Patent Docs

Claim Construction by PTAB in CRISPR Interference Decision

September 24, 2020

By Kevin E. Noonan —

Judge Giles Sutherland Rich's most famous aphorism in patent law is "the name of the game is the claim."* This rubric is important to keep in mind when considering the Patent Trial and Appeal Board's decision on motions issued September 10th in Interference No. 106,115 (see "PTAB Decides Parties' Motions in CRISPR Interference") between Senior Party The Broad Institute, Harvard University, and the Massachusetts Institute of Technology (collectively, "Broad") and Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC").

The focus of the claim construction issue was the meaning of the term "guide RNA," specifically whether it was a generic term encompassing dual-species or single-species ("fused") RNA components of the CRISPR-Cas9 complex, as illustrated in the Decision (taken from the Jinek 2012 reference; Jinek et al., 2012, "A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity," Science 337: 816–21):

In its Motions Nos. 2 and 3, Broad asserted this distinction, relying on portions of the specifications of several of its patents-in-interference. While the term "crRNA" is recited in these Broad specifications, the involved claims recite "guide RNA," "chimeric RNA," and "guide sequence," and as the Decision states, the parties disputed the meaning of this term. Broad noted that "the majority" of their involved claims recite "guide RNA" and that term was not limited to single- or dual-(RNA) molecule embodiments. CVC, for its part, argued that the term should be limited to single-(RNA) molecule species for all Broad's claims-in-interference.

The Board used the "broadest reasonable interpretation" test (that standard was not changed when the Patent and Trademark Office adopted the Phillips test for post-grant review proceedings; see "PTAB Adopts Litigation Standards for Claim Construction in AIA Proceedings"), noting that in applying that standard "the Board's construction cannot be divorced from the specification and the record evidence, and must be consistent with the one that those skilled in the art would reach," citing Microsoft Corp. v. Proxycom, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015).

Broad's argument in favor of construing "guide RNA" as a generic term encompassing both single- and dual-molecule embodiments was based on claims that distinguished between "guide RNA" and "fused guide RNA." Under the principle of claim differentiation, Broad argued that a claim reciting "fused guide RNA" that was dependent on a claim reciting "guide RNA" indicates that the latter term is broader than "fused" guide RNA (citing claim 18, dependent on claim 15, of Broad's Patent No. 8,697,359 in support of this argument). Similarly, Broad cited claim 3 of its Patent No. 8,993,233 that recites a limitation wherein the guide RNA comprises a tracrRNA sequence on a different vector than the nucleic acid encoding the Cas9 protein.

CVC in opposition countered that claim differentiation is not "a rigid rule" and the segregation of guide RNA and Cas9-encoding RNA in the '233 patent did not mandate either guide RNA configuration.

The Board stated that while it agrees with Broad that some of its claims suggest that the term "guide RNA" is generic, in other instances the claims are amenable to a contrary construction of the term. Accordingly, the Decision went on to consider other evidence to see if it rebutted the presumption that these claims had raised.

That evidence included support for Broad's argument that there is no "clear disavowal of scope" not to include both species of guide RNAs in the claims. Broad contended that the phrase is a "term of art" having a plain meaning that encompasses both single- and dual-RNA species. Broad relied on the Jinek reference for support, citing this figure:

accompanied by the caption "In this ternary complex, the dual tracrRNA:crRNA structure acts as guide RNA that directs the endonuclease Cas9 to the cognate target DNA" (emphasis in opinion). Broad further supported this argument with expert testimony (consistent with Broad's interpretation of the figure) that:

The "ternary complex" refers to the three part complex that consists of (1) Cas9, (2) a mature crRNA molecule and (3) a tracrRNA molecule. This is significant because "the dual tracrRNA:crRNA structure" makes up two parts of the three part complex. Otherwise, Jinek 2012 would not have referred to the Cas9:RNA complex as a "ternary complex," but as a binary complex. Thus, the "guide RNA" in that sentence references the dual-guide RNA consisting of separate strands of tracrRNA and crRNA.

The Board found other evidence from the Broad to be "less persuasive." This included expert testimony evaluating CVC's specification in U.S. Serial No. 15/947,680 as reciting "[t]he term 'DNA-targeting RNA' or 'gRNA' is inclusive, referring both to double-molecule DNA-targeting RNAs and to single-molecule DNA-targeting RNAs (i.e., sgRNAs)," which the Board professed was not conclusive with regard to an interpretation that the meaning of "gRNA" meant "guide RNA." Similarly, Broad's expert testified that CVC inventors used the term "guide RNA" inclusively to mean "all crRNA:tracrRNA complexes, whether present as a single or a double-molecule" in a scientific paper (Sternberg et al., 2014, "DNA interrogation by the CRISPR RNA-guided endonuclease Cas9," Nature 507: 62), but the Board stated that "without an explanation of how these specific instances of the terms would have been understood by those in the art at the time, we are not certain they demonstrate uses of 'guide RNA' as a generic term." The same expert also cited CVC witness testimony from earlier Interference No. 105,048 that "guide DNA targeting RNA" includes either single- or dual-guide species, but the Board noted that this term is not the same as the "guide RNA" term as used in Broad's motions in this interference. And the Board rejected out of hand similar statements by CVC counsel in the '048 interference, because counsel "is not one of skill in the art and we are not persuaded that his use of technical terms indicates anything about how they would have been understood by those in the art at the time."

The Board then turned to Broad's assertion of extrinsic evidence, including several contemporaneous scientific journal articles and references, all of which (being published prior to 2011) the Board found irrelevant. In summary the Board states that:

We are not persuaded from the extrinsic evidence cited by Broad that the term "guide RNA" was well known in the art to mean either a single or a dual RNA molecule configuration. In some publications cited by Broad, such as Jinek 2012, the term "guide RNA" is used to refer to a dual molecule RNA configuration. But in other examples, such as CVC's '680 application and Drs. Geider and Carroll's declarations in the prior '048 interference, the specific term "guide RNA" was not actually used. In yet other references, such as Bhaya, Horvath, Rand, and Tolia, the term is used, but not for a complex of the crRNA and tracrRNA. This evidence does not persuade us that the term "guide RNA" had a plain meaning in the art, which "indisputably" included both single- and dual- molecule RNA configurations, as Broad argues.

From this determination that the term "guide RNA" was not understood to be generic at the time of Broad's filings, the Board states that it is not convinced that "the specification must provide a clear intent to exclude a dual-molecule RNA configuration from the term," citing Trs. of Columbia Univ. v. Symantec Corp., 811 F.3d 1359, 1363 (Fed. Cir. 2016), for an explication of the requirements under Phillips v. AWH Corp., 415 F.3d 1303, 1320 (Fed. Cir. 2005 (en banc), in this regard. Broad cited a portion of its specification in support of its argument:

In aspects of the invention the terms "chimeric RNA", "chimeric guide RNA", "guide RNA", "single guide RNA" and "synthetic guide RNA" are used interchangeably and refer to the polynucleotide sequence comprising the guide sequence, the tracr sequence and the tracr mate sequence. The term "guide sequence" refers to the about 20 bp sequence within the guide RNA that specifies the target site and may be used interchangeably with the terms "guide" or "spacer". The term "tracr mate sequence" may also be used interchangeably with the term "direct repeat(s)". An exemplary CRISPR-Cas system is illustrated in FIG. 1.

Broad argued this portion of the specification referenced some (but not all) aspects of the invention to encompass single RNA guide RNA species. Broad also argued that "used interchangeably" does not mean that the listed terms are themselves the same molecules. CVC disputed these characterizations, arguing that "the specification specifically states that the terms 'guide RNA,' 'chimeric RNA,' 'chimeric guide RNA,' and 'single guide RNA' all 'refer to the polynucleotide sequence comprising the guide sequence, the tracr sequence and the tracr mate sequence.'" And CVC further argued that "this portion of the specification defines "guide RNA" as a singular polynucleotide sequence comprising a guide sequence, a tracr sequence, and a tracr mate sequence and corresponding to the fused crRNA and the tracrRNA."

These arguments were persuasive to the Board, which stated that "this paragraph of the Broad specification indicates that 'chimeric RNA,' 'chimeric guide RNA,' 'single guide RNA,' as well as 'guide RNA' include these three components."

The Decision further explicated other portions of the various Broad specifications, to the same effect: the Board is persuaded by CVC's arguments (or not persuaded by Broad's arguments) regarding the status of the term "guide RNA" as a generic term encompassing both single- and dual-RNA species.

The Board offers this conclusion regarding its construction of this sole term:

Our review of the parties' arguments leads us to the conclusion that Broad's use of the term "guide RNA" in its involved claims is not a generic term, but is limited to a single-molecule RNA configuration of the guide sequence and tracrmate, which together make the crRNA, and the tracrRNA sequences. Although some dependent claims, such as claim 18 of the '359 patent, might indicate by claim differentiation that the term "guide RNA" is generic, that presumption is overcome by Broad's specification. The specification of Broad's involved patents, specifically the sentence providing that "guide RNA" and other terms "refer to the polynucleotide sequence comprising the guide sequence, the tracr sequence and the tracr mate sequence" ('359 patent, Ex. 3011, 12:6–10), limits the interpretation of the term. Broad fails to direct us to other uses of the term "guide RNA" in the specification that indicate a dual-molecule RNA configuration and we are not persuaded that the term was so clearly understood the art to be a generic term that only a clear disavowal in the specification would define it to mean a single-molecule RNA configuration. Thus, we are persuaded that the broadest reasonable interpretation of Broad claim term "guide RNA" encompasses only a single-molecule RNA configuration.

The consequences of this claim construction will be the subject of future posts.

*And then there is this ditty sung to the tune of "Camelot":

A law was made 200 years ago here
Grant patents, help promote inventive thought
Today the system's thriving and our credo
Is claim-a-lot

We push the envelope,
Expand the boundaries
Create a circle from a tiny dot
Our product's forged with words
and not in foundries
We claim a lot

Claim-a-lot (claim-a-lot)
I know it sounds a bit bizarre
Lord, we claim-a-lot (oh yes, we claim-a-lot)
Stretch out those claims so far

Though prior art may set some limitations
Restricts our flights of fancy, clever thought
Our efforts, not for naught
Results, so boldly wrought
Construct our patent juggernauts
By claiming quite a lot.

Kramer, Levin, Naftalis & Frankel LLP, Claim-a-Lot, in Pamphlet for N.Y. Intellectual Property Law Association 78th Annual Dinner (Mar. 24, 2000).
Tormasi v. Western Digital Corp. (Fed. Cir. 2020)

September 23, 2020

By Donald Zuhn —

Last month, the Federal Circuit affirmed an Order by the U.S. District Court for the Northern District of California, finding that Appellant Walter A. Tormasi lacked the capacity to sue under Federal Rule of Civil Procedure 17(b). Mr. Tormasi had filed suit against Appellee Western Digital Corp., asserting that Western Digital had infringed claims 41 and 61-63 of U.S. Patent No. 7,324,301.

Mr. Tormasi is an inmate in the New Jersey State Prison, which has a "no-business" rule prohibiting inmates from commencing or operating a business without prior approval from the Administrator (i.e., the chief executive officer of any State correctional facility within the New Jersey Department of Corrections). Without the Administrator's prior approval, Mr. Tormasi formed an intellectual property holding company, Advanced Data Solutions Corp., appointing himself as Director, Chief Executive Officer, President, and Chief Technology Officer. Mr. Tormasi then filed a patent application that issued as the '301 patent (which relates to the art of dynamically storing and retrieving information using nonvolatile magnetic random-access media, specifically hard disk drives). Acting as Director, Mr. Tormasi transferred the rights in the patent application to himself in exchange for all shares of Advanced Data Solutions stock, then transferred the application back to himself, and then twice transferred the '301 patent to himself. In January 2019, Mr. Tormasi filed suit against Western Digital for infringement of the '301 patent. Western Digital moved to dismiss the suit for lack of standing and capacity to sue, and the District Court issued an Order, finding that Mr. Tormasi lacked capacity to sue in view of his violation of the no-business rule.

On appeal, Mr. Tormasi asserted that his lawsuit could not be construed as an unpermitted business activity because he sought to enforce his personal intellectual property rights. A majority of the Federal Circuit disagreed, stating that Mr. Tormasi's attempt to file the lawsuit as a personal action "merely repackages his previous business objectives as personal activities so he may sidestep the 'no business' regulation," and finding the "characterization of his suit as personal, as opposed to related to business, to be without merit." The majority found that "[b]ecause New Jersey prohibits inmates from pursuing a business, and because of Mr. Tormasi's repeated attempts to profit as a business from the ['301] patent, the District Court did not err when it determined that Mr. Tormasi lacked the capacity to bring this suit for patent infringement." The majority therefore affirmed the District Court's Order.

Writing in dissent, Judge Stoll asserted that Mr. Tormasi had not waived his argument that the "no business" rule did not limit the scope of an inmate's capacity to sue under New Jersey law, as the majority had found. Judge Stoll explained that Mr. Tormasi's argument that "imprisonment status or prison behavior is irrelevant to the capacity-to-sue standard," had "fairly preserved" his legal argument that the "no business" rule cannot generally limit the scope of an inmate's capacity to sue. Judge Stoll, therefore, concluded that the "no business" rule should not have been at issue at all.

Tormasi v. Western Digital Corp. (Fed. Cir. 2020)
Nonprecedential disposition
Panel: Circuit Judges Wallach, Chen, and Schall
Opinion per curiam; dissenting opinion by Circuit Judge Stoll
PTAB Decision Denying Broad’s Substantive Motion No. 1 in CRISPR Interference

September 20, 2020

By Kevin E. Noonan —

On September 10th, the Patent Trial and Appeal Board rendered its decision on the parties' Motions in Interference No. 106,115 (see "PTAB Decides Parties' Motions in CRISPR Interference"). Perhaps the decision of most immediate significance was the Board's decision denying the Senior Party's (The Broad Institute, Harvard University, and the Massachusetts Institute of Technology, collectively, "Broad") Substantive Motion No. 1, that Junior Party Junior Party the University of California/Berkeley, the University of Vienna, and Emmanuelle Charpentier (collectively, "CVC") should be estopped in this interference by the PTAB's decision in the earlier 105,048 interference between these parties. What follows is a description and analysis of the Board's reasoning.

The Board is direct in denying Broad's Motion No. 1, saying they have not been persuaded by Broad's arguments. Because the Board dissolved the '048 interference because there was no interference-in-fact, that judgment "neither cancel[ed] nor finally refuse[d] either parties' claims," citing its Judgment. Accordingly, in the Board's view, "the resolution at the end of the '048 interference was that interference between the claims presented at that time did not deprive either party of its claims." Broad's estoppel arguments are based on CVC losing rights to claims directed to eukaryotic embodiments of CRISPR; in the Board's view, the basis for its decision in the '048 Interference is contrary to Broad's characterization.

Turning to specifics, the Board addressed Broad's contention that Rule 127(a)(1) mandated its request relief. The Board disagreed, noting that "[t]he prior CVC claims did not interfere with Broad's claims, whereas Broad does not contest that the currently involved CVC claims do." Accordingly, "it is not clear that the subject matter of the interference is the same, even if the subject matter of Broad's claims is the same." Evidentiarily, the Board's decision states that "Broad fails to provide a sufficient comparison of the subject matter of the two interferences to persuade us that the current interference is, or will be, the same subject matter of the '048 interference and will raise the same issues." Specifically, the Board notes that "Broad fails to compare the count in the current interference, or Broad's proposed counts, with either parties' claims in the prior interference" and that "the current count in the current interference recites a limitation on the RNA configuration that is not recited in the count of the '048 interference." The Board finds further fault with the Broad's arguments in support of its motion in that "whether the prior count and the current count are drawn to the same subject matter is a disputed issue, which is not sufficiently addressed in Broad's Motion 1."

Turning to Broad's argument that CVC is estopped under Rule 127(a)(1) because Junior Party did not request authorization to file a motion to add eukaryotic CRISPR embodiment claims in the '048 Interference, the Board agreed with CVC's argument that the first sentence of Rule 127(a)(1) does not mention estoppel, and that sentence is limited to decisions "disposing all issues of the proceeding." A holding of no interference-in-fact, according to the Board, disposes of no issues other than whether there is an interference-in-fact and thus Rule 127(a)(1) does not apply. Indeed, such a finding precludes the Board from deciding any other issue, states the opinion, citing Berman v. Housey, 291 F.3d 1345, 1352 (Fed. Cir. 2002). Similarly unpersuasive was Broad's citation of PTO comments during the Notice-and-Comment period related to adoption of the current interference rules, because those comments were directed to interferences directed to the same subject matter and "Broad fails to persuade us that the current interference is for the same subject matter as the prior '048 interference." And while not expressly agreeing with CVC, the Board cites the MPEP consistent with CVC's argument that "there is no losing party" resulting from a determination of no interference-in-fact.

Interference estoppel by judgment, according to the Board's opinion, "rests on the principle that a 'judgment in an action precludes relitigation of claims or issues that were . . . raised in [the earlier] proceeding,'" citing In re Deckler, 977 F.2d 1449, 1452 (Fed. Cir. 1992). Stating the Board's basis for its decision most distinctly, the opinion states that "Broad has failed to persuade us that under 37 C.F.R. § 41.127(a)(1) CVC is estopped because Broad fails to persuade us that the subject matter of the current interference is the same as the subject matter of the prior '048 Interference."

The opinion further asserts that the Board's application of its rules here are consistent with its responsibility under 37 C.F.R. § 41.1 "to secure the just, speedy, and inexpensive resolution of every proceeding before the Board."

And with regard to CVC's putative obligation or responsibility to move to file a motion adding claims to eukaryotic CRISPR embodiments in the '048 Interference, the Board noted that CVC had no claims in condition for allowance during that interference. "Because the patentability of such claims to CVC was not certain at the time of the '048 Interference, we agree with CVC that allowing ex parte examination to conclude was preferable" according to the Board, noting that Broad itself had "expressed this view" in response to CVC's request to file a preliminary motion to add a claim and substitute a count in the '048 interference. "Under the facts and circumstances of this interference, where UC believes all of its current claims interfere with all of Broad's claims, there is no reason why UC should need to add a new claim. If UC's claims in other applications are ultimately found to be allowable, UC may suggest additional interferences to the examiner" (emphasis in opinion).

Under this reasoning the Board denied Broad's Motion No. 1 and then turned to the other motions filed by the parties, which will be discussed in future posts.
Conference & CLE Calendar

September 20, 2020

September 22, 2020 – "The Race for a Coronavirus Vaccine: The Intersection of Science and IP Policy" (Morningside IP and IPWatchdog) – 12:00 pm (ET)

September 22, 2020 – "Plausibility at the EPO – Exploring the Legacy of Dasatinib" (Mathys & Squire) – 6:00 to 7:00 pm (GMT Summer Time); 11:00 am to 12:00 pm (ET)

September 23-24, 2020 – Program on Promoting Innovation and Supporting Pro-competitive Collaborations in Life Science Sector (U.S. Patent and Trademark Office and Department of Justice) – 1:00 to 5:20 pm ET

September 23-24, 2020 – Summit on Biosimilars: Legal, Regulatory, and Commercial Strategies for the Innovator and Biosimilars Marketplace (American Conference Institute) – virtual conference

September 23-24, 2020 – FDA Boot Camp (American Conference Institute) – virtual conference

September 24, 2020 – "Latest Developments in the Patentability of AI- and Software-Based Inventions" (Fitch Even) – 12:00 pm to 1:00 pm (ET)

September 29, 2020 – IPWatchdog Virtual CON2020 – The Future of Monetization – 12:45 pm (ET)

September 29, 2020 – IPWatchdog Virtual CON2020 – What Can Armor on WWII Planes & Honeybees Tell Us about Innovation Strategy? – 2:00 pm (ET)

September 29, 2020 – IPWatchdog Virtual CON2020 – Everyone Wants to Be a Unicorn – But What About Patents? – 2:15 pm (ET)

September 30, 2020 – IPWatchdog Virtual CON2020 – Keynote: Louis Foreman, CEO, Enventys Partners, founder of Edison Nation – 12:05 pm (ET)

September 30, 2020 – IPWatchdog Virtual CON2020 – How China is Changing the Global Patent System – 12:45 pm (ET)

September 30, 2020 – IPWatchdog Virtual CON2020 – Solutions for the U.S. Patent System – 2:15 pm (ET)
Joint USPTO-DOJ Program on Promoting Innovation and Supporting Pro-competitive Collaborations in Life Science Sector

September 19, 2020

The U.S. Patent and Trademark Office and Department of Justice will be holding a joint program on September 23-24, 2020 on how patents and copyrights drive value in the life science sector and the effects of collaborations and partnerships, with specific attention paid to the antitrust implications of different cooperation and licensing strategies. The program will include ten sessions over two afternoons (1:00 to 5:20 pm ET):

Day 1 sessions:

• The roles of patents in research and development of therapeutics, diagnostics, and vaccines, particularly during pandemics
• Update on USPTO guidance on the patentability of life science inventions
• Life science patents in practice
• Panel discussion: Are changes to U.S. patent law needed to better support innovation and in life sciences and the development of COVID-19 solutions?
• Copyright and innovation in the life sciences
• Panel discussion: How copyright can create incentives or barriers to building data or information pools, and related licensing

Day 2 sessions:

• Collaboration and licensing strategies
• How do regulation and antitrust enforcement impact competition and incentives for innovation?
• Competition and collaboration: Examining competitive effects and antitrust risks associated with collaborations
• Academics' and economists' views on collaboration and competition

Additional information regarding the program can be found here.
Webinar on Intersection of Science and IP Policy for Coronavirus Vaccine

September 19, 2020

Morningside IP and IPWatchdog and will be offering a webinar entitled "The Race for a Coronavirus Vaccine: The Intersection of Science and IP Policy" on September 22, 2020 at 12:00 pm (ET). Jonathan L. Temte, Associate Dean for Public Health and Community Engagement, University of Wisconsin School of Medicine and Public Health; Melissa Brand, Assistant General Counsel and Director of Intellectual Property, Biotechnology Innovation Organization (BIO); Erika Lietzan, Associate Professor of Law, University of Missouri School of Law; and Gene Quinn of IPWatchdog will participate in a wide-ranging conversation on the topic of COVID-19 and the race toward a coronavirus vaccine, including the science, FDA processes involved, and intellectual property rights.

There is no registration fee for this webinar. However, those interested in registering for the webinar, should do so here.
Webinar on Plausibility at the EPO

September 19, 2020

Mathys & Squire will be offering a webinar entitled "Plausibility at the EPO – Exploring the Legacy of Dasatinib" on September 22, 2020 from 6:00 to 7:00 pm (GMT Summer Time); 11:00 am to 12:00 pm (ET). Anna Gregson and Stpehne Garner of Mathys & Squire LLP will review how the EPO case law has developed since the EPO Board of Appeal revoked Bristol-Myers Squib's dasatinib patent in 2017, and discuss if and how innovators should adjust their filing and drafting strategy in light of the EPO's post-dasatinib approach to plausibility.

While there is no cost to participate in the program, those interested in attending the webinar can register here.
Webinar on Patentability of AI- and Software-Based Inventions

September 19, 2020

Fitch Even will be offering a webinar entitled "Latest Developments in the Patentability of AI- and Software-Based Inventions" on September 24, 2020 from 12:00 pm to 1:00 pm (ET). Thomas F. Lebens and Zachary Van Engen of Fitch Even will provide an update on the latest legal developments in computer software patentability along with guidance on best practices for protecting software-related innovations, covering the following topics:

• Ramifications of recent post-AliceFederal Circuit cases
• Updated USPTO guidelines
• Tips for patent application drafting
• Tips for responding to office actions

While there is no cost to participate in the program, advance registration is required. Those interested in attending the webinar can register here.
USPTO Announces Deferred-Fee Provisional Application Pilot Program to Encourage COVID-19 Related Inventions

September 17, 2020

By Donald Zuhn —

In a notice published in the Federal Register (85 Fed. Reg. 58038) earlier today, the U.S. Patent and Trademark Office announced that it was implementing a deferred-fee provisional patent application pilot program in order to promote the expedited exchange of information about inventions designed to combat COVID–19. In the notice, the Office states that it recognizes that its charge to issue high-quality patents to inventors goes hand-in-hand with the dissemination of important technical information, and that the free-flow of such information is now more important than ever in view of the urgent challenges posed by COVID–19.

Applicants who participate in the pilot program will be allowed to defer payment of the provisional application filing fee (which is currently $280 for large entities) until the filing of a nonprovisional application claiming the benefit of the provisional application in exchange for permitting the Office to make the technical subject matter disclosed in the provisional application available to the public via a searchable collaboration database maintained on the Office's website. In order to qualify for participation in the pilot program, the subject matter disclosed in the provisional application must concern a product or process related to COVID–19, and such product or process must be subject to approval by the U.S. Food and Drug Administration (FDA) for COVID-19 use. According to the notice, a provisional application qualifies for participation in the pilot program if such FDA approval "has been obtained, is pending, or will be sought prior to marketing the subject matter for COVID–19." The notice indicates that such approvals include an Investigational New Drug (IND) application, an Investigational Device Exemption (IDE), a New Drug Application (NDA), a Biologics License Application (BLA), a Premarket Approval (PMA), or an Emergency Use Authorization (EUA). The notice also indicates that the subject requirement for participation in the deferred-fee provisional patent application pilot program is the same as that for participation in the COVID–19 prioritized examination pilot program, which was announced in May (see "USPTO Announces COVID-19 Prioritized Examination Pilot Program").

The requirements to participate in the pilot program are as follows:

1. Applicants must submit a certification and request for participation in the program using form PTO/SB/452.

2. The submission must be in the English language.

3. The submission must include a provisional application cover sheet pursuant to 37 C.F.R. § 1.51(c)(1) (or an Application Data Sheet, which may serve as the provisional application cover sheet).

4. The submission (i.e., provisional application specification, including any drawings, claims, and/or abstract, provisional application cover sheet (or ADS), and form PTO/SB/452) must be filed electronically via the Office's Patent Center, and the specification must be filed in DOCX format to facilitate making the text searchable.

5. The submission must meet the requirements for a provisional application under 35 U.S.C. § 111(b)(1) and 37 C.F.R. § 1.53(c), except for the payment of the basic filing fee, which would be deferred under the pilot program.

The notice indicates that a submission that does not include a legible specification in DOCX format will be handled as a provisional application and not a pilot program submission. However, if a submission does not include a provisional application cover sheet or application size fee (if the latter is required), the Office will give Applicants an extendable two-month time period to submit the missing items.

The technical subject matter of provisional applications accepted to the pilot program will be uploaded by the Office into a searchable public collaborative database, and the submission will be processed as a provisional application. The notice states that the database will also publish the name of the inventor or the first named joint inventor, the provisional application filing date, and the date the submission was placed in the database, but will not publish the provisional application cover sheet.

The notice explains that while a provisional application filing fee is a statutory requirement under 35 U.S.C. § 111(b)(3), the Director is authorized under that same section to allow Applicants to pay that fee after the filing date of the application. However, the notice also explains that the basic filing fee under 37 C.F.R. § 1.16(d) must be paid by the Applicant in order to rely on the provisional application in a later-filed nonprovisional application. Participants in the pilot program will receive a reminder from the Office 10 months after the provisional application filing date indicating that the basic filing fee must be paid not later than 12 months after the provisional application filing date in order to claim the benefit of the filing date of the provisional application in a nonprovisional application.

In a section of the notice entitled "Prior Art Considerations," the Office states that "[a]n inventor's technical disclosure published in the collaboration database cannot be used against the inventor's own corresponding later-filed nonprovisional application in the United States, provided that the later-filed application is filed within one year of the public disclosure." However, the notice also states that:

Special care should be taken where foreign patent protection is desired. Many foreign jurisdictions treat an inventor's public disclosure made within one year of filing as prior art against the inventor's own application unless that earlier disclosure is the subject of a proper priority claim in that jurisdiction. For this reason, applicants should be aware of the prior art implications of their submissions.

Making a submission under the program will result in a public disclosure of the technical subject matter via the Office's searchable collaboration database. Thus, such a public disclosure may be citable as prior art under 35 U.S.C. 102(a)(1) as of the date it publishes. In addition, the complete provisional patent application submitted under the program may become prior art under 35 U.S.C. 102(a)(2) as of the filing date, but only if there has been a proper benefit claim under 35 U.S.C. 119(e) in a later-filed nonprovisional application or international application and the later-filed application has been published or deemed published under 35 U.S.C. 122(b) or has issued as a U.S. patent.

The notice also explains that "[t]here is no provision for withdrawal from the program," and that "[o]nce the technical subject matter of a program submission is made available to the public in the searchable collaboration database on the USPTO's website, that public availability cannot be revoked."

The Office began accepting certifications and requests for participation in the pilot program today and will accept requests for the next 12 months, at which time the program may be extended or terminated by the Office. The notice also indicates that depending on feedback and interest in the pilot program, the technological scope may be expanded beyond COVID–19 to other areas that are the focus of pioneering or rapid innovation. Provisional applications filed prior to September 17, 2020 are not eligible for participation in the pilot program.

The Office will accept public comments regarding the pilot program, but such comments must be received by November 16, 2020 to be considered by the Office. Comments should be sent by e-mail and addressed to Covid19ProvisionalApplication@uspto.gov.
Why Do Insect Vectors Not Get Ill from the Microbes They Transmit? Some Evidence from Malaria-carrying Mosquitos

September 15, 2020

By Kevin E. Noonan —

There are an estimated 219 million cases of malaria per year, leading to more than 400,000 deaths annually according to the World Health Organization. Hemocytes (insect white blood cells) comprise the mosquito immune system and are the basis for immunity to malaria. There are three known hemocyte types: granulocytes (highly phagocytic cells of about 10 to 20 μm in diameter); oenocytoids (8- to 12-μm round cells that produce melanin involved in pathogen encapsulation); and prohemocytes (round cells (4 to 6 μm) with a high nuclear-to-cytoplasmic ratio and are thought to be precursors of the other two cell types). These can be circulating in the hemolymph or resident in tissues like the gut epithelium (where the ookinete stage of the Plasmodium migrates). Upon infection, hemocytes activate and kill Plasmodium parasite by complement activation. Repeated infection is prevented by immunological memory termed "priming" in mosquitos; subsequent infections stimulate release of hemocyte differentiation factor into the hemolymph, which causes granulocyte induction. This priming is effectuated by release of hemocyte differentiation factor (HDF), a combination of lipoxin 4 and evokin, which is a lipocalin carrier.

Against this backdrop of basic mosquito biology, an international team* of researchers reported their results of an in-depth study of mosquito immune system in a paper published in Science entitled "Mosquito cellular immunity at single cell resolution." Using single cell RNA sequencing techniques on individual hemocytes, these researchers analyzed transcriptomes from 5,383 Anopheles gambiae specimens, comparing transcriptomes of circulating hemocytes from mature adult female mosquitos fed either a sugar meal or with a blood meal from Plasmodium-infected or healthy mice. Their results showed the following major cell clusters: two from adipose tissue, one from muscle tissue, and six hemocyte clusters. One adipose-tissue derived cluster expressed several immune-modulatory genes such as CAP-Gly domain containing linker proteins (CLIPs, including CLIPA1, -7, -8, -9, and -14), homeobox transcription factors LRIM1, -4A, -8A, -8B, -9, and -17, lectins (CTL4 and MA2), and Serpin 2 (SRPN2). The other adipose-tissue derived cluster expressed high levels of vitellogenin, a canonical fat-body marker. The six hemocyte clusters had diverse characteristics:

• HC1 showed high mRNAs levels of prophenoloxidases, including PPO4 and PPO9, characteristic of oenocytoids, and contained low levels of leucine-repeat protein 8 (LRR8) mRNA.

• HC2 showed low or absent PPO4 and high LLR8 levels; had a morphology typical of prohemocytes and granulocytes; expressed SPARC, cathepsin-L, and LRR8; had 73% fewer unique molecular identifiers (UMIs) (mean UMI of 413) than cells of the HC3 cluster; and were less differentiated and were thought to constitute prohemocytes.

• HC3 showed low or absent PPO4 and high LLR8 levels; had a morphology typical of prohemocytes and granulocytes; expressed SPARC, cathepsin-L, and LRR8; had a greater number of UMI than cells of the HC2 (mean of 1516); and typical granulocyte morphology, with prominent pseudopodia and abundant granules.

• HC4 showed low or absent PPO4 and high LLR8 levels; had a morphology typical of prohemocytes and granulocytes; shared markers with cells of the HC3 cluster; expressed cyclin B, aurora kinase, and other mitotic markers, which suggests that they are proliferating hemocytes — consistent with this hypothesis, cells in this cluster expressed mitotic markers consistent with proliferation in response to a blood meal which was also consistent with blood-feeding induced DNA synthesis; and a correlation analysis shows these cells to be granulocytes.

• HC5 showed low levels of LLR8 and expressed no PPO4; expressed high levels of an uncharacterized transmembrane protein AGAP007318 (TM7318) and lipopolysaccharide-induced tumor necrosis factor–α transcription factor 3 (LL3); and showed two different morphologies, wherein TM7318-positive cells were present in low abundance (0.5% of granulocytes) that represented a novel, separate giant cell type (25 to 40 μm) they termed "megacytes".

• HC6 showed low levels of LLR8 and no PPO4, were negative to HC4 and HC5 markers but expressed antimicrobial peptides such as defensin 1, cecropins 1, and C-type lysozyme; and also exhibited differential morphologies, whereas cells negative for TM7318 represented small granulocytes that expressed antimicrobial genes (AM Gran) (16.4% of granulocytes).

The transcriptomes were further analyzed and these researchers found that granulocytes formed three major subclusters, one representing the basal state (Gran1) and the others represented by cells activated by blood meal (Gran2) and Plasmodium infection (Gran3). Prohemocytes, on the other hand, clustered into two population subclusters (PHem1 and PHem2), wherein PHem2 seems to be an intermediate between PHem1 and Gran1. The Gran1 cluster was linked to Gran2 and Gran3, with Gran3 being linked to dividing granulocytes. Gran2 also linked to megacytes, and Gran1 linked to antimicrobial granulocytes, as shown in the accompanying figure:

The status of immunological cells in An. gambiae was compared with another insect vector species, Aedes aegypti, known to transmit dengue fever, yellow fever, chikungunya, and Zika virus. When compared with transcriptomes of An. gambiae, cross-species correlation analysis revealed four different cell states, including a proliferating S-phase granulocyte cluster (AaHC6) without a clear An. gambiae equivalent. These researchers appreciated two clusters (AaHC1 and AaHC2) with conserved transcriptome signatures for oenocytoids (99 and 77% correlation, respectively, with AgHC1) and different granulocyte types, including antimicrobial peptide–expressing cells (94% with AgHC6) and proliferating granulocytes (87% with AgHC4). Granulocytes expressed laminins, leucine-rich repeat proteins, scavenger receptors, Toll-like receptor 5, and the transcription factor Rel2. However, megacytes (AgHC5) detected in An. gambiae lacked an obvious counterpart in Aedes, and their characteristic marker (TM7318) was present only in anophelines of the Cellia subgenus (unlike Aedes, these mosquitos are malaria vectors in Africa and Asia).

The researchers summarized their results by saying:

Together, these analyses suggest the existence of a proliferative, oligopotent cell population that can replenish the pool of granulocytes and differentiate into more specialized hemocytes, such as megacytes and antimicrobial granulocytes.

And further:

The conservation of diverse and molecularly well-defined hemocyte types between distantly related mosquito genera and the apparent absence of megacytes in our Ae. aegypti mosquito dataset raise questions as to how the immune systems of these mosquito species have evolved to limit their capacity to transmit parasites and arboviruses to humans. This knowledge will ultimately underpin immunological strategies aimed at interrupting disease transmission by rendering mosquitoes resistant to such pathogens.

* Wellcome Sanger Institute, Cambridge; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health USA; Zoology Department, Stockholm University; Departamento de Biología del Neurodesarrollo, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo; Institute and Department of Physics, University of Cambridge; Molecular Infection Medicine Sweden, Molecular Biology Department, Umeå University

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