Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 1 of 19 PageID #: 20894
`
`IN THE UNITED STATES DISTRICT COURT
`FOR DISTRICT OF DELAWARE
`
`IMPOSSIBLE FOODS INC.,
`
`Plaintiff,
`
` v.
`
`MOTIF FOODWORKS, INC. and
`GINKGO BIOWORKS, INC.,
`
`Defendants.
`
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`
`C.A. No. 22-311 (WCB)
`
`DECLARATION OF HAL ALPER, PH.D.
`
`OF COUNSEL:
`
`Wendy L. Devine
`Kristina M. Hanson
`Shannon P. Gillespie McComb
`Jessica Ramsey
`Susannah M. L. Gagnon
`Joyce K. Yao
`WILSON SONSINI GOODRICH & ROSATI, P.C.
`One Market Plaza
`Spear Tower, Suite 3300
`San Francisco, CA 94105
`Tel: (415) 947-2000
`
`Matthew R. Reed
`WILSON SONSINI GOODRICH & ROSATI, P.C.
`650 Page Mill Road
`Palo Alto, CA 94304
`Tel: (650) 493-9300
`
`Lori P. Westin
`Natalie J. Morgan
`WILSON SONSINI GOODRICH & ROSATI, P.C.
`12235 El Camino Real
`San Diego, CA 92130
`Tel: (858) 350-2300
`
`Dated: January 26, 2024
`11292171 / 20200.00002
`
`David E. Moore (#3983)
`Bindu A. Palapura (#5370)
`Andrew M. Moshos (#6685)
`POTTER ANDERSON & CORROON LLP
`Hercules Plaza, 6th Floor
`1313 N. Market Street
`Wilmington, DE 19801
`Tel: (302) 984-6000
`dmoore@potteranderson.com
`bpalapura@potteranderson.com
`amoshos@potteranderson.com
`
`Attorneys for Plaintiff Impossible Foods Inc.
`
`OF COUNSEL:
`
`Michael T. Rosato
`WILSON SONSINI GOODRICH & ROSATI, P.C.
`701 Fifth Avenue
`Suite 5100
`Seattle, WA 98104
`Tel: (206) 883-2529
`
`

`

`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 2 of 19 PageID #: 20895
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`Introduction and Background ............................................................................................. 1
`
`Prior Declarations ............................................................................................................... 2
`
`Person of ordinary skill in the art ........................................................................................ 2
`
`Background in the Art ......................................................................................................... 2
`
`Response to Dr. Batt’s analysis of the Disputed Claim Terms ........................................... 6
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Term 1—“Promoter Element” ................................................................................ 6
`
`Term 2—“a Mxr1 transcriptional activator sequence” / “a methanol expression
`regulator 1 (Mxr1) transcriptional activator” / “a Mxr1 transcriptional activator
`sequence” .............................................................................................................. 11
`
`Term 6—“sequence to which [the/a] Mxr1 transcriptional activator binds” ........ 13
`
`Term 8—“wherein the [methanol-inducible] promoter element” / “wherein the [at
`least one] methanol-inducible promoter element” ................................................ 16
`
`Term 3—“From P. pastoris” ................................................................................ 16
`
`VI.
`
`Conclusion ........................................................................................................................ 17
`
`i
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`

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`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 3 of 19 PageID #: 20896
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`I.
`
`INTRODUCTION AND BACKGROUND
`
`1.
`
`I, Hal Alper, Ph.D., submit this declaration in support of plaintiff Impossible
`
`Foods Inc.’s (“Impossible”) Claim Construction Brief. I offer this declaration as an expert in the
`
`fields of genetic engineering, synthetic promoter design, yeast engineering, and synthetic
`
`biotechnology. My qualifications and experience in these areas among others are set out in my
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`June 14, 2023 Declaration (D.I. 107) and my curriculum vitae (D.I. 107-1, Ex. A).
`
`2.
`
`As my prior declarations indicate, counsel for Impossible asked for my opinion on
`
`the disputed terms of the Yeast Patents (U.S. Patent Nos. 10,273,492 and 10,689,656) below
`
`based on the understanding of a person of ordinary skill in the art (“POSA”) as of the May 11,
`
`2015 priority date of the Yeast Patents. D.I. 107, ¶¶ 2, 20-21; D.I. 144, ¶ 2.
`
`3.
`
`Impossible has also asked me to offer my opinions on the meaning of the terms
`
`below. I have included the terms and parties’ positions for ease of reference in my discussion
`
`below.
`
`4.
`
`I have formed my opinions using my education, knowledge, and experience
`
`together with my review of the materials cited in this declaration as well as my prior two
`
`declarations. In my analysis throughout this declaration, I have followed the same legal
`
`principles set out in my initial declaration.
`
`5.
`
`I have based my opinions in this declaration on the information and evidence
`
`currently available to me. I reserve the right to change, amend, and supplement my opinions in
`
`response to any new information or evidence made available to me; additional scientific analysis
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`that leads me to conclude that supplementation is necessary; new issues that may arise; and any
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`additional discovery, arguments, evidence, or testimony presented in this case, including any
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`evidence or testimony presented prior to or during trial. I reserve the right to testify with regard
`
`to my qualifications, experience, and the materials I have reviewed.
`
`

`

`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 4 of 19 PageID #: 20897
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`6.
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`I have not provided either trial or deposition testimony in any cases in the past
`
`four years.
`
`7.
`
`I have no financial interest in the outcome of this case. I am being compensated
`
`at my standard consulting rate, which is $950 per hour. My compensation is not related in any
`
`way to the outcome of this lawsuit.
`
`II.
`
`PRIOR DECLARATIONS
`
`8.
`
`I incorporate here my two prior declarations regarding these claim terms in the
`
`Yeast Patents. The first is dated June 14, 2023, and the second is dated July 7, 2023. D.I. 107,
`
`144.
`
`III.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`9.
`
`I stated in my prior declarations that it is my view that a POSA would have a
`
`graduate degree in chemical engineering, biochemistry, microbiology, or a similar discipline,
`
`along with 2 years of experience with recombinant protein expression systems. D.I. 107, ¶ 23.
`
`10.
`
`Dr. Batt opines that a POSA would have a bachelor’s degree in biochemistry,
`
`chemistry, biological sciences, or an equivalent area and at least 3 years of graduate study or
`
`professional experience using recombinant DNA techniques for protein production or general
`
`genetic modification experience. D.I. 334, ¶ 52.
`
`IV.
`
`BACKGROUND IN THE ART
`
`11.
`
`I discussed relevant background for the yeast patents in my prior declarations.
`
`D.I. 107, ¶¶ 27-30. I supplement that here with an effort not to repeat what I have already
`
`discussed.
`
`12.
`
`The Yeast Patents are directed to an invention for production of recombinant
`
`proteins (e.g., heme-containing proteins) in methylotrophic yeast (e.g., Pichia pastoris). Given
`
`the nature of the invention, a POSA would have been knowledgeable of the structural
`
`2
`
`

`

`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 5 of 19 PageID #: 20898
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`components of recombinant protein expression systems. In his declaration, Dr. Batt summarizes
`
`what was known in this regard prior to the priority date of the Yeast Patents. As I discuss
`
`below, I largely agree with his assessment of the state of the art.
`
`13.
`
`Dr. Batt opines regarding the flow of information from DNA to messenger
`
`ribonucleic acid (mRNA) through a process called “transcription” that is carried out by the
`
`enzyme RNA polymerase. D.I. 334, ¶ 37. The mRNA is then “translated” into an amino acid
`
`sequence to yield a protein. Dr. Batt explains that “genes” present in DNA “encode” proteins. I
`
`agree. Id. Skilled artisans often referred to this process as protein expression. A POSA would
`
`have further understood that promoters are adjacent to the gene or in close physical proximity.
`
`14.
`
`Dr. Batt opines that recombinant DNA technology developed in the 1970s made it
`
`possible to express proteins in cells that do not naturally produce those proteins. D.I. 334, ¶ 38. I
`
`agree. A POSA would refer to the nucleic acid and cells used to produce such non-natural
`
`proteins as “recombinant” or “exogenous.” The proteins produced in this manner were typically
`
`referred to as “heterologous” or “exogenous.”
`
`15.
`
`Dr. Batt opines that gene expression leading to the production of protein is
`
`controlled by DNA sequences upstream of the gene and these sequences are often referred to as
`
`promoters. D.I. 334, ¶ 39. He further opines that many promoters, including the AOX1
`
`promoter, had been identified and well-characterized prior to the filing date of the Yeast Patents.
`
`3
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`

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`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 6 of 19 PageID #: 20899
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`I agree. In addition to native promoters, a POSA would have been familiar with methods for
`
`genetically engineering native promoters to produce so-called “synthetic” promoters. See
`
`generally Ex. 1 (discussing promoter engineering methods); Ex. 2 (discussing promoter
`
`engineering methods and providing examples of engineered promoter elements).
`
`16.
`
`Dr. Batt opines that promoters may be “constitutive” or “inducible.” D.I. 334, ¶
`
`40. I agree. Constitutive promoters generally provide a constant level of transcription whereas
`
`inducible promoters provide a more variable level of transcription and are responsive to external
`
`stimuli. The AOX1 promoter is an example of an inducible promoter. Inducible promoters have
`
`a higher transcription rate in the presence of the inducing stimulus than in its absence. A POSA
`
`would have further appreciated that inducible promoters provide a basal level of transcription in
`
`the absence of the inducing stimulus.
`
`17.
`
`Dr. Batt opines that inducible promoters are activated by DNA-binding proteins
`
`that are commonly referred to as “transcriptional activators.” D.I. 334, ¶ 41. I agree.
`
`Transcriptional activator proteins bind to DNA sequences in the promoter and enhance
`
`transcription of the gene by RNA polymerase. As is apparent from Dr. Batt’s diagram,
`
`promoters are typically modular in nature. Id. Promoters may be linked to heterologous genes.
`
`For example, an inducible promoter may be used to drive transcription of a gene that is driven
`
`natively by a constitutive promoter. Additionally, component parts of a promoter (e.g., “core
`
`promoter element” and “upstream activating sequence”) may be separately engineered to alter
`
`transcription dynamics.
`
`4
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`

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`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 7 of 19 PageID #: 20900
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`18.
`
`Dr. Batt opines that upstream activation elements may include multiple binding
`
`sites for transcriptional activators such as Mxr1. D.I. 334, ¶ 42. I agree. However, I disagree
`
`with Dr. Batt’s opinion that AOX1 promoters were not well understood. In my prior
`
`declarations, I discussed literature reflecting that this is not true. E.g., D.I. 144-1 at Ex. G.
`
`19.
`
`Dr. Batt opines that transcriptional activators recognize consensus sequences
`
`within the promoter. D.I. 334, ¶ 43. He further opines that not all instances of a transcriptional
`
`activator consensus sequence in a genome or a recombinant DNA molecule are bound by the
`
`transcriptional activator. That is, transcriptional activators only bind consensus sequences found
`
`in certain contexts. I agree. As Dr. Batt explains, Mxr1 binds its consensus sequence when it is
`
`present in an upstream activator sequence. Id.
`
`20.
`
`Dr. Batt opines that the Mxr1 transcriptional activator specifically binds to sites
`
`which contains the CYCCNY consensus sequence. D.I. 334, ¶ 44. I agree. I note that Dr. Batt’s
`
`opinion here is at odds with his assertion that the AOX1 promoter was not well-understood. Dr.
`
`Batt concedes that the sequences in the promoter bound by transcriptional activators and
`
`repressors were known. Id. He further concedes that it was known that these sequences must be
`
`presented in certain contexts—and that these contexts had been well-characterized prior to the
`
`Yeast Patents. For example, as I discussed in my prior declaration, literature such as the 2009
`
`and 2010 Kranthi papers provided a detailed understanding, expanded on prior literature (e.g.,
`
`Hartner), and defined the sequence necessary for the Mxr1 transcriptional activator protein to
`
`5
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`

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`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 8 of 19 PageID #: 20901
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`successfully bind the promoter it activates. D.I. 144, ¶¶ 25-28; D.I. 144-1 at Ex. G; D.I. 334-4 at
`
`Ex. B-7; D.I. 123-1 at Ex. B22.
`
`21.
`
`Counsel has informed me that patents need not explicitly provide information that
`
`is known in the field of the invention and is in the literature that preceded the patent because
`
`patents are written for people that are experienced in the field of the invention. Applying Dr.
`
`Batt’s definition of a POSA, which includes education and graduate study or years of experience
`
`“using recombinant DNA techniques for protein production or general genetic modification,” a
`
`POSA would have had knowledge of the foregoing information. This is also true if my
`
`definition of a POSA is applied.
`
`22.
`
`Accordingly, because there is no disagreement that a POSA would have
`
`understood the foregoing aspects of recombinant protein expression, the Yeast Patents need not
`
`have included this information in the specification.
`
`V.
`
`RESPONSE TO DR. BATT’S ANALYSIS OF THE DISPUTED CLAIM TERMS
`
`A.
`
`Term 1—“Promoter Element”
`
`Claim Term
`
`“promoter element”
`(all asserted claims)
`
`Impossible’s Proposed
`Construction
`Plain and ordinary meaning
`
`Ginkgo’s Proposed
`Construction
`Indefinite
`
`23.
`
`I discussed this claim term in my prior two declarations. D.I. 107, ¶¶ 63-68; D.I.
`
`144, ¶¶ 17-32. I supplement that here with an effort not to repeat what I have already discussed.
`
`24.
`
`Dr. Batt opines that the term “promoter element” is indefinite because a POSA
`
`would not be able to determine when a given nucleotide sequence would be considered a
`
`“promoter element,” and when it would not be. D.I. 334, ¶¶ 63, 64. I disagree that the term is
`
`indefinite, and I disagree that a POSA would not be able to determine when a given nucleotide
`
`sequence would be or would not be considered a “promoter element.”
`
`6
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`

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`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 9 of 19 PageID #: 20902
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`25.
`
`Dr. Batt further opines that the word “element” does not imply any particular size,
`
`sequence, structure, or function. D.I. 334, ¶ 64. But “element” is not the claim term being
`
`construed. This stripping of “promoter element” from the context in which it is used is
`
`emblematic of Dr. Batt’s analysis. Furthermore, Dr. Batt fails to take into consideration what we
`
`both agree would be within the knowledge of a POSA.
`
`26.
`
`Dr. Batt opines that a POSA would be familiar with the term promoter. D.I. 334,
`
`¶ 65. However, he completely fails to consider that a POSA would also be familiar with the term
`
`“promoter element.” ’656 Patent (D.I. 334-2, Ex. B-3), at 6:36-37 (“Constitutive promoters and
`
`constitutive promoter elements are known in the art.”), 4:60-5:11 (listing art-known promoter
`
`elements).
`
`27.
`
`It is my opinion, and the literature supports, that a POSA would understand a
`
`“promoter element” to be a nucleic acid sequence that drives transcription of a gene. Ex. 3, Li, at
`
`106 (“Most P. pastoris expression systems use the methanol-induced alcohol oxidase (AOX1)
`
`promoter. Upon induction by methanol, the fraction of total soluble protein that is composed of
`
`alcohol oxidase can typically rise to 30%, indicating the power of this promoter element.”)
`
`(emphasis added); Ex. 2 (Redden) at 2 (“As such, two of the most commonly used yeast
`
`promoter elements, the GAL1 inducible promoter and the strong GPD (TDH3) promoter span
`
`over 400 and 600 nucleotides respectively.”) (emphasis added).
`
`28.
`
`A POSA would have also understood that a “promoter element” may comprise
`
`less than a complete native promoter. Ex. 4 (Suppmann) at 2:63-67 (“A ‘promoter’ is a
`
`regulatory nucleotide sequence that stimulates transcription. These terms are understood by
`
`those of skill in the art of genetic engineering. Like a promoter, a ‘promoter element’ stimulates
`
`transcription but constitutes a sub-fragment of a larger promoter sequence.”) (emphasis added).
`
`7
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`

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`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 10 of 19 PageID #: 20903
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`For example, a promoter element may lack sequences determined to be dispensable for driving
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`transcription. Ex. 2 (Redden) at 3-4 (discussing isolation of “minimal” promoter elements).
`
`29.
`
`A POSA would have understood that, even if the promoter element did not
`
`constitute a full-length native promoter, it would still be capable of driving transcription. For
`
`example, Zhang explains that “the terms ‘promoter’ and ‘promoter element’ refer to a
`
`polynucleotide that regulates expression of a selected polynucleotide sequence operably linked to
`
`the promoter, and that effects expression of the selected polynucleotide sequence in cells.” Ex. 5
`
`(Zhang) at 10:44-48; 8:25-29 (“The term ‘operably linked’, as used herein, refers to a
`
`relationship between two nucleic acid sequences wherein the expression of one of the nucleic
`
`acid sequences is controlled by, regulated by or modulated by the other nucleic acid sequence.”).
`
`Indeed, as Dr. Batt concedes, the invention of Impossible’s Yeast Patents is directed to
`
`engineered yeast strains for expression of heterologous proteins. D.I. 334, ¶¶ 53-59.
`
`30.
`
`The Yeast Patents use the terms promoter and promoter element consistent with
`
`their ordinary usage. The patents are directed to genetically engineering methylotrophic yeast to
`
`produce heterologous proteins. ’656 Patent at 3:46-49 (“nucleic acid constructs are provided
`
`herein that allow for genetically engineering a cell to increase the recombinant expression of a
`
`polypeptide”). The patents explain that methanol-inducible promoter elements may be used in
`
`this context to drive transcription of a heterologous nucleic acid encoding a polypeptide. Id. at
`
`3:66-4:2 (“[A] recombinant nucleic acid molecule typically includes an exogenous nucleic acid
`
`that encodes a transcriptional activator operably linked to at least one inducible promoter
`
`element.”), 6:28-32 (“the heterologous nucleic acid encoding a polypeptide of interest can be
`
`operably linked to an inducible promoter element”). None of the provisions in the ’656 patent
`
`identified by Dr. Batt are inconsistent with the ordinary meaning of promoter element—it is a
`
`8
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`

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`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 11 of 19 PageID #: 20904
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`polynucleotide sequence, it regulates (e.g., modulates, drives, directs) expression (which includes
`
`transcription) of a polynucleotide sequence (e.g., a gene). D.I. 334, ¶ 66. A POSA understands
`
`what that structure is with reasonable certainty.
`
`31.
`
`There is no dispute that a POSA would have experience in the field of genetic
`
`engineering and thus would be familiar with the terminology used in the field. D.I. 334, ¶¶ 52,
`
`57. Promoter elements were known by skilled artisans in the field of genetic engineering
`
`including how to use and manipulate such elements to drive transcription of heterologous genes.
`
`32.
`
`In fact, Ginkgo uses the same terminology in its patents and published patent
`
`applications, further showing that a POSA would have understood the meaning of promoter
`
`element. For example, Ginkgo’s United States Patent No. 11,702,665 describes protein
`
`expression systems in which “the nucleic acid molecule is operatively linked to a promoter
`
`element.” Ex. 6. Ginkgo’s WO2015/148680 discloses that “the terms ‘promoter,’ ‘promoter
`
`element,’ or ‘promoter sequence’ refer to a DNA sequence [i.e., a polynucleotide sequence]
`
`which when ligated to a nucleotide sequence of interest is capable of controlling the transcription
`
`of the nucleotide sequence of interest into mRNA.” Ex. 7, [0060]. Ginkgo’s United States
`
`Patent Application No. 2023/0257793 explains that “the present invention describe[s] a method
`
`of engineering a host cell for protein expression.” Ex. 8, [0045]. The publication further
`
`describes “expression systems” with a “promoter comprising an upstream activating sequence
`
`(UAS) and a core promoter element.” Id., [0006], claim 1 (“(a) a first transcriptional unit
`
`comprising: (i) an input promoter comprising an upstream activating sequence (UAS) and a core
`
`promoter element,”). It is simply not credible that a POSA in the field of genetic engineering
`
`would not know with reasonable certainty what was meant by the term “promoter element.”
`
`9
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`

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`33.
`
`Dr. Batt faults the Yeast Patents for not providing a definition of “promoter
`
`element” but fails to explain why the lack of definition leads a POSA to not understand this
`
`common term of art with reasonable certainty. D.I. 334, ¶ 69. As explained above, a POSA
`
`would understand what was meant by the term “promoter element.” The Yeast Patents use the
`
`term consistent with its ordinary meaning and Dr. Batt identifies no disclosure to the contrary.
`
`Dr. Batt faults the patents for allegedly not providing working examples of “promoter elements.”
`
`But this is false. The patent provides multiple working examples of promoter elements that drive
`
`transcription of genes. E.g., ’656 Patent, Example 22 (discussing use of TEF promoter element),
`
`Example 25 (discussing use of AOX1 promoter element).
`
`34.
`
`Dr. Batt opines that the patent does not describe what makes a given nucleotide
`
`sequence a “promoter element.” D.I. 334, ¶ 70. This too is false. The patents explain that
`
`promoter elements were known in the art and are commonly used to drive transcription of genes.
`
`’656 Patent at 6:36-37 (“Constitutive promoters and constitutive promoter elements are known in
`
`the art.”), 4:60-5:11 (listing art-known promoter elements).
`
`35.
`
`Dr. Batt opines that whether a given sequence will successfully function in given
`
`circumstances to modulate, direct, or regulate expression cannot be determined by its sequence
`
`alone; it must be tested. D.I. 334, ¶ 71. Even if this statement is accepted it does not indicate
`
`that a POSA does not know with reasonable certainty the meaning of the phrase “promoter
`
`element.”
`
`36.
`
`Dr. Batt opines that the number of sequences that might comprise a “promoter
`
`element” are “practically infinite” in number. D.I. 334, ¶¶ 72, 73. I disagree. Dr. Batt’s opinion
`
`does not consider the perspective of a POSA: that is, a skilled artisan with experience using
`
`recombinant DNA techniques for protein production or general genetic modification experience.
`
`10
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`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 13 of 19 PageID #: 20906
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`Id., ¶ 52. As Dr. Batt concedes (e.g., id., ¶ 39), and which I agree with, a POSA would have
`
`knowledge of many well-characterized promoters and promoter elements. A POSA would not
`
`consider a “promoter element” to comprise a random assortment of nucleotides, as Dr. Batt
`
`argues.
`
`37.
`
`Dr. Batt opines that even if a promoter element is found within a well-
`
`characterized promoter, a POSA would have no reason to conclude that the same sequence
`
`elsewhere directs or regulates transcription in the same fashion. D.I. 334, ¶ 74. But the claims
`
`do not require the promoter element direct or regulate transcription in the same fashion
`
`regardless of context. The claims simply require operably linking a promoter element to a
`
`nucleic acid such that it may drive transcription.
`
`38.
`
`As for paragraphs 75-78, Dr. Batt argues “promoter element” is indefinite because
`
`the specification does not tell a POSA what causes a promoter element to modulate, direct, or
`
`regulate expression. No such explanation is necessary. The patent explains that promoter
`
`elements were known in the art and commonly used to drive transcription of genes. Even if the
`
`precise mechanism by which a given promoter element drives transcription is unknown, that
`
`does not mean that a POSA does not understand with reasonable certainty what promoter
`
`elements are.
`
`B.
`
`Term 2—“a Mxr1 transcriptional activator sequence” / “a methanol
`expression regulator 1 (Mxr1) transcriptional activator” / “a Mxr1
`transcriptional activator sequence”
`
`Term
`
`Claim Term
`
`a Mxr1 transcriptional activator
`sequence from P. pastoris
`’492 patent, cls. 1, 14
`
`2a
`
`Impossible’s Proposed
`Construction
`Plain and ordinary
`meaning, which is the
`sequence to which the
`Mxr1 transcriptional
`activator protein binds
`
`Ginkgo’s Proposed
`Construction
`a sequence of an Mxr1
`transcriptional activator
`protein
`
`11
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`Case 1:22-cv-00311-WCB Document 339 Filed 01/26/24 Page 14 of 19 PageID #: 20907
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`2b
`
`2c
`
`a first exogenous nucleic acid
`encoding a methanol expression
`regulator 1 (Mxr1) transcriptional
`activator1
`’656 patent, cl. 1
`a nucleic acid encoding a Mxr1
`transcriptional activator sequence
`from P. pastoris
`’656 patent, cl. 26
`
`Plain and ordinary
`meaning, which is the
`nucleic acid encoding
`the Mxr1 transcriptional
`activator protein
`See D.I. 94-1,106, 142.
`
`39.
`
`I discussed this claim term in my prior two declarations. D.I. 107, ¶¶ 52-62; D.I.
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`144, ¶¶ 6-18. I supplement that here with an effort not to repeat what I have already discussed.
`
`40.
`
`Dr. Batt opines that the specification supports his position that terms 2a, 2b, and
`
`2c are directed to the sequences encoding the Mxr1 protein. D.I. 334, ¶¶ 91-98. I disagree. Dr
`
`Batt’s analysis is circular. He focuses only on instances in the specification in which the Mxr1
`
`protein is discussed, and from this concludes that the claims are directed to the Mxr1 protein.
`
`41.
`
`Dr. Batt opines that the lack of discussion of Mxr1 binding sites in the
`
`specification supports his position that terms 2a, 2b, and 2c are directed to the sequences
`
`encoding the Mxr1 protein. D.I. 334, ¶¶ 99-100. I disagree. As Dr. Batt concedes, Mxr1
`
`consensus binding sites were known and well-characterized in the literature.
`
`42.
`
`Dr. Batt opines that the term “encoding” in the claims refers to the “Mxr1
`
`transcriptional activator sequence.” D.I. 334, ¶¶ 103-106, 114-118. I disagree. Dr. Batt’s
`
`construction would mean that claim 1 recites a protein-encoding sequence operably linked to a
`
`promoter element and another protein-encoding sequence (i.e., a sequence encoding an Mxr1
`
`transcriptional activator protein). But this does not make sense in the context of the claims and
`
`1 Ginkgo re-numbers this phrase as “2b” and shortens it to remove “a first exogenous nucleic
`acid encoding” without explanation. Impossible has recited the term as it is recited in prior
`briefing as Term 19.
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`the agreed upon meaning of “operably linked” (which is found in the specification).
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`Specifically, operably linked is used in the specification to describe the relationship of nucleic
`
`acid sequences that drive transcription with nucleic acid sequences that encode proteins.
`
`43.
`
`Dr. Batt opines that his construction is supported by the specification. D.I. 334,
`
`¶¶ 107-112. Again, I disagree on the basis that his logic is circular. While the Yeast Patents do
`
`indeed discuss instances in which Mxr1 is expressed, it does not follow from this discussion that
`
`the claims are directed exclusively to Mxr1 expression and not to Mxr1 binding sites. The plain
`
`language of the claims indicates otherwise.
`
`C.
`
`Term 6—“sequence to which [the/a] Mxr1 transcriptional activator
`binds”
`
`Claim Term
`“sequence to which [the/a]
`Mxr1 transcriptional activator
`binds”
`’656 patent, 1, 26, 28
`
`Impossible
`Plain and ordinary meaning
`
`Indefinite
`
`Ginkgo
`
`44.
`
`Dr. Batt opines that the term “sequence to which [the/a] Mxr1 transcriptional
`
`activator binds” does not inform a POSA with reasonable certainty about the scope of the
`
`invention. D.I. 334, ¶ 123. I disagree.
`
`45.
`
`Dr. Batt opines that the specification does not include disclosure of sequences to
`
`which Mxr1 binds. D.I. 334, ¶ 124. But Dr. Batt concedes that consensus binding sites for Mxr1
`
`were known in the art prior to the Yeast Patents. Id., ¶ 126. No disclosure of binding sites was
`
`necessary for a POSA (who necessarily would be aware of that information in the art) to
`
`understand this claim term.
`
`46.
`
`Dr. Batt opines that there is no known sequence to which the Mxr1 transcriptional
`
`activator binds regardless of surrounding context, i.e., the surrounding DNA sequences, spacing
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`of various DNA sequences, and the host cell itself. D.I. 334, ¶ 125. But the claims do not
`
`require a sequence to which Mxr1 binds in any context. The claims require “a first exogenous
`
`nucleic acid encoding a methanol expression regulator 1 (Mxr1) transcriptional activator
`
`operably linked to at least one methanol-inducible promoter element comprising a sequence to
`
`which the Mxr1 transcriptional activator binds.” That is, the claims require the Mxr1 binding
`
`sequence to be in the context of a methanol-inducible promoter element. Furthermore, as Dr.
`
`Batt opines elsewhere, a POSA would have understood that Mxr1 binding sites are typically in
`
`the upstream activating region. Moreover, as Dr. Batt explains, the binding sites for Mxr1 within
`
`AOX1 were well-characterized. D.I. 334, ¶ 126.
`
`47.
`
`Dr. Batt opines that knowledge of the consensus binding sequence for Mxr1 does
`
`not inform a POSA with reasonable certainty about the scope of the term “sequence to which
`
`[the/a] Mxr1 transcriptional activator binds” for two reasons. D.I. 334, ¶ 127. I disagree as to
`
`both reasons.
`
`48.
`
`Dr. Batt’s conclusion that Mxr1 does not bind to every Mxr1 consensus sequence
`
`in the AOX1 promoter is misleading. D.I. 334, ¶ 128. As Kranthi 2010 identified, the consensus
`
`binding sequence for Mxr1 is CYCCNY. D.I. 334-4, Ex. B-7 at Abstract. In the context of
`
`CYCCNY, “Y” refers to pyrimidines (C’s and T’s)—whereas N refers to any nucleotide.
`
`Kranthi 2010 demonstrated that Mxr1 does not bind to sequences in which a purine (A’s and
`
`G’s) is in the final position (e.g., CTCCTA). That is, Kranthi 2010 demonstrated that the Mxr1
`
`consensus sequence is CYCCNY and Mxr1 binds to each instance of this consensus sequence.
`
`49.
`
`Dr. Batt opines that there are many Mxr1 consensus sequences in the genome.
`
`D.I. 334, ¶ 129. That might be, but the claims are not directed to every Mxr1 consensus
`
`sequence in the genome. This claim term cannot be divorced from its context. The claim is
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`directed to a consensus sequence that is in a recited promoter element that is operably linked to a
`
`specific nucleic acid.
`
`50.
`
`Dr. Batt opines that Mxr1 might bind its consensus sequence in some contexts but
`
`not others. D.I. 334, ¶ 130. Again, that might be, but contexts in which Mxr1 binds its
`
`consensus sequence were known and well-characterized. D.I. 334-4, Ex. B-7 (Kranthi 2010).
`
`That Mxr1 might not bind in other contexts is of no moment. The claims are directed to use of
`
`Mxr1 binding in known contexts such as in methanol-inducible promoter elements.
`
`51.
`
`Dr. Batt opines that testing would be required to determine whether Mxr1 bound
`
`in a particular context. D.I. 334, ¶ 131. Even if testing were required to determine if Mxr1
`
`bound to the “methanol-inducible promoter element comprising a sequence to which the Mxr1
`
`transcriptional activator binds” that would not mean that a POSA would not understand what this
`
`claim term means with reasonable certainty.
`
`52.
`
`Dr. Batt argues that Hartner supports his indefiniteness position. D.I. 334, ¶ 131.
`
`I disagree. Hartner describes a 2 base-pair deletion in pAOX1 that resulted in a decrease in
`
`promoter activity to only 6% of that in wild-type promoters. D.I. 123-1 at Ex. B22. According
`
`to Dr. Batt, this deletion was not in the putative sequence to which Mxr1 binds. D.I. 334, ¶ 131
`
`n. 47. It is not apparent to me why Dr. Batt believes that this mutant promoter (which still drives
`
`transcription) supports Dr. Batt’s indefiniteness opinion. Promoters and promoter e