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  • USPTO on Patent Eligibility — Example 37

    By Michael Borella —

    USPTO SealOn January 7, 2019, the U.S. Patent and Trademark Office published updated examination guidance, instructing the examining corps and the PTAB how they should apply 35 U.S.C. § 101.  On the same day, the USPTO also published the latest in its series of examples of how this application of the § 101 inquiry should be carried out.  This latest set, encompassing examples 37-42, apply the updated guidance (examples 1-36 were previously published over the last four years).

    The USPTO emphasizes that these examples are "hypothetical and only intended to be illustrative of the claim analysis" under the updated guidance.  Furthermore, the examples "should be interpreted based on the fact patterns set forth below as other fact patterns may have different eligibility outcomes."  In other words, even if an applicant's claim recites similar language and functionality as that of one of the examples, that does not mean the applicant's claim is patent-eligible.  Context matters.

    The updated guidance modified only part of the § 101 analysis (step 2A in the USPTO's parlance).  As set forth in Alice Corp. v. CLS Bank Int'l, this step involves determining whether a claim is directed to a judicial exception, such as an abstract idea.  If not, then no § 101 rejection can be made.

    The updated guidance breaks step 2A into a pair of sub-steps:

    • In sub-step 2A(i), one is to determine whether the claim recites a judicial exception, such as an abstract idea.  Abstract ideas are now limited to three categories:  mathematical concepts, certain methods of organizing human activity, and mental processes.

    • If so, then in sub-step 2A(ii), one is to determine further "whether the recited judicial exception is integrated into a practical application of that exception."

    If the claim involves such an exception, the second part of the § 101 analysis (step 2B) is applied to determine whether any element or combination of elements in the claim is sufficient to ensure that the claim amounts to significantly more than the judicial exception.  If this is the case, the claim is patent-eligible under § 101.  If not, it can be rejected.

    Hypothetical Background

    Example 37 relates to relocation of icons on a graphical user interface (GUI).  The background provided by the USPTO is as follows (abbreviated to focus on key aspects):

    [C]omputer users may have a large number of icons on their display, making it difficult to find the icons most used.  The typically available ways to organize icons are alphabetically, by file size, and by file type.  If a computer user wants a non-typical arrangement of icons, the user would need to manually manipulate the icons on their display.

    Accordingly, applicant's invention addresses this issue by providing a method for rearranging icons on a [GUI], wherein the method moves the most used icons to a position on the GUI, specifically, closest to the "start" icon of the computer system, based on a determined amount of use.

    Claim 1

    Claim 1 of Example 37 recites:

    A method of rearranging icons on a graphical user interface (GUI) of a computer system, the method comprising:
        receiving, via the GUI, a user selection to organize each icon based on a specific criteria, wherein the specific criteria is an amount of use of each icon;
        determining, by a processor, the amount of use of each icon over a predetermined period of time; and
        automatically moving the most used icons to a position on the GUI closest to the start icon of the computer system based on the determined amount of use.

    Applying the first sub-step of 2A, the USPTO states that claim 1, under its broadest reasonable interpretation, "covers performance of the limitation in the mind but for the recitation of generic computer components."  In other words, "nothing in the claim element precludes the step from practically being performed in the mind," and "[t]he mere nominal recitation of a generic processor does not take the claim limitation out of the mental processes grouping."  Thus, the claim recites an abstract idea.

    Moving on to the second sub-step, the USPTO notes that the claim "recites the combination of additional elements of receiving, via a GUI, a user selection to organize each icon based on the amount of use of each icon, a processor for performing the determining step, and automatically moving the most used icons to a position on the GUI closest to the start icon of the computer system based on the determined amount of use."  Thus, the claim integrates the mental process into a practical application by reciting "a specific manner of automatically displaying icons to the user based on usage which provides a specific improvement over prior systems."  As a result, the claim is eligible under step 2A because it is not directed to a judicial exception, and step 2B need not be applied.

    Claim 2

    Claim 2 of Example 37 recites:

    A method of rearranging icons on a graphical user interface (GUI) of a computer system, the method comprising:
        receiving, via the GUI, a user selection to organize each icon based on a specific criteria, wherein the specific criteria is an amount of use of each icon;
        determining the amount of use of each icon using a processor that tracks how much memory has been allocated to each application associated with each icon over a predetermined period of time; and
        automatically moving the most used icons to a position on the GUI closest to the start icon of the computer system based on the determined amount of use.

    Key differences between claim 2 and claim 1 are highlighted.

    Applying the first sub-step of 2A, the USPTO states that claim 2 does not recite any of the three types of abstract ideas.  According to the USPTO, the determining step now "requires action by a processor that cannot be practically applied in the mind" because it involves "a processor accessing computer memory indicative of application usage."  The USPTO further states that the claim does not recite either of the other two types of abstract ideas (mathematical relationships and methods of organizing human activity) either.  Like claim 1, claim 2 is eligible under step 2A because it is not directed to a judicial exception, and step 2B need not be applied.

    Claim 3

    Claim 3 of Example 37 recites:

    A method of ranking icons of a computer system, the method comprising:
        determining, by a processor, the amount of use of each icon over a predetermined period of time; and
        ranking the icons, by the processor, based on the determined amount of use.

    Applying the first sub-step of 2A, the USPTO states that claim 3, like claim 1, "covers performance of the [determining] limitation in the mind but for the recitation of generic computer components."  Therefore, claim 3 recites a mental process.  The USPTO notes that the ranking limitation also recites a mental process because "the claim encompasses the user thinking that the most-used icons should be ranked higher than the least-used icons."

    Under the second sub-step of 2A, the USPTO finds that the only additional element is the processor, and that "[t]his generic processor limitation is no more than mere instructions to apply the exception using a generic computer component."  Thus, the claim does not integrate the abstract idea of the recited mental process into a practical application thereof, and the claim is therefore directed to an abstract idea.

    Invoking step 2B, the USPTO similarly concludes that "the additional element in the claim amounts to no more than mere instructions to apply the exception using a generic computer component."  Thus, the 2B analysis follows that of the second sub-step of 2A, resulting in the claim not containing significantly more than the abstract idea.  Accordingly, the claim is patent-ineligible.

    Analysis

    The USPTO makes it clear in this example that the mental process category of abstract ideas is not meant to be taken literally.  It is not limited to steps that are carried out wholly in the human mind.  Instead, a step that (in theory) could be performed in the mind but is recited as being performed by a processor is still considered a mental step.  This is a bit of legal fiction to note well.

    The distinction between claims 1 and 2 is also quite fine.  Claim 1 recites "determining the amount of use of each icon over a predetermined period of time" while claim 2 recites "the amount of use of each icon using a processor that tracks how much memory has been allocated to each application associated with each icon over a predetermined period of time.  While claim 2 is narrower than claim 1, it is not 100% clear why claim 2 is not also reciting a mental process.

    The USPTO's justification for concluding that it does not is that claim 2 involves "a processor accessing computer memory indicative of application usage."  But if we are allowed to ignore the literal meaning of the term "processor" in these claims, why is the processor's use of memory not ignored as well?  Why isn't the "computer" qualifier disregarded to find the term "memory" broad enough to encompass human memory?

    Perhaps the answer is that the combination of a processor and the specific use of the memory is enough to find the claim not directed to a mental process.  But the USPTO is silent in this regard, and it remains difficult to know where to draw the line.

    Further, the determination of whether a recited abstract idea is integrated into a practical application is similarly vague.  In claim 1, such an integration is found because the claim recites specific requirements that leads to an improvement over the prior art.  In claim 3, however, the apparent lack of recited detail was enough to conclude that any such integration was de minimis at best.  Perhaps the absence of any movement of the icons damned claim 3 to abstractness hell.

    From the outset, the Alice test has required a certain suspension of logic in order to follow the Supreme Court's reasoning.  By expanding the test with two additional sub-steps, the USPTO is attempting to provide clarity.  Unfortunately, the USPTO appears to be adopting the same legal fictions that have made the post-Alice § 101 inquiry so subjective in the first place.

  • OPM Announces Federal Office Closure for Monday

    By Donald Zuhn –-

    Washington - Monument & Snow SnowWith reports of between 6 and 11 inches of snow having fallen in parts of Maryland and Northern Virginia, the U.S. Office of Personnel Management (OPM) announced a closure for Monday, January 14, 2019, of Federal offices in the Washington, DC area.  The OPM also announced that emergency employees and telework employees, however, would continue to work on Monday.  The OPM noted that the announcement also did not apply to furloughed employees impacted by the lapse in appropriations, as they are already in a non-work status.  The USPTO has not yet posted a notice on the Office's Operational Status webpage regarding the impact of the closure of Federal offices.  Patent Docs will provide an update as soon as the USPTO does post a notice.

  • PTAB Issues Final Written Decision in Cannabis Patent IPR

    By Nicole Grimm, George "Trey" Lyons, III, and Brett Scott —

    USPTO SealOn January 3, 2019, the U.S. Patent and Trademark Office Patent Trial and Appeal Board (PTAB) issued a Final Written Decision in Insys Development Co., Inc. v. GW Pharma Ltd. (IPR2017-00503), a landmark inter partes review (IPR) decision involving a cannabis patent.  Although the PTAB found claims 1 and 2 to be unpatentable as obvious, the remaining 11 claims that were challenged survived and remain valid (and potentially enforceable).

    At issue in this IPR was U.S. Patent No. 9,066,920 ("the '920 Patent," entitled "Use of one or a combination of phyto-cannabinoids in the treatment of epilepsy"), which was originally assigned to GW Pharma Ltd. and Otsuka Pharmaceuticals Co., Ltd.

    GW Pharma owns an extensive patent portfolio with many patents directed to treating diseases using cannabis-based formulations.  Notably, GW Pharma, along with its U.S. subsidiary, Greenwich Biosciences, made history in the cannabis industry by becoming the first entity to receive FDA approval of a drug (Epidiolex) that contains an active ingredient (cannabidiol or CBD) derived from a cannabis plant.  CBD is a non-psychoactive cannabinoid that can be naturally produced and derived from portions of cannabis plants, typically hemp.

    Insys Development Company, Inc., a pharmaceutical company that focuses on cannabinoids and drug delivery systems, petitioned to cancel all thirteen claims of the '920 Patent as obvious based on three different combinations of references that included scientific articles as well as one of GW Pharma's own published PCT applications.

    Independent claim 1 of the '920 Patent (which the other 12 claims directly or indirectly depend from) recites:

    1.  A method of treating partial seizure comprising administering cannabidiol (CBD), to a patient wherein the CBD is present in an amount which provides a daily dose of at least 400 mg.

    Dependent claim 2 of the '920 Patent recites:

    2.  The method of claim 1, wherein CBD is present in an amount which provides a daily dose of from 400 to 800 mg.

    Before conducting the obviousness analysis, the PTAB considered whether the term "partial seizure" in claim 1 needed to be construed.  Insys argued that "partial seizures" meant seizures that can include secondary generalized seizures.  However, GW Pharma argued that the term did not need to be construed because, even under Insys's construction, Insys had failed to show that a person of ordinary skill in the art (POSA) would have been motivated to increase the dosage of CBD described by one of the primary references and would have had a reasonable expectation of success that the higher dosage could treat partial seizures.  Ultimately, because GW Pharma did not dispute that the asserted references applied to the treatment of partial seizures, the PTAB did not find it necessary to construe the term in order to determine the patentability of the challenged claims.

    Regarding the obviousness challenge, Insys argued that all claims of the '920 Patent were obvious because the primary reference taught treatment of epilepsy with CBD, and a POSA "would have concluded that the claimed daily dosage of at least 400 mg of CBD is predictable, safe, and expected" in view of the combination of asserted references.[1] GW Pharma countered that, at the time of invention, CBD was "at best, a promising candidate for further study" and that a POSA would have "no reasonable expectation that CBD would treat partial seizures at all, let alone at doses of 400 mg or higher," as claimed by the patent.[2]

    The PTAB found that Insys demonstrated by a preponderance of the evidence that claim 1 (the broadest claim of the patent) and dependent claim 2 were obvious over two of the three asserted combinations of references.  Both combinations relied on the same primary reference, which described clinical studies involving administering CBD to epileptic patients.  Although the primary reference described a daily dose of CBD that was less than 400 mg, the PTAB found that the combination of asserted references, when read together, would have led a POSA to reasonably believe that the amount of CBD could be safely increased to the claimed dosage of at least 400 mg/day because, as of the time of invention, "CBD had been shown to be well tolerated in humans without any serious side effects or toxicities at doses up to 600 mg."[3]

    Regarding claims 3-13, Insys argued that those claims were obvious over the asserted combinations of references for the same reasons that claims 1 and 2 were obvious.  GW Pharma argued that Insys failed to identify where most of the limitations of claims 3-13 were disclosed in the prior art, and also did not present expert testimony as to why those dependent claims would be obvious.  The PTAB agreed with GW Pharma on this point, and found that Insys failed to meet its burden to show that claims 3-13 were obvious over any of the asserted combinations of references.

    Although claims 1 and 2 were deemed unpatentable, the '920 Patent remains largely intact following the PTAB's decision with claims that are still fairly broad relative to claim 1.  In particular, dependent claims 6 and 9 only further require that "the CBD is present as a plant extract" and "the CBD is present as a pure or isolated cannabinoid," respectively.

    Whether Insys or GW Pharma will appeal the Final Written Decision remains to be seen.  If they do, there are essentially two routes:  (1) panel rehearing, then potentially the Federal Circuit (and maybe even the Supreme Court); or (2) straight to the Federal Circuit.  Either way, the industry will be watching closely over the next two months to see where the parties go next before the deadline to challenge this opinion passes.

    And, as we have previously noted, this IPR raises some important implications for challenging and enforcing patents in the cannabis space.  One key takeaway from this decision is that the PTAB seemed to treat this cannabis patent just like any other patent subject to an IPR challenge (the fact that cannabis remains a Schedule I drug was not an issue).  Therefore, this decision may provide some clarity (or at least hope) to canna-patent owners and third-party challengers that IPR proceedings (and likely other USPTO post-grant proceedings) are at least one option for challenging cannabis patents.

    Additionally, as canna-patents continue to make their way through the federal courts (including, e.g., one of the first cannabis patent infringement lawsuit underway in the U.S. District Court for the District of Colorado—United Cannabis Corp. v. Pure Hemp Collective Inc. (1:18-cv-01922)), the industry may expect to see even more IPR challenges of cannabis patents, as well as more frequent patent application filings, following the legitimization of canna-patent infringement cases in district courts.

    At bottom, in light of these decisions and others, the message to canna-patent owners and applicants seeking to protect their innovations is what it has always been—obtaining canna-patents is highly valuable for companies in this industry, as these canna-patents will serve as irreplaceable stakeholders as the market continues to normalize and expand.  And the stakes will continue to increase as courts and federal agencies take note.

    [1] Final Written Decision, p. 15.

    [2] Id.

    [3] Final Written Decision, p. 27.

  • Conference & CLE Calendar

    CalendarJanuary 15, 2019 – "Patent Eligibility and Engineered Natural Products — Overcoming 101 Challenges, Leveraging Options to Obtain IP Protection" (Strafford) – 1:00 to 2:30 pm (EST)

    January 16, 2019 – "Top Patent Law Stories of 2018" (McDonnell Boehnen Hulbert & Berghoff LLP) – 10:00 am to 11:15 am (CT)

    January 17, 2019 – "Patent Application Preparation in View of Recent Court Decisions: Updates and Strategies" (Practising Law Institute) – 3:00 pm (Eastern)

    January 17, 2019 – "Preparing for and Navigating PTAB Appeals Before the Federal Circuit — Conducting PTAB Trials With Eye to Appeal, Determining Errors for Appeal, Understanding PTO Practice and Federal Circuit Law" (Strafford) – 1:00 to 2:30 pm (EST)

    January 17, 2019 – "Extraterritoriality: Spotlight After WesternGeco" (Intellectual Property Owners Association) – 2:00 to 3:00 pm (ET)

    January 17, 2019 – "MyUSPTO and USPTO.gov accounts" (U.S. Patent and Trademark Office) – 11:00 am to 12:00 pm (ET)

    January 22, 2019 – "Biologics and Biosimilars: FDA Initiatives and Guidance, Approvals and Exclusivity, Patent Prosecution, Litigation" (Strafford) – 1:00 to 2:30 pm (EST)

    January 22, 2019 – European patent prosecution & litigation webinars with focus on UK, Germany, and EPO & CJEU (D Young & Co) – 1:00 pm, 2:30 pm, and 3:30 pm (GMT)

    January 24, 2019 – "Drafting and Defending Software Patents: Meeting Sections 102, 103 and 112 Requirements" (Strafford) – 1:00 to 2:30 pm (EST)

  • IPO Webinar on Extraterritoriality After WesternGeco

    IPO #2The Intellectual Property Owners Association (IPO) will offer a one-hour webinar entitled "Extraterritoriality: Spotlight After WesternGeco" on January 17, 2019 from 2:00 to 3:00 pm (ET).  Danielle Joy Healey of Fish & Richardson, PC; Prof. Timothy Holbrook of Emory University School of Law; and Thomas Saunders of Wilmer Cutler Pickering Hale and Dorr, LLP will discuss how district courts have applied the Supreme Court's decision in WesternGeco v. ION to date (including in Power Integrations v. Fairchild in the District of Delaware) and the open questions that remain, will analyze relevant case law at both the Supreme Court and the Federal Circuit, and will address the challenges in litigating these issues.  The panel will discuss the following cases:

    Halo v. Pulse (Fed. Circ. 2014)
    NTP v. Rim (Fed. Circ. 2005)
    Microsoft v. AT&T (S. Ct. 2007)
    Cardiac Pacemakers v. St. Jude Medical (Fed. Circ. 2009)
    Life Technologies v. Promega (S. Ct. 2017)

    The registration fee for the webinar is $135 (government and academic rates are available upon request).  Those interested in registering for the webinar can do so here.

  • USPTO Inventor Info Chat Webinar on MyUSPTO and USPTO.gov Accounts

    USPTO SealThe U.S. Patent and Trademark Office will be offering an Inventor Info Chat webinar on January 17, 2019, from 11:00 am to 12:00 pm (ET) to provide a demonstration and discussion of "MyUSPTO and USPTO.gov accounts."  The presentation will demonstrate the customizable homepage that serves as the launch pad into all of USPTO-related activities.  Attendees will see a demo of the docket, news, and other widgets designed to help with daily job activities.

    Additional information regarding this webinar, including instructions for viewing the webinar and registering for the webinar, can be found here.

  • Webinar on Biologics and Biosimilars

    Strafford #1Strafford will be offering a webinar entitled "Biologics and Biosimilars: FDA Initiatives and Guidance, Approvals and Exclusivity, Patent Prosecution, Litigation" on January 22, 2019 from 1:00 to 2:30 pm (EST).  Shana K. Cyr and Mark J. Feldstein of Finnegan Henderson Farabow Garrett & Dunner and Kurt R. Karst of Hyman Phelps & McNamara will provide essential updates on FDA practice and patent law relating to biologics and biosimilars, and will discuss the current state of and recent changes to FDA initiatives, approvals and exclusivities, as well as patent prosecution, post-grant proceedings and litigation.  The webinar will review the following issues:

    • What can we learn from FDA's recent guidance on biologics and biosimilars?
    • How does FDA's recent guidance impact patent strategy?
    • Should your patent strategy for biologics differ from your approach for small molecule drugs?

    The registration fee for the webcast is $297.  Those interested in registering for the webinar, can do so here.

  • Webinar on European Patent Prosecution & Litigation

    D Young & CoD Young & Co will be offering three European patent prosecution & litigation webinars on January 22, 2019.  The three webinars, which will be presented by Antony Craggs (Solicitor Advocate), Garreth Duncan (European Patent Attorney), and Uli Foerstl (Rechtsanwalt), will be offered at the following times (and then will be available on-demand):

    1:00 pm GMT — European patent prosecution & litigation with focus on the UK:

    • Practical application of the new doctrine of equivalents (UK decisions Generics v Yeda, L'Oreal v RN Ventures and Fisher & Paykel v Resmed).
    • Availability and nature of FRAND declarations (UK decisions Unwired Planet v Huawei, Conversant Wireless v Huawei & ZTE, Apple v Qualcomm).
    • Guidance on plausibility and sufficiency (UK decisions Warner-Lambert v Generics).

    2:30 pm GMT — European patent prosecution & litigation with focus on Germany:

    • Indirect infringement and exhaustion of patent rights (German Supreme Court decisions Trommeleinheit and Digitales Buch).
    • Pharmaceutical product compulsory license sought and granted in preliminary injunction proceedings (Federal Patent Court decision Raltegravir).

    3:30 pm GMT — European patent prosecution & litigation with focus on EPO & CJEU:

    • EPO significant cases (T 2026/15, T 2374/16, T 384/15 and T 1280/14).
    • Supplementary protection certificates (CJEU decisions Teva v Gilead, Boston Scientific v Deutsches Patent- und Markenamt).

    While there is no charge to attend the webinar, attendees must register in advance.  Those wishing to register can do so here.

  • Webinar on Drafting and Defending Software Patents

    Strafford #1Strafford will be offering a webinar entitled "Drafting and Defending Software Patents: Meeting Sections 102, 103 and 112 Requirements" on January 24, 2019 from 1:00 to 2:30 pm (EST).  Michael L. Kiklis of Bass Berry & Sims and Stephen G. Kunin of Maier & Maier will guide patent practitioners on how to draft their software patent applications to comply with Section 102, 103 and 112 requirements, will provide guidance on how to defend software patents from attacks under those statutory sections, and will discuss federal court guidance, prosecution guidelines, and offer litigation and prosecution strategies.  The webinar will review the following issues:

    • What are the hurdles for patent counsel to demonstrate a software-related claim is novel and non-obvious during prosecution?
    • What is the best way to defend against Section 102, 103 or 112 attacks at the District Court and the PTAB?

    The registration fee for the webcast is $347.  Those interested in registering for the webinar, can do so here.

  • Guest Post — Linking It Up: Antibody-Drug Conjugates

    By Steve Kennedy* and Anthony D. Sabatelli** —

    As discussed in our previous article, antibody-drug conjugates (ADCs) have emerged as a highly promising class of anti-cancer drugs, and significant technical innovations are being made in all three components of the ADC, i.e., the antibody, the drug payload, and the linker joining them.  The linker has been an area of particular focus, both within pharmaceutical development and the patent space.  The primary considerations for effective ADC linkers are their stability during circulation followed by release at the target site and their method of attachment to the antibody.  The latter can determine the ratio of payload to antibody, formulation homogeneity, and ease of manufacture, and will be the focus of the current article.

    Early ADCs, including the FDA-approved Mylotarg and Kadcyla, were created by directly functionalizing solvent-accessible lysine residues on the antibody using N-hydroxysuccinimide (NHS) esters.  Although this method is convenient, owing to the abundance of solvent-exposed lysine residues and mild reaction conditions required for conjugation, the resulting conjugates of this method are heterogeneous in their conjugation sites and amount of payload conjugated.  Although the average drug-to-antibody ratio (DAR) of a formulation can generally be controlled to the desired range of 3:1-4:1, because there are approximately 90 accessible lysines on the antibodies typically used as scaffolds, a high degree of isomeric variability is still present in these mixtures.  These mixtures can have varying pharmacokinetics, efficacy, and solubility.  Especially considering the contribution of formulation heterogeneity to the temporary withdrawal of Mylotarg from the market, homogeneity is a key goal for next-generation ADC therapies.

    The most common method for designing homogeneous ADCs is to conjugate the linker to cysteine residues on the antibody by reacting maleimide derivatives with cysteine sulfhydryl groups.  Earlier applications, including the FDA-approved Adcetris (U.S. Patent No. 7,829,531), were produced by reducing native interchain disulfide bonds in the antibody to provide accessible cysteines (U.S. Patent No. 7,837,980).  To improve antigen affinity, site-directed mutagenesis is now commonly employed to insert solvent-accessible cysteines that could be used for conjugation.  These engineered antibodies, termed THIOMABs, have been used in the design of several ADCs (U.S. Patent Nos. 8,937,161; 7,723,485; and 9,000,130, and U.S. Patent Application No. 15/592,072).

    Another promising method that has been used for the production of cysteine-linked ADCs, which does not require the engineering of mutant cysteine residues, is disulfide rebridging.  In the human IgG antibodies generally used as templates for ADCs, there are many disulfide bonds.  Some disulfide bonds, particularly intrachain bonds, can be important for proper binding of the target antigen, but several disulfide bonds have been shown to be reducible under mild conditions and nonessential for proper antibody function.  This finding led to academic applications where ADCs were linked through cysteine residues at broken disulfide bonds.  However, a more robust approach, which has seen activity in the biotech and patent arenas, is to bridge disulfide bonds with linkers attached to a cytotoxic payload.  By temporarily reducing and then rebridging the disulfide bond, the structural integrity of the antibody remains intact, improving antigen binding and stability (U.S. Patent No. 9,884,127; U.S. Patent Application Nos. 14/807,234; 14/437,537; 13/412,816; International Publication Nos. WO 2013/190272 and WO 2015/155753; and U.S. Patent Application Publication No. US 2015/0283259).  Particularly interesting, this strategy has recently been used to generate homogeneous ADCs linked to two different payload drugs, potentially allowing for further potency (International Publication No. WO 2018/185526).

    Yet another strategy designed to avoid the disruption of binding sites is conjugation at the N- and C-termini of the antibody.  Since the termini are distant from the antigen binding domains and key structural elements for antibody stability, the termini are promising locations for the addition of the linker and payload.  For example, antibodies have been engineered with a specific amino acid sequence at their C-termini, which allows for the specific conjugation of perfluoroaromatic linkers.  The conjugation of a perfluoroaromatic monomethyl auristatin E (MMAE) derivative  to an engineered cysteine on trastuzumab was shown to retain the native antigen binding affinity and improve potency against HER2 breast cancer cells (International Publication No. WO 2018/140590).

    The recent rapid progress in generating proteins with specific, genetically-encoded non-natural amino acids has led to several interesting applications in ADCs.  Major advantages of non-natural amino acids are that they can contain functional groups not present on native amino acids, allowing for unique chemistry at specific sites and improved homogeneity, and potentially greater stability relative to native amino acids.  Several non-natural amino acids, including p-azidomethyl-N-phenylalanine (U.S. Patent Application Publication No. US 2017/0362334) and p-acetyl-L-phenylalanine (U.S. Application No. 14/786,402) have been engineered into trastuzumab to generate homogeneous ADCs with high efficacy against cancer cells.  Most significantly, both of these ADCs demonstrated improved stability and safety in vivo relative to trastuzumab.

    Although still in its infancy, another means of peptide side chain conjugation used in ADCs shows significant promise.  Several groups have reported enzymatic methods to ligate linkers to antibodies.  This method takes advantage of enzymes that generate post-translational modifications of proteins in a site-specific manner (U.S. Patent Application Publication No. US 2018/0140714).  For example, bacterial transglutaminase has been used to conjugate lysine-containing linker-payload combinations to a glutamine side chain of human IgG1 (U.S. Patent No. 9,717,803).  This strategy yielded a conjugate with improved targeting of tumor cells relative to chemically-conjugated molecules and is under active development.

    In addition to conjugation of linkers to peptide components of the antibody, glycoengineering approaches have shown significant promise as well, and this topic will be discussed in a future article in this series.  As evidenced by the diverse and robust research and IP activity focused on ADC linker chemistries, the linker provides exciting opportunities for both improvements in potency and safety as well as novel ADC IP.  Especially in the ADC arena fraught with overlapping claims on naked antibodies, payloads, and established linkers, new modalities in linker chemistries provide needed avenues for innovation.

    Table 1a Table 1b

    * Steve Kennedy is a Ph.D. Candidate in the Chemistry Department at New York University. He specializes in biophysical characterization of protein complexes and is currently focused on the role of adaptor proteins in signaling pathways. Prior to attending NYU, Steve obtained his B.S. in Chemistry with Cum Laude honors at the University of Massachusetts – Boston, during which time he conducted bioanalytical mass spectrometry method development and lipidomics research.
    ** Dr. Sabatelli is a Partner with Dilworth IP