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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5436_Библиотеки_им_академика_М_И_Перельмана.pdf
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Heavy Chain (HC): The large polypeptide subunit of an antibody.
Human Equivalent Dose (HED): A dose that is predicted to provide the
same level of drug exposure in humans as a dose administered in a pre-
clinical animal model provides in that species (e.g., NOAEL or nontoxic
dose); calculated using a species-specic allometric scale based on body
surface area.
Institutional Review Board (IRB): The entity designated to review and
monitor research involving human participants in the US; often called the
Ethics Committee outside of the US.
International Conference on Harmonisation (ICH): Organization that pro-
vides international guidelines for drug testing.
Investigational New Drug Application (IND): Request from a clinical spon-
sor to obtain authorization from FDA to administer an investigational drug
or biological product to human subjects.
Light Chain (LC): The small polypeptide unit of an antibody.
Master Batch Record (MBR): A written procedure of all manufacturing and
testing methods thatis required to be approved by QA.
Master Cell Bank (MCB): Repository of frozen cell aliquots for the clonal
hybridoma line selected for biological product manufacturing.
Master File: FDA le certifying a manufacturing company based on prior
IND submissions establishing GMP requirements.
Maximum Tolerated Dose (MTD): The highest dose of a drug or therapy
that does not cause unacceptable side effects or toxicity.
Media Fill: Manufacturing run using media performed to demonstrate sterile
operations.
Minimal Clinically Important Difference (MCID): The smallest improve-
ment in treatment outcome that a patient would consider worthwhile.
Multiple-Ascending Dose (MAD): A trial where subjects in each cohort
receive multiple administrations of the same dose of study drug, often over
14 days; the dose for each successive cohort is escalated once safety is
established for the prior cohort.
New Drug Application (NDA): Mechanism to obtain FDA approval for the
sales and marketing of a new drug in the US.
New Molecular Entity (NME): A drug product that is a new chemical entity
not previously approved by FDA.
No Observed Adverse Effect Level (NOAEL): The maximum dose admin-
istered in preclinical safety studies where no undesirable side effects are
seen; sometimes called the nontoxic dose.
Orphan Indication: An FDA designation of a disease or condition that
affects less than 200,000 people in the US or for a treatment that is not
expected to recoup its research and development costs due to pricing
constraints.
D. Mochly-Rosen et al.
181
Pharmacokinetics (PK): Measurements of what the body does to a drug
(absorption, distribution, metabolism, and excretion).
Placebo: A pharmacologically inactive substance used as a comparator in
some clinical trials.
Prescription Drug User Fee Act (PDUFA): US legislation that allows FDA
to collect fees from drug manufacturers to fund the new drug approval
process.
Quality Assurance (QA): Process to comprehensively ensure the production
of a safe and effective drug product by proactively optimizing the drug
manufacturing and packaging process to minimize and eliminate any
defects before they can occur.
Quality Control (QC): Functional unit with the responsibility and authority
to ensure that the drug product meets all pre-established quality standards
before it is released; this process includes reviewing and approving/reject-
ing all procedures and components involved in the manufacturing process,
from acquisition of raw materials to nal packaging.
Randomization: A method based on chance by which study participants are
assigned to a treatment group.
Recombinant DNA (rDNA): DNA constructs that have been articially
manipulated and do not naturally occur in organisms.
Single-Ascending Dose (SAD): A trial where subjects in each cohort receive
a single administration of a given dose of study drug; the dose for each
successive cohort is escalated once safety is established for the prior
cohort.
Sponsor or Applicant: Individual or entity that submits an IND, NDA,
or BLA.
Stability Indicating Assay: Product testing that is performed at designated
time intervals to ensure that API remains intact within prespecied levels
and that impurities remain below prespecied levels. Often done at both
the recommended storage temperature and a higher temperature (e.g.,
37°C), which may accelerate degradation of the drug product.
Surrogate Endpoint: An indirect measure that may be a lab value, imaging,
or clinical measure that is expected to reect more clinically relevant
endpoints.
Therapeutic BLA: Application submitted to CDER for products such as
monoclonal antibodies, cytokines, and growth factors.
US Food and Drug Administration (FDA): The federal Health and Human
Services agency responsible for protecting public health.
Validation (or Qualication of) Assays: A formal process demonstrating
that an assay is specic, reproducible, and precise.
Working Cell Bank (WCB): Frozen aliquots of cells for active use in manu-
facturing and testing.
4 Preparing fortheClinic
182
References
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Biotechnology Innovation Organization (2021) Clinical development success rates and contrib-
uting factors, 2011–2020. Washington DC.Available at: https://go.bio.org/rs/490- EHZ- 999/
images/ClinicalDevelopmentSuccessRates2011_2020.pdf
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tocol items for clinical trials. Ann Intern Med 158:200–207
Chan A-W, Tetzlaff JM, Gøtzsche PC etal (2013b) SPIRIT 2013 explanation and elaboration:
guidance for protocols of clinical trials. BMJ 346:e7586
Cohen SN, Chang ACY, Boyer HW, Helling RB (1973) Construction of biologically functional
bacterial plasmids invitro. Proc Natl Acad Sci 70:3240–3244
Commissioner O of the (2020) Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter
Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new
policies to advance development of safe and effective cell and gene therapies. In: FDA. https://
www.fda.gov/news- events/press- announcements/statement- fda- commissioner- scott- gottlieb-
md- and- peter- marks- md- phd- director- center- biologics. Accessed 28 July 2022
Day S, Jonker AH, Lau LPL, Hilgers R-D, Irony I, Larsson K, Roes KC, Stallard N (2018)
Recommendations for the design of small population clinical trials. Orphanet J Rare Dis 13:195
Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products.
https://www.fda.gov/media/133660/download
Key Abbreviations
AAV Adeno-Associated Virus
CHO Chinese Hamster Ovarian
CFR Code of Federal Regulations
CAPA Corrective and Preventive Actions
CYP Cytochrome P450
DF Dialtration
EMA European Medicines Agency
EU European Union
EBR Executed Batch Records
HPLC High-Performance Liquid Chromatography
NIST National Institute of Standards and Technology
PMDA Pharmaceuticals and Medical Devices Agency
PAI Pre-Approval Inspection
PD Process Development
QP Qualied Person
QSR Quality System Regulations
RFP Request for Proposal
SOP Standard Operating Procedures
SPIRIT Standard Protocol Items: Recommendations for Interventional Trials
TSE Transmissible Spongiform Encephalopathy
UF Ultraltration
WRO Written Response Only
D. Mochly-Rosen et al.
183
Evans CH Jr, Ilstad ST (eds) (2001) Small clinical trials: issues and challenges. Institute of
Medicine, U.S.National Academy of Sciences. National Academies Press, Washington, DC
Fleming TR, Powers JH (2012) Biomarkers and surrogate endpoints in clinical trials. Stat Med
31:2973–2984
(2015) Human Immunodeciency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment
Guidance for Industry. https://www.fda.gov/les/drugs/published/Human- Immunodeciency-
Virus- 1- Infection%2D%2DDeveloping- Antiretroviral- Drugs- for- Treatment.pdf
ICH Ofcial web site: ICH.In: CTD. https://www.ich.org/page/ctd
Khan S, Ullah MW, Siddique R, Nabi G, Manan S, Yousaf M, Hou H (2016) Role of recombinant
DNA technology to improve life. Int J Genomics 2016:e2405954
Köhler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predened
specicity. Nature 256:495–497
Sagonowsky E (2021) The top 20 drugs by worldwide sales in 2020. In: Fierce Pharma. https://
www.ercepharma.com/special- report/top- 20- drugs- by- 2020- sales. Accessed 29 Mar 2022
U.S.Food and Drug Administration (2005) Guidance for Industry. Estimating the maximum safe
starting dose in initial clinical trials for therapeutics in adult healthy volunteers. US.FDA,
Silver Spring. Available at: https://www.fda.gov/media/72309/download
U.S.Food and Drug Administration (2018) Guidance for Industry. E6(R2) Good Clinical Practice:
Integrated Addendum to ICH E6 (R1). US.FDA, Silver Spring. Available at: https://www.fda.
gov/media/93884/download
U.S.Food and Drug Administration (FDA) (2004) Innovation or stagnation: challenge and oppor-
tunity on the critical path to new medical products. U.S.Food and Drug Administration (FDA)
4 Preparing fortheClinic
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5
Technology Transfer
andCommercialization
DariaMochly-Rosen, KevinGrimes, JudyMohr,
KarinImmergluck, EmilyEgeler, JenniferSwantonBrown,
NicholasGaich, EugenioL.de Hostos, GraceHancock,
MaryWang, RobertF.Booth, JuliePapanekGrant,
LeonChen, NinaKjellson, HaimZaltzman, J.JekkieKim,
JohnWalker, AlanMendelson, PeterBoyd,
and ChristopherM.Reilly
Daria Mochly-Rosen, Ed, Kevin Grimes, Ed.
D. Mochly-Rosen (*) · K. Grimes
Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, US
e-mail: sparkmed@stanford.edu; kgrimes@stanford.edu
J. Mohr
McDermott Will & Emery LLP, Menlo Park, CA, US
K. Immergluck
Stanford University, Stanford, CA, US
E. Egeler ∙ J. S. Brown
Stanford University School of Medicine, Stanford, CA, US
N. Gaich
Nick Gaich and Associates, Morgan Hill, CA, US
E. L. de Hostos · G. Hancock · M. Wang
Calibr, Scripps Research Institute, La Jolla, CA, US
R. F. Booth
Curasen Therapeutics, San Carlos, CA, US
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
D. Mochly-Rosen, K. Grimes (eds.), A Practical Guide to Drug Development in
Academia, https://doi.org/10.1007/978-3-031-34724-5_5
186
As academic researchers, some of us may be interested in forming startup compa-
nies to develop and market drugs or diagnostics based on our research. Others may
be happy to license their technology and ndings to an existing company. In either
case, it is essential that your inventions are protected by ling a patent. Unless there
is patent protection to provide a period of exclusive marketing after regulatory
approval, a commercial entity will not be able to realize a return on the considerable
investment in nances and time required for product development.
The invention must be considered novel and non-obvious at the time of patent
ling. Once an invention is in the public domain (e.g., journal article, abstract, con-
ference presentation), it is no longer considered novel by the patent granting agen-
cies. Therefore, if you believe that your discovery has a commercial application, do
not disclose information about it in public without rst ling a patent. Premature
public disclosure is perhaps the chief reason that promising academic inventions are
deemed not patentable and therefore not developed.
Since sharing our discoveries is crucial to the advancement of science and intrin-
sic to the academic mission, expeditious patent ling is critical. Your institution’s
ofce of technology licensing can quickly le a provisional patent that includes
your novel claims along with an abstract of your planned presentation or manuscript
to be submitted for publication. Familiarizing yourself with the people and pro-
cesses of your institution’s technology transfer ofce can save you much time.
J. P. Grant ∙ N. Kjellson
Canaan Partners, Menlo Park, CA, US
L. Chen
The Column Group LLC, San Francisco, CA, US
H. Zaltzman ∙ J. J. Kim
Latham & Watkins LLP, Menlo Park, CA, US
J. Walker
SPARK at Stanford Advisor, Stanford, CA, US
A. Mendelson (Deceased) , , ,
P. Boyd ∙ C. M. Reilly
Former SPARK at Stanford Advisor, Stanford CA, US
D. Mochly-Rosen et al.
187
The next step is nding a commercial partner—a venture capital rm or com-
pany that will be interested in funding the development of your invention. Knowing
how to evaluate potential diagnostic or drug markets and effectively pitch to inves-
tors or commercial partners is very different skill than giving a good scientic lec-
ture. With so much intellectual property (IP) generated in academia, a well-researched
commercial assessment and an organized and effective pitch for the commercial
audience can make potential licensees or investors take notice. The goal is not to
recapitulate the sophisticated marketing plans drawn up in industry, but to highlight
the project’s potential and show some industry savvy.
As you begin exploring the commercial value of your invention, it is essential that
you recognize and avoid any potential conicts of interest. Your institutional compli-
ance ofce can provide guidance regarding how to comply with both institutional rules
and government laws and regulations. Even if you participate in annual compliance
training, make sure to refresh your memory before proceeding with commercial or
clinical activities, so as to avoid the often serious consequences of non-compliance.
This chapter covers important topics that are rarely taught to academic scientists,
including patent law, technology transfer, avoiding conicts of interest, evaluating the
commercial potential of your project, pitching to potential licensees, approaching ven-
ture capitalists, and funding the development of not-for-prot programs. It also dis-
cusses legal and practical considerations for academic founders of a startup company.
5.1 Intellectual Property
JudyMohr
Like them or not, patents are a necessary part of the pharmaceutical business.
Because of the high development costs incurred in obtaining regulatory approval to
market a pharmaceutical product, potential corporate partners and investors insist
that the product be protected by one or more patents with sufcient patent term
remaining after product launch to have an exclusive market position to recoup the
development costs. Furthermore, the generic drug industry is sophisticated and is
rapidly able to manufacture a bioequivalent of a branded product and, possibly, a
bioequivalent product with a minor modication in a non-essential ingredient to
avoid patent claims covering the product. Thus, a company developing a pharma-
ceutical product—whether as a new molecular entity (NME), a new delivery vehi-
cle/platform for a previously approved drug, or a new method of treatment using an
already approved compound—must dene a patent strategy that supports its own
business objectives, yet is also mindful of the inevitable generic competition to the
pharmaceutical product. This section touches on three important aspects in building
any patent portfolio: the consequences of publicly disclosing the invention before
ling for patent protection, patent searching to assess patentability of an invention,
and freedom to operate.
5 Technology Transfer andCommercialization
188
Fig. 5.1 Patent ling timeline. Abbreviations: Mo Month, PCT Patent Cooperation Treaty, US
United States
5.1.1 Public Disclosure andPatent Filing
For an invention to be patentable, it must be “novel and non-obvious” as dened in
patent law. This novelty requirement states that an invention cannot be patented if
the invention is already known anywhere in the world before the ling date of a pat-
ent application for the invention. “Already known” encompasses publications, pub-
lic use or sale, and oral disclosure, such as at a conference or meeting. It also
encompasses an inventor’s own disclosure, such as in a journal or at a conference,
of the invention. Thus, it is very important to not disclose an invention in any public
setting before a patent application has been led.
Figure 5.1 depicts the sequence in a patent ling process. After an invention is
made, a patent application is led. In the US and many other countries, a provisional
patent application is led to secure a patent ling date. Once the provisional patent
application is led, the invention can be disclosed, for example, in a journal article
or at a conference. One year after ling the provisional patent application, an inter-
national patent application with the Patent Cooperation Treaty (PCT) is led, and in
many cases, a US non-provisional patent application is also led. The PCT applica-
tion and US non-provisional patent applications will be published 18months from
the ling date of the provisional patent application. The PCT application is then
led in the PCT member countries where patent protection is desired.
Patent rules in the US provide for a “grace period” to le a patent application
after a public disclosure of the invention by the inventor; the grace period may not
apply in every situation. Also, most other countries do not grant any grace period
between public disclosure and patent ling. Therefore, it is best practice to le a
patent application before any public disclosure of the invention, particularly for
pharmaceuticals for which worldwide market potential is desirable.
Box 5.1: What Surprised an Academic?
If you want to be sure that your invention will never benet patients, publish
your idea and data before ling a patent. Exclusive and preferably worldwide
IP rights are essential to recoup the huge development costs of new drugs and
biologics; without IP protection, no one will develop your drug.—DM-R
D. Mochly-Rosen et al.
189
5.1.2 Patent Searching toAssess Patentability
A rst step in determining a patent strategy for any invention is to know the “lay of
the land” of publications related to the invention. This is a critical step in determin-
ing whether your invention is novel and non-obvious—two essential requirements
for patentability. Your publication search should include both scientic literature
and patent literature. Before beginning a search, make a list of the components of
the invention and draft the proposed product label regarding how a product based on
the invention will be used (i.e., the disease or condition for which FDA approval of
the product will be sought and how it will be dosed). This information should track
closely, if not identically, with the contents of any drafted or led regulatory docu-
ments such as an IND application. Knowing the product components and the
intended label use identies some key words for an initial search of patent literature
(issued patents and published applications) and scientic literature to obtain a solid
understanding of prior publications related to the invention and thus products based
on the invention.
Unless you have some familiarity with patents or patent searching, it may be
easier to start searching in the scientic literature. Search terms identied using the
approach above can be utilized in online databases such as PubMed and Google
®
Scholar. From the scientic literature search, the authors and/or institutions (aca-
demic or commercial) of the most relevant articles should be added to the list of
search terms for searching patent databases.
A search of issued patents and published patent applications is best done using a
combination of several databases. Patents are jurisdictional, so it is necessary to
search both US and international databases to identify patent publications that may
be relevant to patentability. Examination of the following three databases will give
a fairly thorough search (see Sect. 5.1 Resources for website URLs).
1. US Patent and Trademark Ofce (USPTO): The USPTO website has a Patent
Public Search tool with a exible search interface to search issued US patents
and published US patent applications. The search results are hyperlinked to rel-
evant documents, making it easy to review the documents, including highlights
of where the search terms appear in the document. Granted patents and pub-
lished applications can be viewed and downloaded in a familiar two column
format from the Patent Public Search Tool or from other websites, such as
pat2pdf.
2. Espacenet: This database permits searching of worldwide patents and applica-
tions, and using the “advanced search” tab, it can be searched by title, inventor,
applicant (company name), etc. This database also has a tool, INPADOC (inter-
national patent documents), that will identify all counterpart patents and applica-
tions, or “family members,” of a relevant patent or application. For example, if
your search identies a US patent of interest, enter the US patent number in the
“publication number” search eld on the advanced search page, click on the
result, then look for the “INPADOC patent family” link, and click on it to see
whether the US patent has counterpart lings outside the US.
5 Technology Transfer andCommercialization
190
3. World Intellectual Property Organization (WIPO) PatentScope: This data-
base is maintained by WIPO and allows a search of PCT (Patent Cooperation
Treaty) applications for international lings. Both simple and “structured”
(advanced) search options are available for more than a million international pat-
ent applications. The results from a search of the databases can then be reviewed
to identify documents that describe the invention in whole or in part.
5.1.3 Patent Searching toAssess Freedom toOperate
Freedom to operate (FTO) refers to whether a particular action, such as manufactur-
ing or selling a product, can be done without infringing the valid granted patent
rights of another party. Since patent rights are jurisdictional, an FTO analysis needs
to be done in each particular country where the product is to be manufactured
or sold.
The USPTO and Espacenet patent search sites noted above are equally useful for
searching for patents potentially relevant to FTO.A key difference between assess-
ing patentability and assessing FTO is that the latter needs only focus on the claims
of granted patents, whereas the former must consider the disclosure of the entire
patent document.
If the search identies a claim in a granted patent that may be relevant to FTO,
further investigation is needed to ascertain whether it poses an actual barrier to com-
mercializing the product. For example, words in a patent claim may be subject to
denitions in the patent specication (the legal term for the text in a patent that
precedes the patent’s claims and alters the scope of the patent claim); or admissions
may have been made by the patentee while the patent application was being exam-
ined that narrow the meaning of claim terms. Also, fees are required to maintain
patents in force, and if the patent owner has not timely paid the fees, the patent may
no longer be enforceable. A patent attorney is typically required to advise regarding
the legal scope of patent claims.
5.2 Working withtheUniversity Technology Transfer Office
KarinImmergluck
Resources
• US Patent and Trademark Ofce (USPTO): http://www.uspto.gov
• Pat2pdf– A FREE patent search tool: https://www.pat2pdf.org/
• Espacenet: http://worldwide.espacenet.com
• World Intellectual Property Organization (WIPO) PatentScope: http://
www. wipo.int/patentscope/search/en/search.jsf
D. Mochly-Rosen et al.