galcanezumab, which is the first FDA approved humanized monoclonal antibody for treating migraine. Among the sponsors for studies on cannabidiol, GW Pharmaceuticals leads with 44 different trials enrolling 8,714 participants for various conditions such as epilepsy, pain relief during cancer and multiple sclerosis.
Source: Clinical Trials database Fig. 4) Trial enrollment locations
The new drugs were primarily tested in the US (Fig. 4). Drugs like cenegermin, lofexidine hydrochloride, lusutrombopag, plazomicin, sarecycline, fosnetupitant and palonosetron, and tecovirimat have trial locations exclusively in the US. Projected blockbusters including Gilead’s Biktarvy (estimated sales $5.3 billion) and Vertex’s Symdeko (estimated sales $2.7 billion) were predominantly trialled in the US, but had also enrolled participants from Europe, Canada and South America. Cenegermin was under study for eye related conditions such as neurotrophic keratitis, dry eye and glaucoma. Lofexidine hydrochloride was tested for opioid related disorders and withdrawal symptoms. Lusutrombopag was approved to treat thrombocytopenia, a condition where patients suffer from low platelet counts. Plazomicin is an antibacterial drug used to treat urinary tract infection and kidney related disorders. It was also tested for cardiac conditions. Sarecycline is used to treat acne vulgaris. Tecovirimat was approved for smallpox and monkeypox. Fosnetupitant and palonosetron were tested to treat chemotherapy induced nausea and vomiting. China has the second highest enrollment for the trials, but it oversees only 18 of the approved drugs. United Kingdom had third highest enrollment numbers with trial locations for 39 of the 59 drugs. Unsurprisingly, the malarial drug Tafenoquine was primarily tested in endemic regions such as Ethiopia, Thailand, Vietnam, Indonesia, India, Bangladesh, Brazil and Peru.
The projected sales for the 2018 approved drugs is expected to exceed over 42,700 million USD with at least 11 of the 59 drugs exceeding the 1,000 million USD mark. The present data indicates a majority of the trials were funded by industries and are in early stages. The 2018 approved drugs are predominantly oncology and hematology based followed by those targeting infectious diseases, neurological, immunological, respiratory and genetic conditions. Supplementary approvals can be expected in the near future for additional conditions and drug combinations driving their future growth. Increased commercial interest in the drugs may also result in new litigation and generic filings.
Stay tuned to our future updates on medical devices, generics, and competitive benchmarking.
IP competitive intelligence and monitoring in the drug and medical device industry requires understanding of therapeutic areas (technologies, pathways, targets, etc), products (pipeline, formulations, extensions, generics, etc), financial analysis, market dynamics, clinical and regulatory developments, in addition to intellectual property (filings, opposition, prosecution, litigation, licensing). The ability to provide a global view of the competitive landscape obtained from diverse information using a strong data foundation and unbiased approach allows for future-proof portfolio strategy, benchmarking, due diligence, scouting and alerts. Combining diverse information in specially curated dashboards, such as those presented in charts above, and adding actionable intelligence will help decision makers identify threats early and make informed decisions.
About the Authors:
Joshua Immanuel – Joshua is part of the Search and Analytics team at MaxVal. He has experience in performing pre-filing searches, technology landscapes, and market reports.
Ganesh Venkatraman – Ganesh is part of the Search and Analytics team at MaxVal. He has experience in conducting competitive analysis, technology landscapes, patent searches, drafting and prosecution.