UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`SPECTRUM SOLUTIONS LLC,
`Petitioner,
`
`v.
`
`DNA GENOTEK INC.
`Patent Owner.
`
`IPR2022-00774
`Patent 10,000,795
`
`DECLARATION OF VINCENT A. FISCHETTI, PH.D., IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT 10,000,795
`
`Spectrum Ex. 1002
`IPR Petition - USP 10,000,795
`
`
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`SPECTRUM SOLUTIONS LLC,
`Petitioner,
`
`v.
`
`DNA GENOTEK INC.
`Patent Owner.
`
`IPR2022-00774
`Patent 10,000,795
`
`DECLARATION OF VINCENT A. FISCHETTI, PH.D., IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT 10,000,795
`
`Spectrum Ex. 1002
`IPR Petition - USP 10,000,795
`
`
`
`TABLE OF CONTENTS
`
`Page No.
`
`I. BACKGROUND, QUALIFICATIONS, AND PREVIOUS
`TESTIMONY ........................................................................................... 1
`
`A.
`
`B.
`
`Experience and Qualifications ....................................................... 1
`
`Previous Testimony ........................................................................ 3
`
`II. MATERIALS CONSIDERED ....................................................................... 4
`
`III. LEGAL STANDARDS ................................................................................ 4
`
`A.
`
`B.
`
`Prior Art Dates ................................................................................ 4
`
`Obviousness .................................................................................... 4
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART .............................. 7
`
`V. THE ’795 PATENT ....................................................................................... 7
`
`VI. GROUND 1: BIRNBOIM AND STEFAN RENDER OBVIOUS
`CLAIMS 1-3, 5-18 .................................................................................... 8
`
`A.
`
`Introduction to Birnboim ................................................................ 8
`
`1.
`
`2.
`
`3.
`
`Nucleic Acid Preservation at Room Temperature ............... 9
`
`A Composition Having an Anionic Detergent and
`Buffering Agent ................................................................. 10
`
`Heating the Mixture ........................................................... 12
`
`4. Working Examples ............................................................. 12
`
`B.
`
`Introduction to Stefan ................................................................... 13
`
`-i-
`
`
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`C.
`
`Claim 1 Would Have Been Obvious Over Birnboim in
`View of Stefan .............................................................................. 15
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Claim 1 Preamble ............................................................... 15
`
`Limitation 1.a: Obtaining the Sample from a Subject ....... 16
`
`Limitation 1.b: Contacting the Sample with a
`Composition of 1%-8% Anionic Detergent, Buffering
`Agent at pH 5-8.2 ............................................................... 19
`
`Limitation 1.c: Storing the Mixture at Room
`Temperature ....................................................................... 21
`
`Limitation 1.d: Heating the Mixture to Greater than
`or about Equal to 50° C ...................................................... 21
`
`6. Wherein the Composition Stabilizes the Ribonucleic
`Acid at Room Temperature ................................................ 23
`
`7.
`
`A POSA Would Have Been Motivated to Combine
`Birnboim and Stefan with a Reasonable Expectation
`of Success ........................................................................... 24
`
`D.
`
`E.
`
`F.
`
`G.
`
`Claims 2 and 3 Would Have Been Obvious Over Birnboim
`in View of Stefan .......................................................................... 26
`
`Claims 5 and 6 Would Have Been Obvious Over Birnboim
`in View of Stefan .......................................................................... 28
`
`Claims 7 and 16-18 Would Have Been Obvious Over
`Birnboim in View of Stefan ......................................................... 30
`
`Claims 8 and 9 Would Have Been Obvious Over Birnboim
`in View of Stefan .......................................................................... 32
`
`-ii-
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`
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`H.
`
`I.
`
`J.
`
`Claim 10 Would Have Been Obvious Over Birnboim in
`View of Stefan .............................................................................. 33
`
`Claims 11-13 Would Have Been Obvious Over Birnboim in
`View of Stefan .............................................................................. 34
`
`Claims 14 and 15 Would Have Been Obvious Over
`Birnboim in View of Stefan ......................................................... 35
`
`VII. GROUND 2: BIRNBOIM, STEFAN, AND TUGGLE RENDER
`OBVIOUS CLAIM 4 .............................................................................. 37
`
`VIII. GROUND 3: BIRNBOIM, STEFAN, AND HEATH RENDER
`OBVIOUS CLAIM 10 ............................................................................ 38
`
`IX. CONCLUSION ........................................................................................... 40
`
`
`
`
`
`
`-iii-
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`
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`I, Vincent A. Fischetti, Ph.D., declare and state as follows:
`
`1.
`
`I have been retained by Knobbe, Martens, Olson & Bear, LLP, counsel
`
`for Spectrum Solutions (“Spectrum”). I understand that Spectrum is petitioning for
`
`inter partes review of U.S. Patent No. 10,000,795 (the “’795 patent,” Ex. 1001) and
`
`requests that the United States Patent and Trademark Office (“USPTO”) cancel
`
`claims 1-18 of the ’795 patent as unpatentable. The following discussion and
`
`analysis provide my opinion as to why I believe claims 1-18 of the ’795 patent would
`
`have been obvious to a person of ordinary skill in the art (“POSA”) as of October
`
`2006.
`
`I. BACKGROUND, QUALIFICATIONS, AND PREVIOUS TESTIMONY
`A. Experience and Qualifications
`
`2. My experience and qualifications are summarized in my curriculum
`
`vitae, a copy of which is provided as Exhibit 1026.
`
`3.
`
`I am a professor at the Rockefeller University, where I am head of the
`
`Laboratory of Bacterial Pathogenesis and Immunology. I received my B.S. in
`
`bacteriology from Wagner College in 1962 and my M.S. in microbiology from Long
`
`Island University in 1967. I received my Ph.D. in microbiology from New York
`
`University in 1970. I served as a post-doctoral fellow at the Rockefeller University
`
`from 1970 to 1972 and at the Albert Einstein College of Medicine from 1972 to
`
`1973.
`
`1
`
`
`
`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`4.
`
`I became an assistant professor at the Rockefeller University in 1973,
`
`an associate professor in 1978, and a professor in 1990. I am a faculty member in
`
`the David Rockefeller Graduate Program and the Tri-Institutional M.D.-Ph.D.
`
`Program. My major field of expertise is in bacterial pathogenesis, particularly
`
`Streptococcus, Staphylococcus, Bacillus, Pseudomonas, and Acinetobacter to name
`
`a few. Most of my studies deal with human diseases caused by bacterial infections.
`
`I study the mechanism by which these infections occur and devise ways to prevent
`
`or treat these infections.
`
`5.
`
`I am a member of the American Society for Microbiology, the
`
`American Academy for Microbiology, and the National Academy of Inventors. I
`
`currently serve as an Advisory Editor for Trends in Microbiology and the Journal of
`
`Experimental Medicine. I previously served on the editorial board of numerous
`
`publications, including the Journal of Immunology and Infection and Immunity.
`
`Also, from 1989-1999, I served as the Editor-in-Chief of the journal Infection and
`
`Immunity.
`
`6.
`
`I have given more than 150 invited lectures at national and international
`
`conferences, major research institutes, and universities in numerous countries in the
`
`areas of biochemistry, immunology, bacterial pathogenesis, molecular diagnostics
`
`and vaccine development.
`
`2
`
`
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
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`7.
`
`I have authored over 250 original scientific articles and over 90 book
`
`chapters, as well as having co-authored two hard copy textbooks and one electronic
`
`textbook on bacterial pathogenesis. These publications have been in the general
`
`areas of microbiology, immunology, bacterial pathogenesis, molecular diagnostics,
`
`and vaccine development. My work related to a novel anthrax anti-infective was
`
`featured as the cover story on the journal Nature in 2002. I am also an inventor on
`
`numerous U.S. and foreign patents in the areas of streptococcal vaccine
`
`development, bacteriophage
`
`lysins and
`
`lytic enzymes, and methods and
`
`compositions for isolation of cellular components.
`
`8.
`
`Over the course of my career, I frequently used the classes of reagents
`
`cited in the ’795 patent, including detergents and buffers, and other mentioned
`
`reagents. For example, in my work related to analysis of infectious diseases, I
`
`regularly use detergents and buffers to extract and isolate proteins and nucleic acids
`
`from pathogens, including from viruses and bacteria. I have used these reagents in
`
`my work since at least the 1970s.
`
`B.
`
`Previous Testimony
`
`9.
`
`In the past 4 years I testified as an expert witness by deposition in the
`
`following cases:
`
`Camacho v. Norton, Case No. 12-CI-05874 (Kentucky).
`
`Muir v. McLaren Medical Group, et al., Case No. 19-2571-NH (Michigan).
`
`3
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
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`II. MATERIALS CONSIDERED
`
`10. Attached as Exhibit 1027 is a list of documents and materials I have
`
`considered and reviewed in connection with providing this declaration.
`
`III. LEGAL STANDARDS
`
`11.
`
`I am not an attorney. I have not independently researched the law on
`
`patentability. Therefore, the attorneys from Knobbe, Martens, Olson & Bear, LLP
`
`have provided me with guidance as to the applicable patent law in this matter. The
`
`paragraphs below express my understanding of how I must apply current principles
`
`related to patent validity to my analysis.
`
`A.
`
`Prior Art Dates
`
`12.
`
`I understand that a publication qualifies as prior art if it was published
`
`more than one year before the filing date of a patent application.
`
`13.
`
` I understand that the relevant date for determining whether a reference
`
`is prior art may not be the actual filing date of a patent application. I understand that
`
`a patent may be entitled to an earlier effective filing date if the claimed subject matter
`
`was previously described in an earlier patent application. I understand this is
`
`sometimes called a “priority” date of the claimed invention.
`
`B. Obviousness
`
`14.
`
`It is my understanding that a claim is “obvious,” and therefore
`
`unpatentable, if the claimed subject matter as a whole would have been obvious to a
`
`4
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`
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`person of ordinary skill in the art at the time of the alleged invention. I also
`
`understand that an obviousness analysis takes into account the scope and content of
`
`the prior art, the differences between the claimed subject matter and the prior art,
`
`and the level of ordinary skill in the art at the time of the invention.
`
`15.
`
`In determining the scope and content of the prior art, it is my
`
`understanding that a reference is considered appropriate prior art if it falls within the
`
`field of the inventor’s endeavor. In addition, a reference is prior art if it is reasonably
`
`pertinent to the particular problem with which the inventor was involved. A
`
`reference is reasonably pertinent if it logically would have commended itself to an
`
`inventor’s attention in considering his problem. If a reference relates to the same
`
`problem as the claimed invention, that supports use of the reference as prior art in
`
`an obviousness analysis.
`
`16. To assess the differences between prior art and the claimed subject
`
`matter, it is my understanding that the law requires the claimed invention to be
`
`considered as a whole. This “as a whole” assessment requires showing that one of
`
`ordinary skill in the art at the time of invention, confronted by the same problems as
`
`the inventor and with no knowledge of the claimed invention, would have selected
`
`the elements from the prior art and combined them in the claimed manner.
`
`17.
`
`It is my further understanding that the law recognizes several rationales
`
`for combining references or modifying a reference to show obviousness of claimed
`
`5
`
`
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`subject matter. Some of these rationales include: combining prior art elements
`
`according to known methods to yield predictable results; simple substitution of one
`
`known element for another to obtain predictable results; a predictable use of prior
`
`art elements according to their established functions; applying a known technique to
`
`a known method or product ready for improvement to yield predictable results;
`
`choosing from a finite number of identified, predictable solutions, with a reasonable
`
`expectation of success; and some teaching, suggestion, or motivation in the prior art
`
`that would have led one of ordinary skill to modify the prior art reference or to
`
`combine prior art reference teachings to arrive at the claimed invention.
`
`18.
`
`I also understand that an obviousness analysis must consider whether
`
`there are additional factors that would indicate that the invention would not have
`
`been obvious. These factors include whether there was: (i) a long-felt need in the
`
`industry; (ii) any unexpected results; (iii) skepticism of the invention; (iv) a teaching
`
`away from the invention; (v) commercial success; (vi) praise by others for the
`
`invention; and (vii) copying by other companies. I also understand that there must
`
`be a nexus between any such factor and the claimed invention. I am not aware of
`
`any evidence that would suggest that the claims of the ’795 patent would have been
`
`non-obvious.
`
`6
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART
`
`19.
`
`I understand that obviousness is analyzed from the perspective of a
`
`hypothetical person of ordinary skill in the art (“POSA”). I have conducted my
`
`analysis herein from the perspective of a POSA using October 1, 2006 as the relevant
`
`time frame.
`
`20. A POSA of the ’795 patent would have had (1) a Ph.D. in microbiology,
`
`molecular biology, biochemistry, or a related disciple; (2) at least two years of post-
`
`graduate experience in the area of nucleic acid extraction, preservation, and analysis;
`
`and (3) experience with the development or use of nucleic acid extraction
`
`formulations, and the literature concerning nucleic acid extraction, preservation, and
`
`analysis.
`
`V. THE ’795 PATENT
`
`21. The ’795 patent (Ex. 1001) is directed to a method for preserving RNA
`
`at room temperature. Ex. 1001, Abstract.
`
`22. Claim 1 of the ’795 patent reads:
`
`1. A phenol-free method for preserving ribonucleic acid from a
`
`biological sample comprising the steps of:
`
`a. obtaining the sample from a subject;
`
`b. contacting the sample with a composition comprising an
`
`anionic detergent, wherein the anionic detergent is at a concentration of
`
`7
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`
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
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`1% to 8%, and a buffering agent at a pH of about 5 to about 8.2 to form
`
`a mixture;
`
`c. storing the mixture at room temperature; and
`
`d. heating the mixture, wherein the mixture is heated at a
`
`temperature of greater than or about equal to 50° C., wherein the
`
`composition stabilizes the ribonucleic acid at room temperature.
`
`23. The dependent claims add limitations that merely identify one
`
`additional reagent (a protease), recite well-known species of detergents and
`
`buffering agents, recite varied sources of the biological sample, and narrow the pH
`
`range. The method claims of the ’795 patent involve performing simple steps using
`
`well-known reagents to preserve RNA. As I explain below, the claims of the ’795
`
`patent would have been obvious to a POSA as of October 6, 2006, the earliest
`
`possible priority date of the ’795 patent.
`
`VI. GROUND 1: BIRNBOIM AND STEFAN RENDER OBVIOUS
`CLAIMS 1-3, 5-18
`
`A.
`
`Introduction to Birnboim
`
`24. PCT Publication No. WO03/104251 (“Birnboim”) (Ex. 1003) was
`
`published on December 18, 2003. I understand that the earliest possible priority of
`
`the ’795 patent is October 6, 2006. Thus, I understand that Birnboim is prior art to
`
`the ’795 patent. I have been informed by counsel that Genotek pursued patent
`
`applications similar to the ’795 patent in other countries. I understand from counsel
`8
`
`
`
`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`that in some of these countries, the foreign patent office relied on Birnboim as prior
`
`art to reject the pending claims. I have also been informed that Genotek argued
`
`during prosecution of these foreign counterpart applications that Birnboim is not
`
`enabled for RNA preservation, i.e., it did not provide sufficient information for a
`
`POSA to preserve RNA in a biological sample. For this declaration, I have not been
`
`asked to opine on the question of whether Birnboim is enabled for RNA
`
`preservation. It is my understanding that when a reference, such as Birnboim, is
`
`used as prior art, the reference is presumed enabling for all that it teaches. And I
`
`further understand that it would be the patent holder’s (in this case, Genotek’s)
`
`burden to overcome this presumption and establish that the prior art reference is not
`
`enabling. Further, I am providing my analysis below from the perspective of a
`
`POSA in 2006 (the earliest possible priority date of the ’795 patent) based
`
`Birnboim’s 2003 disclosure, and I have supplemented that analysis with the 2003
`
`teachings of Stefan. In that regard, my opinions below do not depend on whether
`
`Birnboim was enabled for RNA preservation at the time of its earliest filing date in
`
`2002.
`
`1.
`
`Nucleic Acid Preservation at Room Temperature
`
`25. Birnboim discloses that “[t]he present invention relates to compositions
`
`and methods for preserving nucleic acids at room temperature for extended periods
`
`of time and for simplifying the isolation of nucleic acids.” Ex. 1003, 1:5-7.
`
`9
`
`
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`Birnboim discloses obtaining a sample from a subject and contacting it with a
`
`disclosed composition, as recited in claim 1 of the ’795 patent. Id., 18:25-29.
`
`Birnboim discloses that the compositions, when mixed with a sample containing
`
`nucleic acids, “preserves the nucleic acids at room temperature under ambient
`
`conditions for extended periods of time. There is no requirement for freezing of the
`
`samples before nucleic acid recovery and purification.” Id., 5:2-5.
`
`26. Birnboim discloses that “[t]he nucleic acid to be preserved by the
`
`composition can be DNA or RNA, including mRNA or viral RNA.” Id., 6:22-23;
`
`see also id., 8:29-30 (“In yet another embodiment, the nucleic acid is DNA or RNA.
`
`If the nucleic acid is RNA, desirably it is mRNA or viral RNA.”), 11:12-14 (defining
`
`“nucleic acid” as “a chain of the nucleotides, including deoxyribonucleic acid
`
`(DNA) or ribonucleic acid (RNA), typically found in chromosomes, mitochodria
`
`[sic], ribosomes, bacteria, or viruses.”). I note that the claims in the published
`
`Birnboim PCT application also recite methods and compositions for preserving
`
`nucleic acids, including dependent claims directed to RNA preservation specifically.
`
`Id., claims 4, 6, 7, 30-32, 50-52, 61, 63, and 64.
`
`2.
`
`A Composition Having an Anionic Detergent and Buffering Agent
`
`27. As I explain below, Birnboim discloses a composition that comprises
`
`an anionic detergent at a concentration of 1% and a buffering agent having a pH in
`
`10
`
`
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`the range of 5-7, and both values are within the ranges recited in claim 1 of the ’795
`
`patent.
`
`28. Birnboim states that the compositions disclosed therein “provide the
`
`advantageous properties of chemical stabilization of nucleic acids and the inhibition
`
`of nucleases….” Id., 14:3-5. Birnboim discloses that the compositions contain
`
`denaturing agents, reducing agents, chelating agents, and buffers to achieve these
`
`advantageous properties. Id., 14:6-15. The denaturing agents are used to lyse cells,
`
`denature proteins, and inactivate nucleases. Id., 21:3-6, 15:28-16:7. Birnboim
`
`discloses specific denaturing agents, including detergents such as “soluble salts of
`
`dodecyl sulfate and other strong detergents.” Id., 16:1-3. In one embodiment,
`
`Birnboim discloses that its composition includes sodium dodecyl sulfate (SDS) as
`
`an anionic detergent at a concentration of 1%, which is within the concentration
`
`range recited by claim 1. Id., 27:25-28:4 (Example 7, Table 3).
`
`29. Birnboim also discloses that buffers are used to stabilize nucleic acids
`
`in the sample by “maintain[ing] an appropriate pH.” Id., 14:6-9. Birnboim discloses
`
`that “RNA is most stable in the pH range of 5.0 to 7.0, desirably a pH of from 6.5 to
`
`6.8” and explains that “the pH of the composition may be adjusted using pH buffers”
`
`including TRIS hydrochloride, HEPES and BES. Id., 14:29-15:3; id., 6:30-7:2 (“For
`
`the preservation of RNA, a pH from about 5.0 to about 7.0, desirably from about 6.5
`
`11
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`to about 6.8 can be used. Again, a buffer, such as BES, can be used to maintain the
`
`pH in a constant range.”).
`
`3. Heating the Mixture
`
`30. Birnboim discloses that heating the composition/sample mixture may
`
`assist the protease digestion of undesired proteins (i.e., nuclease enzymes) in the
`
`mixture. Id., 21:3-12. For example, Birnboim discloses that “incubation at 55 C.
`
`for 4 to 16 hours is sufficient to allow the activated protease to digest the majority
`
`of protein to small peptides or amino acids.” Id., 21:9-11. Birnboim also discloses
`
`examples where the mixture is heated to 50° C and 70° C for a specified incubation
`
`period. Id., 28:1-4 (Table 3, lanes 1-3).
`
`4. Working Examples
`
`31. Birnboim includes several working examples that demonstrate that
`
`Birnboim’s methods preserve nucleic acids in samples for extended periods of time
`
`at room temperature. Id., 26:1-29:18. In Example 3, Birnboim discloses a specific
`
`“nucleic acid-preserving composition” that includes, among other reagents, an
`
`anionic detergent and a buffering agent, just as claim 1 of the ’795 patent recites.
`
`Id., 26:1-9. In Examples 4-6, Birnboim describes using the composition of Example
`
`3 to successfully preserve and stabilize the DNA in saliva samples at room
`
`temperature for up to 62 days. Id., 26:11-27:23. Also, Birnboim discloses in
`
`Example 7 that five additional samples were contacted with a preservation
`
`12
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`
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`composition and incubated at various temperatures (50° C and 70° C) for various
`
`durations. Id., 27:25-28:4. The preservation compositions in lanes 1-3 in Example
`
`7 include sodium dodecyl sulfate (SDS) at a concentration of 1%. Id. Although the
`
`pH of these compositions is 9.5 in order to preserve DNA, Birnboim separately
`
`discloses using a pH in the range of 5-7. Id., 6:30-7:2, 14:29-15:3.
`
`B.
`
`Introduction to Stefan
`
`32. Stefan is a German patent publication that published as an issued
`
`German patent on October 30, 2003. I understand that Stefan is prior art to the ’795
`
`patent. Stefan discloses “a method for stabilising ribonucleic acids,” and Stefan
`
`discloses that the “ribonucleic acid is stabilised for many hours to days” at room
`
`temperature. Ex. 1005 at 1, ¶¶[0018]-[0024].
`
`33. Recognizing the value of preserving RNA, Stefan notes that
`
`“[r]ibonucleic acids have a high level of information content and are more often the
`
`subject of molecular biological diagnostics.” Id., ¶[0002]. Stefan understood that,
`
`compared to DNA, “RNA is much more unstable and therefore more difficult to
`
`handle.” Id. Like the ’795 patent, Stefan recognized that the difficulty in preserving
`
`RNA stems, at least in part, from the ubiquitous presence of enzymes known as
`
`ribonucleases, or RNases, in biological samples: “The RNA degradation by
`
`ubiquitous RNases before, during and after the isolation of RNA is a major problem,
`
`13
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
`
`since the integrity of the RNA is a prerequisite for molecular biological diagnostics.”
`
`Id., ¶[0003]; see Ex. 1001, 1:46-53, 2:46-49, 6:23-26.
`
`34. Stefan explains that rapid RNA degradation within hours of collection
`
`“greatly restricts the possibilities for sample transport” following sample collection.
`
`Ex. 1005, ¶[0004]. And Stefan notes that relying on degraded RNA fragments for
`
`molecular diagnostics “can lead to false negative results because the reduced number
`
`of transcripts in vitro due to degradation does not correlate with the number of
`
`transcripts in vivo.” Id. Thus, Stefan understood in 2002 that, for RNA preservation,
`
`it was important to inhibit degradation caused by endogenous and exogenous
`
`RNases. Id., ¶[0005] (“For the integrity of the RNA, the inhibition of endogenous
`
`RNases during the cell lysis and the avoidance of contamination with exogenous
`
`RNases during the RNA isolation are essential.”)
`
`35. Stefan’s objective was to “provide an improved stabilisation method
`
`for ribonucleic acids.” Id., ¶[0008]. Stefan achieved this objective using a
`
`stabilizing solution containing lithium dodecyl sulfate (LDS), an anionic detergent,
`
`in an amount of 0.1% to 5% (weight/volume), along with other reagents in the
`
`composition, including Tris-HCl, a buffering agent, at a pH of 6.5-8.5. Id., ¶¶[0009],
`
`[0011], claims 6-8 and 11-13.
`
`36. Stefan includes a working example that demonstrates the “RNA-
`
`stabilising buffer” successfully preserves RNA in a sample for an extended period
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`14
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
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`at room temperature. Id., ¶¶[0018]-[0024]. The composition that Stefan used in this
`
`example includes lithium dodecyl sulfate as the anionic detergent at a concentration
`
`of 2% (weight/volume) and Tris-HCl as the buffering agent at a pH of 7.5. Id.,
`
`¶[0018]. Stefan analyzed the RNA preserved in the sample-composition mixture
`
`after incubation periods of 0, 3, 24, and 48 hours. Id., ¶¶[0018], [0023]. Stefan
`
`analyzed the RNA in the mixture via cDNA synthesis and PCR amplification which
`
`was visualized using an Agilent 2100 Bioanalyzer. Id., ¶¶[0018]-[0023]. Stefan
`
`concluded that “the stabilising solution has the effect that the RNA in the stabilising
`
`solution is not degraded or is extremely slowly degraded over at least 1 day and, if
`
`the RNA concentration is appropriate, for 2 days.” Id., ¶[0024].
`
`C. Claim 1 Would Have Been Obvious Over Birnboim in View of Stefan
`
`37. As I explain below, Birnboim discloses each limitation of claim 1 of
`
`the ’795 patent, and Stefan provides a specific working example demonstrating
`
`success in preserving RNA at room temperature. Also, as I explain below, a POSA
`
`would have had a motivation to combine the references with a reasonable
`
`expectation of success.
`
`1.
`
`Claim 1 Preamble
`
`38. The preamble of claim 1 recites: “[a] phenol-free method for preserving
`
`ribonucleic acid from a biological sample . . . .” If the preamble of claim 1 is
`
`considered a limitation of the claim, it is my opinion that Birnboim and Stefan each
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`15
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
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`disclose a phenol-free method for preserving RNA from a biological sample. Phenol
`
`is not required in Birnboim’s compositions and is not used in the working examples.
`
`Ex. 1003, 26:1-27:4; see also id. 5:26-28, 21:30-22:3 (disclosing, but not requiring,
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`phenol). Stefan’s disclosed methods do not use phenol to preserve RNA. Ex. 1005,
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`¶¶[0018]-[0023] (showing Stefan’s “RNA-stabilising buffer” does not include
`
`phenol, nor is phenol used in subsequent processing).
`
`39. Additionally, both Birnboim and Stefan disclose methods for
`
`preserving RNA from a biological sample, as recited in the preamble. Specifically,
`
`Birnboim discloses “collecting, preserving, and recovering nucleic acids” from a
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`sample using the disclosed preservation composition. Ex. 1003, 18:18-19. And
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`Birnboim discloses that “[t]he nucleic acid to be preserved by the composition can
`
`be DNA or RNA, including mRNA or viral RNA” from samples. Id., 6:22-23.
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`Stefan discloses “a method for stabilising ribonucleic acids.” Ex. 1005, ¶[0001].
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`Furthermore, as I explain below, the combination of Birnboim and Stefan discloses
`
`each step that forms the method recited in claim 1, thus fulfilling the preamble.
`
`2.
`
`Limitation 1.a: Obtaining the Sample from a Subject
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`40. Claim 1 recites “a. obtaining the [biological] sample from a subject.”
`
`The ’795 patent discusses saliva as a biological sample, but also indicates that,
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`“while saliva is one source of RNA, other bodily fluids, including blood, and bodily
`
`tissues, can be used.” Ex. 1001, 9:38-40; see also id., 9:40-43 (“The present
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`16
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
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`invention is not intended to be limited to the collection and storage of RNA obtained
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`from sputum, saliva, nasal, anterior nasal and/or nasopharyngeal samples.”).
`
`41. Birnboim discloses the steps of obtaining a biological sample, for
`
`example saliva, from a subject and contacting it with the composition disclosed
`
`therein to preserve the nucleic acids: “A third aspect of the invention features a
`
`method of preserving a nucleic acid contained in sputum that includes the steps of
`
`obtaining sputum from a subject, and contacting the sputum with a composition of
`
`the invention, thus preserving the nucleic acid.” Ex. 1003, 8:13-16.1 Like the ’795
`
`patent, Birnboim focuses much of its disclosure on sputum as the biological sample,
`
`but additionally discloses that the biological sample can be “any sample containing
`
`nucleic acids that has been obtained from or deposited by an animal,” Ex. 1003,
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`11:1-3, and indicates that non-limiting examples include bodily fluids such as
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`“saliva, serum, plasma, blood, urine, mucus, . . . .” Id., 10:27-29.
`
`42. Stefan also discloses obtaining a biological sample from a subject.
`
`Stefan discloses that its method applies broadly to biological samples containing
`
`RNA. For example, in claim 10, Stefan recites “A method for stabilisation of RNA
`
`in a sample, in biological samples, samples containing animal and/or human cells
`
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`1 In this declaration, I have included the bold and/or italics emphasis to quotations
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`unless indicated otherwise.
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`17
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v. DNA Genotek
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`and/or in blood samples. . . .” Ex. 1005, 6. Similarly, Stefan’s claim 2 recites that
`
`the RNA stabilization solution is used “for stabilisation of RNA in a biological
`
`sample,” and claim 4 indicates the composition is used in “stabilisation of RNA in
`
`a cell disruption of animal or human cells.” Id., 5-6. Stefan also includes claims
`
`that are specific to using blood as the biological sample in claims 5 and 21. Id., 6,
`
`7.
`
`43. Furthermore, the working example in Stefan involves obtaining a blood
`
`sample “from a healthy control person.” Id., ¶[0017]. Stefan describes doping four
`
`separate aliquots of the blood sample with a defined number of tumour cells (0, 10,
`
`100, and 1000). Ex. 1005, ¶[0017]. The samples were then processed to remove
`
`“non-binding blood components,” followed by mixing the samples with the “RNA-
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`stabilising buffer.” Id., ¶¶[0017]-[0018]. It is my opinion that the activity described
`
`in Stefan reflects common laboratory techniques at the time for simulating tumour-
`
`containing samples that can be used for nucleic acid analysis. I note that the ’795
`
`patent describes a similar process, where saliva samples were “spiked” with
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`Vesicular Stomatitis Virus (VSV) to test for preservation of viral RNA after a period
`
`of incubation. Ex. 1001, 23:47-53. In addition, Stefan indicates the method for RNA
`
`preservation applies broadly to other biological samples containing RNA. For
`
`example, Stefan’s claim 10 recites “A method for stabilisation of RNA in a sample,
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`in biological samples, samples containing animal and/or human cells and/or in blood
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`18
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`IPR Petition – Patent 10,000,795
`Spectrum Solutions v.
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