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March 2011
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Tuschl II siRNA Assay
Knock-down of nuclear envelope protein Lamin. Elbashir, Harborth et al. Nature May 24 2001. This assay was proposed by Klaus Weber.

Archive for March, 2011

Tekmira’s Complaint About Alnylam

“Alnylam Engaged in an Unlawful Scheme to Gain Access to, Exploit, and Claim Ownership Interests in Tekmira’s Technology” Tekmira said.

1. Alnylam was one of Tekmira’s collaborators. Alnylam began collaborating with TPC and Protiva before they merged in March 2008, and continued collaborating with Tekmira after the merger. In the course of the collaboration relationships, Tekmira made a number of disclosures of its delivery technology to Alnylam. Tekmira did so under the protection of written agreements that restricted Alnylam’s right to use Tekmira’s confidential information and trade secrets and that strictly prohibited Alnylam from disclosing such information to third parties without first obtaining Tekmira’s consent. Tekmira did not grant Alnylam ownership of its delivery technology; the delivery technology remained Tekmira’s property before, during, and after Tekmira’s collaboration with Alnylam.

2. In a carefully orchestrated series of wrongful acts, Alnylam took advantage of its confidential relationship as a collaborator to gain access to and exploit for its own benefit some of Tekmira’s most valuable and highly confidential technology, for purposes and activities that were not authorized by Tekmira. Alnylam abused its confidential status again and again, improperly using Tekmira’s technology to derive additional formulations for Alnylam’s own benefit. Those purported Alnylam formulations actually contain, are based on, and/or are in whole or in part developed from Tekmira’s technology.

3. Alnylam also improperly used Tekmira’s proprietary delivery technology to apply for Alnylam patents, and disclosed Tekmira’s trade secrets and confidential and proprietary information in public patent applications, claiming as its own the very technology that it stole. Tekmira is informed and believes, and thereupon alleges that, to this day, Alnylam is continuing to prosecute patent filings and is using technology that contains, is based on, or is in whole or in part derived from Tekmira’s technology. Alnylam took these actions without Tekmira’s authorization or consent.

4. Alnylam improperly disclosed Tekmira’s proprietary technology to at least one third party without Tekmira’s consent in connection with a business deal. Tekmira is informed and believes, and thereupon alleges, that in doing so, Alnylam either wrongfully claimed Tekmira’s technology as its own, or falsely represented that it was authorized to disclose Tekmira’s technology to the third party.

5. Tekmira is informed and believes, and thereupon alleges, that Alnylam is improperly using the technology that it stole from Tekmira to compete unfairly against it. Based on information it has received, Tekmira believes and alleges that Alnylam is claiming to the industry as a whole, and to specific current and potential pharmaceutical partners, including at least Novartis and Sanofi-Aventis, that Alnylam has developed novel siRNA delivery formulations and lipids that can be obtained from Alnylam instead of Tekmira. Tekmira is informed and believes, and thereupon alleges, that these purported Alnylam formulations and lipids are actually based on, and in whole or in part developed from Tekmira’s technology, that they do not belong to Alnylam, and that Alnylam has no right to use them or to offer them to current or potential industry partners. Read the rest of this entry »

Citations Frequencies for Tuschl and Bass - not the total answer

On February 28th we published an article assessing the relative importance of the three seminal papers relating to the Tuschl I and Tuschl II inventions based upon citation frequency - referencing by other journal papers - of these papers (see here). In many cases comparing citation frequencies between different papers is like comparing apples to oranges. For example, important methodology papers tend to be referenced many more times than other types of papers presenting basic research that can be conceptually important to an inventive methodology paper.

Comparing the seminal papers for Tuschl I and Tuschl II, on the other hand, is like comparing apples to apples because they are dealing with the very same methodology in the process of discovery of what has become known as “short interfering RNA” or “siRNA” - terms coined by Thomas Tuschl in the seminal Tuschl II papers.

It seems reasonable that differences in citation frequencies of the seminal Tuschl I paper (listed below) and the two seminal Tuschl II papers (also listed below) reflect the relative importance of these papers in disclosing the method of siRNA-mediated gene silencing. Note the high number of times these papers were referenced by other papers (data taken from Google Scholar).

Seminal Tuschl I and Tuschl II papers (these can be found in the left sidebar):

March 31, 2000 (Tuschl I paper) - Zamore, PD; Tuschl, T; Sharp, PA; Bartel, DP Cell 101:25-33. – 1878 citations

Jan. 15, 2001 (Tuschl IIA paper) - Elbashir, S; Lendeckel, W; Tuschl, T Genes & Development 15:188-200 (2001). – 2483 citations

May 26, 2001 (Tuschl IIB paper) - Sayda Elbashir, Winfried Lendeckel, Thomas Tuschl et al., Nature 411:494-498. This second Tuschl II paper described for the first time gene silencing by siRNA in mammalian/human cells. – 6308 citations

Comparing the Tuschl I & II papers to the Brenda Bass’ papers in the same time period is not quite apples to apples because she is not disclosing methodology for siRNA-mediated gene silencing. Read the rest of this entry »

Dr. Brenda Bass’ Story

Case Reassigned to Judge Patti B. Saris as related to CA 09-11116-PBS. Judge Richard G. Stearns no longer assigned to the case.

Links to Brenda Bass’ Univ. of Utah webpage, her April 28th 2000 Review cited in this lawsuit, and Russell J. Barron, Lead Attorney for the Univ. of Utah from Pepper Hamilton LLP have been placed in the “Links” and “Key Papers” sections in the left sidebar.

[from Case 1:11-cv-10484-RGS Document 1 Filed 03/22/11]

The Inventions

28. Dr. Bass conceived the inventions of all of the issued claims of Tuschl II and at least some pending claims of Tuschl I well before any date asserted by the currently named inventors.

29. Dr. Bass reduced her inventions to practice well before any date asserted by the currently named inventors of Tuschl I and II. Dr. Bass, with the assistance of her post-doctoral fellow, Dr. Scott Knight, reduced to practice her conception that the RNAse III enzyme Dicer was the key agent of RNAi, and hence, that the resultant molecule would have, inter alia, a 3’ overhang, by treating multicellular animals with dsRNA corresponding to C. elegans Dicer (K12H4.8) well prior to any date asserted by the currently named inventors of Tuschl I and Tuschl II.

30. Dr. Bass conceived treating mammals, including humans, using dsRNA of 21-23 nucleotides with a 3’ overhang well before any date asserted by the currently named inventors of Tuschl I and Tuschl II.

Chronology

31. As an Assistant Professor at the University Dr. Bass researched and analyzed dsRNA binding proteins. She identified a sequence in these proteins, known as a dsRNA binding motif, and searched various gene databases to identify genes that would produce proteins with this dsRNA binding motif.

32. In the course of her search, Dr. Bass identified the C. elegans gene, K12H4.8, that is now known to produce the RNAse III enzyme colloquially known as “Dicer.” As far back as 1993, Dr. Bass understood that Dicer cleaves longer strands of dsRNA into short dsRNA and makes staggered cuts that leave 3’ overhangs (pronounced “3 prime overhangs”) of about two base pairs—or two nucleotides—in length.

33. She identified this gene well before the RNA interference phenomenon (“RNAi”) was demonstrated, and discovered that it has a dsRNA binding motif, two RNase III domains, and a helicase domain. She was the first to discover that this gene plays a role in dsRNA metabolism. A brief primer on RNAi is contained in a September 1, 2009 Memorandum and Order issued in the Whitehead litigation, beginning on page 3. Read the rest of this entry »

Thomas Tuschl’s Compliment for Brenda Bass

[from Case 1:11-cv-10484-RGS Document 1-9 Filed 03/22/11]

This text is from an email by Thomas Tuschl to Philip Zamore on April 5, 2000, complimenting Brenda Bass for her idea about the role of RNase III in RNA interference … but also stating it was “pretty obvious”. The University of Utah has been mining the exhibits from the settled case for this litigation.

Prof. Brenda Bass’ Thoughts about RNAi and RNase III on March 21, 2000

[from Case 1:11-cv-10484-RGS Document 1-6 Filed 03/22/11]

Nine days before the Tuschl I priority date (March 30, 2000) and eight months before the Tuschl II priority date (December 1, 2000), Brenda Bass (Full Prof., Univ. Utah) was conjuring up the role of RNase III in RNA interference. Here are excerpts of her notes on this subject.
(click to enlarge)

From an April 23, 2010, Article on Brenda Bass’ Supposed Role in the Tuschl II Invention

A curious part of this litigation (just settled) is Whitehead’s interest in Professor Brenda Bass at the University of Utah (see “Clutching at Straws…” also by Dirk) as evidenced by her subpoena last fall (see the subpoena document here).

In Dr. Bass’ review published in April of 2000, she speculates about the role of RNase III in generation of the shorter double-stranded RNAi fragments described in the paper by Zamore et al., published on March 31, 2000 the day after the priority date of Tuschl I (speculation can be damaging prior art). At the April 12 hearing two weeks ago, Christopher Morrison (Whitehead Lead Attorney) made a statement to the effect that the claims of Tuschl II were actually the invention of Dr. Bass. It’s odd that Whitehead wishes to invalidate the Tuschl II invention with prior art from Dr. Bass because this seems contradictory to the defendants’ incorporation of Tuschl II inventive matter into Tuschl I.

Judge Saris stated in the hearing that inventorship should be litigated separately. Nevertheless, the issue of inventorship and the allegations against the defendants may be irrevocably intertwined.

Does Dr. Bass disclose prior art that invalidates Tuschl II?
In her year 2000 review, Dr. Bass suggests that a single enzyme performs cleavage of the dsRNA, strand exchange between the dsRNA and matching mRNA, and cleavage of the mRNA at about 23 nucleotide intervals. Read the rest of this entry »

Brenda Bass & University of Utah Sue the ‘Owners’ of Tuschl I & II

[from Case 1:11-cv-10484-RGS Document 1 Filed 03/22/11]

This lawsuit was filed on March 22, 2011, requesting a jury trial.

Dirk Haussecker’s views on this development.

The University of Utah - Plaintiff
v.
Defendants:
Max-Planck-Institute
Max-Planck-Innovation GmbH
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology
University of Massachusetts
Alnylam Pharmaceuticals

COUNT I
Correction of Inventorship under 35 U.S.C. § 256 on U.S. Patent No. 7,056,704 (Tuschl II) – Against all Defendants (Dr. Bass as Sole Inventor)

COUNT II
In the Alternative:
Correction of Inventorship under 35 U.S.C. § 256 on U.S. Patent No. 7,056,704 – Against all Defendants (Dr. Bass as Joint Inventor)

COUNT III
Correction of Inventorship under 35 U.S.C. § 256 on U.S. Patent No. 7,078,196 (Tuschl II) – Against all Defendants (Dr. Bass as Sole Inventor)

COUNT IV
In the Alternative: Correction of Inventorship under 35 U.S.C. § 256 on U.S. Patent No. 7,078,196 – Against all Defendants (Dr. Bass as Joint Inventor)

COUNT V
Declaratory Judgment Under 28 U.S.C. §§ 2201 and 2202 – Against all Defendants

COUNT VI
Conversion – Against Max Planck and Alnylam

COUNT VII
Replevin – Against Max Planck and Alynylam

COUNT VIII
Unjust Enrichment – Against Max Planck and Alnylam

COUNT IX
Common Law Unfair Competition – Against Max Planck and Alnylam

COUNT X
False Advertising in Violation of Mass. Gen. Laws c. 266, § 91 – Against Max Planck and Alnylam

COUNT XI
Violation of Mass. Gen. Laws c. 93A § 11 – Against Max Planck and Alnylam

MORE TO COME

Benitec Tries to Nail Down Gene Silencing Using DNA-Directed RNAi

From news releases by Benetec, Melbourne Australia: On March 21st Benetec announced initiation of a second US Clinical Study in HIV/AIDS lymphoma patients at City of Hope using it’s using it’s DNA-directed RNA interference technology. From 2007 to 2010, Benitec funded the initial clinical development by the City of Hope of an RNA-based HIV/AIDS therapeutic molecule, one component of which is based on its ddRNAi technology – namely a short hairpin (sh)RNA construct targeted at a specific HIV gene. The ddRNAi-based therapeutic candidate was taken into a Phase I/II pilot human clinical trial and produced promising interim results in terms of safety and proof of feasibility.

Details of this new study

Benitec’s Intellectual Property Position:
•Further to the announcement of 17 February 2011, the re-examination certificate for the Graham ‘099 patent [US Patent No. 6,573,099: “Genetic Constructs for Delaying or Repressing the Expression of a Target Gene”] has now been issued by the US Patent and Trademark Office (USPTO) and received last week by Benitec. This effectively reinstates the patent which had been subject to challenge and provides Benitec with the exclusive US rights to ddRNAi technology for research use and as human therapeutics.
• Substantial progress has been made with the Graham patent applications in Europe, where we have recently been informed that all outstanding objections to the pending claims by the European Patent Office have been overcome. Allowance in Europe will result in allowance of the Graham patent applications in every major Western jurisdiction in which it was being pursued. Read the rest of this entry »

Tekmira Files a Lawsuit Against Alnylam

Tekmira, based in Vancouver, British Columbia, said the suit was filed in Massachusetts Superior Court in response to “misappropriation and misuse of trade secrets, know-how and other confidential information, unfair and deceptive trade practices, unjust enrichment, unfair competition and false advertising.”

Tekmira’s news release and also Alnylam’s response.

This lawsuit which was announced yesterday can be found here. We will follow this.

“The damages that Tekmira will be seeking are substantial,” the company said. “Among these damages, Tekmira believes it has rights to Alnylam’s pipeline products.”

A little history on the Tekmira/Alnylam relationship:

In March of 2007 Alnylam and Inex Pharmaceuticals formed an alliance in which Alnylam took a worldwide exclusive license to Inex’s lipid-based siRNA delivery formulations. This deal with Inex was in exchange for access to Alnylam’s IP for oligonucleotide drugs that act through immune stimulation (not RNAi drugs) as well as the right to develop three RNAi drugs based on Alnylam’s IP. In May of 2007 Inex became Tekmira and later coined the term SNALP (stable nucleic acid lipid particle) for their delivery system. SNALP essentially comprises a nucleic acid encapsulated by cationic and fusogenic lipids, all of which are surrounded by a polyethylene glycol coating. Today SNALP is considered one of the better siRNA delivery vehicles and the three-year partnership between Alnylam and Tekmira appears to be strong. [See Dirk Haussecker’s take on this lawsuit and discussion on the promise of SNALP and future prospects for Tekmira.]. Read the rest of this entry »

Where Visitors to RNAiLitigation Went Next in the Last Day

These numbers are changing all the time depending on the subject matter of each new post. Among the last 500 visitors, these links were clicked to leave our site:

255 Dirk Haussecker’s RNAiTherapeutics
40 Conversation between Thomas Tuschl and Klaus Weber
28 Alnylam’s settlement news release
26 That’Z amore by Dean Martin :-)
18 Alnylam’s stock performance
13 Irell & Manella
10 Tekmira’s Complaint
9 Dirk’s review on the business of RNAi
6 Whitehead attorney Glenn Pfadenhauer
5 Alnylam’s response to Tekmira’s Complaint
4 US07056704B2-Tuschl II patent
4 UMass attorney Donald Ware
4 Judge Patti Saris
4 Tekmira’s News release on the complaint
3 EP01309726-Tuschl I patent
3 Alnylam’s attorney Scott McConchie
3 Alnylam Pharmaceuticals

What is siRNA?
Elbashir etal. (left sidebar): "Double-stranded RNA (dsRNA) induces sequence-specific posttranscriptional gene silencing in many organisms by a process known as RNA interference (RNAi) ... 21- and 22-nt RNA fragments are the sequence-specific mediators of RNAi. The short interfering RNAs (siRNAs) are generated by an RNase III–like processing reaction from long dsRNA. Chemically synthesized siRNA duplexes with overhanging 3' ends mediate efficient target RNA cleavage ..." and "... (these) 21-nucleotide siRNA duplexes specifically suppress expression of endogenous and heterologous genes in different mammalian cell(s)..."
Next Court Date
Don't know ... but I'll be there! I will be wearing a long gray beard, sunglasses, and a black Amish hat.
US District Court in Boston