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Intellectual Property Issues for Scientists
strand (T pairs with A, C pairs with G, and G pairs with C). Using the antisense coding sequence of
the disease gene, short antisense DNAs can be developed as medicines. These molecules attach to
disease gene messenger RNAs, preventing the production of disease- causing proteins.
Normally, a 20- base fragment only inuences one gene’s expression and does not affect
other genes. However, antisense medications face obstacles such as in vivo instability of singlestranded DNA and the necessity for effective delivery vehicles. To address stability issues, chemical modications to the DNA chain, like replacing phosphate groups with less readily hydrolyzed
groups, can be employed and potentially copyrighted.
14.8.3 tRansgenic Plants
Plant cells, unlike animal cells, possess a sturdy cell wall, making it challenging to introduce genetic information. Additionally, the cellular environment restricts the movement of vectors within
the cell. Therefore, unique methods are employed, such as directly delivering DNA molecules onto
micronized glass bead surfaces. Once transformed, plants can be conventionally bred. Enhancing
yields, improving nutritional quality, and reducing production costs are objectives of transgenic
plants.
14.8.4 exclusivities foR biological PRoducts
The three primary sources of market exclusivity for biological products are regulatory exclusivities,
patents, and trade secrets or proprietary knowledge. Patents and regulatory exclusivities safeguard a
product’s market for a specied duration. According to the BPCIA, innovative biologic drugs ling
a complete BLA receive 12 years of regulatory exclusivity. Typically, a “twenty- year period” begins
upon patent award and ends twenty years after the application was led in the United States. (The
“twenty- year term” does not apply to patents that were in force on June 8, 1995, or that were issued
from an application led before that date.) The greater of the “twenty- year term” or seventeen years
from the grant date determines the length of a patent in this category. (See 35 U.S.C. 154(c) for further information.) Pediatric exclusivities, patent term extensions, and patent term amendments can
extend baseline exclusivity periods further.
Regulatory exclusivities offer market protection for innovative products, even without patent
protection. In the absence of patents, generic drugs can enter the market after the regulatory exclusivity period. Thus, a biopharmaceutical company’s economic strategy necessitates a strong patent
portfolio acquisition and maintenance.
Patents can be granted at any stage of drug development. For instance, patents claiming the
drug product itself might be issued before or concurrently with NDA or BLA submission. Other
patents, such as those for commercial formulation, tailored delivery systems, or comprehensive
treatment regimens, would likely be granted post- completion of human clinical trials. Additionally,
life cycle management strategies might result in “submarine patents,” inadvertently extending patent
exclusivity.
A submarine patent was led pre- 1995 but issued later due to a delay, such as an interference
proceeding. Remaining hidden in the patent ofce before the application publishing deadline, it
unexpectedly surfaces years later. Consequently, the patent remains hidden at the patent ofce
because it was led before the deadline to publish the application, and it unexpectedly appears submarine. As a result, a patent is given years after technology has advanced, and the patent is valid for
17 years from the issue date, as per the prior statute’s laws.
Moreover, as product development inherently involves innovation, subsequent advancements—
such as improved purication processes or application methods— may offer additional patent
exclusivity. Consequently, regulatory market and patent exclusivity may run concurrently or
independently.
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Trade secret laws differ across states but share a common requirement: the information must offer
economic benet to the owner. The owner has taken and continues to take appropriate measures to
safeguard this information from public disclosure.
Biopharmaceutical companies often exclude certain information— deemed exclusive trade
secrets— from patent disclosures that demand public revelation.
Condentiality under trade secret laws is not limited by statute and can furnish organizations with
a competitive edge. For instance, a biologic manufacturer could monitor critical process controls
used in manufacturing or downstream bioprocess steps for creating a reference product. Keeping
such proprietary knowledge hidden grants the producer a competitive advantage. Manufacturing
process controls, tailored for each product/ process, signicantly inuence the quality and purity of
biological medicinal products.
14.8.5 bRoad coveRage
Numerous patents may cover various aspects of a single biological product, including nucleic acid
and amino acid sequences, expression vectors, production methods, formulations, administration
devices, methods of use, and indications. It’s not uncommon to witness 50 to over 100 patent lings
for one biological product due to the breadth of patentable subject matter. Table 14.4 summarizes
the potential patent arguments applicable to an antibody product.
TABLE 14.4
Possible Patent Claims for Antibody Products
Antibody Product Possible Patent Claims
Amino acid sequence Complete heavy and light chains
Heavy and light chain variable regions
CDR regions
Modications made to the framework, CDR, or Fc regions
Analytical methods Assays developed to monitor the quality or purity of the product
Culture conditions Media components
Culture method/ feed media
Optimized culture conditions
Device Device for administration and use thereof
Diagnostic methods and kits Methods and kits used to identify select patents that are more or less likely to
respond to treatment
Expression system Host cells engineered to express the product
Expression vector Every individual element and combination of the vector elements express the
sequence in a suitable host cell, including promoter, enhancer, other regulatory
sequences, and selection marker
Formulation Pharmaceutical compositions comprising the drug product
Methods of use Broad mechanism- based methods of use
Disease- specic methods of use
Indication- specic treatment regimens corresponding to the product label
Nucleic acid sequence Nucleic acid sequences encoding any or all of the above- listed amino acid sequences
Platform technology Platform technologies and assays used to discover or optimize the structural and
functional features of the product or processes used to manufacture or purify the
product
Purication Chromatography methods claiming the use of resins alone or in series
Optimized conditions
Compositions having a dened level of purity or homogeneity
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14.9 PURPLE BOOK
Intellectual Property Issues for Scientists
On September 9, 2014, the FDA introduced the rst version of the biologic equivalent of the Orange
Book, known as the “Purple Book” is formally known as “Lists of Approved Biological Products
with Reference Product Exclusivity and Biopharmaceutical Interchangeability Evaluations,” and
it contains a list of biological products, including biopharmaceuticals and interchangeable biological products licensed by the FDA under the Public Health Service Act (PHS Act). Unlike the
Orange Book, it does not contain patents unique to the biological innovator product. The lists
include only the date a biological product was approved under section 351(a) of the PHS Act
and if the FDA reviewed the biological product for reference product exclusivity under section
351(k)(7) of the PHS Act. The FDA has determined whether a biological product approved under
section 351(k) of the PHS Act is biopharmaceutical or interchangeable with a reference biological
product, according to the Purple Book (an already- licensed FDA biological product). The reference product that exhibited biopharmaceutical or interchangeability will be classied under the
biopharmaceutical and interchangeable biological products authorized under section 351(k) of the
PHS Act. Separate listings for biological goods controlled by the Center for Drug Evaluation and
Research (CDER) and the Center for Biologics Evaluation and Research (CBER) will be updated
on a regular basis (CBER).
14.10 PATENT TERM EXTENSION
Patents related to human “drug products,” including biological products, might qualify for a regulatory delay extension in the United States. A patent claiming a prescription product, usage technique,
or production method can be extended if it meets six criteria outlined in 35 U.S.C. 156. However,
only one patent term extension is allowed per “drug product.”
Another aspect of the extension is that the patent can be reinstated for up to ve years, considering
a constitutional limit on total patent duration. The product’s total patent life with the extension
cannot exceed 14 years from the approval date. If the product’s patent life post- approval is already
14 years or more, no extension is granted. The extension must be requested within 60 days of the
product’s initial commercial marketing or use permission; it’s not automatic.
14.10.1 Patent teRM adjustMent
14.10.1.1 Factors Affecting a Patent Term
Generic Variations: Although 20 years is the accepted modern standard for patent terms, not all
countries hold to it yet, and other factors cause variation in terms. These include:
• Foreign legal sanctions and their effect, for example, a TRIPS Council decision, required
Canada to extend the duration of some patents issued under 17- year term legislation to
20 years.
• Delays in obtaining a patent before it is granted (which can shorten or lengthen a term).
• Nonpayment of annuity payments, whether on purpose or by mistake, results in a premature lapse.
• Changes in the law can affect the duration of all pending or active proceedings.
• Only a subset of pattents is affected by targeted legal changes (special provisions in the law
for pharmaceutical patents).
14.10.1.2 Pharmaceutical Patent Variations
The pharmaceutical industry commonly receives limited patent term extensions, with some countries allowing extensions for medical devices and agrochemicals. These extensions compensate
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371
patent owners for sales time lost due to mandatory registration requirements (testing safety and
efcacy). These provisions prevent patent owners from infringing their patent property between the
award of the patent and the approval of the marketing authorization, a penalty that no other industry
faces. Different countries have implemented different mechanisms, but they all follow the same
strategy to recover part of the lost exclusivity period.
There are essentially two mechanisms to receive a term extension: expanding the original patent’s scope (as done in the US and Japan) or introducing a new legal instrument that
takes effect after patent expiration, as in the European Union’s Supplementary Protection
Certicate (SPC).
The United States (Hatch- Waxman Act), Japan (19814), and the European Union have enacted
comprehensive term extension provisionsfollowed by Japan in 19814. Two laws from the European
Union date from 1992 and 1996. Unfortunately for knowledge specialists, putting those provisions
in place was not easy. However, implementing these provisions was complex, especially due to
existing national legislation in France and Italy preceding the EU regulations, potentially affecting
certain goods covered by those laws rather than the EU regime.
Several nations, including Australia, Bulgaria, Cyprus, Czech Republic, Estonia, Hungary,
Iceland, Israel, Latvia, Mexico, Moldova, Norway, South Africa, South Korea, Switzerland, and
Taiwan, have enacted or are contemplating patent term extension legislation. Most countries have
adopted a variable- term extension, allowing a maximum extension of 2– 7 years.
14.10.1.3 Annuity Fees and Term Computation
In most developed countries, patent security relies on post- grant payments (annuity fees). In the
United States, these are due at 3.5, 11.5, and 14.5 years after the grant, while in Europe, they are
payable on the third anniversary of ling, even if the patent is still pending. A public registry usually
records payment notices. Annuity payments in many countries increase with patent age, following
a sliding scale.
National patent laws signicantly determine a patent’s duration. For instance, in the United
Kingdom, a patent remains valid for 20 years from the application date. Thus, a UK patent issued on
April 1 would generally expire on March 31, 20 years later. Conversely, in Germany, a patent is valid
for 20 years from the date of the application’s ling for the invention. Though seemingly minor, this
distinction in calculation can be crucial in certain scenarios.
14.10.1.4 Information on Aspects of Patent Term
When dealing with legal status information, it’s crucial never to rely solely on one source. Actual
information and inclusion timelines can vary between sources. Some references may be less updated
due to differing coverage and updating policies. Furthermore, certain sources might only provide
partial details, necessitating careful selection by users.
National registers, if available in searchable formats, hold authoritative information. However,
be cautious about format discrepancies; machine- readable documents within the patent ofce may
not fully align with public web copies. The INPADOC le, now accessible via the esp@cenet®
website (http:// ep.espace net.com), remains the most comprehensive single source for multinational
data. Additionally, note that certain online implementations of these data sources might not directly
link relevant records (such as US reissue or reexamination cases) or other legal instruments (such as
SPCs) to their parent records.
14.10.1.5 USPTO Web Sources
The basic public legal status source of the US Patent and Trademark Ofce is the PAIR service
(http:// pair.uspto.gov). This contains some annuity payment data (although it may be incomplete) and some information on Hatch- Waxman extensions under 35 USC § 156. A specic
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part of the website (www.uspto.gov/ web/ of ces/ pac/ dapp/ opla/ term/ 156.html) discusses these
actions. Hatch- Waxman extensions are issued as a Certicate of Correction to the “master”
patent. They are available in facsimile form (as TIFF les) in the main patent search area of the
website.
14.10.1.6 Other Web Registers
Many patent ofces increasingly provide legal status data on the internet. The web version of the
European Patent Ofce (EPO) Register is free and accessible under the epoline® umbrella (www.
epol ine.org/ regis ter.html). However, this site lacks data on any SPC applications citing a European
Patent as the “basic patent” because the granting or refusal of an SPC is solely within the purview
of individual national governments in Europe. There’s no obligation to feed data back to the EPO
for inclusion in its register.
Other patent ofces with websites that contain legal status information include those in the United
Kingdom (www.pat ent.gov.uk), Germany (www.dpma.de/ index.htm), The Netherlands (www.bie.
nl), and Australia (www.ipau stra lia.gov.au). Typically, such sites are free, but they may require you
to register for a user ID before using them. A limited amount of English- language legal status information is from the free Japan Patent Ofce website (www.jpo.go.jp). Still, more comprehensive
information is only on the fee- based Patolis- e- service.
14.10.1.7 Commercial Online Files
In addition to the web- based sources described above, many electronic les are available on commercial host systems. Most of them have a mixture of general legal status and some actions specic
to the pharmaceutical industry.
14.10.2 non- Patent office souRces
It is vital to note that drug exclusivity is not totally regulated by patents. Other government agencies
have the authority to grant or deny marketing exclusivity. The US Food and Drug Administration’s
Center for Drug Evaluation and Research, for example, maintains approval listings on its website
(www.fda.gov/ cder/ ora nge/ adp.htm). The record of medicine patent expiration can be found in the
electronic edition of the so- called Orange Book (www.fda.gov/ cder/ ob/ defa ult.htm). Based on the
same dataset, there are new versions or derivatives. Minesoft (London, UK, www.mines oft.com) has
created an alternative to the Orange Book, and FOI Services Inc. (Gaithersburg, MD, www.fois ervi
ces.com) publishes Drugs under Patent.
A second mechanism exists in the United States for extending the term of a patent. This second
extension, known as Patent Term Adjustment (PTA), was established by the American Inventors
Protection Act of 1999 (AIA). The AIA empowers the United States Patent and Trademark Ofce
(USPTO) to meet specic deadlines during the patent examination phase. Failure by the USPTO
to meet one or more of the AIA’s time constraints (such as issuing the rst Ofce Action within
14 months of the ling date, responding within four months of an appeal or board decision, and
issuing patents within four months of the issue date) is a common reason for obtaining a patent term
extension. The AIA also stipulates that the initial patent application procedure should be completed
within three years of the actual ling, unless ongoing applications and appeals by the ling party
cause delays. If these deadlines are not met, patent applicants may receive compensation for USPTO
administrative delays in the form of a day- for- day extension of the patent term resulting from the
prolonged examination process. Patent holders can acquire term extensions ranging from a day to
several years. Any time spent responding to USPTO conduct during the patent application will be
subtracted from the PTA granted.
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14.11 FREEDOM- TO- OPERATE OPINIONS
373
All patents and patent applications relevant to the manufacture, use, or sale of a product, such as
a biopharmaceutical product, undergo comprehensive examination in Freedom to Operate (FTO)
decisions. The assessment scrutinizes each patent/ application to determine infringement, invalidity,
or potential expiration before the product’s release. The FTO serves various purposes in biopharmaceutical applications. Its primary function is to provide a well- considered opinion that prevents
courts from imposing treble damages in the event of a biologic product infringing on a patent.
Additionally, it creates a competitive environment for designing around potentially infringed patents
and provides a list of patents that the Reference Product Sponsor (RPS) might claim during the
patent exchange process, as mandated by legislation.
The gene sequence responsible for expressing the substance is part of the composition of matter,
making these patents challenging to avoid. Fortunately, most of these patents are nearing expiration.
Although their expiration dates vary widely, there is concrete data available for evaluation. It’s typical for a span of 2– 4 years to pass between major markets, and therefore, the date of the composition of matter will determine the manufacturing location for the initial launch.
14.11.1 subMaRine Patents
Submarine patents may emerge just as the rst composition of matter patent is close to expiring,
owing to a complex system of cross- licensing and overlapping patent applications led before 1995.
Examples such as interferon- alpha and etanercept illustrate this, both enjoying decades of exclusivity despite contradicting the spirit of patent law. They exploited a aw in the US patenting system,
which has now been rectied. The patent period is currently 20 years from the date of the rst ling,
instead of the 17 years exploited by the submarine patents. Outside the United States, this risk
doesn’t exist, and these patents are impossible to circumvent.
14.11.2 systeM exPRession Patents
Patents cover fundamental speech technology, like the Cabilly patents; these are broader patents.
In this scenario, a biosimilar developer might acquire a license unless Genentech manufactures
the product. This particular patent was due to expire in 20114, and getting around these patents is
unfeasible.
14.11.3 PRocess Patents of oRiginatoR
While much focus centers on composition of matter patents, process patents prove to be the most
challenging. This challenge surfaces as major market cap products like adalimumab and etanercept
approach their expiration dates. Despite potential contests and invalidations of these patents,
their highly detailed specications for protected areas are remarkable. For instance, concerning
etanercept, one must demonstrate that the amino acid composition during upstream processing
doesn’t match the stated distribution. However, most upstream processes don’t track amino acid
composition. The scope of these patents includes media selection, upstream conditions, buffer
pH and structure, downstream purication columns, their order of use, and even claims of higher
purity.
With a signicant number of bioprocessing patents held by both the originator and third parties,
dening a suitable manufacturing method has proven to be exceedingly difcult and technically
challenging. Patents that specify amino acid composition during upstream processing demonstrate
the challenges; ironically, this is not a standard examination. Even the media’s composition remains
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unknown to the producer. However, upon publication of such patents, it becomes the developer’s
responsibility to research this aspect.
14.11.4 thiRd- PaRty PRocess Patents
While bypassing originator process patents is difcult, third- party patents referencing a specic
product or product class are also potential hurdles. In certain instances, a biosimilar developer must
devise an alternative manufacturing route to circumvent the originator patent and then conduct a
thorough review of third- party patents.
14.11.5 foRMulation coMPosition
Early biological product pioneers underestimated the signicance of these patents, but now we
observe formulation patents aimed at raising the bar for demonstrating similarity. Despite the
intention of keeping biosimilar developers out of the market, this approach hasn’t succeeded
if agencies require equivalent quality. Agencies, recognizing this, might allow alternative
formulations.
14.11.6 lifecycle foRMulation PRojections
As a composition of matter patent nears expiration, a recent trend involves altering the formulation,
such as shifting from a lyophilized formulation to a solution or adopting a high- concentration subcutaneous formulation instead of an intravenous solution. This change aims to make the product
more user- friendly, posing a challenging marketing task. However, once the new formulation is
launched, obtaining reference samples for biosimilar product testing becomes challenging, assuming
any intellectual property issues are resolved.
14.11.7 alteRnate offeRing
Even though the original product might have had limited presentations initially, these can evolve
over time, mostly to enhance usability, like the use of prelled syringes or injectors instead of vials.
Such changes impact marketing and delivery, complicating reimbursements.
14.11.8 indications and dosage
Initially disregarded by early biological drug pioneers, patents specifying particular product uses, like
indications, have become standard. Several patents will cover almost any large molecule approaching
expiration, including specic doses, conditions of use, and dosing schedules. For instance, AbbVie
holds a patent prescribing precisely 40 mg of adalimumab every other week. These patents aimed to
prevent biosimilar products resembling those already on the market, assuming regulatory authorities
wouldn’t permit different dosing or indications. However, realizing the risk, regulatory agencies
are open to alternative suggestions. Nevertheless, these can pose signicant challenges. Recently
emerged patents have surprised major biosimilar developers who may have heavily invested in clinical trials only to nd out they can’t market the drugs after the trials. A biosimilar developer doesn’t
need to investigate existing intellectual property but rather anticipate potential future developments.
14.11.9 deliveRy devices
Since these devices are unique to the product, even if they are distributed by software manufacturing rms to many customers, the originator may hold multiple patents on the delivery device. The
chosen device signicantly impacts the biosimilar’s marketability.
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14.11.10 develoPing fReedoM to oPeRate
375
Determining the freedom- to- operate for a biopharmaceutical rm requires a multifaceted strategy
to identify all relevant patents and patent applications. Starting with a list of search terms is crucial.
At a minimum, this list should include parties involved in discovery and substance manufacture, as
well as alternate names for the biologic used in the development process.
Given the convoluted history of biologic products involving multiple parties, it’s feasible that
several parties hold patents covering a single product. A university or a cutting- edge biotech company may discover a molecular target or lead molecule, subsequently choosing whether to license,
sell, or partner with a pharmaceutical company for product development. As the medication research
continues, any or all involved parties could possess patents on the nal product.
To identify patents claiming the amino acid sequence used to express the biologic product, one
can scan sequence databases after identifying the specic amino acid sequence. The Basic Local
Alignment Search Tool (BLAST) available at http:// blast.ncbi.nlm.nih.gov/ Blast.cgi is a public
sequence database suitable for such searches. Additionally, commercial databases like GenomeQuest
are available as alternative search providers.
A comprehensive search of a patent database is necessary once the search criteria are determined.
Although several publicly accessible databases like the USPTO and the EPO exist, they lack support
for open- ended operators, making information retrieval more challenging compared to paid databases
with more powerful search capabilities. In addition to product- specic patents/ applications, it is crucial to check for generic methods for producing the biologic, such as media and conditions for cultivating the cell line and expressing and purifying monoclonal antibodies and proteins. For example,
Genentech obtained a general process patent (enter 6331415 at http:// patft.uspto.gov/ netah tml/ PTO/
srch num.htm) known as Cabilly II for monoclonal antibody expression. This patent, obtained after
a lengthy prosecution involving interference actions and re- examination, was issued in 2001 with a
priority claim dating back to 1983. Despite this priority, the patent expired on December 18, 2018,
after 17 years in effect. Its claim 1 specically involves a technique for producing an antibody molecule in a single host cell comprising at least the heavy and light chains’ variable domains.
After entering the search criteria into the chosen database, hundreds, if not thousands, of patents
will need to be sifted through. Relevant patents concerning the biopharmaceutical applicant’s cell
line, media, production technique, bioreactor technology, purication process, formulation, and
tests should be selected from the search results. Analyzing these patents claim by claim is crucial to
assess their relevance to the applicant’s market freedom, forming the foundation for the Freedomto- Operate (FTO) nal opinion.
Determining the expiration dates and total number of patents to be examined is essential. This
involves considering the ling date of claims, any patent term adjustments by the USPTO, impact
of terminal disclaimers, patent term extensions due to regulatory approval delays, and the timely
payment of maintenance fees. Identifying the expiration dates is critical as patents expiring before
the planned product launch may become irrelevant to the study.
The FTO opinion must evaluate each argument to ascertain whether current processes, products,
or therapeutic indications breach the patent. The latest set of claims needs examination to gauge
the likelihood of infringement based on the claims’ interpretation at the time and the probability
of patent issuance for patent applications. It is assumed that the patent application is likely to be
violated. Consequently, this application should be included in a watch list to monitor prosecution
during the development of a biopharmaceutical product.
If patents are not due to expire before launch and are likely to be found infringing, the biopharmaceutical applicant must strategize upon receiving the FTO opinion. If designing around patent claims
is unfeasible due to cost, time, or product alteration issues, challenging the patent or requesting a
license from the patent owners becomes an option. If the decision is to contest the patent, an invalidity opinion must be drafted. This opinion can be utilized to craft a post- grant appeal against a
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patent or used as a negotiating tool during the patent exchange process under the provisions of the
BPCIA legislation.
After the USPTO has granted a patent, three avenues for contesting it are available: ex parte reexamination, inter partes review, and post- grant review. Each option has its own set of advantages
and disadvantages. Ex parte re- examination is the most cost- effective method as it does not require
the challenger to be named. However, once the initial appeal is led, the challenger cannot participate further, and the re- examination is conducted solely by the patent reviewing corps, taking
approximately two years to complete.
Early in the product lifecycle, a strategy for managing the product’s lifecycle is developed. As
the product advances through multiple production and regulatory approvals, a comprehensive and
intensive intellectual property strategy becomes imperative. Proposals for specic treatments and
doses arise following the success of numerous clinical trials. Patents continually emerge, especially when composition or gene sequence patents are nearing expiration. The authors anticipate that
limitations on drug manufacture, formulation, and use will dissuade biopharmaceutical companies
from entering the market. They also speculate that product design modications might lead the FDA
to no longer classify them as biopharmaceuticals.
14.12 CONCLUSION
In the formulation of biopharmaceutical products, intellectual property plays a signicant role.
Despite being a legal concern for most, the complexities in biological drug technology make it a
concern for all scientists involved in biopharmaceuticals. Given the potential patentability of the
process and high nancial stakes, litigation is common among biopharmaceutical companies. This
chapter aims to educate team members in development, manufacturing, and marketing on avoiding
litigation, a prime contributor to the high cost of development and market entry delays.
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